Type 2 diabetes mellitus in adults: clinical guidelines

List of Abbreviations

AH – arterial hypertension

BP – blood pressure

GLP-1 RA – glucagon-like peptide-1 receptor agonist (ATC classification A10BJ glucagon-like peptide-1 analogues)

ASCVD – atherosclerotic cardiovascular disease

ATC – Anatomical Therapeutic Chemical classification

ARB – angiotensin II receptor blocker (ATC classification C09CA angiotensin II receptor antagonists)

WHO – World Health Organization

GLP-1 – glucagon-like peptide-1

DBP – diastolic blood pressure

DME – diabetic macular edema

DN – diabetic nephropathy

DNP – diabetic neuropathy

DOAP – diabetic osteoarthropathy

DR – diabetic retinopathy

LEAD – lower extremity artery disease

ACEI – angiotensin-converting enzyme inhibitor (ATC classification C09AA ACE inhibitors)

CHD – coronary heart disease

DPP-4i – dipeptidyl peptidase-4 inhibitor (ATC classification A10BH dipeptidyl peptidase-4 inhibitors)

SRI – short-acting insulin (ATC classification A10AB fast-acting insulins and analogues for injection)

ИМ – myocardial infarction

BMI – body mass index

SGLT-2i – sodium-glucose cotransporter 2 inhibitor (ATC classification A10BK sodium-glucose cotransporter 2 inhibitors)

TCC – total contact cast

VRAI – very rapid-acting insulin (ATC classification A10AB fast-acting insulins and analogues for injection)

URAI – ultra-rapid-acting insulin (ATC classification A10AB fast-acting insulins and analogues for injection)

CLTI – chronic limb-threatening ischemia

PRL – panretinal laser photocoagulation

ABI – ankle-brachial index

INN – international nonproprietary name

MRI – magnetic resonance imaging

MSCT – multislice computed tomography

IFG – impaired fasting glucose

CGM – continuous glucose monitoring

NPH – Neutral Protamine Hagedorn

IGT – impaired glucose tolerance

ACS – acute coronary syndrome

LE – life expectancy

OGTT – oral glucose tolerance test (medical service code A12.22.005 Glucose tolerance test)

SU – sulfonylurea (ATC classification A10BB sulfonylurea derivatives)

OAD – oral antidiabetic drug (ATC classification A10B blood glucose lowering drugs, excl. insulins)

eGFR – estimated glomerular filtration rate

RF – Russian Federation

SBP – systolic blood pressure

DM – diabetes mellitus

T1D – type 1 diabetes mellitus

T2D – type 2 diabetes mellitus

DF – diabetic foot

GFR – glomerular filtration rate

CVD – cardiovascular disease

TZD – thiazolidinediones (ATC classification A10BG Thiazolidinediones)

LCE – level of confidence of evidence

GRS – grade of recommendation strength

PA – physical activity

LVEF – left ventricular ejection fraction

RF – risk factor

FGM – flash glucose monitoring

CKD – chronic kidney disease

XE – bread unit

HDL-C – high-density lipoprotein cholesterol

LDL-C – low-density lipoprotein cholesterol

CHF – chronic heart failure

ECG – electrocardiography, electrocardiogram

EchoCG – echocardiography

3P-MACE – 3-point major adverse cardiovascular events composite endpoint

HbA1c – glycated hemoglobin

PCSK9 – proprotein convertase subtilisin/kexin type 9 (ATC classification C10AX other lipid-modifying agents)

** – the medicinal product is included in the list of vital and essential drugs for medical use

*** – included in the list of medical devices provided during the provision of medical care under the state guarantee program for free medical care to citizens

# – a medicinal product used off-label (contrary to the indications, contraindications, routes of administration, and dosages contained in the package leaflet)

Terms and Definitions

Insulin analogues are a form of insulin in which certain modifications have been made to the human insulin molecule. An analogue acts in the same way as insulin, but with pharmacokinetic/pharmacodynamic differences that may provide advantages

Arterial hypertension is a syndrome characterized by an elevation in systolic BP $\ge$ 140 mm Hg and/or diastolic BP $\ge$ 90 mm Hg in essential hypertension and symptomatic arterial hypertension, leading to target organ damage

Basal (long-acting) insulin – intermediate-acting insulin – NPH insulin (ATC classification A10AC intermediate-acting insulins and analogues for injection), long-acting or ultra-long-acting insulin (ATC classification A10AE long-acting insulins and analogues for injection)

Basal insulin regimen – continuous subcutaneous insulin infusion via a pump (ambulatory insulin infusion pump***, ambulatory insulin infusion pump with integrated blood glucose meter***) in an automatic mode at a user-defined rate (constant or varying throughout the day), or administration of long-acting insulin

Insulin boluses – administration of short-acting (rapid-acting, ultra-rapid-acting) insulin required to maintain target postprandial glycemia and to correct hyperglycemia

Glucose variability – fluctuation (spread) of blood glucose or interstitial fluid glucose levels over a specific period of time

Hyperglycemia – blood glucose level above the normal range

Hypoglycemia – blood glucose level below the normal range

Glycemia – blood glucose concentration

Glycated hemoglobin (HbA1c) – an indicator reflecting the average blood glucose level over the past 2–3 months

Diabetic neuropathy – a complex of clinical and subclinical syndromes, each characterized by diffuse or focal damage to peripheral and/or autonomic nerve fibers resulting from diabetes mellitus

Diabetic nephropathy – specific renal involvement in diabetes mellitus manifesting as nodular glomerulosclerosis as a result of metabolic and hemodynamic factors affecting renal microcirculation, modulated by genetic factors

Diabetic osteoarthropathy – painless, progressive destruction of one or more foot joints in the setting of neuropathy

Diabetic retinopathy – a specific late neuromicrovascular complication of diabetes mellitus, typically progressing sequentially from changes associated with increased permeability and occlusion of retinal vessels to the development of neovascularization and fibroglial tissue

Diabetic macular edema – retinal thickening associated with fluid accumulation in the intercellular space of the neuroepithelium due to disruption of the blood-retinal barrier and an imbalance between fluid transudation and its reabsorption by retinal pigment epithelium cells. Diabetic macular edema can develop at any stage of diabetic retinopathy

Incretins – gastrointestinal hormones released in response to food intake that stimulate insulin secretion

Insulin – a hormone that regulates blood glucose levels by stimulating glucose uptake by tissues. The term is also used to refer to medications (ATC classification A10A Insulins and analogues)

Insulin resistance – impaired biological response to exogenous or endogenous insulin

Intensified (basal-bolus) insulin therapy – an insulin regimen involving multiple daily injections of short-acting (rapid-acting, ultra-rapid-acting) insulin and basal insulin, or continuous subcutaneous infusion of ultra-rapid-acting insulin via an insulin pump***

Coronary artery disease – a term encompassing a group of diseases whose underlying pathological process is a mismatch between the heart's blood supply demand and its actual delivery due to rapidly progressive coronary atherosclerosis

Critical limb ischemia – a condition characterized by a severe reduction in blood flow through the main arteries of the lower extremities, leading to soft tissue hypoxia and threatening limb viability

Lipodystrophy – pathological alteration of adipose tissue at insulin injection sites

Continuous glucose monitoring – continuous measurement of glucose levels in the interstitial fluid using subcutaneously placed sensors, followed by conversion into plasma glucose values

Prediabetes – a carbohydrate metabolism disorder that does not meet the criteria for diabetes mellitus but exceeds normal blood glucose values (includes any of the following: impaired fasting glucose and impaired glucose tolerance)

Type 2 diabetes mellitus remission – maintenance of normal glycemia and glycated hemoglobin levels in the absence of pharmacotherapy for at least 1 year after metabolic (bariatric) surgery

Self-monitoring of blood glucose – independent determination of blood glucose by patients at home using a blood glucose meter or a continuous glucose monitoring system

Type 1 diabetes mellitus – a polygenic, multifactorial disease based on immune-mediated or idiopathic destruction of pancreatic $\beta$-cells, leading to absolute insulin deficiency

Type 2 diabetes mellitus – a carbohydrate metabolism disorder caused by predominant insulin resistance and relative insulin deficiency, or predominant insulin secretory defect with or without insulin resistance

Frailty – an age-associated syndrome whose main clinical manifestations are fatigue, unintentional weight loss, decreased mobility, and muscle weakness. The development of frailty is underpinned by sarcopenia, age-related muscle atrophy

Therapeutic patient education – a set of measures aimed at preparing patients to manage their disease

Functionally dependent older adults – individuals who regularly require outside assistance with activities of daily living due to deterioration in their functional status. They are characterized by a lower life expectancy and a higher risk of hospitalization

Functionally independent older adults – individuals who do not require assistance with activities of daily living, or require minimal assistance (e.g., when needing to travel to locations outside their usual routine distance)

Carbohydrate choice (bread unit) – an amount of food containing 10–12 grams of carbohydrates

Chronic kidney disease – a non-nosological concept defined as structural or functional abnormalities of the kidneys present for more than 3 months with implications for health

Chronic heart failure – a syndrome developing as a result of impaired cardiac filling and/or emptying capacity, occurring amid an imbalance of vasoconstrictor and vasodilator neurohormonal systems, accompanied by inadequate perfusion of organs and systems, and manifesting with symptoms such as shortness of breath, weakness, palpitations, and fatigue, and, upon progression, fluid retention in the body (edema syndrome)

Target plasma glucose level – individually determined plasma glucose level fasting, before meals, 2 hours postprandial, at bedtime, and overnight

Insulin pen – a device for injecting insulin and glucagon-like peptide-1 receptor agonists

3P-MACE – 3-point major adverse cardiovascular events composite endpoint (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke)

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Diabetes mellitus (DM) is a group of metabolic diseases characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Chronic hyperglycemia in DM is associated with damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels.

Type 2 diabetes mellitus (T2DM) is a disorder of carbohydrate metabolism caused by predominant insulin resistance and relative insulin deficiency, or a predominant secretory defect with or without insulin resistance [1–3].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

T2DM is a disease with a complex, multifactorial pathogenesis.

The main pathogenetic mechanisms are considered to be impaired insulin secretion and insulin resistance, though the number of novel defects causing chronic hyperglycemia in T2DM is constantly growing [4]:

Ø Impaired insulin secretion;

Ø Insulin resistance (insulin resistance of muscles, liver, and adipose tissue is of the greatest importance);

Ø Reduced incretin effect (incretins are gastrointestinal hormones produced in response to food intake that stimulate insulin secretion; glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide are of the greatest importance);

Ø Impaired secretion of glucagon, a hormone synthesized in the pancreatic α-cells whose effects oppose those of insulin;

Ø Increased renal glucose reabsorption (due to increased activity of type 2 sodium-glucose cotransporters (SGLT2) located predominantly in the proximal renal tubules).

In recent years, the role of immune dysregulation/chronic inflammation, gut microbiota alterations, and other factors in pathogenesis has also been discussed [5].

1.3 Epidemiology of the Disease or Condition

The prevalence of DM is increasing worldwide. According to the International Diabetes Federation, the number of patients with DM aged 20–79 years worldwide exceeded 537 million at the end of 2021 [6]. In the Russian Federation (RF), according to the Federal DM Register as of January 1, 2022, there were 4.9 million registered patients (3.34% of the population), of whom 9.3% (4.5 million) had T2DM, 5.6% (272 thousand) had type 1 DM, and 2.1% (102 thousand) had other types of DM, including 9,729 individuals with gestational DM [3].

However, these data underestimate the true number of patients because they only account for detected and registered cases. For instance, the results of a large-scale Russian epidemiological study (NATION) confirm that only 54% of T2DM cases are diagnosed through routine clinical practice attendance, while in 46% of patients, DM is detected solely through active screening [7]. Thus, the actual number of patients with DM in the RF is at least 10 million (about 7% of the population).

1.4 Features of Coding the Disease or Condition

E11.2 - Type 2 diabetes mellitus with renal complications

E11.3 - Type 2 diabetes mellitus with ophthalmic complications

E11.4 - Type 2 diabetes mellitus with neurological complications

E11.5 - Type 2 diabetes mellitus with peripheral circulatory complications

E11.6 - Type 2 diabetes mellitus with other specified complications

E11.7 - Type 2 diabetes mellitus with multiple complications

E11.8 - Type 2 diabetes mellitus with unspecified complications

E11.9 - Type 2 diabetes mellitus without complications

R73.0 - Abnormal glucose tolerance test

R73.9 - Hyperglycemia, unspecified

1.5 Classification of the disease or condition

The 1999 World Health Organization (WHO) classification with amendments is used in the RF (Table 1)

Table 1. Classification of diabetes mellitus (World Health Organization, 1999, with amendments) [1, 2, 8].

1Excluding overt DM

Unlike the ICD-10 classification, Russian and foreign practice uses the terms type 1 DM (instead of insulin-dependent DM) and type 2 DM (instead of non-insulin-dependent DM).

In 2019, the WHO published a new classification of DM introducing hybrid forms of DM and unclassifiable DM [9]. Currently, the Russian Association of Endocrinologists recommends continuing to use the 1999 classification, taking into account potential difficulties with ICD-10 coding.

The concept of diabetes severity is excluded from the diagnosis formulation. The severity of diabetes is determined by the presence of complications, the characteristics of which are indicated in the diagnosis.

Due to the introduction of individualized treatment goals, the concepts of compensation, subcompensation, and decompensation are inappropriate in the formulation of the diagnosis in patients with DM. Following the complete formulation of the diagnosis, the individual target level of glycemic control should be indicated (see Section 3.1 Therapeutic Goals).

1.6 Clinical presentation of the disease or condition

T2DM most commonly develops in individuals over 40 years of age who are overweight or obese (especially with an abdominal fat distribution), but it can also occur at a younger age and in individuals with normal weight.

A hallmark of the disease is a prolonged asymptomatic course. Detection most frequently occurs either incidentally or during routine health checks in patients with conditions commonly associated with T2DM: obesity, coronary heart disease (CHD), arterial hypertension (AH), gout, and polycystic ovary syndrome. In the absence of screening, diagnosis may be delayed by 7–9 years from disease onset.

Risk factors for T2DM are listed in Table 2.

Table 2. Risk factors for type 2 diabetes mellitus [3, 10].

Abdominal obesity serves as the primary risk factor for T2DM and is largely the cause of observed insulin resistance. However, the clinical manifestation of T2DM occurs when β-cell dysfunction is added to pre-existing insulin resistance. Autoantibodies against β-cells are absent in T2DM. Insulin resistance in T2DM manifests in relation to both endogenous and exogenous insulin. Endogenous insulin is typically produced in normal or increased amounts. This is usually sufficient to prevent diabetic ketoacidosis, and patients with T2DM are not prone to it, except in cases of acute conditions accompanied by increased insulin demand (acute inflammatory states, surgical interventions, acute myocardial infarction (MI), stroke, etc.). Patients with T2DM typically show a good response to oral glucose-lowering drugs.

As a rule, patients with T2DM present with overweight (or obesity) alongside various manifestations of the metabolic syndrome: AH, atherogenic dyslipidemia, hyperuricemia, microalbuminuria, and blood coagulation disorders.

In 20–30% of patients, the first manifestation of T2DM may be MI, stroke, vision loss, or other complications.

The unfavorable prognosis in patients with T2DM is determined by the development of macro- and microvascular complications.

The leading cause of death in patients with T2DM is cardiovascular disease, the prevalence of which among patients with T2DM is 2–4 times higher than that in individuals without DM [4].

2. Diagnostics, medical indications and contraindications for diagnostic methods

The WHO has approved the following diagnostic criteria for DM and other glycemic disorders (Table 3) [1, 2, 8].

Table 3. Diagnostic criteria for diabetes mellitus and other glycemic disorders (World Health Organization, 1999–2013)

1 Diagnosis is established based on laboratory glycemic measurements.

2 Serum may be used.

3 The diagnosis of DM should always be confirmed by repeat glycemic testing on subsequent days, except in cases of unequivocal hyperglycemia with acute metabolic decompensation or obvious symptoms. Gestational DM can be diagnosed based on a single glycemic measurement.

4 In the presence of classic symptoms of hyperglycemia.

Conversion of blood glucose from mmol/L to mg/dL: mmol/L × 18.02 = mg/dL

Fasting means the blood glucose level in the morning after a period of fasting of at least 8 hours and no more than 14 hours.

Random means the blood glucose level at any time of day regardless of food intake.

OGTT – oral glucose tolerance test. Performed in case of borderline glycemic values to clarify the diagnosis.

OGTT procedure guidelines:

The OGTT should be performed in the morning following at least 3 days of unrestricted diet (more than 150 g of carbohydrates per day) and normal physical activity. The test must be preceded by an overnight fast of 8–14 hours (water is permitted). The last evening meal should contain 30–50 g of carbohydrates. After fasting blood collection, the patient must drink 75 g of anhydrous glucose or 82.5 g of glucose monohydrate dissolved in 250–300 ml of water within no more than 5 minutes. Smoking is not permitted during the test. A repeat blood draw is performed after 2 hours.

To prevent glycolysis and erroneous results, glucose concentration must be determined immediately after blood collection, or the blood must be centrifuged immediately after collection, stored at 0–4°C, or collected in a tube containing a preservative (sodium fluoride).

Contraindications to OGTT:

Ø during an acute illness;

Ø during short-term administration of medications that increase glycemia levels (glucocorticosteroids (ATC classification S01BA), thyroid hormones, thiazide diuretics (ATC classification C03AA), beta-blockers (ATC classification C07), etc.).

Transitory hyperglycemia

Hyperglycemia detected during an acute infection, trauma, stress, myocardial infarction, acute cerebrovascular accident, or extensive surgery may be transitory (stress-induced), usually resolves spontaneously after the disappearance of the triggering factor, and should not be classified as a diagnosis of DM on its own. 4–12 weeks after eliminating the potential cause of transitory hyperglycemia in individuals with a fasting venous plasma glucose level < 7.0 mmol/l, an OGTT and/or glycated hemoglobin (HbA1c) test should be performed to reclassify the degree of carbohydrate metabolism disorder.

2.1 Complaints and Anamnesis

Type 2 DM typically remains undiagnosed for a long time due to the absence of any visible manifestations. There may be nonspecific complaints of weakness, fatigue, and memory impairment. In chronic hyperglycemia in type 2 DM, the following may occur: polydipsia (up to 3–5 L/day); pruritus; polyuria; nocturia; weight loss; furunculosis, fungal infections; poor wound healing. The patient's initial presentation to a doctor may be due to various manifestations of micro- and macroangiopathies, leg pain, or erectile dysfunction.

The disease most commonly develops in middle and older age, and a positive family history of type 2 DM is very frequent. Risk factors for type 2 DM that should be considered during history taking are listed in Table 2.

2.2 Physical Examination

There are no specific signs of type 2 DM that can be detected on physical examination. General propaedeutic principles of patient examination must be followed.

2.3 Laboratory Diagnostics

Comments: Hyperglycemia detected in the presence of an acute infection, trauma, or stress may be transitory and should not be classified as a diagnosis of DM on its own. The diagnosis of DM in asymptomatic individuals should never be established based on a single elevated blood glucose value. In this case, a repeat confirmation with a diabetic-range glucose value is required, either fasting, during an OGTT, or via a corresponding HbA1c value. Plasma glucose testing in the medical services nomenclature A09.05.023 is defined as a blood glucose test.

Comments: The HbA1c test must be performed using a method certified according to the National Glycohemoglobin Standardization Program (NGSP) or the International Federation of Clinical Chemistry (IFCC) and standardized according to the reference values adopted in the Diabetes Control and Complications Trial (DCCT).

An HbA1c level of ≤6.0% (≤42 mmol/mol) is considered normal.

According to World Health Organization recommendations, an HbA1c level >6.0 and <6.5% (>42 and <48 mmol/mol) does not allow for any diagnosis on its own, but does not exclude the possibility of diagnosing DM based on blood glucose levels.

In the absence of symptoms of acute metabolic decompensation, the diagnosis must be established based on two values in the diabetic range, for example, a twice-determined HbA1c or a single HbA1c determination + a single blood glucose determination.

Limitations in the use of HbA1c:

- in rapid-onset DM, such as certain cases of type 1 DM in children, the HbA1c level may not be significantly elevated despite the presence of classic symptoms of DM.

- laboratory and individual variability, therefore decisions to modify therapy should be made taking into account other glycemic control assessment data.

- non-glycemic factors that distort HbA1c levels.

Factors increasing HbA1c levels: anemias (iron, vitamin B12, folic acid deficiency), chronic alcohol consumption, use of salicylates, opioids, splenectomy, marked hyperbilirubinemia.

Factors decreasing HbA1c levels: pregnancy (II and III trimesters), hemolytic anemias, administration of iron supplements, vitamin B12, erythropoietins, high-dose vitamin E, C and other antioxidants, antiretroviral therapy, ribavirin and interferon-α treatment, acute blood loss, blood or red blood cell transfusion, reticulocytosis, splenomegaly, rheumatoid arthritis, chronic liver disease, marked hypertriglyceridemia.

Factors increasing or decreasing HbA1c levels: hemoglobinopathies, end-stage renal disease, genetic factors, fetal hemoglobin, methemoglobin.

In this case, fructosamine determination may be used, which evaluates plasma glucose levels over the preceding 3 weeks, but its diagnostic and target values have not yet been established.

2.4 Instrumental Diagnostics

Specific instrumental diagnostics for type 2 diabetes are not performed; however, for screening and diagnosing complications, various studies are performed as indicated and listed in Section 7, Additional Information.

2.5 Other Procedures

The diagnosis of type 2 diabetes is established solely based on blood glucose or HbA1c levels exceeding the diabetic range. Differential diagnosis of type 2 diabetes is usually not required; however, in rare cases, additional workup is necessary to rule out other types of diabetes.

Comments: C-peptide is a protein cleaved from the proinsulin molecule during insulin release in equimolar amounts. Lacking secretory activity, C-peptide serves as an additional biological marker of insulin secretion. The basal C-peptide level in healthy individuals is 1.1–4.4 ng/mL. In type 1 diabetes, the C-peptide level is reduced or undetectable. Following stimulation with glucose or a standard carbohydrate breakfast, the C-peptide level does not significantly increase in patients with type 1 diabetes, whereas it increases significantly in type 2 diabetes.

Comments: Autoantibodies to β-cell antigens (ICA, GADA, IAA, IA-2A, Zn-T8A) are immunological markers of autoimmune insulitis. The test is performed for the differential diagnosis of type 2 diabetes from type 1 diabetes and latent autoimmune diabetes in adults (LADA). The presence of two or more specific autoantibodies is characteristic of the development of type 1 diabetes.

Comments: When type 2 diabetes develops at a young age, differential diagnosis with monogenic forms of diabetes (MODY) may be required.

Due to the prolonged asymptomatic course of the disease, the high probability of complications already present at the time of detection, the need to assess and correct cardiovascular risk factors, the possible presence of comorbid conditions affecting treatment selection, and to ensure the safe use of glucose-lowering drugs, patients with newly diagnosed type 2 diabetes require an additional workup immediately upon diagnosis.

- complete blood count (CBC) in patients with diagnosed type 2 diabetes (immediately in emergency conditions) to rule out or confirm the presence of a concomitant inflammatory process and anemia [3, 22].

- general clinical blood chemistry (glucose, creatinine, urea, uric acid, total protein, total bilirubin, aspartate aminotransferase, alanine aminotransferase, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, potassium, sodium) in patients with diagnosed type 2 diabetes for subsequent safe pharmacological correction of hyperglycemia and risk factors, as well as to identify complications [3, 22].

- assessment of the estimated glomerular filtration rate (eGFR) in patients with diagnosed type 2 diabetes to determine renal function [23].

- urinalysis in patients with diagnosed type 2 diabetes to check for urinary tract infections [3, 22].

- determination of albumin or the albumin-to-creatinine ratio in a morning urine sample in patients with diagnosed type 2 diabetes to verify diabetic nephropathy [23]. The determination of albumin or the albumin-to-creatinine ratio in urine is performed in the absence of inflammatory changes in the routine urinalysis or Nechyporenko urine test.

- eye examinations by an ophthalmologist for all patients with type 2 diabetes at the time of diagnosis, and at least annually thereafter, to detect diabetic retinal changes [24–30].

- foot examination, sensory assessment, and palpation of peripheral arterial pulses in patients with diagnosed type 2 diabetes to verify potential complications [3, 31–35].

- resting ECG recording in patients with diagnosed type 2 diabetes to screen for cardiovascular pathology [3].

GRS CLOE 5Grade of Recommendation Strength C (Level of Evidence – 5)

Comments: Determining eGFR is important for ensuring the safe use of glucose-lowering drugs. If a urinary tract infection is detected, it must be treated. Some patients may present with ketonuria.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Treatment of type 2 diabetes includes:

1. medical nutrition therapy;

2. physical activity;

3. glucose-lowering medications;

4. self-monitoring of blood glucose;

5. disease management education;

6. surgical treatment (metabolic surgery) in case of obesity.

Treatment of type 2 diabetes requires a multifactorial strategy: in addition to adequate glycemic control, targets for blood pressure and lipid metabolism should be achieved; medications that reduce cardiovascular risk should be used; and lifestyle should be modified (including physical activity, weight loss when indicated, smoking cessation, etc.). Multifactorial interventions can not only significantly reduce the risk of microvascular and cardiovascular complications, but may also lead to a substantial reduction in mortality in patients with type 2 diabetes [36].

Lifestyle modification is the cornerstone of type 2 diabetes therapy and must be maintained throughout the entire course of the disease.

Disease management education and patient motivation must begin immediately and accompany treatment throughout its entire course.

3.1 Therapeutic goals

3.1.1 Glycemic control indicators (individualized treatment goals)

Comments: For the majority of patients with type 2 diabetes, a target HbA1c level of less than 7.0% is appropriate [38, 41, 45].

The algorithm for the individualized selection of HbA1c treatment targets is presented in Table 4. These target values do not apply to pregnant women.

Table 4. Algorithm for individualized selection of HbA1c treatment targets1, 2

1 These target values do not apply to pregnant women.

2 Normal level according to DCCT standards: up to 6%.

3 Coronary artery disease (history of myocardial infarction, coronary artery bypass grafting/stenting, angina pectoris); history of stroke; lower extremity arterial disease (symptomatic).

4 The main criteria for the risk of severe hypoglycemia are: history of severe hypoglycemia, asymptomatic hypoglycemia, long duration of diabetes, CKD stages 3–5, dementia.

5 For the definition of patient categories, see Section 7.9, Specifics of Type 2 Diabetes Mellitus in Older Age.

Note: It should be borne in mind that biological and chronological age often do not coincide; therefore, the definitions of young, middle, and old age are relatively conventional. At the same time, the concept of "life expectancy" (LE) allows for a better assessment of the patient's general condition and the clinical significance of developing complications than age alone. Even in older age, LE can be quite high, and in such cases, setting excessively lenient individual treatment targets should be avoided.

The correspondence of HbA1c to target pre- and postprandial plasma glucose levels1 is shown in Table 5.

Table 5. Correspondence of HbA1c to target pre- and postprandial plasma glucose levels1

1 These target values do not apply to pregnant women.

2 Normal level according to DCCT standards: up to 6%.

Table 6 shows the correspondence of HbA1c to the mean daily plasma glucose level over the last 3 months.

Table 6. Correspondence of HbA1c to the mean daily plasma glucose level over the last 3 months.

MDPG — mean daily plasma glucose

MDPG (mmol/L) = 1.5944 × HbA1c (%) – 2.594 [47]

Comments: Standardized CGM metrics and their target values in patients with type 2 diabetes are presented in Table 7 [48]. For patients undergoing CGM, it is recommended that after formulating the diagnosis, as part of individual glycemic control targets, in addition to HbA1c, fasting/pre-prandial/bedtime/nighttime plasma glucose levels and 2-hour post-prandial glucose, at least the recommended time in range should be specified.

Table 7. Standardized continuous glucose monitoring metrics and their target values in patients with type 2 diabetes mellitus

1Including values >13.9 mmol/L, 2Including values <3.0 mmol/L

3.1.2 Target lipid profile parameters

Comments: The choice of target LDL-C levels is presented in Table 8.

Table 8. Choice of target low-density lipoprotein cholesterol levels in patients with type 2 diabetes mellitus

Note: LDL-C — low-density lipoprotein cholesterol.

1 Conversion from mmol/L to mg/dL: mmol/L × 38.67 = mg/dL.

2 Proteinuria, eGFR < 45 mL/min/1.73 m2, eGFR 45–59 mL/min/1.73 m2 + microalbuminuria, left ventricular (LV) hypertrophy, or retinopathy.

3 Patient age (type 1 diabetes ≥35 years or type 2 diabetes ≥50 years), arterial hypertension, dyslipidemia, smoking, obesity.

3.1.3 Target blood pressure levels

Comments: Target BP levels are presented in Table 9.

Table 9. Choice of target blood pressure levels (subject to good tolerability)

The lower limit of target BP values applies to individuals receiving antihypertensive therapy

3.2 Glucose monitoring

For self-monitoring of blood glucose, it is recommended to use blood glucose meters intended for individual use. Currently, there are glucose meters with adjustable individual target glycemic ranges, as well as those featuring wireless data transmission of glucose levels to medical specialists, relatives, or a special smartphone application for remote monitoring.

Individual blood glucose meters must comply with GOST R ISO 15197-2015 regarding analytical and clinical accuracy [64]. At plasma glucose levels <5.6 mmol/L, 95% of measurements must deviate from the reference analyzer by no more than ±0.8 mmol/L; at plasma glucose levels ≥5.6 mmol/L, 95% of measurements must deviate from the reference analyzer by no more than ±15%.

In healthcare settings, in addition to laboratory analyzers, professional-use blood glucose meters (multi-user, hospital-grade) should be used.

Continuous glucose monitoring (CGM) systems measure glucose in the interstitial fluid continuously at 5-15 minute intervals using subcutaneously implanted sensors. There is a time lag between the displayed interstitial and capillary glucose values (on average 8-10 minutes, up to a maximum of 20 minutes). Thus, when blood glucose levels are stable, the displayed values will be close to capillary glucose levels. However, during rapid increases or decreases in blood glucose, the displayed value will generally be lower or higher, respectively.

Currently available CGM systems can be divided into three categories:

1) "Blind" CGM or professional CGM allows retrospective evaluation of glucose levels over a short period (from a few days to 2 weeks). The primary purpose of this method is the objective assessment of the glycemic profile (including glucose variability), detection of hidden episodes of hypo-/hyperglycemia to adjust ongoing treatment, and patient education. During the use of these systems, the patient must perform parallel self-monitoring of blood glucose using glucometers for subsequent calibration;

2) Real-time CGM reflects the current glucose level, trends (direction and rate of glucose change), and a historical glucose graph (including variability). They feature alarms that are activated when glycemia reaches threshold values, when these values are predicted, or when the threshold rate of glycemic change is reached. During the use of these systems, the patient must perform parallel self-monitoring of blood glucose using glucometers for subsequent calibration. Some real-time CGM models transmit glucose data to a smartphone, from where it can be saved to an internet server and used for remote monitoring;

3) Intermittently scanned CGM or flash glucose monitoring (FGM) does not display glucose levels automatically, but only when a scanner (reader) or a smartphone with a special application is brought into close proximity to the sensor. FGM provides information on the current glucose level, trends (direction and rate of glucose change), and a historical glucose graph (including variability). Calibration is not required during FGM use.

Given the large volume of information accumulated during use and the resulting difficulties in visual interpretation by specialists, periodic downloading of CGM and FGM data with subsequent analysis using specialized software (including ambulatory glucose profile) is necessary. Various indicators of glucose variability, as well as the time spent in target, hypoglycemic, and hyperglycemic ranges, can be analyzed.

Currently, real-time CGM and FGM do not replace traditional blood glucose self-monitoring with glucometers! The use of real-time CGM and FGM may be beneficial for patients with type 2 diabetes receiving intensified insulin therapy (multiple daily insulin injections or insulin pump***) who initially perform self-monitoring of blood glucose at least 4 times a day, especially pregnant women, as well as those with impaired hypoglycemia awareness.

Comments: The frequency of self-monitoring of blood glucose depends on the degree of achievement of target glycemic control levels and the type of glucose-lowering therapy:

o at the onset of the disease and when target levels of glycemic control are not achieved – at least 4 times a day (before meals, 2 hours after meals, at bedtime, periodically at night);

o thereafter (upon achieving target levels of glycemic control) depending on the type of glucose-lowering therapy:

Ø on intensified insulin therapy: at least 4 times a day (before meals, 2 hours after meals, at night, periodically at night); additionally before and after physical exertion, when hypoglycemia is suspected, and prior to activities potentially hazardous to the patient and others (e.g., driving a vehicle or operating complex machinery);

Ø on oral glucose-lowering therapy and/or GLP-1 RA and/or basal insulin: at least 1 time a day at different times + 1 glycemic profile (at least 4 times a day) per week; reducing the frequency of self-monitoring is possible when using only drugs with a low risk of hypoglycemia;

Ø on premixed insulin: at least 2 times a day at different times + 1 glycemic profile (at least 4 times a day) per week;

Ø on dietary therapy: at least 1 time per week at different times of the day.

Comments: Multi-user glucometers have higher measurement accuracy compared to individual glucometers and withstand repeated disinfection cycles in accordance with well-validated methods provided by the manufacturer. The multi-user glucometer must be disinfected after each blood glucose measurement for each patient using agents with fungicidal, antibacterial, and antiviral activity that do not affect the functional properties of the meter.

Comments: "Blind" CGM can be useful both in outpatient and inpatient settings for:

Ø detecting nocturnal hypo- and hyperglycemia;

Ø assessing an expanded list of glycemic control indicators, including: time in range / hypoglycemia / hyperglycemia, glycemic variability, etc.

Comments: The use of real-time CGM or FGM should be considered in this category of patients in the following situations:

- severe hypoglycemia (≥1 time in the past year);

- frequent episodes of mild hypoglycemia;

- impaired awareness of hypoglycemia;

- high glycemic variability regardless of HbA1c levels;

- time in range less than 50% according to "blind" CGM data.

Comments: Real-time CGM and FGM do not replace traditional self-monitoring of blood glucose with blood glucose meters. The increasing measurement accuracy in modern real-time CGM and FGM systems allows for a significant reduction in the frequency of traditional blood glucose self-monitoring with a meter. FGM can be used instead of a blood glucose meter for making clinical decisions, except in certain cases (hypoglycemia, rapid blood glucose fluctuations, or if symptoms do not match system readings).

3.3 Non-pharmacological treatments

3.3.1 Nutritional recommendations.

Comments: Given that nutrition is an important lifestyle component and strongly impacts quality of life, personal preferences must be taken into account when formulating nutritional recommendations. In general, this is not about rigid dietary restrictions that are difficult to implement on a long-term basis, but about the gradual development of a dietary pattern that meets current therapeutic goals.

Comments: Weight loss provides a positive effect regarding glycemic control, lipids, and blood pressure, especially early in the disease course. The weight loss process is most effective when combined with physical activity and educational programs. Sudden, non-physiological dietary restrictions and fasting are contraindicated.

Comments: Recommendations are formulated based on an analysis of the current dietary pattern and metabolic goals.

Comments: General nutritional recommendations for overweight are reflected in Appendix C "Nutrition for Overweight". Moderate consumption of non-caloric sweeteners is acceptable for patients with T2D to replace dietary sugar [98, 112–114].

Comments: In other cases, a practically oriented assessment may be sufficient [96].

Comments: It is also important to include foods rich in mono- and polyunsaturated fatty acids (fish, vegetable oils) in the diet.

Comments: One standard unit corresponds to 15 g of ethanol, or approximately 40 g of spirits, or 140 g of wine, or 300 g of beer. Alcohol consumption increases the risk of hypoglycemia, including delayed hypoglycemia, in patients receiving secretagogues and insulin. Education and continuous monitoring of knowledge regarding hypoglycemia prevention are necessary.

Alcohol consumption poses a serious threat in the presence of pancreatitis, severe neuropathy, hypertriglyceridemia, and alcohol dependence.

3.3.2 Physical activity recommendations

Comments: Physical activity is selected individually, taking into account the patient's age, diabetes complications, comorbid conditions, and tolerability. Some patients with pronounced complications and comorbidities, especially ASCVD, that limit physical activity may be prescribed medical gymnastics.

Comments: In patients with T2D receiving insulin, glucose-lowering drugs stimulating insulin secretion (and very rarely other glucose-lowering agents), physical activity can cause hypoglycemia [145].

Contraindications and precautions are determined by the presence of diabetes complications and comorbidities.

The risk of CHD requires mandatory ECG testing (stress tests, etc., as indicated) before starting a physical activity program.

3.4 Pharmacotherapy

3.4.1 General principles of pharmacotherapy

An individualized approach to each patient with T2D is a priority when choosing treatment tactics.

Lifestyle modification (rational nutrition and increased physical activity) and education in disease management principles are an integral part of treatment and should be carried out throughout the entire course of the disease.

Classes of glucose-lowering drugs (ATC classification A10 drugs for the treatment of diabetes mellitus) used in the Russian Federation for the treatment of T2D, indicating their mechanisms of action, are listed in Table 10.

Table 10. Glucose-lowering drug classes and their mechanism of action

Metformin** is the primary drug for initiating pharmacotherapy in the majority of patients with T2D. Metformin** should be used as part of glucose-lowering therapy throughout the entire treatment period, provided the drug is tolerated and there are no contraindications.

At any stage of treatment, it is necessary to assess individual patient characteristics (especially indications of high ASCVD risk or existing ASCVD, chronic heart failure (CHF), chronic kidney disease (CKD), obesity, high risk of hypoglycemia) and highlight the patient's dominant clinical problem (Table 12 "Personalization of the choice of glucose-lowering drugs depending on the patient's dominant clinical problem", Appendix B Physician Action Algorithms "Choice of preferred glucose-lowering drug depending on the dominant clinical problem").

In patients with a history of high ASCVD risk or established ASCVD, HF, or CKD, the choice of glucose-lowering therapy can significantly affect individual prognosis, and the inclusion of GLP-1 RAs or SGLT2is with proven benefits in these conditions is a disease-modifying approach to treatment. Moreover, if such patients have achieved glycemic control targets using other agents, the inclusion of a drug with proven benefits from the SGLT2i and/or GLP-1 RA classes should be considered, replacing non-class agents.

When prescribing glucose-lowering drugs, contraindications must be taken into account, and current approved prescribing information (SmPC) should be used.

The duration of action, dosing frequency, and doses of glucose-lowering drugs are presented in Appendix A3.

The choice of pharmacotherapy is determined based on the patient's dominant clinical problem and the baseline level of glycemic control (Appendix B, Physician Action Algorithms: "Recommended pace of treatment intensification in patients with type 2 diabetes mellitus depending on baseline HbA1c level", "Selection of the preferred glucose-lowering drug depending on the dominant clinical problem").

Depending on how much the baseline level exceeds the individual target HbA1c of a particular patient, either monotherapy or combination treatment may be chosen at the start of treatment, which in certain clinical situations will include SGLT2is and/or GLP-1 RAs with proven benefits in ASCVD, high ASCVD risk, HF, and CKD (see "Recommended pace of treatment intensification in patients with type 2 diabetes mellitus depending on baseline HbA1c level" in Appendix B "Physician Action Algorithms").

Monitoring the efficacy of glucose-lowering therapy by HbA1c level is performed every 3 months. Modification (intensification) of glucose-lowering therapy in case of its ineffectiveness (i.e., failure to achieve individual HbA1c targets) is performed no later than 6 months (in individuals with a low risk of hypoglycemia, it is advisable to do so no later than 3 months).

It is advisable to assess the adequacy of ongoing glucose-lowering therapy, previous individual target values of glycemic control, and the patient's current health status every 6–12 months (confirming previous treatment goals or modifying them, determining the presence of ASCVD risk factors or ASCVD, CKD, HF, obesity, and hypoglycemia risk, presence or absence of contraindications to ongoing therapy, etc.).

If the baseline HbA1c level is within the target range or exceeds the individual target level by less than 1.0%, treatment can be initiated with monotherapy (metformin** is the preferred drug for most patients in the absence of contraindications). In case of metformin** intolerance or contraindications, other drugs may be prescribed taking into account recommendations for personalized selection of glucose-lowering agents. At this stage, drugs with a low risk of hypoglycemia are preferred. An HbA1c reduction rate of ≥ 0.5% over 6 months of follow-up is considered effective.

In treatment-naive patients with type 2 diabetes without ASCVD, HF, and CKD, early initiation of combination therapy may have advantages regarding long-term maintenance of glycemic control even with a slight exceedance of the target HbA1c level (e.g., initial combination of a DPP-4 inhibitor with metformin in the VERIFY study compared to initial metformin therapy with subsequent addition of a DPP-4 inhibitor).

Deintensification and modification of therapy are possible at any stage of treatment.

If the baseline HbA1c level exceeds the individual target level by 1.0–2.5%, a combination of 2 glucose-lowering drugs should be considered as starting therapy. When using combination therapy, its rationality, as well as recommendations for the personalized selection of glucose-lowering drugs, should be taken into account. At this stage, drugs with a low risk of hypoglycemia are preferred. An HbA1c reduction rate of ≥ 1.0% over 6 months of follow-up is considered effective.

If the baseline HbA1c level exceeds the individual target level by more than 2.5%, this situation is often characterized by pronounced glucose toxicity, to reduce which insulin therapy (or a combination of insulin with other glucose-lowering drugs) must be initiated; subsequent discontinuation of insulin therapy may be possible.

If at the onset of the disease the baseline HbA1c level exceeds the individual value by more than 2.5%, but there are no severe clinical symptoms of metabolic decompensation (progressive weight loss, thirst, polyuria, etc.), treatment can be started with an alternative option: a combination of 2 or 3 glucose-lowering drugs acting through different mechanisms of hyperglycemia development.

When using combination therapy, its rationality, as well as recommendations for the personalized selection of glucose-lowering drugs, should be taken into account. SUs, insulin, and GLP-1 RAs can provide a rapid glucose-lowering effect. SGLT2is exert a significant glucose-lowering effect regardless of blood insulin levels, but should not be used in conditions with severe insulin deficiency. An HbA1c reduction rate of ≥ 1.5% over 6 months of follow-up is considered effective.

Comparative efficacy, advantages, and disadvantages of glucose-lowering drugs are presented in Table 11.

Table 11. Comparative efficacy, advantages, and disadvantages of glucose-lowering drugs

It should be borne in mind that in certain clinical situations (presence of ASCVD, high risk of ASCVD, CHF, CKD, obesity, risk of hypoglycemia), certain classes of glucose-lowering drugs (or individual agents) have proven advantages (Table 12).

Table 12. Personalization of glucose-lowering drug selection based on the patient's dominant clinical problem

1A limited number of studies have been conducted in a population predominantly consisting of patients with a history of high ASCVD risk / multiple CVD risk factors:

Ø Dulaglutide** in the REWIND trial (69% of participants with a history of high ASCVD risk: age ≥55 years with coronary, carotid, or lower extremity arterial stenosis, or left ventricular hypertrophy) demonstrated a 12% reduction in primary endpoint events compared to placebo [149];

Ø Dapagliflozin** in the DECLARE-TIMI 58 trial, in which 60% of participants had multiple ASCVD risk factors, demonstrated a 17% reduction in the composite endpoint (reduction in cardiovascular death and hospitalization for heart failure) [150]

2 CHD (history of MI, coronary artery bypass graft surgery/stenting, angina pectoris), cerebrovascular disease, symptomatic lower extremity arterial disease

3 In large randomized controlled trials (RCTs) conducted in diverse populations of patients with T2D, SGLT2i showed the following results:

Ø Empagliflozin** in EMPA-REG OUTCOME (98% of participants with ASCVD): 14% reduction in the 3P-MACE composite primary endpoint (cardiovascular death, non-fatal MI, non-fatal stroke), 32% reduction in all-cause mortality, 38% reduction in cardiovascular mortality, and 38% reduction in hospitalization for heart failure [151];

Ø Canagliflozin in the CANVAS program (65% of participants with ASCVD and 35% with risk factors): 14% reduction in the 3P-MACE composite primary endpoint (see above), 33% reduction in hospitalization for heart failure [152];

Ø Dapagliflozin** in DECLARE-TIMI 58 (40% of participants with ASCVD and 60% with risk factors): a trend toward a reduction in the 3P-MACE composite endpoint that did not reach statistical significance; a 17% reduction in the incidence of composite primary endpoint events (hospitalization for heart failure and/or cardiovascular death). A subanalysis in patients with a history of MI also showed a 16% reduction in the 3P-MACE composite endpoint [150].

Ø Ertugliflozin** in VERTIS CV (99.9% of participants with ASCVD): 30% reduction in hospitalization for heart failure [153].

4 SGLT2i that demonstrated renal benefits in large RCTs (see above) in cardiovascular risk assessment of glucose-lowering drugs (canagliflozin, dapagliflozin**, empagliflozin**, ertugliflozin**).

5 Improved glycemic control may contribute to some extent.

6 See Table 11 "Comparative Efficacy, Advantages, and Disadvantages of Glucose-Lowering Drugs", including GFR restrictions.

When using combinations, the rationality of drug pairings should also be considered (Table 13).

Table 13. Rational combinations of glucose-lowering drugs

Notes:

+ Rational combination;

NR Irrational combination;

1 Except for confirmed cases of severe insulin resistance;

2 Including insulin analogues

Comments: Indications, contraindications, and restrictions in the prescribing information for specific glucose-lowering drugs should be considered in each case.

When prescribing a combination of 3 glucose-lowering drugs, the rationality of combining each drug with the other two must be verified.

If treatment intensification is necessary, the sequence of prescribing glucose-lowering drugs is not strictly regulated and should be determined on an individual basis. In individuals receiving insulin as part of combination therapy, treatment intensification may be continued by adding other glucose-lowering drugs (provided all agents used in the combination are rationally paired). When choosing various combinations, recommendations for personalized selection of glucose-lowering drugs must also be taken into account (Table 12).

Combinations of 2 glucose-lowering drugs belonging to the same class (e.g., 2 SUs) are irrational.

Most oral glucose-lowering drugs are available in combination formulations, and injectable glucose-lowering drugs are available as fixed-ratio combinations of GLP-1 RAs and basal insulin.

Irrational combinations of glucose-lowering drugs include:

Ø Sulfonylureas + Glinides;

Ø GLP-1 RAs + DPP-4 inhibitors;

Ø Two sulfonylureas;

Ø TZDs + insulin (except for confirmed cases of severe insulin resistance);

Ø SGLT2 inhibitors (SGLT1/2 inhibitors, SGLT1 inhibitors) + DPP-4 inhibitors, or glinides, or sulfonylureas.

It is necessary to take into account the GFR level when prescribing glucose-lowering drugs (Table 14).

Table 14. Glucose-lowering drugs approved for use at various stages of chronic kidney disease

1 For CKD G3b–5, dose adjustment of the drug is required.

It is necessary to remember the increased risk of hypoglycemia in patients on insulin therapy as kidney disease progresses from CKD G1–2 to G3–5, which requires a reduction in the insulin dose.

2 Do not initiate if eGFR < 25 mL/min/1.73 m² (can be continued in patients already receiving therapy)

3 Do not initiate if eGFR < 30 mL/min/1.73 m² (can be continued if albuminuria > 300 mg/day in patients already receiving therapy).

Comments: Given the extensive clinical experience, efficacy, safety, availability, and potential cardiovascular benefits, metformin** is most frequently used to initiate pharmacotherapy for type 2 diabetes (in the absence of contraindications and with good tolerability) [3]. The possibility of vitamin B12 deficiency development with long-term use should be taken into account. The prolonged-release tablet formulation has better tolerability.

Comments: Modern treatment of type 2 diabetes, acknowledging the complexity of its pathogenesis, highlights the importance of simultaneously addressing specific abnormalities leading to hyperglycemia from the time of diagnosis. A slight delay in achieving the target level of glycemic control increases the risk of diabetic complications. The 5-year VERIFY trial demonstrated a significant advantage of combination therapy with metformin** and vildagliptin** over sequential intensification in patients with newly diagnosed type 2 diabetes in achieving and maintaining a stable level of target glycemic control. Patients receiving the combination showed a significantly slower loss of glycemic control compared to patients receiving metformin** alone with subsequent addition of vildagliptin**. Earlier, in the EDICT study, it was shown in patients with recently diagnosed type 2 diabetes that combination therapy (metformin**/pioglitazone/exenatide) is more effective than the classical stepwise approach. A series of short-term studies (24–26 weeks) of combination therapy with SGLT2 inhibitors (canagliflozin, dapagliflozin**, empagliflozin**) and metformin** in patients with type 2 diabetes (treatment-naive) showed its superiority over monotherapy.

Comments: ASCVD includes: coronary heart disease (history of myocardial infarction, coronary artery bypass grafting/stenting, angina pectoris), cerebrovascular accident, lower extremity artery disease (with symptoms).

In studies conducted in diverse populations of patients with type 2 diabetes, SGLT2 inhibitors showed the following results:

Ø Empagliflozin** in the EMPA-REG Outcome trial (98% of participants with ASCVD): a 14% reduction in the combined primary 3P-MACE endpoint (cardiovascular death, non-fatal MI, non-fatal stroke), a 32% reduction in all-cause mortality, a 38% reduction in cardiovascular mortality, and a 38% reduction in heart failure hospitalization rates [151];

Ø Canagliflozin in the CANVAS program (65% of participants with ASCVD and 35% with risk factors): a 14% reduction in the combined primary 3P-MACE endpoint (see above), and a 33% reduction in heart failure hospitalization rates [152];

Ø Dapagliflozin** in DECLARE-TIMI 58 (40% of participants with ASCVD and 60% with risk factors): a trend toward a reduction in the 3-MACE combined endpoint that did not reach statistical significance; a 17% reduction in the rate of events of the combined primary endpoint (heart failure hospitalization and/or cardiovascular death). A subanalysis in patients with a history of MI also demonstrated a 16% reduction in the 3P-MACE combined endpoint [150].

Ø Ertugliflozin** in VERTIS CV (99.9% of participants with ASCVD): a 30% reduction in heart failure hospitalization rates [153].

A systematic review and meta-analysis of three studies (34,322 patients, 60.2% with ASCVD) showed that SGLT2 inhibitors provide moderate benefits regarding MACE, which are limited solely to patients with ASCVD. At the same time, SGLT2 inhibitors provide clear benefits in reducing heart failure hospitalizations or the progression of CKD regardless of the presence of ASCVD or a history of heart failure [163].

In studies conducted on varying populations of patients with T2D, several GLP-1 receptor agonist drugs demonstrated a reduction in cardiovascular risk:

Ø Liraglutide in the LEADER trial (85% of participants had ASCVD): liraglutide therapy reduced cardiovascular risk (a 13% reduction in 3P-MACE), the risk of cardiovascular death by 22%, and the risk of all-cause mortality by 15% [161].

Ø Semaglutide** in the SUSTAIN-6 trial (83% of participants with established ASCVD) showed a 26% reduction in combined primary endpoint events compared to placebo. No statistically significant differences were found in cardiovascular death as a secondary endpoint [162].

Ø Dulaglutide** (31% of participants with ASCVD) in the REWIND trial showed a 12% reduction in primary endpoint events compared to placebo [149].

A meta-analysis covering GLP-1 RA and SGLT2 inhibitor trials (total of 77,242 participants) showed that GLP-1 RAs and SGLT2 inhibitors similarly reduce the combined 3P-MACE endpoint in patients with ASCVD; however, SGLT2 inhibitors have a more pronounced effect on preventing heart failure hospitalizations and the progression of CKD [166].

Comments: See Section 7.2 Diabetic Nephropathy.

Comments: The use of SGLT2 inhibitors in individuals with ASCVD and risk factors is accompanied by benefits such as a reduction in heart failure hospitalizations or the progression of renal pathology regardless of the presence of ASCVD or a history of heart failure [163]. In the REWIND trial, in which 69% of participants had only cardiovascular risk factors, the use of dulaglutide** was associated with a 12% reduction in 3P–MACE [149].

3.4.2 Insulin therapy

From the time of diagnosis, patients with T2D should be informed about the possible prescribing of insulin, given the progressive nature of the disease.

The characteristics of insulin preparations used in the treatment of patients with T2D in the Russian Federation are listed in Table 15.

Table 15. Characteristics of insulin preparations used in the treatment of patients with type 2 diabetes mellitus

1 Must be thoroughly mixed before administration

In clinical practice, switching from one insulin to another occurs quite frequently. When transferring a patient from one insulin to another, it is necessary to follow the following algorithm of requirements to best ensure patient safety [178]:

1. In case of different INNs.

• Switching from one insulin product to another must be carried out strictly according to medical indications, only under the supervision of a physician, and requires more frequent self-monitoring of glucose levels, patient education, and dose adjustment of the newly prescribed insulin.

• The switch can be made from one insulin product to another both within the same ATC classification group and with a change of the ATC group (for example, switching from human insulin to an insulin analogue and vice versa).

2. In the case of the same INN.

• Switching patients from one insulin to another with proven interchangeability (i.e., proven bioequivalence in terms of pharmacokinetics, pharmacodynamics, and safety of action) generally does not require more frequent self-monitoring of glucose levels, patient education, or dose adjustment of the newly prescribed insulin. With proven bioequivalence, all indications, contraindications, and adverse reactions in special patient groups are extrapolated to the biosimilar from the package leaflet of the reference product.

• Switching patients from one insulin to another within the same INN, but with different pharmacokinetics and pharmacodynamics, must be carried out according to the rules specified for products with different INNs.

3. In the event of adverse events during either the initiation of insulin therapy or the switch from one insulin product to another, which include worsening of glycemic control, a significant change in insulin requirement/dose, or the development of allergic reactions, reporting to the Federal Service for Surveillance in Healthcare is mandatory.

4. The decision to switch from one insulin product to another is made by the physician taking into account the current package leaflet.

Comments: Temporary prescription of insulin therapy is possible. Once glucose toxicity is eliminated, switching to other glucose-lowering drugs is possible.

Comments: Achieving maximum doses of initial glucose-lowering drugs is not required to initiate insulin therapy.

Initiation of insulin therapy is possible with basal insulin, premixed insulins, fixed-ratio combinations of basal insulin and GLP-1 RAs, multiple injections of short-acting insulin (rapid-acting insulin analogues, short-acting human insulins) and basal insulin (Table 16).

Before planned initiation of insulin therapy, it is necessary to train the patient in self-monitoring of glycemia; warn about the possibility of hypoglycemia, inform about its symptoms, elimination, and prevention methods; review dietary principles (carbohydrate counting when using short-acting insulin (rapid-acting insulin analogues, short-acting human insulins) or premixed insulins/combinations).

Insulin therapy should also be prescribed in the presence of contraindications to or intolerance of other glucose-lowering drugs; in case of ketoacidosis; when surgery is necessary, or during acute intercurrent illnesses and exacerbations of chronic diseases accompanied by decompensation of carbohydrate metabolism (temporary switch to insulin therapy is possible).

Insulin can be combined with other glucose-lowering drugs, with the exception of irrational combinations (Table 13).

Table 16. General principles for selecting an insulin therapy regimen in type 2 diabetes mellitus

1 Except for irrational combinations

Comments: Usually, basal insulin is added at a dose of 10 IU per day or 0.1–0.2 IU per kg of body weight; titration is performed once every 3–7 days by 2 IU based on the fasting plasma glucose level.

Given the simple titration regimen, the potential for achieving an excessive dose of basal insulin within the glucose-lowering therapy should be taken into account. Often, the daily dose of basal insulin exceeds 0.5 IU/kg, there is a large difference between bedtime and morning fasting glycemia levels, hypoglycemia occurs, and there is high daily variability of glycemia parameters [188].

The fixed-ratio combination of basal insulin and GLP-1 RAs, compared with the use of basal insulin, allows a greater proportion of patients to achieve the target HbA1c level without increasing the frequency of hypoglycemia and weight gain [185–187].

Comments: similar benefits can be obtained in a situation where intensification of glucose-lowering treatment is necessary in patients with type 2 diabetes already receiving basal insulin: switching to a fixed-ratio combination of basal insulin and GLP-1 RAs is accompanied by an improvement in glycemic control without weight gain and hypoglycemia compared with switching to premixed insulins [189].

Comments: With comparable glucose-lowering efficacy, NPH insulins are associated with a higher risk of hypoglycemia compared to long-acting and ultra-long-acting insulin analogues [180, 190, 191].

Insulin glargine** 300 U/mL and insulin degludec** are characterized by a lower risk of hypoglycemia compared to insulin glargine** 100 U/mL [203].

Comments: Premixed insulin preparations (combinations) are usually prescribed 1–2 times daily at a dose of 10–12 U/day or 0.3 U/kg of body weight; titration is individualized, depends on the type of insulin, and is guided by fasting plasma glucose and/or pre-dinner glucose levels.

Comments: Typically, the distribution of RAIA/FAIA/RHI and basal insulin when prescribing intensified insulin therapy is 50%/50%. Basal insulin is generally prescribed at a dose of 10 U/day or 0.1–0.2 U/kg of body weight, and RAIA/FAIA/RHI at 4 U or 10% of the basal insulin dose before main meals. Basal insulin titration is performed by 2 U every 3–7 days based on fasting plasma glucose levels, while RAIA/FAIA/RHI doses depend on pre-meal plasma glucose levels and the planned carbohydrate intake (see Appendix B: Food Exchange System). Glycemic self-monitoring is performed at least 4 times a day.

Comments: Compared to RHI, FAIA preparations have a faster onset of action and an earlier peak, which allows for a reduced interval between injection and meal, as well as a decrease in postprandial glycemic excursion.

Comments: Indications for intensifying insulin therapy in type 2 diabetes: failure to achieve individual treatment targets on the previous insulin regimen within 3–6 months; further dose titration in a single injection is limited due to a large single dose (increased risk of hypoglycemia); dietary patterns require intensification of insulin therapy. Options for intensifying insulin therapy in type 2 diabetes are shown in Table 17.

Table 17. Possible options for intensifying insulin therapy in type 2 diabetes mellitus

1 Except for irrational combinations

The general flowchart of recommendations for insulin therapy in type 2 diabetes mellitus is presented in Appendix B: Clinical Action Algorithms "Initiation, Optimization, and Intensification of Insulin Therapy in Type 2 Diabetes Mellitus".

Comments: Insulin dose adjustment should be performed daily, taking into account daily self-monitoring data and dietary carbohydrate content, until individual target glycemic control parameters are reached. There are no limitations on the insulin dose. When planning insulin supplies for a patient, a conventional average daily dose should be used, which includes not only basal and prandial insulin, but also insulin for correcting hyperglycemia and checking the patency of the insulin needle.

Recommended insulin delivery devices:

Ø insulin syringes 100 U/mL (the concentration on the insulin vial must match the concentration on the insulin syringe);

Ø insulin pen injectors (ready-to-use (pre-filled with insulin) or with replaceable insulin cartridges);

Ø insulin pumps*** (wearable insulin infusion pumps), including those with continuous glucose monitoring

Insulin injection technique:

RHI is injected 20–30 minutes before a meal when glycemia is close to normal. FAIA (RAIA) is injected immediately before a meal when glycemia is close to normal, and if necessary, can be injected immediately after a meal.

If pre-meal glycemia is elevated, it is recommended to increase the time interval between the injection of RHI/FAIA/RAIA and the meal.

Recommended subcutaneous injection sites are:

Ø Abdomen within the following boundaries: approximately 1 cm above the pubic symphysis, approximately 1 cm below the lower rib, approximately 1 cm away from the umbilicus, and laterally to the mid-lateral line. Moving too far laterally across the anterior abdominal wall is not recommended in thin patients, as the thickness of the subcutaneous adipose tissue decreases, increasing the risk of intramuscular injection. Injections/infusions should also be avoided in the umbilical region and the midline of the abdomen, where the subcutaneous adipose tissue is thin.

Ø Anterolateral aspect of the upper third of the thighs.

Ø Upper outer aspect of the buttocks and the outer aspect of the lumbar region.

Ø Middle outer (posterior) third of the arms. The arm area is generally not recommended for self-injection due to the high risk of intramuscular drug administration (inability to form a skin fold).

The type of insulin should be considered when choosing injection sites. The preferred injection site for human RHI is the abdomen, as insulin absorption is the fastest there. NPH insulins should be injected into the buttock or thigh, as these sites have a slower absorption rate. Premixed human insulin preparations (RHI/NPH insulin) should be injected into the abdomen to increase the absorption rate of RHI.

PRCIA ( basal insulin analogs, long- and ultra-long-acting insulin analogs) can be injected into all recommended injection sites.

Insulin should be injected into healthy subcutaneous adipose tissue; intradermal and intramuscular (i.m.) injections, as well as scars and areas of lipodystrophy, should be avoided.

In some cases, dividing relatively large insulin doses into two separate consecutive injections at different sites may be preferable. There is no universal threshold for dose splitting, but generally, it is considered for doses of 40–50 IU of insulin at a concentration of 100 IU/mL.

Proper rotation of injection sites must always be observed to prevent lipodystrophy, which leads to impaired insulin absorption and glycemic variability. It is important to administer each subsequent injection at least 1 cm away from the previous one and to utilize all available injection sites.

To prevent the transmission of infectious diseases, insulin pens, insulin pen cartridges, and insulin vials are intended for single-patient use only.

Insulin supplies should be stored at +2–8 °C. Insulin vials or pens currently in use for daily injections may be stored at room temperature (up to +30 °C) for up to 4 weeks (insulin detemir** — 6 weeks, insulin degludec** — 8 weeks); insulin should be at room temperature prior to injection.

NPH insulin and premixed insulin formulations (RCI/NPH insulin and PRCIA/protaminated PRCIA) should be thoroughly mixed before injection.

Comments: Insulin injections using 4-mm pen needles can be given at a 90° angle, regardless of age, sex, or BMI. If patients must use needles > 4 mm in length or insulin syringes, a skin fold and/or a 45° injection angle may be required to avoid intramuscular injection.

Pain perception during insulin injections may be influenced by needle length, diameter, manufacturing process, presence of lubricant, and needle tip sharpening technology. A 5-bevel needle tip design is intended to reduce the resistance encountered as the needle passes through tissues, thereby minimizing injection pain for the patient [227].

Comments: According to the manufacturer's instructions for insulin pens, needles must be used only once.

Comments: If lipodystrophy is detected, retraining in insulin injection technique is necessary.

3.5 Surgical treatment

Comments: Metabolic surgery may be considered in patients with type 2 diabetes and a BMI ³ 30 kg/m2 (³ 27.5 kg/m2 for Asian populations) who have failed to achieve weight loss and glycemic control with non-surgical treatment [251–255].

Comments: Components of required monitoring for patients after bariatric surgery, as well as post-bariatric nutritional support, are presented in Table 18.

Table 18. Monitoring of patients after bariatric surgery and post-bariatric nutritional support.

3.6 Other treatment

3.6.1 Therapeutic patient education

According to WHO decisions, therapeutic patient education is an independent branch of medicine and a crucial component of chronic disease management, primarily diabetes mellitus [258].

Education is an integral part of therapeutic management in type 2 diabetes and should continue throughout the course of the disease. Diabetes management necessarily includes education on self-monitoring of blood glucose and disease self-management principles.

Comments: The goals and objectives of education should be tailored to the patient's current clinical status. Patients who have not previously undergone education (initial cycle) or those who have already completed education (refresher cycles) are referred to the "Diabetes School" to maintain their knowledge base and motivation or when new therapeutic goals are established. The "Diabetes School" office is a structural subdivision of a medical organization providing primary health care and specialized medical care in the field of endocrinology, delivering group therapeutic education for patients with diabetes according to structured programs depending on the type of diabetes and treatment method, with mandatory practical training in the skills necessary for disease self-management.

Comments: Education can be conducted either individually or in patient groups. The content of educational programs must comply with accepted standards for the diagnosis and treatment of diabetes mellitus, and their structure must take into account basic pedagogical principles. The programs should have a strictly practical focus and be easily comprehensible.

Mandatory sections of educational programs:

Ø general information on diabetes mellitus;

Ø nutrition;

Ø physical activity;

Ø self-monitoring of blood glucose;

Ø glucose-lowering drugs;

Ø insulin therapy (in detail for patients receiving insulin);

Ø hypoglycemia;

Ø late complications of diabetes mellitus;

Ø follow-up examinations in diabetes mellitus.

Most of the educational time should be devoted to the practical training of skills necessary for self-management of the disease. First of all, this concerns self-monitoring of blood glucose, insulin injection technique, rules for adjusting insulin doses, foot care, and self-measurement of blood pressure.

3.6.2 Pain management

General principles of analgesic therapy in patients with type 2 diabetes do not differ from those in the general population. Most often, this therapy has to be used for the treatment of patients with painful diabetic neuropathy.

Comments: For types of pharmacotherapy, see section 7.4 Diabetic neuropathy.

3.7 Hypoglycemia

Hypoglycemia is the main limiting factor in achieving target glycemia values in patients with type 2 diabetes. Currently, the following classification of hypoglycemia is adopted [46]:

Level 1: plasma glucose levels from 3.0 to < 3.9 mmol/L (with or without symptoms) in patients with diabetes receiving glucose-lowering therapy indicate a risk of hypoglycemia and require the initiation of measures to correct hypoglycemia, regardless of the presence or absence of symptoms.

Level 2: plasma glucose levels < 3.0 mmol/L, with or without symptoms – clinically significant hypoglycemia requiring immediate treatment.

Level 3: severe hypoglycemia — hypoglycemia within the above range with such cognitive impairment (including loss of consciousness, i.e., hypoglycemic coma) that requires the assistance of another person for correction.

Clinical presentation of hypoglycemia:

Autonomic symptoms: palpitations, tremor, skin pallor, sweating, mydriasis, nausea, severe hunger, restlessness, anxiety, aggressiveness.

Neuroglycopenic symptoms: weakness, impaired concentration, headache, dizziness, drowsiness, paresthesia, visual disturbances, confusion, disorientation, dysarthria, impaired motor coordination, altered mental status, coma; seizures and other neurological symptoms are possible [3, 284, 285].

Comments: The main cause of hypoglycemia: excess insulin in the body relative to the intake of carbohydrates from outside (with food) or from endogenous sources (hepatic glucose production), as well as during accelerated carbohydrate utilization (muscle work).

Triggering factors:

Ø overdose of insulin, sulfonylureas, or glinides: patient error, malfunction of the insulin pen injector, insulin pump***, or glucometer, intentional overdose; physician error (too low glycemic target level, excessively high doses);

Ø changes in insulin pharmacokinetics: high titer of insulin antibodies, incorrect injection technique;

Ø increased insulin sensitivity: prolonged physical exercise, early postpartum period, adrenal or pituitary insufficiency;

Ø skipped meals or insufficient carbohydrate intake, alcohol consumption, dietary restriction for weight loss (without a corresponding reduction in the dose of glucose-lowering drugs); delayed gastric emptying (in autonomic neuropathy), vomiting, malabsorption syndrome;

Ø pregnancy (first trimester) and breastfeeding.

Comments: For mild hypoglycemia (not requiring assistance from another person) – intake of 1–2 XE (bread units) of fast-acting carbohydrates: sugar (2–4 lumps of 5 g each, preferably dissolved), or honey or jam (1–1.5 tablespoons), or 100–200 ml of fruit juice, or 100–200 ml of sugar-sweetened soda, or 4–5 large dextrose tablets (3–4 g each), or 1–2 tubes of carbohydrate syrup (10 g of carbohydrates each).

If hypoglycemia is caused by long-acting insulin, especially at night, an additional 1–2 XE of slow-acting carbohydrates (bread, porridge, etc.) should be consumed.

Comments: In case of severe hypoglycemia (requiring assistance from another person, with or without loss of consciousness):

Ø position the patient on their side, clear the oral cavity of food residues;

Ø in case of loss of consciousness, sweet solutions must not be poured into the oral cavity (risk of asphyxia!);

Ø if consciousness is not restored after IV administration of 100 ml of 40% dextrose solution, initiate IV infusion of a 5–10% dextrose solution and hospitalize;

Ø if the cause is an overdose of a long-acting glucose-lowering drug, IV infusion of a 5–10% dextrose solution should be continued until glycemia normalizes and the drug is completely eliminated from the body;

Ø neurologist consultation.

Comments: Glucagon** can be administered by both medical personnel and the patient's relatives. #The route of administration has undergone clinical trials, but this route of administration is not listed in the drug's package insert in the Russian Federation at the time of publication of the clinical guidelines.

In patients hospitalized for severe hypoglycemia, injuries to the cardiovascular and nervous systems are most common. Therefore, it is necessary to consider the potential need for consultation with a neurologist and cardiologist, as well as additional studies for differential diagnosis with other conditions involving loss of consciousness, including brain MRI, ECG, Holter ECG monitoring, duplex scanning of brachiocephalic arteries, etc.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Specific medical rehabilitation is not required for patients with type 2 diabetes. Rehabilitation measures for patients with type 2 diabetes may include sessions with a medical psychologist, and social adaptation involving specialists and social workers.

Specific rehabilitation methods in the presence of complications are indicated in the respective sections.

Comments: Sanatorium-resort organizations may be recommended – balneological resorts with drinking mineral waters and natural mineral waters for external balneotherapeutic use. It is advisable to use factors such as dietary therapy and exercise therapy (physiotherapy). Specific rehabilitation methods in the presence of complications are indicated in the respective sections.

5. Prevention and Dispensary Observation

5.1 Prevention of type 2 diabetes mellitus

The ubiquitous increase in the number of patients with type 2 diabetes is a consequence of adverse lifestyle changes (excessive nutrition, sharp decrease in physical activity, chronic stress, etc.) and the resulting increase in the prevalence of obesity.

Principles of type 2 diabetes prevention:

- active screening of risk groups;

- active lifestyle modification;

- pharmacotherapy (indicated if the desired weight loss and/or normalization of carbohydrate metabolism parameters cannot be achieved in individuals with prediabetes, or if previous attempts have been unsuccessful).

Prediabetes is a disorder of carbohydrate metabolism that does not meet the criteria for diabetes mellitus, but exceeds normal blood glucose values (includes any of the following: impaired fasting glucose [IFG] and impaired glucose tolerance [IGT]).

For diagnostic criteria for prediabetes, see Table 3 in Section 2, Diagnosis of the Disease.

The required frequency of screening for type 2 diabetes and prediabetes is shown in Table 19.

Table 19. Frequency of screening for type 2 diabetes mellitus and prediabetes

1 The main risk factors for type 2 diabetes are listed in Table 2 in Section 2, Diagnosis of the Disease.

2 See the questionnaire "Do you have prediabetes or type 2 diabetes?" [295, 296] (Appendix G1).

Comments: The following tests can be used for screening:

Ø fasting plasma glucose

or

Ø OGTT with 75 g of glucose (diagnostic criteria and rules for performing OGTT - see Section 2, Diagnosis of the Disease)

or

Ø HbA1c >6.0 and <6.4% (advisable to follow up with an OGTT or fasting plasma glucose measurement).

When choosing a screening test, the advantages and disadvantages of each should be taken into account.

OGTT is the only method to detect IGT. However, as a screening method, it has significant drawbacks that limit its use: it is time- and labor-intensive (requires preparation for several days prior and 2 hours directly for the procedure, requires the patient to arrive fasting, and adherence to specific rules that are difficult to routinely maintain in medical organizations [see "Rules for Performing OGTT"]). In addition, the OGTT has high variability.

HbA1c as a screening method has certain advantages: it does not require prior fasting and can be performed at any time, has low variability, and characterizes glucose metabolism over a long period (taking this into account, performing HbA1c in individuals with prediabetes is preferred during routine health check-ups [dispensarization]). Results may be distorted in certain conditions (hemoglobinopathies, anemia, severe hepatic and renal impairment, etc.).

Comments: Moderate-intensity physical activity includes brisk walking, swimming, cycling, dancing, etc., lasting at least 30 minutes on most days of the week. Dietary recommendations generally do not differ from those for type 2 diabetes (see Section 3.3.1, Dietary Recommendations).

Achieving these goals in individuals with IGT reduces the risk of developing type 2 diabetes by 58% [297, 298].

Comments: The use of metformin** in individuals with IGT reduces the risk of developing type 2 diabetes by 31% [298]. For the prevention of diabetes in prediabetes, metformin** is taken during or after meals in a total daily dose of 1000–1700 mg, divided into 2 doses (extended-release metformin** 500–750 mg, 2 tablets once daily) in the absence of contraindications. With long-term use, the potential development of vitamin B12 deficiency should be considered. The duration of pharmacotherapy is determined individually.

5.2 Dispensary follow-up of patients without complications

Comments: Anemia is common in CKD, requiring the determination of hemoglobin and erythrocyte levels.

Comments: Additional biochemical tests are prescribed according to indications.

Comments: For patients with type 2 diabetes and eGFR < 60 mL/min/1.73 m², it is advisable to evaluate this parameter twice a year.

Comments: If a urinary tract infection is detected, it must be treated. Ketonuria may be detected in some patients.

Comments: Biochemical analysis of a morning urine sample is performed starting from the time of diagnosis and thereafter at least once a year. For patients with type 2 diabetes and albuminuria ≥ 3 mg/mmol, it is advisable to evaluate this parameter twice a year. The test is performed in the absence of inflammatory changes in the general urinalysis or Nechyporenko test. To calculate the albumin/creatinine ratio, the medical service nomenclature uses "determination of albumin in urine" and "determination of creatinine level in urine."

5.3 Prevention and dispensary follow-up of patients with complications

Issues related to the prevention of complications of type 2 diabetes and the follow-up of such patients are discussed in the respective sections.

6. Organization of Medical Care

Indications for hospitalization in a medical organization:

o Planned form; inpatient or day-hospital setting:

Ø need for initiation and adjustment of insulin therapy in severe disease decompensation;

Ø initiation of pump-based insulin therapy;

Ø initiation of anticonvulsant therapy (ATC classification N03A antiepileptic drugs) for painful diabetic peripheral neuropathy;

Ø presence of an infected wound defect in diabetic foot syndrome;

Ø critical limb ischemia in patients with diabetic foot syndrome;

Ø development of nephrotic syndrome and significant reduction in renal filtration function;

Ø clinically significant worsening of the underlying disease, its complications, or comorbidities.

o Emergency, urgent form; inpatient setting:

Ø diabetic ketoacidosis, precomatose state, diabetic ketoacidotic coma, hyperosmolar hyperglycemic state (precoma, coma), lactic acidosis, hypoglycemic coma;

Ø hypoglycemic state accompanied by disorientation, impaired motor coordination, speech disorders, seizures, altered consciousness;

Ø any life-threatening conditions in patients with type 2 diabetes mellitus.

Indications for patient discharge from a medical organization

Ø stable improvement in condition, when the patient can continue treatment in an outpatient clinic or at home without detriment to health;

Ø if it is necessary to transfer the patient to another healthcare organization;

Ø gross violation of the regimen;

Ø upon the written request of the patient or their legal representative, provided that discharge does not threaten the patient's life and is not dangerous to others. In this case, discharge may only be carried out with the permission of the head physician of the medical institution or their deputy for clinical work.

7. Additional Information

The development and progression of the disease complications have the greatest impact on the life prognosis in patients with diabetes mellitus. The principles of diagnosis, treatment, rehabilitation, and prevention of late complications of diabetes mellitus are set out in this section. In patients with diabetes mellitus, certain diseases and conditions (such as cardiovascular diseases) differ from those in individuals without diabetes, which must be taken into consideration when determining management tactics. Treatment of elderly patients with diabetes mellitus and during pregnancy has specific features both in the selection of individual treatment goals and optimal (safe) therapy regimens.

7.1. Acute complications (emergencies)

Detailed diagnosis, clinical presentation, and treatment of acute complications of type 2 diabetes mellitus are outlined in the relevant clinical guidelines.

The clinical presentation, diagnosis, and treatment of hypoglycemia are described in Section 3.6 Hypoglycemia.

7.2 Diabetic nephropathy

Diabetic nephropathy (DN) is a specific kidney lesion in diabetes mellitus manifested as nodular glomerulosclerosis as a result of the impact of metabolic and hemodynamic factors on renal microcirculation, modulated by genetic factors [307].

Chronic kidney disease (CKD) is a supranosological concept defined as structural or functional kidney abnormalities persisting for more than 3 months with health implications [307].

DN develops in 20-40% of patients with type 2 diabetes mellitus [308]; diagnosis of the complication simultaneously with the disease is possible. The development of DN significantly increases the risk of cardiovascular pathology and the cost of treatment [309].

According to the CKD concept, the stage of renal pathology is assessed by the eGFR value, which is recognized as most fully reflecting the number and total volume of nephron work, including functions related to non-excretory processes (Table 20). In addition, three categories of albuminuria are distinguished (Table 21) [23].

Table 20. Stages of chronic kidney disease by glomerular filtration rate [23]

1To establish a diagnosis of CKD in this case, the presence of markers of kidney damage is also required. In their absence, CKD is not diagnosed.

Table 21. Classification of chronic kidney disease by albuminuria level

1 ACR – albumin-to-creatinine ratio in a single morning urine portion

2 UAE – urinary albumin excretion

3 Including nephrotic syndrome (UAE >2200 mg/24 hours [ACR >2200 mg/g; >220 mg/mmol])

Formulation of diabetic nephropathy (DN) diagnosis in accordance with the CKD classification:

Ø DN, CKD G1 (2, 3, 4, or 5) A2

Ø DN, CKD G1 (2, 3, 4, or 5) A3

Ø DN, CKD G3 (4 or 5) A1 (i.e., regardless of the albuminuria level);

Ø DN, CKD G5 (renal replacement therapy);

Ø in case of normalization of albuminuria parameters during nephroprotective therapy in patients with preserved eGFR ≥ 60 mL/min/1.73 m2, the diagnosis of DN, CKD is retained with the formulation: DN, CKD G1-2 A1 (regression of albuminuria during nephroprotective therapy).

Specific symptoms of DN at the CKD G1-3 A1-2 stage are absent in patients with type 2 diabetes mellitus. At the CKD G4-5 stage, weakness, drowsiness, fatigue, pronounced persistent edema, stably elevated blood pressure, nausea, and sometimes vomiting without relief are noted. At the CKD G3-5 A3 stage, edema of the feet, lower legs, sometimes thighs, face, decreased appetite, and increasing and constantly elevated blood pressure are observed.

Diagnostics

Comments: For patients with type 2 diabetes mellitus and albuminuria ≥ 3 mg/mmol and/or eGFR <60 mL/min/1.73 m2, it is advisable to evaluate these parameters 2 times a year. The albumin-to-creatinine ratio in a single (preferably morning) urine portion correlates with high sensitivity and specificity with daily urinary albumin excretion. Determining only albumin without creatinine in a single urine portion does not provide such an accurate ratio, as it does not account for the effect of urine dilution due to varying hydration. Since clinical practice continues to evaluate only albumin in a single urine portion, the results of this test should be interpreted as follows (values corresponding to albuminuria levels according to the CKD classification): no more than 20 mg/L – A1; >20 to 200 mg/L – A2; > 200 mg/L – A3.

Comments: The diagnosis of DN is based on the presence of increased albuminuria and/or decreased eGFR in the absence of symptoms of primary renal pathology. Kidney damage in patients with type 2 diabetes mellitus generally has a complex (multifactorial) origin. In patients with type 2 diabetes mellitus, DN can also be diagnosed in the absence of diabetic retinopathy (a moderately sensitive and specific marker), as well as with a decrease in eGFR against the background of normoalbuminuria [310]. Given the variability, establishing a diagnosis of DN requires at least a 2-fold study of the albumin-to-creatinine ratio or albumin concentration in a single urine portion (using quantitative methods only) and eGFR over a period of 1 to 3 months. Transient increases in urinary albumin excretion are possible with marked hyperglycemia, intense physical exertion, a high-protein diet, fever, and menstruation. eGFR is calculated taking into account the plasma creatinine level using a validated formula (preferably the CKD-EPI formula, which correlates best with reference [clearance] methods of determination). Determination of GFR by clearance methods is necessary during pregnancy, morbid obesity (BMI ≥40 kg/m2), underweight (BMI ≤15 kg/m2), vegetarianism, myodystrophy, paraplegia, quadriplegia, non-standard body sizes (amputated limbs), acute kidney injury, kidney transplant, prescription of nephrotoxic drugs, and determination of the initiation of renal replacement therapy. With rapidly increasing albuminuria, the sudden development of nephrotic syndrome, a rapid decrease in eGFR, and changes in the urinary sediment (hematuria, leukocyturia, cylindruria), an alternative or additional cause of renal pathology can be suspected.

Treatment

Comments: Consuming this amount of protein compared to a higher level slows down the decline in eGFR. A diet containing more than 1.3 g/kg/day is associated with increased albuminuria, rapid decline in renal function, and cardiovascular mortality. Protein intake of no more than 0.8 g/kg/day does not affect glycemic control, cardiovascular risk, or the decline in eGFR. For patients on dialysis, a higher protein intake is necessary, as impaired nutritional status is a major problem for dialysis patients [312].

Comments: 2.3 g of sodium corresponds to 5 g of table salt.

Comments: Sodium and potassium intake must be individualized taking into account comorbidity, medications used, blood pressure levels, and laboratory data

Comments: In individuals with type 2 diabetes and CKD, as in the general population, regular and sufficient physical activity provides cardiometabolic, renal, and cognitive benefits, improves quality of life, enhances insulin sensitivity, lowers inflammatory markers, and improves endothelial function. However, patients with CKD have limitations that hinder participation in regular exercise and high-intensity activities, primarily related to age and, consequently, the risk of falling. Muscle mass loss and the development of complications such as anemia, peripheral neuropathy, autonomic neuropathy, and functional capacity limitations occur in parallel with declining renal function in these patients. Despite such limitations, recommending physical activity during a routine visit is important for patients in almost all situations, despite competing challenges and a lack of specific resources. Prior to initiating a physical activity program, it is necessary to assess physical tolerance, the risk of adverse events (primarily falls), and accessibility taking into account the severity of CVD.

Comments: In patients with advanced stages of CKD, the target HbA1c level should be individualized taking into account the high risk of hypoglycemia. Metformin** is considered the first-line drug for all patients with type 2 diabetes, including those with CKD. Metformin** is contraindicated in patients with type 2 diabetes and CKD with eGFR < 30 ml/min/1.73 m2. During therapy with metformin**, eGFR monitoring is required; dose re-evaluation (titration) at eGFR < 45 ml/min/1.73 m2. It is not recommended to initiate metformin** therapy at eGFR < 45 ml/min/1.73 m2. Metformin** intake is discontinued during examinations involving intravenous administration of iodinated radiocontrast agents due to the potential drug concentration and subsequent development of lactic acidosis. The ADVANCE and ADVANCE-ON trials showed that achieving optimal glycemic control using modified-release gliclazide** leads to a 21% reduction in the risk of development and progression of diabetic nephropathy, and a 65% reduction in the risk of end-stage renal disease in individuals with type 2 diabetes [41, 318]. The choice of other glucose-lowering drugs and their doses in patients with type 2 diabetes and CKD is determined by eGFR, the risk of hypoglycemia and CKD progression, and cardiovascular pathology (Tables 12 and 14 in Section 3.4 Pharmacotherapy).

Comments: SGLT-2 inhibitors should be considered for patients with type 2 diabetes and CKD as an add-on therapy to metformin** to achieve target glycemic control or as an alternative in case of intolerance or contraindications to metformin**. Several large randomized trials of these agents in patients with type 2 diabetes and established CVD or CVD risk factors (EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58, VERTIS CV) evaluated renal outcomes as secondary endpoints alongside cardiovascular outcomes. Empagliflozin** significantly reduced the risk of development or progression of nephropathy by 39%, and doubling of serum creatinine with a corresponding eGFR ≤ 45 ml/min/1.73 m2 by 44% compared to placebo [323]. Canagliflozin significantly reduced the risk of albuminuria progression by 27% and the risk of eGFR decline, progression to end-stage renal disease, or renal death by 40% compared to placebo [152]. Dapagliflozin** significantly reduced the composite of an eGFR decline ≥40% to < 60 ml/min/1.73 m2, development of end-stage renal disease, or renal death by 47% compared to placebo [150]. Ertugliflozin** showed a trend toward significance in the secondary renal endpoint, which included doubling of plasma creatinine, initiation of renal replacement therapy, and renal death [153], however, a broader analysis of renal outcomes including eGFR assessment (sustained decline of 40%), i.e., comparable to the aforementioned studies, showed a significant benefit for the renal endpoint (34% risk reduction compared to placebo), similar to other SGLT-2 inhibitor trials [324]. The placebo-controlled CREDENCE trial demonstrated significant renal outcome benefits as a primary endpoint in patients with type 2 diabetes and CKD receiving canagliflozin therapy [325]. The placebo-controlled DAPA-CKD trial demonstrated a significant benefit in reducing the primary composite endpoint (sustained eGFR decline ≥50%, end-stage renal disease, renal or cardiovascular death) with dapagliflozin** therapy in patients with CKD regardless of the presence or absence of type 2 diabetes on top of maximally tolerated renin-angiotensin-aldosterone system blockade [326]. In addition to renal effects, SGLT-2 inhibitors demonstrate cardiovascular benefits.

Comments: GLP-1 receptor agonists should be considered for patients with type 2 diabetes and CKD at high risk of cardiovascular events as an add-on therapy to metformin** to achieve target glycemic control or as an alternative in case of intolerance or contraindications to metformin** and SGLT-2 inhibitors. Several large randomized trials of these agents in patients with type 2 diabetes and established CVD or CVD risk factors (LEADER, SUSTAIN-6, REWIND) evaluated renal outcomes as secondary endpoints alongside cardiovascular outcomes. Liraglutide significantly reduced the risk of development or progression of nephropathy (composite of persistent macroalbuminuria, doubling of plasma creatinine, development of end-stage renal disease, renal death) by 22% compared to placebo [161]. Semaglutide** significantly reduced the risk of development or progression of nephropathy (composite of persistent albuminuria (urine albumin-to-creatinine ratio > 30 mg/mmol), doubling of plasma creatinine, development of end-stage renal disease) by 36% [162]. Dulaglutide** significantly reduced the composite of persistent macroalbuminuria (urine albumin-to-creatinine ratio >33.9 mg/mmol), persistent eGFR decline of 30% or more, and initiation of renal replacement therapy by 15% [149]. In addition to renal effects, GLP-1 receptor agonists demonstrate cardiovascular benefits. GLP-1 receptor agonists (liraglutide, dulaglutide**, semaglutide**) can be used at eGFR ≥ 15 ml/min/1.73 m2 with greater benefit for reducing CVD than for the progression of CKD and heart failure.

Comments: The dosing regimen of ACE inhibitors and ARBs should be individualized taking into account the patient's eGFR values and the drug's pharmacokinetic characteristics specified in the instructions.

Comments: HTN is a significant risk factor for the development and progression of CKD. Antihypertensive therapy reduces the risk of albuminuria and cardiovascular events. In patients with established CKD (eGFR < 60 mL/min/1.73 m2 and/or urine albumin-to-creatinine ratio > 30 mg/mmol), ACE inhibitors and ARBs reduce the risk of progression to end-stage CKD. A BP level of less than 130/80 mm Hg may be considered as a target based on individual benefits and risks. ACE inhibitors and ARBs are first-line drugs for the treatment of HTN in patients with type 2 DM, HTN, eGFR < 60 mL/min/1.73 m2, and/or urine albumin-to-creatinine ratio > 30 mg/mmol, as they have proven benefits in preventing CKD progression. ACE inhibitors and ARBs have comparable benefits and risks. At a lower level of albuminuria (albumin-to-creatinine ratio 3–30 mg/mmol), therapy with ACE inhibitors and ARBs demonstrates a reduction in progression to a higher level of albuminuria (albumin-to-creatinine ratio > 30 mg/mmol) and cardiovascular events, but not in progression to end-stage CKD. In the absence of CKD, ACE inhibitors and ARBs are used for blood pressure control, but have no advantages over other classes of antihypertensive drugs. Mineralocorticoid receptor antagonists (ATC classification C03DA aldosterone antagonists) (spironolactone**, eplerenone) are effective in the treatment of resistant hypertension, reduce albuminuria according to short-term studies in patients with CKD, and may provide additional cardiovascular benefits [338, 339]. However, they increase episodes of hyperkalemia when used in dual therapy (in combination with an ACE inhibitor or ARB). The placebo-controlled FIDELIO-DKD trial demonstrated a significant benefit in renal outcomes as a primary endpoint (end-stage renal disease, eGFR decline ≥40%, renal death) in patients with type 2 DM and CKD receiving therapy with a selective mineralocorticoid receptor antagonist [340].

Comments: Detailed recommendations for the management of CKD complications (see relevant clinical guidelines).

Comments: Nephrologist consultations for patients with type 2 diabetes and stage G4 CKD (eGFR < 30 mL/min/1.73 m2) can reduce costs, improve care, and delay dialysis therapy [341].

Prevention of diabetic nephropathy is only possible with timely identification and correction of risk factors for the development and progression of complications.

Dispensary follow-up (dispensary observation) includes monitoring depending on the stage of diabetic nephropathy (Table 22).

Table 22. Monitoring according to the stage of diabetic nephropathy

7.3 Diabetic retinopathy

In diabetes mellitus, retinal damage manifests as diabetic retinopathy (DR) and/or diabetic macular edema (DME). Detailed guidelines on the management of patients with cardiovascular pathology are presented in the relevant clinical guidelines.

Diabetic retinopathy (DR) — a specific late neuromicrovascular complication of diabetes mellitus, typically progressing sequentially from changes associated with increased permeability and occlusion of retinal vessels to the appearance of neovascularization and fibroglial tissue. It is one of the manifestations of generalized microangiopathy.

Diabetic macular edema (DME) — retinal thickening associated with fluid accumulation in the intercellular space of the neuroepithelium due to disruption of the blood-retinal barriers and an imbalance between fluid transudation and its reabsorption capacity. DME can develop at any stage of DR.

The pathogenesis of DR is rooted in ischemia developing due to occlusion of retinal capillaries. The cause of impaired retinal perfusion is vascular endothelial damage (endothelial stress) under conditions of hyperglycemia, leading to thrombus formation in the capillary bed. Retinal ischemia leads to increased expression of vascular endothelial growth factor (VEGF). An increase in VEGF production above a critical level contributes to the development of the main clinical manifestations of diabetic retinal damage – DME and neovascularization [297, 298].

The frequency of DR development is determined by the duration of diabetes mellitus. Given that type 2 diabetes may remain undiagnosed for a long time, DR in patients with type 2 diabetes is often detected at the time of diagnosis. According to the Federal Diabetes Register in the Russian Federation as of January 1, 2021, DR was registered in 13.5% of patients with type 2 diabetes [3, 344].

The classification of DR proposed by Kohner E. and Porta M. (1991) distinguishes three main stages of the disease [345].

1. non-proliferative DR;

2. pre-proliferative DR;

3. proliferative DR.

Clinical changes characteristic of each stage of DR are presented in Table 23.

Table 23. Characteristics of fundus changes in various stages of diabetic retinopathy

Currently, the most comprehensive classification is the 1991 classification by the Early Treatment Diabetic Retinopathy Study Group (Early Treatment Diabetic Retinopathy Study – ETDRS) [346], which can also be used in clinical practice (Appendix A3).

Diagnostics

Comments: There may be no complaints for a long time despite disease progression. Patients with DR may complain of decreased visual acuity and floaters. In DME, patients report distorted vision (metamorphopsias), a «spot» in front of the eyes, and decreased visual acuity. With complications of proliferative DR (preretinal and intravitreal hemorrhages), patients may complain of decreased vision, a «spot», or a «grid» before the eyes, and with retinal detachment, of decreased vision and a «veil» in the visual field. Complaints of decreased visual acuity generally require immediate specialized treatment. When neuropathy develops with involvement of cranial nerve III and VI, patients may complain of ocular deviation, diplopia, and drooping of the upper eyelid. From the general medical history, it is important to clarify the duration of diabetes and the degree of disease control (blood glucose and glycated hemoglobin levels), the presence of arterial hypertension, lipid profile parameters, and the presence of macrovascular or other microvascular complications of diabetes [3].

Comments: Due to the specific nature of the disease and the absence of an acute onset, type 2 diabetes may remain undiagnosed for several years, which significantly increases the risk of DR. About 20% of patients with type 2 diabetes have signs of DR at the time of diabetes diagnosis. Therefore, patients must undergo a comprehensive ophthalmological examination immediately upon being diagnosed with type 2 diabetes. Referral for examination is made by the endocrinologist. The scope of diagnostic procedures is determined by the ophthalmologist (see relevant clinical guidelines). At a minimum, fundus biomicroscopy under conditions of mydriasis should be performed.

Regular annual examinations of all patients with type 2 diabetes are crucially important for the timely identification of individuals at risk of developing severe DR, preventing its progression, and avoiding vision loss. There may be an absence of symptoms for a long period, even in the presence of proliferative DR and DME.

Treatment

Comments: To achieve this goal interdisciplinary management of patients should be implemented.

Comments: The use of angioprotectors, antioxidants (ATC classification A16A Other alimentary tract and metabolism products), enzyme preparations, and vitamins for the treatment of DR in type 2 diabetes patients lacks a robust evidence base.

Comments: Standard panretinal PRP is usually performed over several sessions [349, 350]. Sessions of panretinal PRP can be carried out in both inpatient and outpatient settings under maximum drug-induced mydriasis [220, 231, 365, 366].

Comments: When there are indications for panretinal PRP, it should be performed regardless of the HbA1c level and without waiting for a substantial improvement in glycemic control.

Comments: Currently, intravitreal administration of anti-angiogenic agents (angiogenesis inhibitors) is the first-line therapy for DME involving the center of the macula. It should be taken into account that when combining laser photocoagulation and intravitreal anti-angiogenic therapy, the functional effect of delayed laser treatment is superior [370, 373–378]. In each clinical case, the final decision on the indications for treatment with anti-angiogenic agents and the choice of injection regimen is made by the ophthalmologist based on the evaluation of the clinical picture and disease course.

Prevention and follow-up care

Comments: Target levels are presented in Section 3.1 Therapeutic Goals.

Comments: The frequency of ophthalmologic examinations for patients with type 2 diabetes is presented in Table 24.

Table 24. Frequency of ophthalmologic examinations for patients with type 2 diabetes mellitus

Comments: When planning the schedule of examinations by an ophthalmologist, it should be taken into account that the risk of development and progression of DR and DME increases in certain patient conditions associated with hormonal status disorders (pregnancy, post-artificial abortion state, and others).

In the event of an unexpected decrease in visual acuity or the appearance of any visual symptoms, an examination by an ophthalmologist should be performed as soon as possible, regardless of the scheduled visit date.

7.4 Diabetic neuropathy

Diabetic neuropathy (DN) is a complex of clinical and subclinical syndromes, each characterized by diffuse or focal damage to peripheral and/or autonomic nerve fibers resulting from diabetes mellitus.

Sensorimotor neuropathy is a somatic nervous system disorder accompanied by reduced sensitivity of various modalities, interosseous muscle atrophy, joint stiffness, and characteristic foot deformity.

Autonomic neuropathy is a disorder of the sympathetic and parasympathetic divisions of the peripheral nervous system.

The main pathogenetic mechanisms of DN are recognized to be the activation of the polyol glucose metabolism pathway, angiopathia vasa nervorum, oxidative stress, myo-inositol deficiency, and nitric oxide insufficiency. In type 2 diabetes, lipid metabolism disorders also play a significant role. All of this leads to a decrease in nerve fiber conduction velocity.

According to epidemiological studies, the prevalence of DN in impaired glucose tolerance is 10–13%, and in overt type 2 diabetes, 35–55% [31].

Classification of diabetic neuropathy [3, 384]

A. Diffuse neuropathy:

1. Distal symmetric polyneuropathy:

Ø With predominant involvement of small nerve fibers

Ø With predominant involvement of large nerve fibers

Ø Mixed (most common)

2. Autonomic neuropathy:

- Cardiovascular:

Ø Reduced heart rate variability

Ø Resting tachycardia

Ø Orthostatic hypotension

Ø Sudden death (malignant arrhythmia)

- Gastrointestinal:

Ø Diabetic gastroparesis (gastropathy)

Ø Diabetic enteropathy (diarrhea)

Ø Decreased large bowel motility (constipation)

- Urogenital:

Ø Diabetic cystopathy (neurogenic bladder)

Ø Erectile dysfunction

Ø Female sexual dysfunction

- Sudomotor dysfunction:

Ø Distal hypohidrosis/anhidrosis

- Impaired hypoglycemia awareness

B. Mononeuropathy (mononeuritis of various locations) (atypical forms):

1. Isolated cranial or peripheral nerve lesions

2. Mononeuritis of various locations (provided polyneuropathy is excluded)

C. Radiculopathy or polyradiculopathy (atypical forms):

1. Radiculoplexopathy (lumbosacral polyradiculopathy, proximal motor amyotrophy)

2. Thoracic radiculopathy

D. Non-diabetic neuropathies comorbid with diabetes mellitus:

1. Entrapment syndromes

2. Chronic inflammatory demyelinating polyneuropathy

3. Radiculoplexopathy

4. Acute painful small-fiber neuropathy

Comments: There is no single classification of diabetic neuropathy in modern medical literature and guidelines for the diagnosis and treatment of nervous system disorders in patients with diabetes mellitus proposed by various medical communities. The term "diffuse" used in the classification above primarily reflects the severity and extent of nerve fiber damage.

According to modern data, the link between autonomic neuropathy and unrecognized hypoglycemia is not obvious.

Stages of neuropathy

I. Preclinical

II. Clinical manifestations

III. Complications

For the vast majority of patients with type 2 diabetes and diabetic neuropathy, typical complaints include lower extremity pain (various intensities of foot pain at rest, more often at night and in the evening, numbness, paresthesia, coldness of the feet, calf and foot muscle cramps, paresthesia, burning feet), skin dryness, muscle atrophy, and characteristic toe deformities (hammer toe).

Comments: It should be remembered that the clinical picture of a large number of other diseases shares similar complaints that are non-specific for diabetic neuropathy. Therefore, when taking a history, attention must be paid to the presence of concomitant diseases not directly related to diabetes mellitus that may contribute to the pathogenesis of lower extremity pain (arthrosis, venous insufficiency, radiculopathy, etc.). All patients with type 2 diabetes and trophic foot ulcers must undergo an assessment of ulcer tenderness to identify neuropathic wounds. It should be remembered that previous injuries, surgical interventions on the lower extremities, or acute cerebrovascular accidents accompanied by varying degrees of nerve conduction impairment in the lower extremities can lead to unilateral sensory changes. General principles of treatment for any neuropathic ulcers in patients with diabetes should be followed.

Diagnostics

Comments: Diagnostic scales can be used to diagnose diabetic neuropathy, for example:

Neuropathy Symptom Score (NSS) [390–393]. A score >5 indicates the presence of severe neuropathy (Appendix G2);

The Michigan Neuropathy Screening Instrument (MNSI) [394–397]. A score >2 suggests the presence of neuropathy (Appendix G3);

DN4 questionnaire for the diagnosis of painful neuropathy [398, 399]. A score >4 indicates a neuropathic nature of the pain (Appendix G4).

Comments: To diagnose diabetic neuropathy, a thorough medical history, assessment of thermal (or tactile) sensory thresholds, and vibration perception using a 128 Hz graded tuning fork are sufficient [31, 32, 384, 386, 389]. Currently, there are no reliable laboratory tests to confirm the presence of diabetic neuropathy.

Comments: The reliability of the obtained results is increased by additionally assessing other types of sensation (vibration using a 128 Hz graded tuning fork, pain, temperature) and/or tendon reflexes [31, 385, 389, 405].

Comments: Performing electroneuromyography of peripheral nerves in a patient with a chronic foot wound defect is impractical, as it significantly complicates the examination, and its result does not affect the development of the treatment plan.

Treatment

Comments: Optimization of glycemic control helps prevent or delay the development of diabetic neuropathy in patients with type 2 diabetes.

Comments: Drugs used to treat the painful form of distal polyneuropathy are listed in Table 25.

Table 25. Drugs used for the treatment of painful diabetic neuropathy

Rehabilitation

Prevention and follow-up care

Currently, the only method for preventing the progression of DPN is achieving and maintaining individual target ranges for carbohydrate and lipid metabolism [394, 410, 411]. Assessment of peripheral sensitivity status should be performed at least once a year. The presence of comorbid conditions of the central nervous system and peripheral nerves of various etiologies, as well as peripheral artery disease, can accelerate the progression of DPN and worsen the clinical prognosis.

7.5 Diabetic osteoarthropathy

Diabetic osteoarthropathy (DOAP), neuroarthropathy, or Charcot foot is a painless, progressive destruction of one or more joints of the foot against the background of DPN.

As a result of motor fiber demyelination, weakness of the foot ligamentous apparatus develops, leading to joint instability. Autonomic neuropathy leads to denervation of the vascular wall and, consequently, the development of arteriovenous shunts and increased blood flow, which leads to the activation of bone tissue resorption and osteopenia. The bone loses not only density but also elasticity, making the foot skeleton less resistant to trauma. As a rule, the triggering factor for DOAP is minor mechanical trauma unnoticed by the patient. An external impact of minor force leads to bone fractures, subluxations, and joint dislocations. The situation is aggravated by the absence of protective pain sensitivity. The patient continues to bear weight on the injured limb, which leads to the involvement of new bones and joints in the process. Osteochondral fragmentation and marked joint degeneration develop. In severe cases, the foot may completely lose its weight-bearing function, which may require amputation. It has been proven that patients with DPN have a higher incidence of osteoarticular changes compared to individuals without neurological disorders.

Various studies on DPNP have revealed a high frequency of its development in patients with a diabetes duration of more than 12 years, regardless of age and sex. In the majority of examined subjects, the process is unilateral, whereas bilateral involvement occurs in only 9–25% of cases. As a rule, these are individuals with long-term diabetes decompensation, regardless of its type and treatment methods. It was noted that in 73% of patients, prior deformations or injuries were not registered [385].

Classification

The clinical picture of DPNP distinguishes between acute and chronic stages. The acute stage is characterized by the predominance of inflammatory processes in response to existing damage.

The classification of DPNP is presented in Table 26.

Table 26. Classification of diabetic neuroarthropathy based on clinical presentation, MRI/MSCT findings [412]

Diagnostics

Comments: The diagnosis of DPNP is established based on characteristic anamnestic data, complaints, and clinical presentation (hyperthermia, deformity, edema of the affected limb), as well as the results of instrumental and laboratory diagnostic methods. In typical cases, the diagnosis is straightforward [3, 385, 414]. There are currently no specific markers of bone metabolism or laboratory tests for diagnosing osteoarthropathy. Radiography remains the primary method of instrumental and differential diagnosis of DPNP. At the same time, radiographs reflect hypertrophic or atrophic changes occurring in response to injury. In typical cases, no additional instrumental diagnostic methods are required to establish the diagnosis in the chronic stage of DPNP.

Comments: The main difficulties arise when diagnosing the acute stage of the complication, when, despite a typical clinical picture, radiographic changes are absent, as well as during the differential diagnosis between DPNP and osteomyelitis. In this regard, special attention should be paid to the fact that the absence of changes on radiographs in the presence of a clinical picture (edema, hyperthermia, foot deformity) does not rule out DPNP. Discrepancy between the clinical and radiological pictures is quite common in the early stages of complication development (“preliminary stage”, “stage 0”). In such situations, a carefully taken medical history, clinical examination including neurological tests, and MRI will help diagnose DPNP with a high degree of probability.

Comments: In the presence of DPNP with a plantar ulcer, it is necessary to perform a differential diagnosis between the acute stage of DPNP and osteomyelitis. This is of key importance for prescribing adequate antibiotic therapy and choosing the surgical correction tactics.

The combination of positron emission tomography and computed tomography (PET/CT) allows for high-precision detection of the localization of pathological changes in the earliest stages, tracking the stages of development, and quantitatively assessing the metabolic activity of the process to monitor the progression of the complication.

Treatment

Comments: The complex of therapeutic measures for DPNP is determined by the stage of the complication. The main goal of treatment in the acute stage of the process is to prevent the development of further deformity and trauma to the foot. To achieve this goal, methods of maximum offloading of the affected limb are used—application of a TCC or the use of an orthopedic device (orthosis). Limb immobilization should be initiated as early as possible. In the presence of a clinical picture corresponding to the acute stage of DPNP (edema, foot hyperthermia) and the absence of instrumental confirmation (X-ray-negative stage, impossibility of MRI), the therapeutic tactics should be the same as for a confirmed diagnosis of DPNP. A relative contraindication to applying a non-removable TCC variant in DPNP is the presence of a skin ulcer defect requiring daily monitoring and dressing changes. An absolute contraindication to applying a TCC (both non-removable and removable variants) is the presence of an extensive purulent-destructive process requiring mandatory surgical debridement.

Comments: Currently, there is no convincing evidence of the efficacy of drug therapy for DPNP (bisphosphonates, calcitonin). Furthermore, bisphosphonates are contraindicated in renal impairment, which is frequently detected in patients with long-standing and poorly controlled diabetes mellitus.

Comments: The goal of therapeutic and preventive measures at the consolidation stage (chronic stage) is to prevent foot trauma, new fractures, and the formation of plantar ulcer defects. At this stage, there is no need for maximal continuous limb immobilization. After removing the TCC, a gradual expansion of the physical activity regimen is recommended. As intermediate methods of foot fixation and offloading, a removable TCC can be used part-time, alongside orthopedic devices. The choice of footwear is of fundamental importance in the chronic stage. Footwear requirements depend on the type of lesion and the resulting foot deformity. If foot deformity is minimal, continuous wearing of prophylactic footwear for patients with type 2 diabetes is sufficient.

• It is recommended to obtain a consultation from an orthopedic trauma surgeon for patients with pronounced foot deformity or rocker-bottom foot deformity to resolve the issue of manufacturing custom orthopedic footwear [422, 423].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: Recently, reconstructive surgery for diabetic Charcot neuroarthropathy (DCN) has become increasingly widespread. The primary indication for surgical interventions on the foot is the failure of conservative treatment methods, manifested by recurrent plantar ulcer defects and/or the inability to maintain foot stability during walking. Surgical intervention must strictly correspond to the set task. If instability in the ankle or other joints predominates, arthrodesis with rigid internal fixation is used. In cases of recurrent ulcer defects, exostectomy is performed followed by surgical wound debridement. If the ulcer defect is complicated by osteomyelitis, antimicrobial therapy, exostectomy, and surgical wound debridement are performed. Quite frequently, shortening of the Achilles tendon is identified, which leads to additional foot deformity and an increase in loading pressure on the forefoot. Such patients are indicated for Achilles tendon lengthening surgery. Postoperative management tactics completely correspond to the management of a patient with the acute stage of DCN: immobilization, including the manufacture of a total contact cast (TCC), and graduated expansion of the activity regimen after healing.

Rehabilitation

Comments: The adequacy of the manufactured orthopedic footwear must be regularly evaluated by the attending physician (endocrinologist, surgeon, diabetic foot specialist) and replaced at least once a year.

Prevention and follow-up care

Prevention of DCN progression includes maintaining education on foot care rules, professional podiatric care if necessary, continuous wearing of ready-made or custom orthopedic footwear, and dynamic follow-up by an endocrinologist and trauma-orthopedic surgeon at the place of residence.

7.6 Cardiovascular features in type 2 diabetes mellitus

Arterial hypertension (AH) is a syndrome of elevated systolic blood pressure (BP) ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg in essential hypertension and symptomatic AH, leading to target organ damage.

Coronary artery disease (CAD) is a term combining a group of diseases whose pathological process is based on a mismatch between the heart's blood supply demand and its actual delivery due to rapidly progressive coronary atherosclerosis.

7.6.1 Features of arterial hypertension in type 2 diabetes mellitus

More than 60% of patients with an established diagnosis of type 2 diabetes suffer from AH [425].

An elevation in office systolic BP ≥ 140 and/or office diastolic BP ≥ 90 mm Hg may indicate the presence of AH (Table 27).

Table 27. Definition of arterial hypertension by office and out-of-office blood pressure values (EHS/ESC 2018) [426].

The classification of AH by BP levels in individuals over 18 years of age is presented in Table 28. If systolic BP (SBP) and diastolic BP (DBP) values fall into different categories, the severity grade of AH is assessed by the higher category.

Table 28. Classification of AH by blood pressure level (EHS/ESC 2018) [426]

Diagnostics

All patients with type 2 diabetes and AH should undergo a collection of complaints and medical history [426, 427]. In patients with type 2 diabetes, as in individuals without diabetes, blood pressure elevation can be asymptomatic. When taking the medical history, it is necessary to determine the duration of AH, blood pressure elevation levels, the presence of hypertensive crises, previous antihypertensive therapy: used antihypertensive drugs, their efficacy and tolerability; assess risk factors for AH development: a family history of AH or other cardiovascular diseases, smoking, unhealthy diet, obesity, low physical activity; and patient personality traits. Laboratory and instrumental diagnostics for patients with AH and type 2 diabetes are similar to those for patients without diabetes and are presented in the relevant clinical guidelines [426, 427].

Comments: Studies have shown that BP values obtained from home measurements correlate more strongly with cardiovascular risk compared to office measurements.

Treatment

The main goal of treatment for patients with AH and type 2 diabetes, as in the general population, is to maximally reduce the risk of cardiovascular complications and death from them. Achieving this goal requires not only lowering BP to the target level, but also correcting all modifiable factors (smoking, dyslipidemia, hyperglycemia, obesity), preventing, slowing the progression rate and/or reducing target organ damage, as well as treating associated and comorbid conditions. Some glucose-lowering drugs have demonstrated the ability to reduce cardiovascular risk (including cardiovascular mortality) in patients with ASCVD (Table 12).

Comments: Target BP levels for patients with AH and type 2 diabetes are presented in Table 9. Target BP should be achieved taking into account the patient's age and individual characteristics, including the tolerability of the achieved BP levels.

Comments: Lifestyle modification measures include:

1) restriction of salt intake to < 5 g/day [437];

2) increased consumption of vegetables up to 300 g per day, nuts, unsaturated fatty acids – olive oil; low consumption of red meat; consumption of low-fat dairy products; fish consumption at least twice a week [438];

3) weight control (maintaining BMI 20–25 kg/m², waist circumference < 102 cm in men and < 88 cm in women) [439];

4) alcohol consumption of no more than 14 units per week for men and 7 units per week for women (1 unit = 125 ml of wine or 250 ml of beer) [440];

5) smoking cessation [441];

6) regular aerobic exercise for 30–40 minutes 5–7 days a week [442].

Comments: In patients with AH ≥ 150/90 mm Hg, pharmacological therapy should be initiated with an acceptable combination of two medicinal products, preferably in a single pill. In patients with BP < 150/90 mm Hg, it is advisable to consider prescribing monotherapy. The algorithm for prescribing pharmacological therapy for AH is presented in the relevant clinical guidelines [426, 427].

7.6.2 Features of coronary artery disease in type 2 diabetes mellitus

DM is an independent risk factor for ASCVD. The presence of DM increases the risk of coronary artery disease (CAD) by 2–4 times. By the age of over 40, 40–50% of patients with DM develop at least one ASCVD. More than half of patients already suffer from CAD at the time of DM type 2 diagnosis verification. The course of CAD depends on the duration of DM. In many cases, CAD is asymptomatic. Patients with DM have a high frequency of painless ("silent") forms of CAD and MI: up to 60% of MIs can be mildly symptomatic. Patients with DM are characterized by multivessel, diffuse lesions of the coronary bed and marked coronary artery calcification. Mortality from acute coronary syndrome (ACS) in patients with DM is 2–3 times higher.

Diagnostics

Examination of patients with DM to verify CAD is generally similar to diagnostic approaches in patients without DM with appropriate indications for exercise stress tests, myocardial perfusion imaging, and coronary angiography. Taking complaints and medical history should be performed in all patients with DM type 2 suspected of having CAD. Assessment of pain sensations in CAD is conventionally carried out in 3 categories: localization, character, and relationship with physical exertion. If all the listed criteria are present, typical exertional angina should be diagnosed. Patients with DM type 2 are characterized by a high frequency of mildly symptomatic (painless) and atypical course of CAD. An important aspect in the diagnosis of CAD for patients with DM type 2 is the assessment of CAD risk factors [449]:

Ø family history of CAD (female relative <65 years and male relative <55 years);

Ø body weight and fat redistribution, history assessment, BMI (obesity ≥30 kg/m2), and waist circumference (abdominal obesity >94 cm in men and >80 cm in women);

Ø physical activity – assessed currently and in the past;

Ø dyslipidemia (decreased HDL-C and increased LDL-C);

Ø arterial hypertension (≥140/90 mmHg);

Ø tobacco smoking – current, past, and intensity;

Ø albuminuria and serum creatinine level with eGFR;

Ø patient's age at the onset of hyperglycemia, family history of DM, vascular complications (transient ischemic attack, acute cerebrovascular accident, intermittent claudication, critical lower limb ischemia, stenosing atherosclerosis of brachiocephalic arteries), fasting plasma glucose level, HbA1c level.

Comments: To diagnose CAD in patients with DM type 2, research methods similar to those for patients without DM with appropriate indications and contraindications are used [449]:

Ø exercise tests: treadmill test, cycle ergometry;

Ø single-photon emission computed tomography (perfusion scintigraphy) of the myocardium with stress;

Ø stress echocardiography with dobutamine;

Ø coronary CCTA;

Ø coronary angiography.

Comments: Treadmill exercise testing under 12-lead ECG monitoring has lower sensitivity and specificity compared to stress echocardiography. However, due to its simplicity and wide availability, it can be used as an initial diagnostic method in patients with suspected CAD.

Comments: CAD verification should be performed in patients with DM type 2 who present with symptoms and/or complaints. In other cases (in the absence of complaints or with atypical complaints), the decision on the feasibility of CAD screening is made taking into account the assessment of cardiovascular risk factors [449].

Treatment

Comments: Lifestyle modification measures include:

Ø smoking cessation;

Ø reduction of dietary fat content <35%, saturated fats <10%, and monounsaturated fats >10% of total caloric intake;

Ø moderate physical activity ≥150 min/week;

Ø aerobic exercises and resistance training, their combinations are possible.

Comments: Recommended target blood pressure levels in patients with CAD and DM type 2 are presented in Table 9.

Comments: In patients with DM type 2, preference should be given to metabolically neutral and highly selective beta-blockers [449].

Comments: Recommended target LDL-C levels in patients with CAD and DM type 2 are presented in Table 8.

Comments: Recommendations on lipid-lowering therapy in individuals with DM are presented in Table 29. Treatment should be carried out taking into account the patient's individual characteristics and the presence of contraindications [56, 459].

Table 29. Recommendations for lipid-lowering therapy in patients with diabetes mellitus

PCSK-9 – proprotein convertase subtilisin/kexin type 9

1Risk factors include: arterial hypertension, smoking, chronic kidney disease, albuminuria, family history of early ASCVD, LDL-C level ≥ 2.5 mmol/L,

2Therapy with HMG-CoA reductase inhibitors is carried out concurrently with lifestyle modification measures.

Comments: Acetylsalicylic acid** therapy is generally not indicated for patients with diabetes mellitus without cardiovascular disease. While acetylsalicylic acid** therapy in patients with diabetes is associated with a reduced risk of cardiovascular events, it is also associated with a significant increase in the rate of major bleeding events [467, 468].

Comments: In the THEMIS trial, which included 19,220 patients with type 2 diabetes aged over 50 years without a history of myocardial infarction and stroke, ticagrelor** at a dose of 60 mg twice daily combined with acetylsalicylic acid** statistically significantly reduced the relative risk of the composite endpoint (including cardiovascular death, non-fatal myocardial infarction, or stroke) by 10% compared with acetylsalicylic acid** monotherapy. The greatest reduction was observed in the subgroup of patients with a history of percutaneous coronary intervention. In the COMPASS trial [470], which included 27,395 patients with established atherosclerotic cardiovascular disease (coronary artery disease, prior myocardial infarction, peripheral artery disease), the mean age of patients was 68 years, and 38% of patients had diabetes. According to the study data, the combination of rivaroxaban** at 2.5 mg twice daily and acetylsalicylic acid** 100 mg daily compared with acetylsalicylic acid** 100 mg daily monotherapy significantly reduced the incidence of cardiovascular events (stroke by 42%, cardiovascular death by 22%). When deciding to prescribe such therapy, the bleeding risk must be assessed.

Comments: The need for myocardial revascularization should be determined individually in each clinical case, taking into account the severity of coronary artery lesion, the patient's general condition, and the presence of comorbid diabetic complications [473, 474].

The strategy of follow-up (dispensary observation) and rehabilitation in patients with coronary artery disease and type 2 diabetes after myocardial revascularization is similar to that in patients without diabetes and is presented in the relevant clinical guidelines [449].

Glucose-lowering therapy in patients with acute coronary syndrome

The presence of acute coronary syndrome in a patient with type 2 diabetes is not an indication for switching to insulin therapy if the target glycemic range is maintained. Many patients can continue their previously prescribed glucose-lowering therapy [475]. Indications for prescribing insulin are generally the same as in patients without acute coronary syndrome. Patients with diabetes and acute coronary syndrome may remain on their prior glucose-lowering therapy, including modern agents (SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors [except for saxagliptin**]), provided it maintains the target glycemic range. In procedures involving radiocontrast agents (ATC classification V08 radiocontrast media), SGLT2 inhibitors should be temporarily discontinued. Glibenclamide** should be avoided due to the high risk of hypoglycemia and impaired ischemic preconditioning [150–152, 475, 476].

Metformin** is contraindicated in patients with diabetes and acute coronary syndrome due to the risk of lactic acidosis in the event of tissue hypoxia and unestablished effects on early and long-term clinical outcomes of acute coronary syndrome [477]. Thiazolidinediones in patients with type 2 diabetes who develop acute coronary syndrome may contribute to the development of heart failure, which serves as a rationale for their discontinuation [478, 479].

7.6.3 Features of chronic heart failure in type 2 diabetes mellitus

Heart failure (HF) is a syndrome developing as a result of impaired cardiac filling and/or emptying capacity, occurring under conditions of an imbalance between vasoconstrictor and vasodilator neurohormonal systems, accompanied by inadequate perfusion of organs and systems, and manifested by symptoms: dyspnea, weakness, palpitation, and increased fatigue, and, as it progresses, fluid retention in the body (edema syndrome).

The most common cause of heart failure in patients with type 2 diabetes is coronary artery disease. A complex of pathophysiological changes (autonomic nervous system dysfunction, glucotoxicity, oxidative stress) can lead to a significant reduction in coronary reserve and the development of heart failure in the absence of coronary artery disease.

Diagnostics

Diagnostic principles and staging are identical in patients with and without diabetes. The diagnostic algorithm for heart failure is presented in the relevant clinical guidelines [480, 481].

Comments: Measuring natriuretic peptide levels in patients with type 2 diabetes will in many cases help determine the etiology of dyspnea, especially in patients with nephropathy.

Comments: Echocardiography is the most widely available diagnostic method in patients with suspected heart failure. This study makes it possible to assess myocardial structures and functions to clarify the diagnosis of heart failure (with preserved, mildly reduced, or reduced ejection fraction) and determine management tactics. Echocardiography can be used as an initial test when natriuretic peptide testing is not available.

Treatment

Principles of heart failure treatment in patients with diabetes are similar to those in individuals without diabetes and are presented in the relevant clinical guidelines [480, 481].

Interventions used in the treatment of patients with heart failure to reduce morbidity and mortality have the same effect regardless of the presence or absence of diabetes.

Prevention, follow-up (dispensary observation), and rehabilitation

The strategy for prevention, follow-up (dispensary observation), and rehabilitation of patients with type 2 diabetes and heart failure involves eliminating risk factors for its progression (blood pressure control, smoking cessation, adherence to fluid intake and body weight control, salt intake restriction, maintaining target lipid levels, dynamic physical exercise) and is presented in the relevant clinical guidelines [480, 481].

Specifics of glucose-lowering therapy in patients with type 2 diabetes and heart failure

Comments: In the EMPA-REG OUTCOME, CANVAS, and DECLARE-TIMI 58 trials, the use of SGLT2 inhibitors demonstrated a reduction in heart failure hospitalizations in patients with type 2 diabetes. In the EMPA-REG OUTCOME trial, empagliflozin** reduced all-cause mortality by 32% and hospitalization for heart failure by 35%. In the DECLARE trial, dapagliflozin** led to a reduction in the composite endpoint (cardiovascular death and hospitalization for heart failure). In patients with heart failure with reduced left ventricular ejection fraction ≤ 40% and type 2 diabetes, the use of dapagliflozin** and empagliflozin** (compared with placebo) in addition to standard therapy was accompanied by a significant reduction in the risk of heart failure progression and cardiovascular death compared with placebo, as well as improvement in heart failure symptoms [151, 152, 482–485].

Comments: Metformin** has been used for many years in patients with type 2 diabetes; its safety in treating patients with diabetes, including those with heart failure, has been well studied. However, it is contraindicated in patients with severe renal or hepatic impairment, as well as in decompensated heart failure due to the risk of lactic acidosis.

For medicinal products belonging to other classes of glucose-lowering drugs, clear advantages when used in individuals with heart failure have not been demonstrated. In clinical trials, GLP-1 receptor agonist therapy in patients with type 2 diabetes and atherosclerotic cardiovascular disease did not increase or decrease the rate of hospitalizations for heart failure decompensation, while reducing the risk of cardiovascular events [161, 162, 487, 488].

Sulfonylureas (except glibenclamide**) and insulin may be used with caution in patients with type 2 diabetes and heart failure (in addition to other glucose-lowering drugs proven to reduce the risk of cardiovascular events or when such drugs are contraindicated) to achieve glycemic control targets [489]. Randomized clinical trials with sulfonylureas in heart failure have not been conducted. In some retrospective studies, sulfonylureas had no effect on cardiovascular mortality in patients with type 2 diabetes and heart failure [490]. At the same time, in other studies, compared with metformin** monotherapy, sulfonylurea monotherapy resulted in increased cardiovascular mortality [154, 491].

Comments: The SAVOR-TIMI 53 trial demonstrated an increase in hospitalizations for heart failure decompensation in patients with type 2 diabetes and heart failure receiving saxagliptin** therapy. Other DPP-4 inhibitors in patients with type 2 diabetes and heart failure in large randomized trials (EXAMINE, TECOS, CARMELINA) did not increase the risk of heart failure decompensation and the rate of heart failure-related hospitalizations [493–495].

Comments: Thiazolidinediones cause sodium and water retention, increasing the risk of heart failure progression, and therefore their prescribing is not recommended in patients with heart failure.

7.6.4 Features of lower extremity artery disease in type 2 diabetes mellitus

Lower extremity artery disease (LEAD) in patients with diabetes is considered within the context of atherosclerotic cardiovascular disease. Numerous risk factors for LEAD have been identified: genetic predisposition to atherosclerosis, age over 45 years, smoking, hypertension, obesity, poor control and long duration of diabetes, dyslipidemia, chronic kidney disease, hyperhomocysteinemia [385]. The prevalence of LEAD in patients with diabetes ranges from 10% to 40%, reaching 50% in the presence of chronic lower extremity trophic ulcers. Progression of LEAD can lead to critical limb ischemia [385, 496]. Long-standing type 2 diabetes, especially complicated by diabetic nephropathy, is characterized by Monckeberg's arteriosclerosis—diffuse medial arterial calcification [497]. There is currently no single classification of LEAD in diabetes. The use of previously proposed Fontaine-Pokrovsky and Rutherford classifications is impractical as they do not reflect the severity of chronic arterial insufficiency in diabetes [3].

Diagnostics

Comments: Palpation of lower extremity pulses may be difficult or impossible in patients with severe peripheral edema or significant foot and leg deformity [499].

Symptoms of intermittent claudication (pain, discomfort in the lower extremity muscles (most commonly in the calf muscles, less commonly in the buttocks, thighs, and feet) occurring during physical exertion; pain or discomfort in the lower extremities at rest, worsening in the supine position) may be absent in individuals with concomitant neuropathy. In this case, emphasis should be placed on examining the extremities, assessing skin color and hair growth [500].

Comments: A normal ABI is greater than 0.9. An ABI >1.3 indicates arterial wall stiffness and requires confirmation of conduction abnormalities by other diagnostic methods.

Treatment

Rehabilitation

Rehabilitation of patients includes maintaining individual target levels of carbohydrate and lipid metabolism, blood pressure, education on foot care rules, and professional podiatric care if necessary [509].

Prevention and follow-up care

Preventive measures for LEAD should be aimed at maintaining blood flow in the affected limb, preventing the formation of trophic ulcers, and preventing limb loss [3, 507].

7.6.5 Features of chronic limb-threatening ischemia in type 2 diabetes mellitus

Critical limb ischemia (CLI) is a condition characterized by a marked reduction in blood flow through the major arteries of the lower extremities, leading to soft tissue hypoxia and threatening their viability.

Classification

There is currently no single classification of CLI in diabetes. The use of previously proposed Fontaine-Pokrovsky and Rutherford classifications is impractical because they do not reflect the severity of chronic arterial insufficiency in diabetes [3]. There is a WIfI (Wound, Ischemia, foot Infection) limb loss risk stratification system based on the assessment of wound depth, peripheral blood supply status, and the severity of the infectious process (Appendix A3) [510].

Diagnostics

The diagnosis of CLI is established based on:

Ø constant ischemic pain at rest requiring regular analgesia for more than two weeks;

Ø presence of an ulcer or gangrene of the toes or foot against the background of tibial artery systolic pressure ≤ 50 mmHg or toe pressure ≤ 30 mmHg [503, 507].

Comments: Due to the necessity of using an iodine-containing contrast agent (ATC classification V08A radiocontrast media, iodine-containing), the procedure should be performed with caution due to the risk of contrast-induced nephropathy and (rarely) severe allergic reactions. It is necessary to provide prophylaxis for contrast-induced nephropathy in all patients with type 2 diabetes (assessment of GFR, discontinuation of loop diuretics (ATC classification C03CA), ACE inhibitors, ARBs, SGLT-2 inhibitors, and metformin**, administration of rehydration therapy in the early perioperative period).

Treatment

Comments: The decision on the revascularization method can be made by a cardiovascular surgeon in cooperation with an endovascular surgeon and an endocrinologist. For patients with type 2 diabetes and pre-dialysis chronic kidney disease, the availability of a hemodialysis unit is required when choosing a medical facility.

Rehabilitation

Comments: Administration of anticoagulant and dual antiplatelet therapy in patients with DM requires evaluation of the fundus and timely panretinal laser photocoagulation [385].

Prevention and follow-up care

The mainstay of CLTI prevention is achieving and maintaining individual glycemic targets, controlling cardiovascular risk factors (smoking cessation, achieving and maintaining individual blood pressure and LDL-C targets), and regular physical exercise. Patients who have undergone lower extremity artery revascularization for CLTI require follow-up by a local endocrinologist and surgeon, with lower extremity duplex ultrasound scanning performed at 3 and 6 months after surgical treatment, and subsequently twice a year.

7.7 Diabetic foot syndrome

Definition, risk groups, and classification

Diabetic foot syndrome (DFS) is defined as infection, ulceration, and/or destruction of deep tissues associated with neurological abnormalities and/or a reduction in macrovascular blood flow in the lower extremity arteries

DFS is a multidisciplinary problem managed by specialists across various fields (endocrinologists, surgeons, vascular surgeons, orthopedic traumatologists). Patients are typically hospitalized in purulent and/or vascular surgery departments, and all of the above-mentioned specialists should be involved in their care.

The following individuals may be considered at risk for developing DFS [423, 519, 520]:

- patients with peripheral neuropathy of any etiology;

- patients with peripheral artery occlusive disease;

- patients with foot deformities of any etiology;

- blind and visually impaired individuals;

- lonely patients and elderly individuals;

- individuals with alcohol abuse and smokers.

Risk group stratification and the organization of patient follow-up are carried out by an endocrinologist and/or a diabetic foot clinic specialist [3].

Classifications of diabetic foot syndrome

Currently, several classifications of DFS are used, based on the understanding of the core pathogenetic mechanisms underlying this diabetic complication. They account for the severity of peripheral nervous system damage, the peripheral arterial bed, the size of the wound defect, and the severity of the infectious process.

Depending on the involvement of the main pathogenetic components, the following clinical forms of DFS are distinguished [3, 521]:

- Neuropathic form

- Trophic foot ulcer

- Diabetic neuroosteoarthropathy (DNOAP)

- Ischemic form

- Neuroischemic form

The WIfI classification (Wound, Ischemia, Foot infection), proposed in 2015 and presented in Appendix A3, takes into account wound size, peripheral blood supply, and the severity of the infection, allowing for the most comprehensive assessment of lesion severity and prognostic evaluation of treatment [522].

International experts recommend abandoning the classification of DFS by clinical forms and relying solely on the WIfI classification as the most informative for adequately assessing lesion severity and developing treatment strategies [521].

Diagnostics

Comments: All patients with DFS must be evaluated for potential peripheral nerve dysfunction (see Section 7.4 Diabetic neuropathy). Patients with DFS and signs of peripheral arterial occlusion are managed as having critical lower limb ischemia, which poses a threat of limb loss (see Section 7.6.5 Specifics of critical lower limb ischemia in patients with type 2 diabetes mellitus). A comprehensive assessment and comparison of various diagnostic methods are required, followed by a discussion of the findings with an endovascular surgeon / vascular surgeon (possessing adequate experience and good outcomes in performing revascularizations in this category of patients) within a multidisciplinary team dedicated to DFS patient management [523].

Comments: Local signs of wound infection include purulent exudate, erythema, hyperthermia, edema (tissue induration), and pain in the wound (or tenderness upon palpation). A diagnosis of wound infection is established in the presence of 2 or more of the specified signs in the absence of other potential causes of inflammation (trauma, gout, diabetic osteoarthropathy, etc.). Systemic signs of infection include fever, leukocytosis, central nervous system depression (lethargy), worsening renal failure, decompensation of carbohydrate metabolism, and ketoacidosis. However, due to the frequent hyporeactivity of the immune system in DM (especially in elderly patients), fever and leukocytosis may be absent even in severe wound infection.

The following severity degrees of wound infection in DFS are distinguished:

1. Uninfected ulcer/wound

2. Mild infection. An infection involving only the skin and subcutaneous tissue. The aforementioned signs of wound infection* are present without signs of deeper structure involvement or systemic inflammatory response. The radius of the erythema zone is less than 2 cm.

3. Moderate infection. Extensive inflammation of the skin and subcutaneous tissue (same signs of infection + radius of the erythema zone greater than 2 cm) OR involvement of deeper structures (abscess, osteomyelitis, septic arthritis, fasciitis)

4. Severe infection. Systemic inflammatory response syndrome (SIRS), consistent with the modern understanding of sepsis. Its confirmation requires the presence of two or more of the following criteria:

□ Body temperature greater than 38 °C or less than 36 °C

□ Heart rate > 90 bpm

□ Tachypnea (respiratory rate > 20 breaths/min)

□ PaCO2 (partial pressure of CO2 in arterial blood) < 32 mm Hg

□ Leukocyte count greater than 12 or less than 4 thousand per µL

□ Left shift in the leukocyte differential (10% or more immature (band) forms of leukocytes)

Comments: Tissue samples for analysis must be taken from different sites, as microflora may vary across different areas of the defect. In patients with neuro-ischemic and ischemic forms of DFS, it is necessary to identify not only aerobic but also anaerobic microorganisms and determine their susceptibility to modern antibacterial drugs. A bacterial load exceeding 1x106 per gram of tissue or the detection of β-hemolytic Streptococcus is considered clinically significant [532–535].

Comments: Radiography remains the primary method for evaluating the condition of bones and joints, allowing for the reliable identification of osteolysis foci (osteomyelitis) [536–540].

Treatment

Correction of carbohydrate and lipid metabolism disorders in patients with DFS should be performed concurrently with wound defect management. For patients with DFS and diagnosed dyslipidemia and hypertension, statin therapy and blood pressure normalization are mandatory [3].

Comments: Possible offloading methods include a total contact cast (TCC), a removable cast walker, a wheelchair, and crutches.

Comments: Alternatively, a half-shoe (cast shoe) can be used. The use of offloading devices is contraindicated in fistulous osteomyelitis, critical limb ischemia, and gangrene; it is ineffective for lesions of the calcaneus and ankle joint. In these cases, orthotic management is recommended.

Comments: Surgical debridement aims to remove all necrotic and non-viable tissues and prepare the wound bed for healing. Surgical, mechanical, ultrasonic methods, or a combination thereof can be used [550]. The debridement method is chosen individually based on the wound condition, the patient's general condition, and the clinical facilities available. After debridement, the wound must be covered with a sterile atraumatic dressing. Repeated debridement of the wound defect may be required during the course of treatment.

Comments: The selected dressing should maintain a moist wound environment, control exudate levels, and prevent periwound maceration. It must be securely fixed to the wound to avoid trauma caused by mobility.

A crucial aspect of treating trophic ulcers in patients with DFS is wound infection control.

Comments: Both classical surgical debridement and modern technologies (hydro-surgical equipment, ultrasonic cavitation) can be used. In the presence of critical limb ischemia, surgical debridement of the wound is hazardous as it may lead to an expansion of the necrosis zone.

Comment: An important condition when choosing a systemic antibacterial drug is a preliminary assessment of renal nitrogen-excreting function, as a reduction in the dose of the systemic antibacterial drug may be required. Drugs from the aminoglycoside group (gentamicin**, tobramycin**, amikacin**, netilmicin, etc.), amphotericin B**, and certain first-generation cephalosporins are strictly contraindicated even in patients with initial manifestations of diabetic nephropathy [3].

Comments: The feasibility and strategy of revascularization (percutaneous endovascular revascularization, surgical revascularization, hybrid intervention) are determined by weighing the risks of the intervention against its potential benefits, as well as the prognosis for preserving the weight-bearing function of the limb upon foot wound healing. The patient's preferences must also be taken into account. If a purulent-necrotic focus is present, its primary surgical debridement must be performed prior to the revascularization procedure [523].

Comments: To this end, it is necessary to discontinue diuretics (if possible), ACE inhibitors/ARBs, SGLT2 inhibitors, and potentially nephrotoxic drugs 48 hours before and after the procedure. On the eve of surgery and postoperatively, administer 500–1000 ml of normal saline IV drip under diuresis control.

Additional (adjuvant) methods of wound treatment in DFS.

In the absence of healing against the background of standard therapy, adjuvant methods can be used (growth factor preparations (ATC classification D03AX Other cicatrizing agents), local negative pressure).

Comments: The use of NPWT is strictly contraindicated in patients with severe limb ischemia (TcpO2 < 30 mmHg), osteomyelitis, phlegmon, and foot gangrene [563, 565].

Prevention

A prerequisite for preventing the recurrence of trophic ulcers and possible limb amputation in patients with DFS is ensuring continuity of care and a multidisciplinary approach in organizing long-term follow-up for this category of patients.

Comments: The goal of training is to foster correct daily foot care behavior and increase adherence to prescribed therapy. Special attention should be paid to elderly individuals, especially those with visual impairment. As a rule, they cannot care for their feet independently and require qualified external assistance. Patients of any age with lower extremity trophic ulcers are not eligible for group training. Classes with them are conducted exclusively on an individual basis.

Comments: High-risk groups for foot trophic ulcers include individuals with significant arterial insufficiency, severe neuropathy, a history of foot ulcers, and severe hyperkeratosis. The adequacy of custom orthopedic footwear must be regularly evaluated by the attending physician (endocrinologist, surgeon, diabetic foot specialist) and replaced at least once a year. The frequency of relapses is also reduced by daily foot inspection by the patient (or a relative) and adherence to foot care rules. Professional podiatric care procedures, which should be performed by a specially trained nurse in a diabetic foot clinic setting, play an important role [568].

7.8 Management of type 2 diabetes mellitus during pregnancy

Pregnancy developing against the background of diabetes mellitus is associated with risks to the health of the mother and fetus. Planning pregnancy and maintaining physiological glucose levels in pregnant women with diabetes helps reduce the frequency of complications and improves pregnancy course and outcomes [569, 570].

Detailed data on pregnancy management and delivery are presented in the relevant clinical guidelines of the specialized professional association.

Comments: An effective method of contraception should be used until a proper examination and preparation for pregnancy have been carried out. When planning pregnancy, it is necessary to determine the HbA1c level, serum creatinine, urine albumin-to-creatinine ratio, thyroid-stimulating hormone level, and prescribe folic acid** at a dose of at least 400 mcg, and potassium iodide preparations** at 150 mcg.

Comments: Treatment targets for this period correspond to: HbA1c < 6.5%, fasting/preprandial plasma glucose < 6.1 mmol/L, 2-hour postprandial plasma glucose < 7.8 mmol/L. It is necessary to inform female patients with type 2 diabetes mellitus and their family members about potential risks to the mother and fetus in the absence of satisfactory glycemic control at the time of conception and during pregnancy.

Comments: When planning pregnancy, it is necessary to switch a female patient with type 2 diabetes mellitus to insulin therapy due to the non-permeability of the placenta to insulin preparations [577–580]. If pregnancy occurs while on oral glucose-lowering therapy, such medications must be discontinued and insulin therapy initiated.

Comments: Standardized CGM metrics and their target values in female patients with type 2 diabetes mellitus during pregnancy are presented in Table 30 [48].

Table 30. Standardized continuous glucose monitoring metrics and target values in pregnant women with diabetes mellitus type 2

* Including values < 3.0 mmol/L

Comments: Structured patient education on the principles of intensified insulin therapy in a basal-bolus regimen is required for female patients with type 2 diabetes. Conversion to continuous subcutaneous insulin infusion (insulin pump therapy) is possible at the pregnancy planning stage [589].

Comments. Alternative individual glycemic control targets may be defined (in the presence of vascular complications of diabetes mellitus).

Comments: The timing and method of delivery are determined by obstetric indications. To ensure a comprehensive approach to delivery and postpartum management, delivery in a specialized maternity hospital is recommended.

7.9 Features of type 2 diabetes mellitus in the elderly

There is no single universal definition of the term "elderly age".

With regard to medical guidelines in developed countries, the definition of "elderly age" most frequently refers to individuals over 65 years of age [597, 598].

Diagnostic criteria for diabetes mellitus in the elderly do not differ from those for the general population (see Section 2 Diagnostics). However, it should be noted that in some elderly patients, HbA1c levels may be inaccurate due to comorbid conditions affecting erythrocyte lifespan [10].

Features of type 2 diabetes mellitus in elderly individuals [4]:

Ø Clinical features:

Ø frequently asymptomatic course (absence of specific complaints of polyuria, thirst, dry mouth);

Ø micro- and macroangiopathies are often already present at the time of diabetes diagnosis;

Ø multiple comorbid pathologies.

o Laboratory features:

Ø absence of fasting hyperglycemia in a number of patients;

Ø frequent predominance of isolated postprandial hyperglycemia;

Ø increase in the renal glucose threshold with age.

o Psychosocial features:

Ø disease progression in conditions of social isolation and financial hardship;

Ø cognitive impairment (memory decline, learning difficulties, etc.).

Elderly patients with type 2 diabetes mellitus should undergo regular screening for cognitive impairment, depression, and major geriatric syndromes (detailed in the relevant clinical guidelines) [599, 600].

Treatment

Selection of individual treatment goals in elderly patients with diabetes mellitus (glycemic control parameters):

The selection of individual treatment goals in elderly patients with type 2 diabetes mellitus depends on multiple factors: the patient's life expectancy; comorbid conditions, primarily the cardiovascular status; risk of hypoglycemic states; preservation of cognitive functions; and functional activity category [597, 601].

Definition of functional categories for elderly patients with diabetes mellitus:

Elderly patients with type 2 diabetes mellitus require personalized recommendations taking into account varying levels of dependence on external assistance [601].

o Patient category: functionally independent

Patients who can live independently and do not require external support for activities of daily living (or require minimal support).

o Patient category: functionally dependent

Patients who experience impairments in performing routine activities of daily living (e.g., dressing, personal hygiene), which increases the need for additional medical and social support and the risk of hospitalization.

Among these patients with reduced functional activity, two groups require special consideration (those with frailty syndrome and those with dementia).

Subcategory A:

Frailty. Patients with this syndrome are characterized by increased fatigue, weight loss, limited mobility and muscle strength, and an increased risk of falls. The "Age Is No Obstacle" questionnaire can be used to screen for frailty [599, 602] (Appendix G5).

Subcategory B:

Dementia: Patients with dementia present with cognitive impairment leading to a loss of self-care abilities (memory decline, disorientation in time and space, personality changes). Somatically, patients with dementia may remain stable for a long time.

o Patient category: End of life

Life expectancy less than 6 months.

The algorithm for selecting individual glycemic control targets based on HbA1c in elderly patients is presented in Table 31.

Table 31. Algorithm for individualized selection of treatment goals for diabetes mellitus in the elderly based on HbA1c1 [3]

1 Normal level according to DCCT standards: up to 6%.

2 IHD (history of myocardial infarction, coronary artery bypass grafting/stenting, angina pectoris); history of stroke; lower extremity arterial disease (symptomatic).

3 The main criteria for the risk of severe hypoglycemia are: history of severe hypoglycemia, asymptomatic hypoglycemia, long duration of diabetes mellitus, CKD stages G3-5, dementia.

Note: It should be taken into account that even in older age, life expectancy can be quite high, and in such cases, individual treatment goals should not be set too high. In good general health, some elderly patients with type 2 diabetes may be prescribed lower individual target HbA1c levels [603]. In addition, it must be taken into account that conditions in which HbA1c levels may be skewed (e.g., anemia and CKD) are significantly more common in older age.

Dietary features

Dietary restrictions, including those for weight loss, should be used with caution and only if they lead to a clinically significant improvement in carbohydrate or lipid metabolism, blood pressure, or other important health indicators. The potential adverse effects of hypocaloric nutrition on bone tissue, vitamin intake, and the development of sarcopenia should be kept in mind.

There is no need to recommend a strictly defined amount of carbohydrates to elderly patients with normal body weight who are not receiving insulin therapy. When using short-acting (ultra-short-acting) insulin, a practically oriented assessment of the amount of carbohydrates in food is possible

Physical activity features

Regular physical activity is highly desirable, but it must be strictly individualized according to the patient's general physical condition, the presence and severity of complications and comorbidities. Walks of 30–60 minutes daily or every other day are recommended.

Drug therapy

Requirements for glucose-lowering drugs in elderly patients with type 2 diabetes:

o minimal risk of hypoglycemia;

o absence of nephro-, hepato-, and cardiotoxicity;

o minimal drug-drug interactions;

o ease of use.

It should be borne in mind that glucose-lowering therapy in elderly patients is quite often excessive, which increases the risk of hypoglycemia. In this case, deintensification (deprescribing, simplification) of treatment can be carried out, especially in patients who have achieved their individual HbA1c target. Treatment deintensification can be achieved by reducing the dose, switching to a drug with a lower risk of hypoglycemia, or withdrawing drug therapy.

Comments: DPP-4 inhibitors have a favorable safety profile, maintain their efficacy regardless of age, do not increase body weight, can be used in renal impairment, and have been sufficiently well studied in the elderly [604–610].

DPP-4 inhibitors are preferred over sulfonylureas for treatment intensification in the elderly due to the low risk of hypoglycemia [610].

SGLT-2 inhibitors have shown significant benefits in individuals with ASCVD, HFrEF, and CKD, with elderly patients experiencing benefits comparable to those of younger individuals. It should be taken into account that the risk of complications associated with hypovolemia is somewhat higher in the elderly. Exercise caution in case of fracture risk.

GLP-1 receptor agonists (liraglutide, dulaglutide**, semaglutide**) have shown significant benefits in patients with ASCVD, but weight loss may be undesirable in some elderly patients.

Comments: Caution regarding the prescription of sulfonylureas (SUs) to elderly patients is due to the age-related increase in the risk of hypoglycemia [611]. Treatment with SUs is started at doses half as low as in younger age; in individuals with irregular eating habits, the use of long-acting SUs is undesirable; in individual cases, short-acting drugs are preferred. Glibenclamide** is not recommended for elderly patients with type 2 diabetes due to the highest risk of hypoglycemia among SUs [612, 613].

Comments: TZDs can promote fluid retention and worsen the course of heart failure, which is common in elderly patients [614], as well as increase the risk of fractures [615].

Comments: Intensified insulin therapy is possible only if the elderly patient retains cognitive functions, after training in the basic rules of insulin therapy and self-monitoring of blood glucose levels. In patients with type 2 diabetes who previously received long-term intensified insulin therapy, if cognitive impairment occurs, a simpler regimen should be considered (e.g., switching to pre-mixed insulin).

7.10 Vaccination

The importance of routine vaccination for individuals with type 2 diabetes has increased due to the 2019 coronavirus disease (COVID-19) pandemic. Preventing vaccine-preventable infections not only directly prevents morbidity but also reduces the number of hospitalizations, which can additionally lower the risk of acquiring infections such as COVID-19. Patients with type 2 diabetes should be vaccinated in accordance with age recommendations and epidemiological indications.

Comments: Influenza is a common, vaccine-preventable infectious disease characterized by high mortality and morbidity in vulnerable populations, including both young and elderly people, and individuals with chronic conditions. Influenza vaccination administered to individuals with type 2 diabetes significantly reduces the number of hospitalizations for influenza and diabetes. Pre-epidemic influenza vaccination is primarily indicated for individuals at high risk for influenza and adverse complications, which includes individuals with type 2 diabetes.

Comments: Like influenza, pneumococcal pneumonia is a common, preventable disease. Individuals with T2D have an increased risk specifically for the bacterial form of the disease, predominantly nosocomial, with a high mortality rate (up to 50%). Pneumococcal vaccination can be administered year-round. If a mass influenza vaccination campaign is planned, it is convenient to administer this vaccine simultaneously with the pneumococcal immunization before the onset of the acute respiratory viral infection and influenza season, which aligns with World Health Organization recommendations. Vaccination does not require any dose adjustment of glucose-lowering drugs or insulin preparations.

Comments: Compared to the general population, individuals with T2D are more likely to contract hepatitis B. This may be due to contact with infected blood or improper equipment use (glucose monitoring devices or contaminated needles). Vaccination against hepatitis B, due to the higher probability of transmission, is recommended for patients with T2D under 60 years of age. For patients aged 60 years and older, the hepatitis B vaccine may be administered at the discretion of the attending physician based on the patient's likelihood of acquiring hepatitis B.

Comments: Patients with T2D have a 3-4 times higher risk of hospitalization, complicated disease course, and adverse outcomes from the novel coronavirus infection COVID-19 caused by the SARS-CoV-2 virus compared to individuals without diabetes. The most significant risk factors for a more severe disease course and fatal outcomes of COVID-19 in patients with T2D are poor glycemic control (glycated hemoglobin HbA1c>9%), age over 65 years, presence of obesity, and diabetes complications [652].

General contraindications to vaccination:

- hypersensitivity to any component of the vaccine or a vaccine containing similar components;

- history of severe allergic reactions;

- severe post-vaccination complications (anaphylactic shock, severe generalized allergic reactions, convulsive syndrome, temperature above 40 °C, etc.) to the administration of the first vaccine component serve as a contraindication to administering the second component;

- acute infectious and non-infectious diseases, exacerbation of chronic conditions (in such cases, vaccination is performed 2–4 weeks after recovery or remission. For mild acute respiratory infections or acute gastrointestinal infections, vaccination is performed after normalization of body temperature).

Additional contraindications to vaccination in patients with T2D:

- acute complications of T2D (diabetic ketoacidosis, hyperosmolar hyperglycemic state, lactic acidosis, severe hypoglycemia).

Caution during vaccination:

- required in patients with marked metabolic decompensation of T2D.

The decision to vaccinate is made by the physician after a general physical examination of the patient including measurement of body temperature (if the temperature exceeds 37 °C, vaccination is deferred), and after the patient signs an informed consent form.

7.11 Hypogonadism

Comments: T2D and hypogonadism frequently coexist and mutually exacerbate each other. The principles of hypogonadism management, including testosterone therapy (indications, contraindications, and monitoring), are outlined in the draft of relevant guidelines [658]. The literature does not provide studies demonstrating a specific glycated hemoglobin threshold at which carbohydrate metabolism must be corrected first, and only upon reaching that target level should a man's androgen status be evaluated and hypogonadism treated if necessary. Therefore, concurrent treatment of hypogonadism alongside interventions for metabolic compensation is permissible [653, 654].

Criteria for Evaluating the Quality of Medical Care

Table 32. Criteria for assessing the quality of medical care in type 2 diabetes mellitus

Table 33. Quality assessment criteria for specialized medical care in type 2 diabetes mellitus

References

Appendix A1. Working Group Composition

1. Dedov Ivan Ivanovich – Academician of the Russian Academy of Sciences, D.Sc. (Medicine), Professor; President of the National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation; President of the Russian Association of Endocrinologists (RAE); Chief freelance endocrinologist of the Ministry of Health of the Russian Federation. dedov@endocrincentr.ru

2. Shestakova Marina Vladimirovna – Academician of the Russian Academy of Sciences, D.Sc. (Medicine), Professor; Director of the Diabetes Institute, National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation; Chief Scientific Secretary and Member of the Board Presidium of the Russian Association of Endocrinologists (RAE); Member of the European Association for the Study of Diabetes (EASD); Member of the American Diabetes Association (ADA); Co-chair of the Section on Cardiovascular Complications of Diabetes Mellitus at the Russian Society of Cardiology; Member of the Higher Attestation Commission (VAK) Expert Council on Therapeutic Sciences. shestakova.mv@gmail.com

3. Mayorov Alexander Yuryevich - D.Sc. (Medicine), Professor, Head of the Department of Diabetes Forecasting and Innovation, National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation; President of the Russian Diabetic Association; Member of the Russian Association of Endocrinologists (RAE); Member of the European Association for the Study of Diabetes (EASD); Member of the American Diabetes Association (ADA); Member of the Diabetes Education Study Group (DESG). education@endocrincentr.ru

4. Shamkhalova Minara Shamkhalovna – D.Sc. (Medicine), Professor, Head of the Department of Diabetic Kidney Disease and Post-Transplant Rehabilitation, National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation; Member of the Russian Association of Endocrinologists (RAE); Member of the American Diabetes Association (ADA). shamkhalova@mail.ru

5. Sukhareva Olga Yuryevna – Ph.D. (Medicine), Leading Researcher at the Department of Diabetic Kidney Disease and Post-Transplant Rehabilitation, National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation; Member of the Russian Association of Endocrinologists (RAE); Member of the European Association for the Study of Diabetes (EASD). olgasukhareva@mail.ru

6. Galstyan Gagik Radikovich - D.Sc. (Medicine), Professor, Head of the Diabetic Foot Department, National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation; Chief freelance endocrinologist of the Moscow Region Ministry of Health; Member of the Russian Association of Endocrinologists (RAE); Member of the European Association for the Study of Diabetes (EASD); Member of the American Diabetes Association (ADA). galstyangagik964@gmail.com

7. Tokmakova Alla Yuryevna – D.Sc. (Medicine), Chief Researcher at the Diabetic Foot Department, National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation; Member of the Russian Association of Endocrinologists (RAE). alla-tokmakova@yandex.ru

8. Nikonova Tatyana Vasilyevna – D.Sc. (Medicine), Head of the Department for Drug Supply and Regulation of Medical Device Circulation, Coordination Council of the National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation; Member of the Russian Association of Endocrinologists (RAE); Member of the European Association for the Study of Diabetes (EASD). tatiana_nikonova@mail.ru

9. Surkova Elena Viktorovna - D.Sc. (Medicine), Professor, Chief Researcher at the Diabetes Therapy Department, National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation; Member of the Russian Association of Endocrinologists (RAE); Member of the Diabetes Education Study Group (DESG). elenasurkova@mail.ru

10. Kononenko Irina Vladimirovna - Ph.D. (Medicine), Head of the Research and Development Department, Coordination Council of the National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation; Member of the Russian Association of Endocrinologists (RAE). shakhtarina@bk.ru

11. Egorova Daria Nikitichna – Ph.D. (Medicine), Leading Researcher at the Diabetic Foot Department, National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation; Member of the Russian Association of Endocrinologists (RAE). egorovadasha@yandex.ru

12. Ibragimova Lyudmila Ibragimovna - Ph.D. (Medicine), Leading Researcher at the Diabetes and Pregnancy Center, National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation; Member of the Russian Association of Endocrinologists (RAE); Member of the European Society of Endocrinology - Young Endocrinologists and Scientists (EYES). ibragimovaliudmila@gmail.com

13. Shestakova Ekaterina Alekseevna – Ph.D. (Medicine), Leading Researcher at the Department of Diabetes Forecasting and Innovation, National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation; Member of the Russian Association of Endocrinologists (RAE). katiashestakova@mail.ru

14. Klefortova Inna Igorevna – Ph.D. (Medicine), Head of the Department for Inpatient Care Coordination, Endocrinologist at the Department of Diabetic Kidney Disease and Post-Transplant Rehabilitation, National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation; Member of the Russian Association of Endocrinologists (RAE). iklefort@mail.ru

15. Sklyanik Igor Alexandrovich – Ph.D. (Medicine), Researcher at the Department of Diabetes Forecasting and Innovation, National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation; Member of the Russian Association of Endocrinologists (RAE). sklyanik.igor@gmail.com

16. Yarek-Martynova Ivona Yanovna – Ph.D. (Medicine), Deputy Chief Physician, Leading Researcher at the Department of Diabetic Kidney Disease and Post-Transplant Rehabilitation, National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation; Member of the Russian Association of Endocrinologists (RAE); Member of the European Association for Cardiovascular Prevention and Rehabilitation (EACPR). iwonamj@mail.ru

17. Severina Anastasia Sergeevna – Ph.D. (Medicine), Leading Researcher at the Department of Diabetic Kidney Disease and Post-Transplant Rehabilitation, National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation; Member of the Russian Association of Endocrinologists (RAE). ansev1@mail.ru

18. Martynov Sergey Andreevich – D.Sc. (Medicine), Head of the Office for Extracorporeal Renal Pathology Treatment Methods, National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation; Member of the Russian Dialysis Society (RDS); Member of the European Renal Association – European Dialysis and Transplant Association (ERA – EDTA). smartynov@inbox.ru

19. Vikulova Olga Konstantinovna – D.Sc. (Medicine), Head of the Department of Endocrinopathy Epidemiology, National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation; Member of the Russian Association of Endocrinologists (RAE). olga-vikulova-1973@yandex.ru

20. Kalashnikov Viktor Yuryevich – Corresponding Member of the Russian Academy of Sciences, D.Sc. (Medicine), Professor, Head of the Coordination Council – Deputy Director of the National Medical Research Center for Endocrinology of the Ministry of Health of Russia for the Coordination of Endocrinological Services, Head of the Department of Cardiology and Vascular Surgery, National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation. victor9368@gmail.com

21. Bondarenko Irina Ziyatovna – D.Sc. (Medicine), Chief Researcher at the Department of Cardiology and Vascular Surgery, National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation. iz_bondarenko@mail.ru

22. Gomova Irina Sergeevna – Ph.D. (Medicine), Functional Diagnostics Physician at the Department of Cardiology and Vascular Surgery, National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation. ivist08@yandex.ru

23. Rozhivanov Roman Viktorovich – D.Sc. (Medicine), Professor, Chief Researcher at the Department of Andrology and Urology, National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation. rrozhivanov@mail.ru

24. Starostina Elena Georgievna – D.Sc. (Medicine), Professor at the Department of Endocrinology, Faculty of Advanced Medical Training, Moscow Regional Research Clinical Institute named after M.F. Vladimirsky of the Moscow Region Ministry of Health; Member of the Russian Association of Endocrinologists (RAE); Member of the European Association for the Study of Diabetes (EASD). elena.starostina59@yandex.ru

25. Ametov Alexander Sergeevich – D.Sc. (Medicine), Professor, Head of the Department of Endocrinology, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation; Member of the Board of the Russian Association of Endocrinologists (RAE); Member of the European Association for the Study of Diabetes (EASD); Member of the American Diabetes Association (ADA). alexander.ametov@gmail.com

26. Antsiferov Mikhail Borisovich – D.Sc. (Medicine), Professor, Chief Physician of the Endocrinological Dispensary of the Moscow Healthcare Department, Professor at the Department of Endocrinology, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation; Chief freelance endocrinologist of the Moscow Healthcare Department; Member of the Board of目 the Russian Association of Endocrinologists (RAE). antsiferov@rambler.ru

27. Bardymova Tatyana Prokopyevna – MD, Professor, Head of the Department of Endocrinology, Irkutsk State Medical Academy of Continuing Education – Branch of the Russian Medical Academy of Continuing Professional Education of the Ministry of Health of the Russian Federation; Chief freelance endocrinologist of the Ministry of Health of the Irkutsk Region; Member of the Board of the Russian Association of Endocrinologists (RAE). tpbardymova@mail.ru

28. Bondar Irina Arkadyevna – MD, Professor, Head of the Department of Endocrinology, Novosibirsk State Medical University of the Ministry of Health of the Russian Federation; Chief freelance endocrinologist of the Ministry of Health of the Russian Federation in the Siberian Federal District; Member of the Board of the Russian Association of Endocrinologists (RAE). ibondar2008@gmail.com

29. Valiyeva Farida Vadutovna – MD, Professor, Head of the Department of Endocrinology, Kazan State Medical University of the Ministry of Health of the Russian Federation; Chief freelance endocrinologist of the Ministry of Health of the Russian Federation in the Privolzhsky Federal District; Member of the Board of the Russian Association of Endocrinologists (RAE). val_farida@mail.ru

30. Demidova Tatyana Yulyevna – MD, Professor, Head of the Department of Endocrinology, Faculty of General Medicine at the Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation; Member of the European Association for the Study of Diabetes (EASD). t.y.demidova@gmail.com

31. Kiseleva Tatyana Petrovna – MD, Professor, Professor at the Department of Faculty Therapy, Endocrinology, Allergology and Immunology, Ural State Medical University of the Ministry of Health of the Russian Federation; Chief freelance endocrinologist of the Ministry of Health of the Russian Federation in the Ural Federal District; Member of the Board of the Russian Association of Endocrinologists (RAE); Chairperson of the Regional Public Organization "Sverdlovsk Association of Endocrinologists". kistapet@mail.ru

32. Klimontov Vadim Valeryevich – MD, Professor of the RAS, Deputy Head of the Branch for Research, Head of the Laboratory of Endocrinology, Research Institute of Clinical and Experimental Lymphology – Branch of the Federal Research Center "Institute of Cytology and Genetics, SB RAS"; Member of the European Association for the Study of Diabetes (EASD). klimontov@mail.ru

33. Mkrtumyan Ashot Musayelovich – MD, Professor, Head of the Department of Endocrinology and Diabetology, A.I. Yevdokimov Moscow State University of Medicine and Dentistry of the Ministry of Health of the Russian Federation; Head of the Research Department of Endocrine and Metabolic Disorders, A.S. Loginov Moscow Clinical Scientific Center of the Moscow City Health Department; Member of the Board of the Russian Association of Endocrinologists (RAE); Member of the European Association for the Study of Diabetes (EASD); Member of the American Diabetes Association (ADA). vagrashot@mail.ru

34. Petunina Nina Alexandrovna – Corresponding Member of the RAS, MD, Professor, Head of the Department of Endocrinology, Faculty of General Medicine, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation; Chief freelance endocrinologist of the Ministry of Health of the Russian Federation in the Central Federal District; Member of the Board of the Russian Association of Endocrinologists (RAE); Member of the European Association for the Study of Diabetes (EASD); Member of the American Diabetes Association (ADA). napetunina@mail.ru

35. Ruyatkina Lyudmila Alexandrovna – MD, Professor at the Department of Emergency Therapy with Endocrinology and Occupational Pathology, Novosibirsk State Medical University of the Ministry of Health of the Russian Federation; Member of the Russian Association of Endocrinologists (RAE); Member of the European Association for the Study of Diabetes (EASD); Chairperson of the Novosibirsk Association of Endocrinologists. larut@list.ru

36. Suplotova Lyudmila Alexandrovna – MD, Professor, Head of the Endocrinology Course, Department of Therapy with Courses in Endocrinology, Functional and Ultrasound Diagnostics, Institute of Continuing Professional Development, Tyumen State Medical University of the Ministry of Health of the Russian Federation; Chief freelance endocrinologist of the Department of Health of the Tyumen Region; Vice-President of the Russian Association of Endocrinologists. suplotovala@mail.ru

37. Ushakova Olga Vyacheslavovna - MD, Associate Professor at the Department of General Practice and Preventive Medicine, Institute for Advanced Training of Healthcare Specialists of the Ministry of Health of the Khabarovsk Krai; Chief freelance endocrinologist of the Ministry of Health of the Russian Federation in the Far Eastern Federal District; Chief freelance endocrinologist of the Ministry of Health of the Khabarovsk Krai; Member of the Board of the Russian Association of Endocrinologists (RAE). oluschk@mail.ru

38. Khalimov Yury Shavkatovich – MD, Professor, Head of the Department and Clinic of Military Field Therapy, S.M. Kirov Military Medical Academy; Chief Endocrinologist of the Ministry of Defense of the Russian Federation; Chief freelance endocrinologist of the Health Committee of the Government of St. Petersburg; Member of the Board of the Russian Association of Endocrinologists (RAE). yushkha@gmail.com

Conflict of interest:

None of the working group members had any conflict of interest during the development of these clinical guidelines, specifically personal interest in obtaining, personally or through a company representative, material gain or other advantage that affects or may affect the proper performance of their professional duties and other obligations, including those related to the development and review of clinical guidelines, due to a contradiction between the personal interest of said persons and the interests of patients.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Endocrinologists;

2. General practitioners/therapists;

3. General practitioners.

Table 1. Scale for grading levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Scale for grading levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for grading the levels of evidence (LoE) for prevention, diagnostic, treatment and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions)

Procedure for updating clinical guidelines

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1) Injection and infusion technique in the treatment of diabetes mellitus. Guidelines https://apicr.minzdrav.gov.ru/static/МР102.PDF

2) Characteristics of glucose-lowering drugs.