Contents · 12 sections
In a nutshell. The basis of type 2 diabetes therapy is metformin + lifestyle modification. In the presence of ASCVD/HF/CKD, preferred agents are GLP-1 receptor agonists (semaglutide, liraglutide) and SGLT-2 inhibitors (empagliflozin, dapagliflozin) regardless of HbA1c. Insulin is indicated for decompensation, pregnancy, and severe hyperglycemia. Target HbA1c is individualized: 6.5–7% in young patients, 7.5–8% in elderly patients with a high risk of hypoglycemia.
1. Classes of glucose-lowering drugs
| Class | Examples | Mechanism |
|---|---|---|
| Biguanides | Metformin | ↓ hepatic gluconeogenesis, ↑ insulin sensitivity |
| Sulfonylureas | Gliclazide, glimepiride | Stimulation of insulin secretion by β-cells |
| Meglitinides | Repaglinide | Short-term stimulation of insulin secretion |
| Thiazolidinediones | Pioglitazone | PPAR-γ agonist — ↑ insulin sensitivity |
| α-Glucosidase inhibitors | Acarbose | ↓ intestinal carbohydrate absorption |
| DPP-4 inhibitors (gliptins) | Sitagliptin, vildagliptin | ↑ endogenous GLP-1 and GIP |
| GLP-1 receptor agonists | Liraglutide, semaglutide, dulaglutide | Glucose-dependent insulin secretion, ↓ appetite, gastroparesis |
| SGLT-2 inhibitors | Empagliflozin, dapagliflozin | ↓ renal glucose reabsorption, glucosuria |
| Insulins | Aspart, lispro, glargine, degludec | Insulin replacement |
2. Metformin — first-line therapy
- Mechanism: AMPK activation → ↓ hepatic glucose production, ↓ insulin resistance.
- HbA1c reduction by 1–1.5%.
- Pros: does not cause hypoglycemia, promotes weight loss, proven reduction in cardiovascular events.
- Side effects: diarrhea, flatulence (transient); rare lactic acidosis (discontinue if eGFR < 30 mL/min).
- Discontinue 48 hours prior to radiocontrast procedures in patients with eGFR 30–60.
3. SGLT-2 inhibitors
- Block sodium-glucose cotransporter 2 in the proximal renal tubules → glucosuria (50–80 g/day) → ↓ glucose and weight.
- HbA1c reduction by 0.5–1%.
- Empagliflozin (EMPA-REG OUTCOME), dapagliflozin (DAPA-HF, DECLARE) — ↓ cardiovascular mortality, ↓ heart failure hospitalizations, slowing CKD progression.
- Side effects: urogenital infections, euglycemic DKA, rare Fournier's gangrene, polyuria.
- Specific indication: patient with heart failure or CKD (eGFR > 20) — regardless of diabetes status.
4. GLP-1 receptor agonists
- Semaglutide (Ozempic/Rybelsus — oral form), liraglutide (Saxenda — at a 3 mg dose for weight loss), dulaglutide.
- Mechanism: glucose-dependent ↑ insulin secretion, ↓ glucagon, delayed gastric emptying, ↓ appetite.
- HbA1c reduction by 1–1.5%, body weight loss of 4–15 kg.
- Semaglutide and liraglutide — ↓ MACE in patients with ASCVD.
- Side effects: nausea, vomiting, pancreatitis (rare).
- Contraindications: personal or family history of medullary thyroid carcinoma or MEN 2.
- The newest agent is tirzepatide (dual GLP-1/GIP receptor agonist) with a record HbA1c reduction of up to 2% and weight loss of up to 20%.
5. DPP-4 inhibitors
- Sitagliptin, vildagliptin, alogliptin, linagliptin.
- Mechanism: DPP-4 inhibition → ↑ endogenous incretins (GLP-1 and GIP).
- HbA1c reduction by 0.5–0.8%.
- Pros: weight-neutral, minimal risk of hypoglycemia.
- Saxagliptin and alogliptin are associated with an ↑ risk of HF hospitalization.
- Do not combine with GLP-1 receptor agonists (excessive stimulation).
6. Sulfonylureas
- Gliclazide MR, glimepiride, glibenclamide (not recommended).
- Stimulate β-cells independently of glucose → risk of hypoglycemia, especially in the elderly.
- HbA1c reduction by 1–1.5%.
- Second-line option under budget constraints; superseded by SGLT-2 inhibitors and GLP-1 RAs.
7. Thiazolidinediones
- Pioglitazone — a PPAR-γ activator.
- HbA1c reduction by 0.8–1%, lipid improvement.
- Side effects: weight gain, edema, ↑ risk of CHF, fractures in women, ↑ risk of bladder cancer (debated).
- Contraindicated in NYHA functional class III–IV CHF.
8. Insulin therapy
Indications in type 2 diabetes
- Pronounced hyperglycemia (HbA1c > 10%, glucose > 16.7 mmol/L) with symptoms.
- Pregnancy and pregnancy planning.
- Severe comorbidities (myocardial infarction, stroke, sepsis, surgery, renal/hepatic impairment).
- Failure of oral therapy.
Regimens
- Basal: long-acting insulin (glargine 100/300, degludec) 0.1–0.2 IU/kg at bedtime.
- Basal-bolus: basal + prandial analog (aspart, lispro, glulisine).
- Premixed: NovoMix 30/70 BID.
- Pump therapy — mainly for type 1 diabetes.
9. ADA/EASD 2023 algorithm
- Cardiovascular history:
- ASCVD → GLP-1 RA or SGLT-2 inhibitor with proven benefit.
- CHF → SGLT-2 inhibitor.
- CKD (eGFR 20–60) → SGLT-2 inhibitor; if eGFR < 20 or albuminuria > 200 — GLP-1 RA.
- Weight focus: GLP-1 RAs (semaglutide, tirzepatide) — maximum weight ↓.
- Cost minimization: metformin + sulfonylureas or TZDs.
- Minimal hypoglycemia: GLP-1 RAs, SGLT-2 inhibitors, DPP-4 inhibitors, metformin, TZDs.
10. Glycemic control targets
| Group | Target HbA1c |
|---|---|
| Young, without comorbidities | < 6,5 % |
| Most adults | < 7,0 % |
| Elderly, severe complications, risk of hypoglycemia | < 8,0 % |
| Pregnancy | < 6,0 % |
11. Hypoglycemia
- Level 1: < 3.9 mmol/L with symptoms.
- Level 2: < 3.0 mmol/L.
- Level 3: with altered mental status/seizures.
- Correction: 15 g of fast-acting carbohydrates (juice, glucose tablets) — the "15/15" rule.
- Severe: glucagon 1 mg IM, 40% glucose IV.
12. FAQ
When to start SGLT-2 inhibitors and GLP-1 RAs — immediately or after metformin failure?
In ASCVD/CHF/CKD — from day one, regardless of HbA1c. Metformin remains the baseline, but does not preclude early initiation of cardioprotective classes.
What is the danger of euglycemic DKA with SGLT-2 inhibitors?
It develops at glucose levels of 10–15 mmol/L during infection, fasting, alcohol use, or surgery. If symptoms occur — check blood/urine ketones, discontinue the drug, administer insulin.
Can metformin be used in CKD?
Yes, but with dose adjustment: eGFR > 45 — full dose, 30–45 — max 1000 mg/day, < 30 — discontinue.
When to switch from oral therapy to insulin?
At HbA1c > 10%, symptomatic hyperglycemia, complications, intercurrent illnesses, pregnancy, surgery.
How to manage diabetes in the ICU?
Discontinue oral agents, switch to insulin — basal + correctional; glucose target 7.8–10 mmol/L.
See also: Diabetes and its complications (DKA) · CHF · Glucocorticoids · Thyroid gland · Pharmacology catalog