Expansion
Reduce hepatic output, increase secretion, increase sensitivity, or increase excretion
Mnemonic
Group by mechanism, which also predicts the side effects:
- Metformin - a biguanide, reducing hepatic gluconeogenesis and improving insulin sensitivity. No hypoglycaemia, weight neutral, causes gastrointestinal upset and B12 deficiency, and risks lactic acidosis in renal impairment
- Sulphonylureas (gliclazide) - stimulate insulin release by closing the K-ATP channel. Cause hypoglycaemia and weight gain
- DPP-4 inhibitors (-gliptins) - prolong incretin action. Weight neutral
- GLP-1 agonists (-tides) - injected incretin mimetics. Weight loss, nausea, pancreatitis
- SGLT2 inhibitors (-flozins) - block renal glucose reabsorption. Weight loss, cardiovascular and renal benefit, but genital infections, and euglycaemic ketoacidosis
- Pioglitazone - PPAR-gamma agonist. Weight gain, fluid retention, avoided in heart failure
“Only the sulphonylureas and insulin cause hypoglycaemia”, which is the fact that governs driving advice and sick day rules.
"-flozins for the heart and kidney, -tides for the weight" captures why the newer agents are chosen ahead of older ones despite similar glucose lowering.
Expansion
| Class | Mechanism | Key points |
|---|---|---|
| Metformin | Reduces hepatic gluconeogenesis, increases sensitivity | Weight neutral, no hypoglycaemia, lactic acidosis risk in renal failure |
| Sulfonylureas | Close beta cell KATP channels, increasing insulin release | Hypoglycaemia and weight gain |
| DPP-4 inhibitors | Prolong endogenous GLP-1 | Weight neutral, well tolerated |
| GLP-1 agonists | Incretin mimetic | Weight loss, cardiovascular benefit, injectable |
| SGLT2 inhibitors | Block renal glucose reabsorption | Weight loss, cardiac and renal benefit, genital infection, euglycaemic ketoacidosis |
| Pioglitazone | PPAR-gamma agonist, increases sensitivity | Weight gain, fluid retention, fracture risk |
| Acarbose | Inhibits alpha-glucosidase | Flatulence limits use |
Metformin remains first line for its efficacy, safety, weight neutrality and cost.
The choice of second agent is increasingly driven by comorbidity rather than glucose lowering alone: SGLT2 inhibitors for heart failure and chronic kidney disease, and GLP-1 agonists for obesity and established atherosclerotic disease.