Anti-Diabetic Drugs — Insulins, Oral Agents, Incretin Drugs and Choosing by Comorbidity

Anti-diabetic (glucose-lowering) drugs are best learnt by what they do to insulin. Some add insulin (insulin itself), some squeeze more insulin out of the beta cell (sulfonylureas, meglitinides), some make insulin work better (metformin, thiazolidinediones), some amplify the gut incretin signal (DPP-4 inhibitors, GLP-1 receptor agonists, the dual GIP/GLP-1 agonist tirzepatide) and some work independently of insulin (SGLT2 inhibitors in the kidney, alpha-glucosidase inhibitors in the gut).

Insulins are grouped by how quickly they act and how long they last. Rapid-acting analogues are taken just before meals; regular (short-acting) insulin needs food within about 30 minutes of the injection; basal insulins provide a background level over the day.

• Hypoglycaemia is by far the most common adverse effect of insulin; others are weight gain, hypokalaemia (insulin drives potassium into cells) and lipodystrophy or pain at injection sites.
• Intravenous insulin is used in hospital when close glucose control is needed — diabetic ketoacidosis, hyperosmolar hyperglycaemic state and severe hyperkalaemia.
• Insulin is essential in type 1 diabetes, because beta-cell function is absent or near-absent.

Metformin (a biguanide) lowers glucose by decreasing hepatic glucose production, reducing intestinal glucose absorption and improving insulin sensitivity. It lowers both fasting and post-meal glucose, is weight-neutral (sometimes modest weight loss) and is unlikely to cause hypoglycaemia on its own. It is not significantly metabolised by the liver and is cleared by the kidney.

• GI upset (diarrhoea, nausea, bloating) is the most common problem — up to 30% of users; reduce it with slow titration and extended-release tablets.
• Vitamin B12 deficiency with long-term use — ADA advises periodic B12 testing, especially with anaemia or neuropathy.
• Lactic acidosis — boxed warning, rare (about 1 in 30,000). Risk factors: renal or hepatic impairment, older age, surgery, hypoxia, alcohol.
• Iodinated contrast: stop metformin before contrast in people with reduced eGFR or other lactic-acidosis risk factors.
• Other uses: PCOS, prevention of type 2 diabetes and antipsychotic-associated weight gain.

Both classes bind the sulfonylurea receptor (SUR1) of the beta-cell ATP-sensitive potassium channel. Closing the channel depolarises the membrane, opens voltage-gated calcium channels, and the calcium influx triggers insulin release. Because this happens regardless of blood glucose, both can cause hypoglycaemia.

• Glipizide, glimepiride and gliclazide cause less hypoglycaemia than glibenclamide (glyburide).
• Glimepiride has lower affinity for cardiac SUR2A and is not associated with increased cardiovascular risk.
• Sulfonylurea overdose: IV dextrose can trigger further insulin release and recurrent hypoglycaemia — octreotide blocks this by inhibiting beta-cell calcium influx.
• Do not combine a meglitinide with a sulfonylurea — same mechanism.

Thiazolidinediones (TZDs) — pioglitazone and rosiglitazone — bind PPAR-γ, a nuclear transcription factor. They increase adiponectin and GLUT4 expression, raise insulin-dependent glucose uptake in muscle and fat and reduce hepatic gluconeogenesis. They are true insulin sensitisers and do not cause hypoglycaemia alone.

• Fluid retention and heart failure: dose-related fluid retention in up to 20% — PPAR-γ stimulates sodium reabsorption in the collecting duct (the same site as aldosterone). Avoid or use the lowest dose in NYHA class III–IV heart failure.
• Weight gain: subcutaneous fat expansion plus fluid.
• Fractures: higher risk, mainly distal limb bones (forearm, wrist, ankle, foot), especially in postmenopausal women.
• Bladder cancer: pioglitazone has been linked with bladder cancer in some studies — do not use in active bladder cancer.
• Liver: troglitazone was withdrawn for hepatotoxicity; check liver function at baseline and periodically.

The incretins GLP-1 (from intestinal L cells) and GIP (from K cells) are released within minutes of a meal and boost glucose-dependent insulin secretion. Natural GLP-1 survives less than 2 minutes because the enzyme DPP-4 breaks it down. Two drug strategies follow: block DPP-4 so endogenous incretins last longer (gliptins), or give a DPP-4-resistant GLP-1 receptor agonist at pharmacological levels.

Tirzepatide is a single molecule that activates both the GIP and GLP-1 receptors. ADA 2026 recommends a dual GIP/GLP-1 agonist in adults with type 2 diabetes, obesity and symptomatic HFpEF, and notes that adding a GLP-1 agonist (or tirzepatide) to metformin usually lowers HbA1c by 1% to 2% or more. Do not combine a GLP-1 agonist with a DPP-4 inhibitor — there is no added glucose-lowering benefit.

SGLT2 in the proximal convoluted tubule reabsorbs filtered glucose and sodium. Gliflozins (empagliflozin, dapagliflozin, canagliflozin, ertugliflozin) inhibit it, reducing glucose reabsorption by 30% to 60%, lowering the renal threshold for glucose and producing glycosuria. HbA1c falls 0.5% to 1%, with modest weight loss and lower blood pressure. The natriuresis also reduces preload and afterload — the basis of their heart and kidney protection.

• Heart failure: reduce HF hospitalisation in both reduced and preserved ejection fraction (ADA 2026: recommended in HF irrespective of HbA1c).
• CKD: slow kidney disease progression; KDIGO 2024 calls them foundational therapy. Their glucose-lowering effect is reduced at eGFR < 45, but kidney and heart benefits persist.
• Genital mycotic infections — the most frequently reported adverse event, especially in women. Fournier gangrene is rare but life-threatening.
• Euglycaemic DKA — anion-gap metabolic acidosis and ketosis with glucose below 250 mg/dL; withhold the drug before scheduled surgery (ADA: e.g. 3–4 days), during critical illness or prolonged fasting.
• Amputation risk — most strongly associated with canagliflozin.
• Intravascular volume depletion — watch volume status and blood pressure, especially when ill or fasting; urinary tract infections and pyelonephritis also occur.

Acarbose, miglitol and voglibose competitively inhibit brush-border enzymes (glucoamylase, sucrase, maltase, isomaltase) that break complex carbohydrates into absorbable sugars. Carbohydrate absorption is delayed, so the post-meal glucose rise is blunted. They are taken with the first bite of a meal. Acarbose does not inhibit lactase.

• Flatulence is the commonest side effect (about 78%), plus diarrhoea and abdominal pain — undigested carbohydrate is fermented by colonic bacteria.
• Acarbose and voglibose are poorly absorbed; miglitol is absorbed completely and excreted by the kidney.
• Acarbose has rare links with hepatitis.

The ADA Standards of Care in Diabetes 2026 (section 9) ask for a person-centred choice that weighs glycaemic effect, heart, kidney, liver and weight effects, hypoglycaemia risk, cost and preferences. Initial combination therapy can be considered to reach goals faster.

• When to start insulin: symptoms of hyperglycaemia, or HbA1c > 10% or glucose ≥ 300 mg/dL — regardless of other therapy.
• Without severe hyperglycaemia, GLP-1-based therapy is preferred to insulin for initial or add-on treatment.
• If insulin is started, continue other glucose-lowering drugs and combine with a GLP-1 agonist where possible.