Sulfonylureas

Sulphonylureas are oral insulin secretagogues that lower glucose by stimulating pancreatic beta cell insulin release, independent of glucose level. They are inexpensive, widely available and effective, but cause hypoglycaemia and weight gain.

Mechanism. They bind the SUR1 subunit of the ATP-sensitive potassium channel in beta cells, closing it. The resulting depolarisation opens voltage-gated calcium channels, and calcium entry triggers insulin exocytosis. A functioning beta cell mass is required.

Pharmacokinetics. Well absorbed orally, highly protein bound, metabolised in the liver. Glibenclamide forms active metabolites that accumulate in kidney impairment. Gliclazide and glipizide form inactive metabolites. Reduces HbA1c by 1 to 1.5%.

First generation agents. Tolbutamide and chlorpropamide are largely obsolete. Chlorpropamide causes hyponatraemia and an alcohol flush reaction.

Choice. Gliclazide, glimepiride and glipizide are preferred over glibenclamide because of lower rates of severe hypoglycaemia, particularly in older adults and kidney impairment.

• Type 2 diabetes: add to metformin when HbA1c is over target and cost or access limits other options. Start at the low end of the range, taken with or just before breakfast, and titrate every 1 to 2 weeks.
• Maturity onset diabetes of the young (HNF1A and HNF4A): sulphonylureas at low dose are first-line.
• Neonatal diabetes (KCNJ11, ABCC8): high-dose glibenclamide under specialist care.
• Combinations: with metformin, insulin or pioglitazone. Not combined with a meglitinide because they act at the same target.
• Kidney function: gliclazide and glipizide acceptable to eGFR 30 mL/min with caution. Avoid glibenclamide at eGFR under 60 mL/min. Start glimepiride at 1 mg.

Special groups. Pregnancy: avoid, insulin is used. Breastfeeding: avoid because of neonatal hypoglycaemia. Children: not routinely used apart from monogenic diabetes. Older adults: avoid glibenclamide, favour gliclazide or glipizide. Liver impairment: avoid in severe disease. Regional: haemolysis is possible in G6PD deficiency, which is frequent in parts of East Africa; check status where it is feasible. Fasting for Ramadan raises hypoglycaemia risk, so gliclazide or glimepiride are used with dose reduction.

Adverse effects. Hypoglycaemia, which may be prolonged (24 to 72 hours with glibenclamide or renal failure), weight gain of 2 to 4 kg, nausea, rash and cholestasis. Cardiovascular safety is neutral for modern agents.

Contraindications. Type 1 diabetes, ketoacidosis, pregnancy, breastfeeding, and severe renal or hepatic impairment (avoid).

Interactions. Fluconazole, miconazole, co-trimoxazole, clarithromycin, fluoroquinolones, warfarin, salicylates and alcohol increase hypoglycaemia. Rifampicin lowers effect. Beta blockers mask warning symptoms.

Overdose and refractory hypoglycaemia. Glucose 10 to 20% infusion is given, with admission for at least 24 hours. Octreotide 50 micrograms subcutaneously every 6 to 12 hours is added for recurrent hypoglycaemia despite glucose.

Monitoring. Fasting glucose, HbA1c every 3 months, renal function annually, weight.

Referral and escalation. Severe or recurrent hypoglycaemia, hypoglycaemia in kidney impairment, or poor response after 6 months at maximum dose.