hydrochlorothiazide × metformin

Thiazides cause dose-dependent hyperglycemia and insulin resistance (especially at doses ≥ 25 mg/day) via hypokalemia and reduced insulin secretion. Metformin's effect is blunted and glycemic control worsens.

Use the lowest hydrochlorothiazide dose of 12.5 mg/day – the diabetogenic effect is minimal at this dose. Check glucose and HbA1c at 4–8 weeks after initiation. Keep potassium above 4.0 mmol/L – correcting hypokalemia improves glycemic control.