Metformin remains first-line in Type 2 diabetes for most patients. It works primarily by reducing hepatic glucose production (gluconeogenesis) and improving insulin sensitivity. It is weight-neutral to modestly weight-reducing, low cost, and has decades of safety data. The main limitation is GI intolerance (nausea, diarrhea) — taking it with food and using extended-release formulations reduces this significantly. It should be dose-adjusted or held in acute kidney injury or before contrast procedures.
GLP-1 receptor agonists (semaglutide/Ozempic/Wegovy, liraglutide/Victoza, tirzepatide/Mounjaro) have transformed diabetes and obesity care. They mimic incretin hormones, stimulating insulin secretion in a glucose-dependent manner, slowing gastric emptying, and reducing appetite centrally. The result: significant A1C reduction, substantial weight loss (10–20%+ with tirzepatide), and proven cardiovascular risk reduction in patients with established CVD. GI side effects (nausea, vomiting) are common early and dose-dependent.
SGLT2 inhibitors (empagliflozin/Jardiance, dapagliflozin/Farxiga, canagliflozin/Invokana) work by blocking glucose reabsorption in the kidney, causing glucose excretion in urine. Beyond glucose lowering, they have demonstrated profound heart failure and chronic kidney disease benefits independent of diabetes status. They are now first-line agents for patients with heart failure or diabetic nephropathy. Side effects include genital mycotic infections and, rarely, diabetic ketoacidosis (including at near-normal glucose levels).
Insulin remains essential for Type 1 diabetes and for many patients with advanced Type 2 diabetes who have exhausted endogenous insulin production. Modern basal insulins (glargine, degludec) have flat, predictable pharmacokinetic profiles with low hypoglycemia risk. Insulin initiation is often delayed in Type 2 diabetes due to patient reluctance — a consequence of how insulin has been framed culturally as a 'last resort' rather than a physiologically appropriate medication.