Endocrinology / Metabolic · Medicine Class
Multiple mechanisms — insulin secretagogues, insulin sensitizers, incretin-based, renal glucose excretion, direct insulin replacement
Modern diabetes pharmacotherapy targets multiple pathophysiological pathways in type 2 diabetes. Metformin activates AMPK to reduce hepatic gluconeogenesis and improve insulin sensitivity. Sulfonylureas close pancreatic beta-cell KATP channels, triggering insulin secretion independently of glucose — risking hypoglycemia. GLP-1 receptor agonists mimic the incretin hormone GLP-1: stimulating glucose-dependent insulin secretion, suppressing glucagon, slowing gastric emptying, and reducing appetite centrally. DPP-4 inhibitors prevent GLP-1 degradation, amplifying endogenous incretin effects. SGLT2 inhibitors block the sodium-glucose cotransporter 2 in the renal proximal tubule, promoting urinary glucose excretion and providing volume depletion, BP reduction, and organ-protective effects independent of glycemia. Insulin replaces the missing or insufficient endogenous insulin of type 1 and advanced type 2 diabetes.
Metformin (Glucophage)
First-line for type 2 diabetes. Reduces hepatic glucose output. Low hypoglycemia risk. GI side effects (take with food, start low). Contraindicated eGFR<30 (lactic acidosis risk). Inexpensive.
Semaglutide (Ozempic/Wegovy/Rybelsus)
Most important diabetes/obesity drug in a decade. Weekly injection (Ozempic, diabetes) or oral (Rybelsus). High-dose (Wegovy) for obesity. Cardiovascular outcome benefit (SUSTAIN-6). GI side effects prominent but improve with slow titration.
Tirzepatide (Mounjaro/Zepbound)
GLP-1/GIP dual agonist. Superior glucose lowering and weight loss (20-22%). Cardiovascular outcome trial ongoing. Similar GI profile to GLP-1 agonists.
Empagliflozin (Jardiance)
SGLT2 inhibitor. EMPA-REG OUTCOME: 38% reduction in CV death. HF benefit (EMPEROR-Reduced). CKD benefit. UTI/genital yeast infection risk. Euglycemic DKA (rare, more common in type 1).
Dapagliflozin (Farxiga)
SGLT2 inhibitor. DAPA-HF: reduced HF outcomes even in non-diabetic patients. DAPA-CKD: renal protection. FDA-approved for HF and CKD without diabetes.
Sitagliptin (Januvia)
DPP-4 inhibitor. Well-tolerated, low hypoglycemia risk, weight-neutral. Modest glucose lowering. TECOS trial: cardiovascular safety confirmed. Possible hospitalization for heart failure risk.
Glipizide (Glucotrol)
Sulfonylurea. Effective glucose lowering but hypoglycemia risk (can be severe, especially in elderly). Weight gain. Shorter-acting, less hypoglycemia than glyburide.
Insulin Glargine (Lantus/Basaglar/Toujeo)
Long-acting basal insulin. Once-daily injection. No peak. Basis of basal-bolus insulin regimens. Required in type 1 diabetes; used in advanced type 2. Hypoglycemia and weight gain inherent to insulin therapy.
Other glucose-lowering agents — additive hypoglycemia risk when combining insulin or sulfonylureas with any other antidiabetic
Beta-blockers — may mask hypoglycemia symptoms (sweating preserved; tachycardia masked)
Corticosteroids — significant hyperglycemia; may require insulin initiation or dose escalation
Diuretics and dehydration — SGLT2 inhibitors cause osmotic diuresis; additional diuretics increase hypotension and DKA risk
Contrast media — hold metformin 48 hours before and after iodinated contrast in patients with eGFR <60 (lactic acidosis risk if contrast-induced nephropathy develops)
Metformin has been first-line for type 2 diabetes for decades due to efficacy, safety, low hypoglycemia risk, and very low cost. Current ADA guidelines recommend metformin as a preferred initial agent unless contraindicated. However, guidelines now recognize that for patients with established cardiovascular disease, heart failure, or CKD, GLP-1 receptor agonists or SGLT2 inhibitors with proven cardiovascular and renal benefit should be considered early — potentially as first agents added to metformin or even as initial therapy when cardiorenal risk is very high. The 'best' medication is individualized based on comorbidities, cost, tolerability, and HbA1c reduction needed.
GLP-1 receptor agonists (semaglutide, liraglutide, tirzepatide) mimic the incretin hormone GLP-1, producing glucose-dependent insulin secretion (minimal hypoglycemia risk), glucagon suppression, appetite reduction, and slowed gastric emptying. They produce the greatest weight loss of any non-insulin glucose-lowering drug (5-10% for older agents; 15-22% with semaglutide and tirzepatide at anti-obesity doses). Cardiovascular outcome trials demonstrated significant reductions in major adverse cardiovascular events in high-risk patients. This combination of glucose lowering, weight loss, and cardiovascular protection — along with once-weekly dosing — drove unprecedented demand, leading to global shortages of semaglutide (Ozempic, Wegovy) in 2022-2024.