Obesity / insulin resistance

In the phase 3 SURMOUNT-1 RCT (n=2539, non-diabetic obesity), once-weekly tirzepatide produced mean weight loss of 15-20.9% vs 3.1% with placebo at 72 weeks, with improvement in all cardiometabolic measures.

In the phase 3 STEP 1 RCT (n=1961, overweight/obesity without diabetes), once-weekly semaglutide 2.4 mg gave mean weight change of -14.9% vs -2.4% with placebo at 68 weeks plus improved cardiometabolic risk factors.

In a phase 3 RCT (n=38), 32.3% of Bardet-Biedl syndrome patients aged >=12 reached >=10% weight loss after 52 weeks of setmelanotide (p=0.0006); results were inconclusive in Alstrom syndrome.

In a phase 1b RCT (n=95), cagrilintide co-administered with semaglutide 2.4 mg was well tolerated and produced mean bodyweight reductions of ~15-17% at 20 weeks, exceeding placebo-plus-semaglutide.

In a phase 2 RCT (n=338, obesity), retatrutide for 48 weeks produced least-squares mean weight loss up to 24.2% at 12 mg vs 2.1% with placebo, with dose-related GI adverse events.

In a phase 2 RCT (n=203, obesity), tesofensine 0.5 mg with energy-restricted diet induced 9.2% mean weight loss vs 2.0% with diet plus placebo at 24 weeks, but raised heart rate by ~7.4 bpm.

Metformin is the most commonly used treatment to increase insulin sensitivity in insulin-resistant conditions including obesity, acting via AMPK activation and increased GLUT4-mediated peripheral glucose uptake.