Latest GLP-1 research

SELECT, semaglutide and cardiovascular outcomes (Lincoff et al., NEJM 2023)

Randomized 17,604 adults with established cardiovascular disease, overweight/obesity, and no diabetes to semaglutide 2.4 mg weekly vs placebo. Primary endpoint: composite of cardiovascular death, nonfatal MI, or nonfatal stroke. Result: HR 0.80 (20% relative reduction) for MACE at ~3.3 years median follow-up. This was the first large trial to demonstrate cardiovascular benefit of a GLP-1 in a primary obesity indication, independent of diabetes.

FLOW, semaglutide in chronic kidney disease (Perkovic et al., NEJM 2024)

Randomized participants with type 2 diabetes and chronic kidney disease to semaglutide 1.0 mg vs placebo; stopped early for efficacy. Reported ~24% relative reduction in the composite primary endpoint of major kidney and cardiovascular outcomes. Established semaglutide as having specific renal benefits beyond glycemic control.

STEP-HFpEF, semaglutide and heart failure with preserved ejection fraction (Kosiborod et al., NEJM 2023)

In obesity-related HFpEF, semaglutide 2.4 mg improved symptom scores and 6-minute walk distance over placebo, with concurrent weight loss. Important for the framing that some benefit may be related to weight loss itself, some to direct semaglutide effects.

SURMOUNT program, tirzepatide

SURMOUNT-1 through SURMOUNT-4 have established tirzepatide's weight-loss magnitude (up to ~22% at 15 mg), its efficacy in T2D with obesity, its effect on obstructive sleep apnea (SURMOUNT-OSA), and its value for weight maintenance after an initial loss phase. SURMOUNT-MMO (cardiovascular outcomes) is underway.

TRIUMPH, retatrutide

TRIUMPH-1 (Phase 2) reported ~24% weight loss at 48 weeks on 12 mg. The Phase 3 TRIUMPH program includes weight-loss, T2D, MASH, obstructive sleep apnea, osteoarthritis, and cardiovascular outcomes trials. First Phase 3 readouts are in progress.

REDEFINE, cagrisema (cagrilintide + semaglutide)

Novo Nordisk's Phase 3 program for the fixed-dose combination of cagrilintide (amylin analog) and semaglutide. Early topline readouts reported somewhat below initial Phase 2 expectations on magnitude but still meaningful weight loss; full publications pending.

Themes emerging from the latest data

• Cardiorenal benefits extend beyond glycemic control for the GLP-1 class.
• Triple agonism (retatrutide) appears to push weight loss higher but adds mechanism-related tradeoffs.
• Muscle preservation remains the biggest open research question the field is racing to address.
• Weight maintenance post-treatment continues to show weight regain on discontinuation, implying chronic use for chronic disease, mirroring other chronic-disease drug classes.