PMID-38740993 — SELECT 4-Year: Long-term Weight Loss Effects (Ryan Nat Med 2024)

[DRAFT — authored 2026-04-19. Citation verified against PubMed/Nature Medicine 2026-04-19. Manifest spec'd DOI but PMID is available — filename uses PMID per verification-rule preference.]

Citation

Ryan DH, Lingvay I, Deanfield J, Kahn SE, Barros E, Burguera B, Colhoun HM, Cercato C, Dicker D, Horn DB, Hovingh GK, Jeppesen OK, Kokkinos A, Lincoff AM, Meyhöfer SM, Oral TK, Plutzky J, van Beek AP, Wilding JPH, Kosiborod MN. Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial. Nat Med. 2024;30(7):2049-2057. doi: 10.1038/s41591-024-02996-7. PMID: 38740993. PMCID: PMC11271387.

External URL: PubMed

Study Design

Design: Prespecified analysis of long-term weight loss effects in the SELECT trial
Parent trial: SELECT — semaglutide 2.4 mg vs placebo in 17,604 adults with overweight/obesity + preexisting CVD, without T2D
Follow-up: Up to 208 weeks (mean ~40 months)
Population: Full SELECT cohort with weight data at follow-up

Key Findings

Weight change at 208 weeks

Measure	Semaglutide	Placebo
Mean weight change	−10.2%	−1.5%
Waist circumference	−7.7 cm	−1.3 cm
Waist-to-height ratio	−6.9%	−1.0%

BMI category shift

Over 2 years: More than half of semaglutide-treated adults moved down ≥1 BMI category, compared with 16% on placebo
Over 2 years: 12% of semaglutide-treated adults reached a healthy BMI (≤25 kg/m²), compared with 1% on placebo

Durability

Weight loss continued over 65 weeks and was sustained for up to 4 years
Clinically meaningful weight loss occurred in both sexes, all races, body sizes, and geographic regions

Safety

Serious adverse events were FEWER with semaglutide vs placebo over 4-year follow-up

Mechanism decoupling

Cardiovascular benefits (20% MACE reduction from SELECT primary) occurred independently of baseline adiposity and the magnitude of weight loss — suggesting mechanisms beyond pure weight reduction

Clinical Relevance

Ryan 2024 SELECT 4-year is the most important durability evidence for semaglutide in chronic weight management. It is the counterweight to the STEP 4 + STEP 1 Extension withdrawal findings — both are true simultaneously:

WITH continued therapy: Weight loss sustained at mean −10.2% through year 4; progressive BMI-category shift over time.
WITHOUT continued therapy (STEP 4 + STEP 1 Extension): 2/3 of weight loss regained within 12 months of withdrawal.
Combined message: Chronic therapy is required to sustain weight and cardiometabolic benefits. This is the evidence base for the "chronic therapy" framing used throughout M5.
Cardiovascular mechanism insight: CV benefit is not driven solely by weight loss — points to direct anti-inflammatory, endothelial, and metabolic mechanisms.

Linked Peptides

Semaglutide

Related Lessons

Lesson 5.2 — Semaglutide Deep Dive (long-term durability; paired with STEP 4 + STEP 1 Extension withdrawal findings)
Lesson 5.4 — Durability framework

Related Studies

PMID-37952131 – SELECT Cardiovascular Outcomes Trial — parent CV primary outcome
PMID-33755728 – STEP 4 Rubino Weight Maintenance Withdrawal — withdrawal counterpoint
PMID-35441470 – STEP 1 Extension Wilding Weight Regain After Withdrawal — withdrawal extension

PMID-38740993 – SELECT 4-Year Long-term Weight Loss Ryan