Summary: In a prespecified analysis of the SELECT trial, weekly semaglutide 2.4 mg reduced first major adverse cardiovascular events by 20% versus placebo (HR 0.80, 95% CI 0.72-0.90) in 17,604 overweight or obese adults with established atherosclerotic cardiovascular disease but without diabetes. The cardiovascular benefit was consistent across baseline HbA1c subgroups and across categories of HbA1c change, indicating that the effect was not explained by glycaemic improvement.
PICO Summary
| Element | Detail |
|---|---|
| Population | 17,604 adults with overweight or obesity and established atherosclerotic cardiovascular disease but without diabetes (mean age 61.6 years, 72.3% male); prespecified analysis of the multinational, double-blind SELECT randomised controlled trial. Baseline HbA1c was <5.7% in 33.5%, 5.7% to <6.0% in 34.6%, and 6.0% to <6.5% in 31.9%. |
| Intervention | Subcutaneous semaglutide 2.4 mg once weekly. |
| Comparison | Matching placebo once weekly, on a background of standard cardiovascular care. |
| Outcome | First MACE (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) was reduced by 20% overall (HR 0.80, 95% CI 0.72-0.90). The reduction was not shown to differ across baseline HbA1c subgroups and was consistent with the overall result for all endpoints except all-cause mortality, and consistent across categories of HbA1c change (<-0.3, -0.3 to 0.3, and >0.3 percentage points) from baseline to week 20. Subgroup-specific hazard ratios with confidence intervals and interaction p-values were not reported in the abstract; absolute risk reduction and NNT were likewise not reported. |
Semaglutide CV benefit independent of HbA1c (SELECT)
Prespecified RCT analysis · obesity, no diabetes · ~40 months
Semaglutide 2.4 mg cut first MACE by 20% in non-diabetic adults with obesity and established ASCVD, and the benefit held across every baseline HbA1c stratum and category of HbA1c change. The cardiovascular effect is not explained by glucose lowering.
Expert Commentary
This prespecified analysis addresses a mechanistically important question: was the cardiovascular benefit of semaglutide in SELECT driven by glucose lowering? The answer offered is no. The 20% relative reduction in first MACE (HR 0.80, 95% CI 0.72-0.90) was observed across baseline HbA1c subgroups spanning normoglycaemia to the pre-diabetic range, and across categories of HbA1c change to week 20, supporting cardiovascular mechanisms that are largely independent of glycaemia. It should be read as a secondary, hypothesis-supporting analysis of an already-positive trial rather than as fresh proof of efficacy, and the consistency claim rests on absence of demonstrated subgroup heterogeneity, which is not the same as proven uniformity given the limited power within strata. One weighed limitation is that all-cause mortality was the single endpoint not consistent across baseline HbA1c groups, a signal that warrants caution before extrapolating uniformity to every outcome. The trial was sponsored by the manufacturer, so independent replication strengthens confidence. Can I use this with my patients? Yes, for the normoglycaemic patient with established atherosclerotic disease and obesity, this reassures that cardiovascular benefit need not wait on glycaemic change. Clinicians should frame the indication around cardiovascular risk, not HbA1c, and watch the mortality signal in longer follow-up.
References
Lingvay I, Deanfield J, Kahn SE, et al. Semaglutide and Cardiovascular Outcomes by Baseline HbA1c and Change in HbA1c in People With Overweight or Obesity but Without Diabetes in SELECT. Diabetes Care. 2024;47(8):1360-1369. doi:10.2337/dc24-0764