SELECT Cardiovascular Outcome Trial: Old Lessons and New Learning

Donna Ryan, MD, FTOS; Robert F. Kushner, MD; A. Michael Lincoff, MD; et al.
ObesityWeek 2024 – Oral presentation

Key messages

In the SELECT trial, semaglutide delivered CV benefits in patients with overweight or obesity, establishing these conditions as modifiable risk factors.
Recent findings highlight potential in broader indications including kidney disease and inflammation, with particularly promising results for prediabetes.
Long-term safety findings are consistent with findings for other GLP-1RA.

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Background

What do we already know about this topic?

Accordion content

Semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1RA).
People with overweight or obesity and high cardiovascular (CV) risk – without established diabetes – are candidates for secondary prevention.
The rationale for the SELECT study was that mediating risk factors via weight loss and drugs such as semaglutide can lead to CV event reduction.
Previous CV outcomes trials with obesity medications have not shown positive results, and many were stopped early.

How was this study conducted?

SELECT: an event-driven, placebo-controlled trial.^1-4
Participants had overweight or obesity (body mass index [BMI] ≥27 kg/m²), established cardiovascular disease (CVD), no prior diabetes (HbA1c <6.5%), and age ≥45.
17,604 patients were randomized to semaglutide or placebo in addition to standard of care for underlying CVD.
Primary outcome: composite of CV death, non-fatal myocardial infarction, or non-fatal stroke.
Targeted safety focused on investigator-reported serious adverse events (SAE), AEs leading to discontinuation, and prespecified AEs of special interest (acute pancreatitis, malignant neoplasm, and events related to COVID-19 or the gallbladder).
Prespecified analyses looked at a number of areas including CV outcomes in people with prior HF, weight change as a mediator of CV benefit, and mortality outcomes.

Findings

What does this study add?

At baseline in SELECT, mean age was 61.6 and 28% were female; mean BMI was 33 and HbA1c 5.78%.
Overall, 24% had prior HF, and CV risk factors included a mean systolic blood pressure of 131 and a mean LDL cholesterol of 78 mg/dL; 88% were on a statin.
Mean follow-up was 40 months.
For the primary composite CV outcome, there were 701 events with placebo (8.0%) compared to 569 for semaglutide (6.5%); a hazard ratio of 0.80.
The primary endpoint was consistent across subgroup analyses, including sex, age, BMI, and HbA1c.
Participants on semaglutide had lower SAEs (33.4% versus 36.4% for placebo); largely driven by a decrease in CV events.
Gastrointestinal disorders were the most commonly reported AE, consistent with other GLP-1RA studies.
There were no unexpected safety concerns, and no difference between groups in serious psychiatric disorders, acute pancreatitis, or malignant neoplasm.
Among 4,286 patients with prior HF at enrollment, semaglutide reduced the risk of major adverse cardiovascular events (MACE) and hospitalization.
These CV benefits did not differ among patients with HF with a reduced or preserved ejection fraction (HFrEF/HFpEF).
Patients treated with semaglutide had lower rates of all-cause mortality, driven by similar reductions in CV and non-CV death.
In two-thirds of participants with prediabetes, semaglutide delivered a 73% reduction in progression to diabetes compared to placebo, along with a significant decrease in HbA1c.
SELECT also demonstrated improved kidney outcomes, with improvements in both urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) with semaglutide compared to placebo.
Exploration of inflammatory markers in SELECT suggests weight loss is associated with a reduction in high-sensitivity C-reactive protein (hsCRP).
But semaglutide effects on hsCRP occur early – prior to major weight loss – and are also seen in people without significant weight loss.
Among participants who remained on semaglutide for at least 1 year, the peak body weight change was 13.5% – achieved at a median of 19 months.

Perspectives

How does this study impact clinical practice?

SELECT was a rigorous study and provides precise evidence about the use of semaglutide in people at CV risk.
This trial is the first to demonstrate that a medication for obesity can result in disease modification and reduction of CV events.
These data legitimize the use of obesity treatment as a pathway to disease modification and upstream management.
Additionally, the 4 years of observation reconfirm semaglutide efficacy and safety.
HFrEF patients are at the highest absolute risk of CV events, but despite concerns raised by trials of liraglutide, HFrEF patients in SELECT had important reductions in MACE and the HF composite.
In patients with obesity-related HFpEF, semaglutide markedly improves functional capacity and quality of life.
Semaglutide produces consistent reductions in MACE regardless of baseline adiposity.
The CV benefits of semaglutide appear to extend to people with normoglycemia and are also independent of baseline kidney function.
SELECT also suggests that semaglutide reduces inflammatory markers implicated in CV risk.
Taken together, these data have important implications for clinical practice across obesity, cardiology, renal disease, and diabetes.
Semaglutide is FDA-approved for secondary prevention of CV events.

Source: Ryan D, Kushner R, Lincoff AM, et al. SELECT Cardiovascular Outcome Trial: Old Lessons and New Learning. Presented at ObesityWeek® 2024.

The information and data provided are for informational purposes only. The author(s) of the original presentation had no involvement in the creation of this content.

References

Ryan DH, Lingvay I, Deanfield J, et al. Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial. Nat Med 2024;30(7):2049–57.
Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med 2023;389(24):2221–32.
Deanfield J, Verma S, Scirica BM, et al. Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial. Lancet 2024;404(10454):773–86.
Scirica BM, Lincoff AM, Lingvay I, et al. The Effect of Semaglutide on Mortality and COVID-19-Related Deaths: An Analysis From the SELECT Trial. J Am Coll Cardiol 2024;84(17):1632–42.