2023 Top Story in Diabetes: The SELECT Trial
I chose the SELECT trial1,2 as the story of the year because of its likely "game-changing" effect on clinical practice.
The GLP-1 receptor agonists (GLP-1 RAs) have been shown to reduce MACE in high-risk individuals with type 2 diabetes (T2D). In the largest meta-analysis of these glucose-lowering agents, which included eight trials, the point estimate for the MACE benefit calculated to 0.86 (95% CI, 0.80–0.93).1 The corresponding hazard ratio for myocardial infarction (MI) was 0.90 (95% CI, 0.83–0.98), for stroke was 0.83 (95% CI, 0.76–0.92), and for cardiovascular (CV) death was 0.87 (95% CI, 0.80–0.94). Based on these data, GLP-1 RAs are now favored in most clinical practice guidelines in patients with T2D and either with overt or at high risk for CV disease (CVD). SGLT2 inhibitors also fall into this category and are additionally preferred in the setting of heart failure (HF) and/or chronic kidney disease.
Two GLP-1 RAs, liraglutide and semaglutide (along with the dual GLP-1/GIP co-agonist tirzepatide), are also approved in the US as weight-loss agents for those with obesity who do not necessarily have diabetes. The natural research question that stems from this background is whether these therapies also improve CV outcomes in high-risk CV patients with high BMI when diabetes does not complicate the clinical picture.
Therefore, SELECT studied 17,000 patients aged 45 years old with a BMI of 27 kg/m2 and established CVD. They were randomized to once-weekly subcutaneous injections of semaglutide 2.8 mg versus matching placebo. At baseline, the mean age of the participants was 62 years, weight was 97 kg, BMI was 33 kg/m2, and HbA1c was 5.8% (with about two-thirds classified as having prediabetes). They had generally good kidney function, and both blood pressure and lipid levels were under good control. About 68% of patients had a past history of MI as their sole inclusion criterion, 18% had stroke only, 4% had peripheral arterial disease only, and 8% had multiple vascular territories involved.
Mean follow-up extended to more than 39 months. The primary outcome was the three-point MACE composite used in CV outcome trials (nonfatal MI, nonfatal stroke, and CV death). This occurred in 569 of 8803 patients (6.5%) randomized to active semaglutide therapy versus 701 of 8801 patients (8.0%) on placebo, calculating to a hazard ratio of 0.80 (95% CI, 0.72–0.90; P < .001).
Key secondary outcomes, including components of the primary and major prespecified subgroups, revealed results that were directionally concordant with the main findings. For example, the hazard ratio for CV death was 0.85 (95% CI, 0.71–1.01; P = .07), for nonfatal MI was 0.72 (95% CI, 0.61–0.85), for nonfatal stroke was 0.93 (95% CI, 0.74–1.15), for all-cause death was 0.81 (95% CI, 0.71–0.93), and for HF hospitalization was 0.82 (95% CI, 0.71–0.96). The results for all outcomes after CV death were hypothesis-generating because of the hierarchical statistical design of the trial.
Other endpoints included more weight loss in the active therapy group (placebo-adjusted, −8.5 kg), and lower HbA1c (−0.32%, absolute) and CRP (−38%).
This relative risk reduction of 20% for the primary MACE outcome is numerically larger than what has been observed in most prior GLP-1 RA CV outcome trials in T2D, but falls within the lower bound of the confidence interval for MACE reported by the Sattar et al meta-analysis of GLP-1 RA therapy in T2D (HR, 0.86; 95% CI, 0.80–0.93),1 suggesting a similar effect in the SELECT cohort.
No new safety concerns were raised. However, adverse events leading to permanent discontinuation of the trial medication occurred in about 17% in the semaglutide group and 8% in the placebo group (P < .001), predominately due to the known gastrointestinal side effects of the GLP-1 RA class.
SELECT is the first study of its kind to show that a GLP-1–based therapy directed at weight loss in a large group of patients with overweight or obesity and CVD actually reduces future CV events. Such a strategy must now be considered standard of care in this population. Clinicians treating high BMI patients with CVD have an additional tool in their toolbox to not only reduce weight but also improve their clinical CV outcomes. Given the large number of patients who may fit the inclusion criteria of SELECT, an important pragmatic question is how do we extend the benefits of GLP-1 therapy to them? Also, just as importantly, how can we as a society afford the requisite costs of such high-priced therapeutics that now appear to be so widely indicated?
We look forward to additional manuscripts from the SELECT investigators, including cost-effectiveness analyses. Another important inquiry will be to determine how much of the CV benefit of semaglutide is linked to the weight loss. Is the drug still effective from a CV perspective when no or minimal weight loss occurs? Moreover, is more weight loss better — that is, does this impact MACE to an even greater extent?
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Additional Info
- Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023 Nov 11. doi: 10.1056/NEJMoa2307563. Online ahead of print.
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Inzucchi SE. Semaglutide and Cardiovascular Outcomes in Patients With Obesity Without Diabetes [abstract of Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023 Nov 11. doi: 10.1056/NEJMoa2307563. Online ahead of print]. PracticeUpdate Diabetes 2023 Nov 23. Accessed November 22, 2023.
- Sattar N, Lee MMY, Kristensen SL, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol. 2021;9(10):653-622.
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