CardioNerds Journal Club is a monthly forum for CardioNerds to discuss and breakdown recent publications on twitter and are produced with a corresponding infographic and detailed blog post. For more information, check out the CardioNerds Journal Club Page. This Journal Club focuses on the SELECT Trial

Table of contents for the The SELECT Trial summary:

• Visual abstract
• Summary
• References
• Credits
• Twitter Archive

Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes

A. Michael Lincoff, M.D., Kirstine Brown‑Frandsen, M.D., Helen M. Colhoun, M.D.,

John Deanfield, M.D., Scott S. Emerson, M.D., Ph.D., Sille Esbjerg, M.Sc.,

Søren Hardt‑Lindberg, M.D., Ph.D., G. Kees Hovingh, M.D., Ph.D.,

Steven E. Kahn, M.B., Ch.B., Robert F. Kushner, M.D., Ildiko Lingvay, M.D., M.P.H.,

Tugce K. Oral, M.D., Marie M. Michelsen, M.D., Ph.D., Jorge Plutzky, M.D.,

Christoffer W. Tornøe, Ph.D., and Donna H. Ryan, M.D.,

for the SELECT Trial Investigators* 

https://www.nejm.org/doi/full/10.1056/NEJMoa2306963

Relevant literature

Obesity is associated with various cardiovascular (CV) risk factors as type 2 diabetes and hypertension. It is also independently associated with cardiovascular morbidity and mortality.¹ GLP-1 agonists such as semaglutide are known to be highly effective in weight loss in both diabetic and non-diabetic patients. They are also known to be associated with reduced cardiovascular mortality in patients with type 2 diabetes, however cardiovascular benefit of these agents in non-diabetic patients have yet to be explored.

In a meta-analysis⁶ of eight trials with 60080 patients (ELIXA, LEADER, SUSTAIN-6, EXSCEL, Harmony Outcomes, REWIND, PIONEER 6, and AMPLITUDE-O) , treatment with a GLP-1 receptor agonist led to a 14% relative risk reduction in three-point MACE (HR 0·86 [95% CI 0·80–0·93]; p<0.001 . GLP-1 receptor agonist use led to a reduction in components of the composite MACE endpoint separately including risk of death from cardiovascular causes, fatal or non-fatal myocardial infarction, and fatal or non-fatal stroke. Furthermore, treatment with a GLP-1 receptor agonist reduced the risk of death from any cause and risk of hospital admission for heart failure.

Study Objectives

To evaluate if semaglutide 2.4 mg subcutaneously once weekly is superior to placebo when added to standard of care for preventing major adverse cardiovascular events in patients with established CVD and overweight or obesity but without diabetes. 

Trial design has been published previously.⁷

–          Multi-center, double-blind, randomized, placebo-controlled, event-driven superiority trail

–          804 participating clinical sites in 41 countries

Enrollment Criteria

Intervention

o  1:1 double-blinded non-stratified randomization to receive either 2.4mg semaglutide SC weekly or placebo

o   Initial dose of 0.24mg weekly x 4 weeks, uptitrated to 0.5, 1.0, 1.7, and eventually 2.4mg every 4 weeks

§  If significant adverse effects encountered, patients could be placed on slower uptitration, pause treatment, or continue reduced maintenance dose therapy

o   Placebo/semaglutide discontinued if:

• Patients became/planned to become pregnant
• Developed pancreatitis
• Calcitonin level ≥ 100 ng/L
  
• Patients were to continue on treatment if diabetes was diagnosed after initiation of treatment/placebo

Primary Outcome

• Composite of death from cardiovascular causes, nonfatal MI, nonfatal stroke, (assessed in time-to-first-event analysis)

Secondary Outcome:  (all assessed in time-to-first-event analysis)

•  Death from cardiovascular causes
• Composite heart failure end-point (death from CV causes or hospitalization/urgent medical visit for heart failure)
• Death from any cause

Statistical Analysis

o   Event-driven trial designed to provide 90% power to detect relative risk reduction of 17% for primary endpoint (HR 0.83) at overall one-sided significance level of 0.025

o   Required minimum 1225 primary end-point events accrued

o   Intention-to-treat analysis performed

o   Hazard ratios and 95% confidence intervals generated with Cox proportional hazard model

Baseline Characteristics

• 17604 patients randomized between Oct. 2018 and March 2021 (8803 semaglutide, 8801 placebo arm)
• Mean age 61.6±8.9 years, 12,732 (72.3%) were male.
• Mean BMI 33.3±5.0, 12,580 patients (71.5%) met the BMI criterion for obesity (≥30).
• More than three quarters of the patients had had a previous myocardial infarction, and nearly one quarter had chronic heart failure.
• Mean follow-up of 39.8±9.4 months.

Outcomes

Primary and Secondary Outcome

Patients in the semaglutide study arm experienced a significantly lower rate of the primary outcome (cardiovascular composite end-point) (6.5% vs 8.0%, HR 0.80 (95% CI 0.72-0.90)

No significant difference in rates of cardiac death (HR 0.85, 95% CI 0.71-1.01) however significantly lower rates of heart failure (HR 0.82, 95% CI 0.71-0.96) and all-cause mortality (HR 0.81, 95% CI 0.71-0.93)

Adverse Events

• Rates and types of adverse events were fairly similar between control and intervention groups
• Permanent premature discontinuation of semaglutide or placebo occurred in 2351 patients (26.7%) in the semaglutide group and 2078 (23.6%) in the placebo group

• In obese and overweight patients with cardiovascular comorbidities but without diabetes, treatment with weekly semaglutide was superior to placebo in reducing the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke at a mean follow-up of 39.8 months.

Limitations and Considerations

• BMI cutoff used is in between the typical cutoffs for overweight and obese
• Limited generalizability given that the majority of patients included were Caucasian, with only 12.5% African American
• male predominant population studied, with only 27.7% females
• It remains to be demonstrated if treatment with semaglutide has a cardioprotective and preventative benefit in patients who do not have pre-existing cardiovascular disease

1. Powell‐Wiley TM, Poirier P, Burke LE, et al. Obesity and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2021;143:e984‐e1010.
2. Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, et al. A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management. N Engl J Med. 2015;373(1):11-22. doi:10.1056/nejmoa1411892 
3. Davies MJ, Bergenstal R, Bode B, Kushner RF, Lewin A, Skjøth TV, et al. Efficacy of Liraglutide for Weight Loss Among Patients With Type 2 Diabetes: The SCALE Diabetes Randomized Clinical Trial. JAMA. 2015;314(7):687-699. doi:10.1001/jama.2015.9676 
4. Sorli C, Harashima SI, Tsoukas GM, Unger J, Karsbøl JD, Hansen T, Bain SC. Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial. Lancet Diabetes Endocrinol. 2017 Apr;5(4):251-260. doi: 10.1016/S2213-8587(17)30013-X. Epub 2017 Jan 17. PMID: 28110911.
5. Wilding JPH, Batterham RL, Calanna S, Davies M, Gaal LFV, Lingvay I, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384(11):989-1002. doi:10.1056/nejmoa2032183 
6. Sattar N, Lee MMY, Kristensen SL, et al. Cardiovascular, mortality, and kidney outcomeswith GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomized trials. Lancet Diabetes Endocrinol 2021; 9: 653-62.
7. Ryan DH, Lingvay I, Colhoun HM, et al. Semaglutide effects on cardiovascular outcomes in people with overweight or obesity (SELECT) rationale and design. Am Heart J 2020; 229: 61-9.