Identifying Mechanisms of Benefit and Whom to Treat

Neha J. Pagidipati, MD, MPHDisclosures

J Am Coll Cardiol. 2024;84(17) 

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Several trials have documented the cardiovascular (CV) benefits of the glucagon-like peptide-1 receptor agonist (GLP-1 RA) semaglutide, including the SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity), STEP-HFpEF (Effect of Semaglutide 2.4 mg Once Weekly on Function and Symptoms in Subjects with Obesity-related Heart Failure with Preserved Ejection Fraction), and FLOW (Evaluate Renal Function with Semaglutide Once Weekly) trials. Two questions that have emerged from these trials are as follows. 1) Does weight loss mediate the CV benefits of semaglutide? 2) Are there certain groups who benefit more from semaglutide treatment than others, particularly in the context of constrained access and resources? In this issue of JACC, we discuss the results of 6 secondary analyses from these semaglutide trials that address these questions. This editorial summarizes the findings of the substudies (Table 1), synthesizes the information that clinicians can use in their practice, and poses new questions for future research.

Before the publication of the SELECT trial, which reported the CV benefits of semaglutide 2.4 mg weekly vs placebo among individuals with overweight or obesity and atherosclerotic CV disease, no antiobesity therapy had improved major CV outcomes in a randomized prospective trial.^[1] Yet, the early separation of event curves in SELECT, before significant weight loss occurred, cast doubt on whether weight loss could account for the entire CV benefit. Subsequent analyses from the STEP-HFpEF program, which showed that reductions in N-terminal pro–B-type natriuretic peptide levels as a surrogate marker for severity of heart failure (HF) were independent of weight loss, further questioned the role of weight loss as the mechanism of benefit in the setting of obesity-related HF with preserved ejection fraction (EF).^[2]

In this issue of JACC, several studies raise additional questions about the disconnect between CV benefit and weight loss with semaglutide. Verma et al^[3] studied the effect of sex on the relationship between semaglutide and CV outcomes in SELECT. This was insightful because women achieved greater weight loss with semaglutide than did men, but CV outcomes with semaglutide were proportionately similar between the sexes, indicating that the extent of weight loss was not tied to the magnitude of benefit.

In a subanalysis of the STEP-HFpEF program, Solomon et al^[4] showed first-of-its-kind data indicating that semaglutide directly affected cardiac structure and function in obesity-related HF with preserved EF. In this analysis, changes in left atrial volume were directly related to the extent of weight loss, but the changes in left ventricular diastolic function and right ventricle size were not, indicating that some cardiac effects were mediated by weight loss and some were not.

A reduction in inflammation has been proposed as a potential mechanism for the CV benefit of semaglutide, with weight loss posited as a mechanism for inflammation reduction. However, Verma et al^[5] found in the STEP-HFpEF program that the effect of semaglutide on HF outcomes was consistent across baseline C-reactive protein levels, and the degree of C-reactive protein reduction was independent of the degree of weight loss. In another refutation of the weight-loss hypothesis, Verma et al^[6] found benefit of semaglutide in both those with and without atrial fibrillation but noted a greater benefit of semaglutide on KCCQ-CSS in individuals with atrial fibrillation. However, the reductions in weight was similar in both groups, arguing against weight loss as the sole mechanism of benefit.

In addition to elucidating whether the benefit of semaglutide is mediated entirely by weight loss, understanding the populations who will benefit from this treatment has both clinical and public health importance. Two studies presented in JACC identify additional groups in whom semaglutide promises benefit. Pratley et al^[7] analyzed the FLOW trial to evaluate the effect of semaglutide 1 mg weekly among individuals with chronic kidney disease and type 2 diabetes and found an overall improvement in the composite outcome of HF events or CV death.7 Of note, the treatment effect did not seem to be related to whether individuals had HF at baseline, their baseline EF, or type of HF (HF with preserved vs reduced EF). Although there are several limitations of this analysis, including that only two-thirds of those with HF had a reported EF at baseline, few had HF with reduced EF, and HF events were not centrally adjudicated, the results indicate potential benefits across the spectrum of HF. In a separate study of causes of death in the SELECT trial, Scirica et al^[8] found a benefit of semaglutide on non-CV death, which was most commonly caused by infection. Semaglutide appeared to reduce the risk of death caused by COVID-19 infection among those who developed COVID-19, though it did not affect the risk of contracting the virus.

As we speed toward an increased understanding of the many, sometimes unexpected, benefits of GLP1RA, the mechanisms of benefit for HF, atherosclerotic CV disease, kidney, and COVID-19–related outcomes remain some of the most important unanswered questions. What is becoming clear is that pathways beyond weight loss are playing a role, and the benefits of semaglutide, which extend to both CV and non-CV outcomes, appear to be generally consistent across subgroups. What does this mean for practicing clinicians? First, GLP-1 RA are not simply “weight loss drugs,” but rather are CV and kidney risk-reduction agents that fall squarely within the scope of practice of cardiologists. Further, if individuals taking these agents do not lose weight, this does not necessarily preclude CV or kidney benefit. Finally, given that a broad population is likely to benefit from these therapies, access and availability issues must rapidly be addressed by the pharmaceutical industry, insurers, and policy-makers alike to ensure improved, equitable health for all.