Semaglutide’s heart benefits may partly involve reduced inflammation

In more than 17,000 adults with established heart disease, researchers tracked an inflammatory marker alongside weight and cardiovascular events to explore what may lie behind semaglutide’s heart benefits.

Study: Effect of Semaglutide on the Inflammatory Biomarker High-Sensitivity CRP in Patients With Established Cardiovascular Disease and Overweight or Obesity in SELECT: A Prespecified Secondary Analysis. Image Credit: Edugrafo / Shutterstock

In a recent study published in the journal Circulation, researchers conducted a prespecified secondary analysis of data from the landmark SELECT trial to investigate relationships among semaglutide treatment, systemic inflammation, weight loss, and cardiovascular outcomes.

The SELECT trial included 17,604 participants, all of whom had overweight or obesity and established atherosclerotic cardiovascular disease (ASCVD) without diabetes. Baseline high-sensitivity C-reactive protein (hsCRP) data were available for 17,485 participants. The study specifically investigated the relationships among hsCRP, changes in body weight, semaglutide treatment, and major adverse cardiovascular events (MACEs).

Study findings revealed that once-weekly semaglutide (2.4 mg) treatment led to rapid, sustained reductions in hsCRP (37.8% placebo-corrected at week 104) across baseline hsCRP categories and major clinical subgroups. Participants’ baseline hsCRP itself was identified as a prognostic marker associated with future cardiovascular events and mortality.

Background

Atherosclerosis is a chronic inflammatory disorder characterized by arterial plaque accumulation, with plaque progression and disruption potentially impairing blood flow or triggering thrombosis, resulting in a greatly increased risk of heart attacks or strokes.

Previous research has consistently demonstrated that elevated circulating concentrations of hsCRP can serve as a biomarker (physiological proxy) of systemic inflammation, with several studies using these concentrations to predict risks of myocardial infarction, stroke, and cardiovascular mortality independently of other cardiovascular risk factors.

Parallel physiological and biochemical research has shown that excess adiposity is associated with persistent, low-grade inflammation involving immune cells, including macrophages, and the release of inflammatory mediators from adipose tissue.

GLP-1 receptor agonists (GLP-1 RAs) have become important therapies for obesity and metabolic disease and have demonstrated cardiovascular benefits in several patient populations. However, the extent to which changes in inflammation contribute to these benefits, particularly in people with ASCVD and overweight or obesity without diabetes, remains incompletely understood.

About the study

The present study aimed to address these persistent empirical ambiguities by analyzing biomarker and outcome data from the landmark phase 3 SELECT trial. The study’s sample dataset was derived from records across 804 sites in 41 countries, which together comprised 17,604 participants (age ≥45 years), all of whom demonstrated established ASCVD (prior myocardial infarction, stroke, or symptomatic peripheral artery disease) and a body mass index (BMI) ≥27 kg/m2. Participants with a prior history of diabetes or HbA1c ≥6.5% were excluded from the final dataset.

The phase 3 trial methodology randomized all participants to receive either once-weekly subcutaneous semaglutide (escalated to 2.4 mg; “experimental cohort”) or equivalent volumes of placebo (“control cohort”). Cohorts were generated in a 1:1 ratio and were concurrently treated with standard medical therapy, with a mean follow-up of 39.8 months.

Researchers examined whether baseline hsCRP predicted subsequent cardiovascular events, how hsCRP changed over time alongside body weight, and whether changes in hsCRP could partly account for semaglutide’s cardiovascular benefits.

Study findings

The study’s analyses supported hsCRP’s prognostic value, finding that participants who demonstrated higher baseline hsCRP levels were at significantly higher risk of future adverse clinical outcomes.

For example, MACE-specific analyses found that, compared with participants with baseline hsCRP < 2 mg/L, those with hsCRP ≥10 mg/L had approximately twice the risk of MACEs (HR = 2.17, 95% CI: 1.81–2.58). Estimates for cardiovascular death (HR = 3.94, 95% CI: 3.04–5.08) and all-cause mortality (HR = 3.40, 95% CI: 2.77–4.14) indicated more than threefold higher risks.

Semaglutide produced a 37.8% placebo-corrected reduction in geometric mean hsCRP levels at week 104. Notably, hsCRP reductions emerged remarkably early: hsCRP fell by 12% at 4 weeks and 19% at 8 weeks, in a subgroup of 6,011 European participants who underwent additional early laboratory testing. At these time points, participants had not reached the full 2.4 mg weekly dose, with the dose at 0.5 mg/week by week 8, and average body weight loss measured 1.4% and 2.8%, respectively.

Statistical models further found that semaglutide lowered hsCRP consistently across baseline low-density lipoprotein (LDL) cholesterol tertiles, cardiovascular entry criteria, and baseline statin use (88% of the cohort). Women exhibited a significantly larger proportional decrease in hsCRP than men (estimated treatment ratio = 0.56 vs 0.65, P < 0.0001).

Greater weight loss with semaglutide was associated with larger reductions in hsCRP. However, decreases were also evident before substantial weight loss and among participants with minimal or no weight loss. The authors cautioned that these findings do not establish a weight-independent anti-inflammatory mechanism because changes in adipose tissue, diet, GLP-1 receptor signaling, or other biological processes could also contribute.

Conclusions

The present study supports the use of elevated baseline hsCRP as a marker of residual cardiovascular risk and shows that semaglutide is associated with rapid and sustained reductions in hsCRP. These reductions were greater with increasing weight loss but also appeared before substantial weight loss and among participants with minimal or no weight reduction.

Importantly, the substudy cannot establish whether reduced inflammation directly mediates semaglutide’s cardiovascular benefits. Time-dependent Cox modeling showed that accounting for changes in hsCRP partially attenuated the estimated cardiovascular benefit of semaglutide, suggesting that changes in inflammation may contribute to some, but not all, of the observed reduction in MACEs. hsCRP is also a single inflammatory biomarker and is not itself considered a pathogenic mediator.

Moving forward, measuring hsCRP may help clinicians identify residual cardiovascular risk in people with overweight or obesity and established ASCVD, although the study did not establish hsCRP as a marker for selecting patients most likely to benefit from semaglutide.

SELECT was funded by Novo Nordisk, and several study authors were company employees or shareholders or reported other financial relationships with the company.