Semaglutide Enhances Heart Failure Outcomes in Obesity

Subanalyses presented in one of the first late-breaking science presentations at the 2024 European Society of Cardiology Congress show that semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist firmly established in the type 2 diabetes space for its ability to increase insulin production and suppress glucagon production,¹ has potential to improve outcomes among patients with obesity-related heart failure with preserved ejection fraction (HFpEF).

Among the many purported benefits connected with semaglutide are that it can promote weight loss, improve cardiovascular health, and reduce inflammation.² However, what many continue to debate as a wonder or miracle drug—because of reported adverse effects that include diarrhea, heartburn, nausea, vomiting rash, decreased urination, vision changes, rapid heartbeat, and fainting or dizziness³—is fast accumulating evidence of its impact on heart failure.

These data from the STEP-HFpEF program show benefits in patients with atrial fibrillation (aFib), as well as improvements in inflammation. These findings add to the many accolades semaglutide has already received and build on data presented at last year’s ESC Congress, which showed that among patients who took this once-weekly medication, there were gains in their 6-minute walk test and important biomarker improvements.⁴

Mikhail Kosiborod, MD | Image Credit: Saint Luke's Mid America Heart Institute

Semaglutide and Atrial Fibrillation

A subanalysis of data from the STEP-HFpEF and STEP-HFpEF DM trials⁵ showed that patients with aFib—45% of the STEP-HFpEF program population—have greatly benefited from the GLP-1 receptor agonist, with demonstrated improvements in their heart failure–related symptoms, physical limitations, and exercise abilities, as well as reductions in C-reactive protein (CRP) and N-terminal pro b-type natriuretic peptide (NTproBNP) , biomarkers of inflammation⁶ and heart failure,⁷ respectively.

Presented by principal investigator Mikhail Kosiborod, MD, of Saint Luke's Mid America Heart Institute, Kansas City, this subanalysis compared outcomes from twice-weekly 2.4-mg semaglutide in patients living with aFib (n = 518)—a known risk factor for heart failure and stroke—and those who do not have the condition (n = 627). This is an area of study lacking data on patient outcomes, Kosiborod stated, so he and his team wanted to know if the presence of baseline aFib and patient clinical characteristics would mitigate semaglutide’s efficacy.

“We know that obesity is a key risk factor for the development and progression of both heart failure with preserved ejection fraction atrial fibrillation,” he explained. “However, whether the effects of semaglutide in this patient group differ in people, both with and without atrial fibrillation and across different atrial fibrillation subtypes, has not been fully examined.”

The patients who had aFib were older (72 vs 67 years) and had a slightly higher body mass index (BMI) (37.1 vs 36.8 kg/m²), a higher Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (KCCQ-CSS) (59.4 vs 58.3), more cases of NYHA class III/IV disease (33.8% vs 29.5%), lower left ventricular ejection fraction (55% vs 58%), and more prescriptions for diuretics, beta-blockers, ACE inhibitors/angiotensin receptor blockers, mineralcorticoid receptor antagonists, SGLT2 inhibitors, and antithrombotics.

Semaglutide led to a 7.5-point overall improvement (P < .001) for KCCQ-CSS. In patients who did and did not have aFib, the difference in KCCQ-CSS was significant: 11.5 vs 4.3 points, respectively (P = .001). This effect was also observed when patients were stratified by aFib type: permanent (12.8 points), persistent (9.2 points), and paroxysmal (12.2 points) (P = .019). Body weight dropped 8.4% overall (P < .001), with only a slight difference from patients who did not have aFib, at –8.4% vs –8.3%, respectively, and in the 3 aFib subtypes there again were marked changes: –8.2% in permanent, –6.8% in persistent, and –9.5% in paroxysmal (P = .60). Six-minute walk distance (6MWD) improved by 17.1 meters overall, and there was a 38% difference in distance between the aFib (21.7 m) and no-aFib (13.6 m) groups. Treatment ratios for CRP and NTproBNP vs baseline levels were 0.64 and 0.82 overall, and similar between the aFib and no-aFib groups (0.64 vs 0.64 and 0.84 vs 0.81, respectively), with the 3 aFib subtypes for both biomarkers having lower treatment ratios.

Subodh Verma, MD, PhD, FRCSC, FAHA, FCAHS | Image Credit: University of Toronto

Semaglutide and Inflammation

Subodh Verma, MD, PhD, FRCSC, FAHA, FCAHS, University of Toronto and St. Michael’s Hospital, continued to STEP-HFpEF discussion by presenting on changes in inflammation among patients with obesity-related HFpEF.⁸ He explained that there is a fine line in the relationship between adiposity and inflammation, and that this is “a key driver of HFpEF pathobiology but has not been specifically evaluated in patients with obesity-related HFpEF.”

Close to 70% of patients had signs of inflammation in the STEP-HFpEF program.

Overall, although higher levels of CRP were seen in patients who were female and younger, and had a higher BMI, Verma emphasized, “the reduction in CRP appears to be independent of baseline levels of CRP and there was no relationship between weight loss with CRP reduction from semaglutide vs placebo. The magnitude of CRP reduction was similar across the 3 patient groups.”

Goals of this subanalysis were to use CRP to evaluate inflammation, measure semaglutide’s efficacy vs placebo, and show associated changes from baseline CRP and heart failure outcomes, with dual primary outcomes of change in KCCQ-CSS and body weight. The 3 categories of baseline CRP were below 2 mg/L (n = 332), at least 2 to less than 10 mg/L (n = 591), and 10 mg/L or more N = 218), with those in the below 2 mg/L group slightly older than the other 2 groups: 71 vs 69 and 67 years, respectively. Baseline BMIs were 35, 37, and 40 kg/m², respectively, and baseline waist circumferences were 117, 120, and 124 cm. Baseline NTproBNP was highest in the CRP above 10 mg/L group (486 pg/mL), but LVEF and KCCQ scores were similar: 56% (<2 mg/L) and 57% (> 2 to < 10 mg/L and > 10 mg/L) and 61 (<2 mg/L), 59 (> 2 to < 10 mg/L), and 56 points (> 10 mg/L), respectively. Most cases of NYHA class II disease were seen in the lowest baseline CRP group (73%), and class III/IV disease, the highest baseline CRP group (40%). More in the highest baseline CRP group also were on loop diuretics (69% vs 62% and 55% of the > 2 to < 10 mg/L and <2 mg/L groups, respectively).

The overall change in KCCQ-CSS by CRP level was 7.5 points, with those in the > 2 to < 10 mg/L group having the greatest change (8.6 points [P = .34]). Bodyweight losses changes were close to equal, at 8.4% overall, and 8.2%, 8.3%, and 8.6% decreases seen in the smallest to the largest baseline CRP groups, respectively (P = .95).

For the confirmatory secondary end points at 52 weeks—changes in 6MWD, hierarchical composite end point win ratio, and NTproBNP ratio to baseline—the benefits were more pronounced in those with baseline CRP of at least 2 to less than 10 mg/L, but these differences were not statistically significant, even though greater semaglutide-mediated reduction in NTproBNP were seen with greater drops in CRP, Verma said.

Verma noted that in patients who lost less than 5%, at least 5% to less than 10%, at least 10% to less than 15%, at least 15% to less than 20%, and 20% or more of their body weight, semaglutide showed consistent results with CRP reduction via adjusted treatment ratios: 0.76, 0.70, 0.69, 0.72, and 0.96 (P =.92).

References

1. How does semaglutide work? Mayo Clinic. Accessed August 30, 2024. https://diet.mayoclinic.org/us/blog/2024/how-does-semaglutide-work/

2. Preszler LB. The health benefits of semaglutide—beyond weight loss. Mayo Clinic. July 2, 2024. Accessed August 30, 2024. https://mcpress.mayoclinic.org/living-well/health-benefits-of-semaglutide-beyond-weight-loss

3. Semaglutide injection. MedlinePlus. Updated April 20, 2024. Accessed August 30, 2024. https://medlineplus.gov/druginfo/meds/a618008.html

4. Caffrey M. Results for semaglutide show obesity is a “root cause” of HFpEF; payer coverage needed, Kosiborod says. The American Journal of Managed Care^®. August 25, 2023. Accessed August 30, 2024. https://www.ajmc.com/view/results-for-semaglutide-show-obesity-is-a-root-cause-of-hfpef-payer-coverage-needed-kosiborod-says

5. Verma S, Butler J, Borlaug BA, et al. Atrial fibrillation and semaglutide effects in obesity-related HFpEF: prespecified patient level analysis of STEP-HFpEF and STEP-HFpEF DM trials. Presented at: ESC Congress; August 30-September 2, 2024; London England. https://esc365.escardio.org/presentation/290207

6. Mehta N, Luthra NS, Corcos DM, Fantuzzi G. C-reactive protein as the biomarker of choice to monitor the effects of exercise on inflammation in Parkinson’s disease. Front Immunol. 2023;14:1178448. doi:10.3389/fimmu.2023.1178448

7. Panagopoulou V, Deftereos S, Kossyvakis C, et al. NTproBNP: an important biomarker in cardiac diseases. Curr Top Med Chem. 2013;13(2):82-94. doi:10.2174/1568026611313020002

8. Verma S, Petrie MC, Borlaug BA, et al. Inflammation in obesity-related HFpEF: the STEP-HFpEF programme. Presented at: ESC Congress; August 30-September 2, 2024; London England. https://esc365.escardio.org/presentation/290208