Wegovy improves symptoms, physical function for obesity-related heart failure with diabetes
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Key takeaways:
- Semaglutide 2.4 mg improved symptoms, mobility for people with obesity-related HF and diabetes.
- Benefits were consistent despite less weight loss seen for people with vs. without type 2 diabetes.
ATLANTA — Adults with obesity, HF with preserved ejection fraction and type 2 diabetes saw marked improvements in HF symptoms and physical function with semaglutide 2.4 mg compared with placebo, despite less than typical weight loss.
Excess adiposity plays a key role in the development and progression of both HF with preserved ejection fraction (HFpEF) and type 2 diabetes, and people with obesity-associated HFpEF and diabetes typically have a much greater symptom burden and worse functional status, Mikhail Kosiborod, MD, FACC, FAHA, cardiologist at Saint Luke’s Mid America Heart Institute and professor of medicine at the University of Missouri-Kansas City School of Medicine, said during a presentation at the American College of Cardiology Scientific Session. Previous research showed semaglutide 2.4 mg (Wegovy, Novo Nordisk) significantly reduced HF-related symptoms and physical limitations among adults with HFpEF and obesity but without diabetes, leading researchers to explore the drug’s benefits in those who do have diabetes.
“This study offers clear confirmation — in an independent second trial with a separate patient population — of very large benefits on symptoms and physical limitations due to HF with semaglutide vs. placebo,” Kosiborod told Healio. “We see these benefits, which are very consistent with what we saw in the original STEP-HFpEF trial ... even though there is 40% less weight loss. This means that the benefits cannot all be attributed to weight loss. There are other mechanisms at play here.”
Benefits seen despite less weight loss
As Healio previously reported, in the first STEP-HFpEF trial semaglutide 2.4 mg significantly reduced HF symptom burden among adults with HFpEF and obesity but without diabetes. In that study, semaglutide 2.4 mg also improveed body weight and 6-minute walk distance.
For the new STEP-HFpEF-DM analysis, Kosiborod and colleagues analyzed data from 616 adults with HFpEF, a BMI of 30 kg/m2 or higher and type 2 diabetes. The median age of participants was 69 years, 44.3% were women, median BMI was 36.9 kg/m2 and median diabetes duration was 8 years. Most participants received diuretics, renin angiotensin system blockers and beta-blockers; 32.5% received mineralocorticoid receptor antagonists and 32.8% received SGLT2 inhibitors.
Researchers randomly assigned participants to semaglutide 2.4 mg or placebo for 52 weeks. Primary endpoints were change from baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score (range, 0-100) and change in body weight. Confirmatory secondary endpoints included change in 6-minute walk distance and a hierarchical composite endpoint that included death, HF events, differences in the change in KCCQ score and 6-minute walk distance, and change in C-reactive protein.
The findings were simultaneously published in The New England Journal of Medicine.
At 52 weeks, mean change from baseline in KCCQ score was 13.7 points with semaglutide 2.4 mg and 6.4 points with placebo, for an estimated difference of 7.3 points (95% CI, 4.1-10.4; P < .001).
Mean change in body weight from baseline was –9.8% with semaglutide 2.4 mg and –3.4% with placebo, for an estimated difference of –6.4 percentage points (95% CI, –7.6 to –5.2; P < .001).
The confirmatory secondary endpoints favored semaglutide over placebo, with an estimated between-group difference in change in 6-minute walk distance of 14.3 m (95% CI, 3.7-24.9; P = .008). The win ratio for the hierarchical composite end point was 1.58 (95% CI, 1.29-1.94; P < .001) and the estimated treatment ratio for change in C-reactive protein level was 0.67 (95% CI, 0.55-0.8; P < .001).
Serious adverse events occurred in 17.7% of patients assigned semaglutide 2.4 mg and 28.8% assigned placebo.
Potential for combination therapy in HFpEF
Kosiborod noted that there was still a significant difference in change in KCCQ summary score from baseline to 52 weeks even with concomitant SGLT2 inhibitor use, with a treatment difference of 5.3 vs. 8.3 for those who did or did not receive SGLT2 inhibitors, respectively (P for interaction = .35). Those receiving SGLT2 inhibitors also experienced a mean 4.7% decrease in body weight with the addition of semaglutide 2.4 mg vs. placebo compared with a mean 7.2% body weight reduction for those not on an SGLT2 inhibitor (P for interaction = .04).
“This [drug] works regardless of SGLT2 inhibitor use,” Kosiborod told Healio. “It really changes the paradigm in terms of managing obesity in the setting of HFpEF. Obesity is not just a comorbidity; it is a root cause and a target for intervention. This is going to open up a whole new avenue of research with obesity drugs as treatment for HFpEF.”
“We know that these two classes of medications have complementary, not overlapping, benefits,” Kosiborod told Healio. “The standard of care in the future will likely include SGLT2 inhibitors and GLP-1 receptor agonists together, at least for those with the obesity-related HF phenotype.”
Reference:
Perspective
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Gregg C. Fonarow, MD, FACC, FAHA, FHFSA
The findings of this trial are clinically actionable and highly complementary to those of STEP-HFpEF. Together, they establish semaglutide at a target dose of 2.4 mg once weekly as a standard of care in patients with obesity-associated HF with preserved ejection fraction and type 2 diabetes.
This therapy reduces HF-related symptoms and physical limitations. Further, there was improved 6-minute walk distance and a decreased risk for HF hospitalizations or other events. Patients achieved greater weight loss and reduced inflammation as indexed by C-reactive protein levels. Therapy was well tolerated with fewer serious adverse events with semaglutide 2.4 mg compared with placebo.
SGLT2 inhibitor plus GLP-1 receptor agonist therapy can alter the trajectory of HFpEF in individuals with a BMI of 30 kg/m2 or above, with or without type 2 diabetes. Clinicians have, for the first time, a combination cardiometabolic therapeutic regimen for these patients that can substantially improve health status and functional capacity, along with decreasing HF hospitalization risk.
Ensuring these new findings are effectively translated into clinical practice in eligible patients represents the next step forward in the care of HFpEF.
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Kosiborod MN. Featured clinical research I. Presented at: American College of Cardiology Scientific Session; April 6-8, 2024; Atlanta.
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