Tirzepatide shows ‘practice-changing’ CV benefits for obesity-related heart failure
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Key takeaways:
- Zepbound reduced risk for CV death or worsening HF by 38% vs. placebo in adults with HF with preserved ejection fraction and obesity.
- The dual-incretin agonist also improved functional capacity.
CHICAGO — In adults with HF with preserved ejection fraction and obesity, treatment with tirzepatide cut risk for CV death or worsening HF by 38% compared with placebo, with a parallel improvement in health status and exercise tolerance.
Findings from the SUMMIT trial, the first major CV outcomes trial in adults with HFpEF with obesity, also demonstrated that treatment with tirzepatide (Zepbound, Eli Lilly), a long-acting GLP-1/GIP receptor agonist FDA approved for chronic weight management, was associated with a substantial reduction in systemic inflammation and a decrease in body weight.
“Essentially, obesity-related HFpEF is a disease of angry adipocytes,” Milton Packer, MD, distinguished scholar in cardiovascular science at Baylor University Medical Center and visiting professor at Imperial College London, told Healio during a press conference at the American Heart Association Scientific Sessions. “These are very angry cells. They are in full-scale endocrine rebellion and the rest of the body suffers. There are data that GIP receptor agonism has an additional anti-inflammatory effect in addition to GLP-1, but these are lab data and we do not yet know how that translates into the clinical setting.”
High-risk patient group
The double-blind, randomized, placebo-controlled trial, simultaneously published in The New England Journal of Medicine, included 731 adults with HFpEF (defined as an EF 50%) and a BMI of 30 kg/m2 or greater from 129 centers across nine countries. Researchers randomly assigned participants tirzepatide 15 mg once weekly (n = 364) or placebo (n = 367) for at least 52 weeks (median follow-up, 104 weeks). The mean age of participants was 65 years; 53.8% were women and 70% were white. At baseline, mean 6-minute walk distance was 302.8 m and 46.9% of participants had a hospitalization or urgent care visit for worsening HF in the previous 12 months.
The coprimary endpoints were a composite of adjudicated CV death or worsening HF and change from baseline to 52 weeks in the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score. Researchers also assessed 6-minute walk distance, body weight and high sensitivity C-reactive protein.
The SUMMIT cohort was enriched for high risk, Packer said; the trial did not require elevated N-terminal pro-B-type natriuretic peptide levels for entry.
“These patients were really impaired,” Packer said. “Very low KCCQ scores, very poor kidney function, very limited exercise tolerance. Half had a recent HF decompensation and the levels of C-reactive protein were markedly elevated.”
Greatest benefit for worsening HF
A composite of CV death or a worsening HF event occurred in 9.9% of participants in the tirzepatide group and 15.3% in the placebo group, for an HR of 0.62 (95% CI, 0.41-0.95; P = .026).
Assessing individual endpoints, worsening HF events occurred in 8% of tirzepatide participants and in 14.2% of placebo participants, for an HR of 0.54 (95% CI, 0.34-0.85), whereas adjudicated CV deaths occurred in 2.2% and 1.4% of tirzepatide and placebo participants, respectively (HR = 1.58; 95% CI, 0.52-4.83).
“This benefit was driven primarily by an effect on worsening HF requiring hospitalization or urgent IV drug therapy,” Packer said.
Participants in the tirzepatide group showed marked improvements in functional capacity; mean KCCQ scores at 52 weeks were 19.5 and 12.7 in the tirzepatide and placebo groups, respectively, for a between-group difference of 6.9 (95% CI, 3.3-10.6; P < .001).
Participants in the tirzepatide group also experienced greater weight loss (between-group difference, –11.6 percentage points; P < .001), improved performance in 6-minute walk distance (median between-group difference, 18.3; P < .001) and saw a substantial reduction in hsCRP level (between-group difference, –34.9 percentage points; P < .001).
Safety with tirzepatide was consistent with prior clinical trials, with 4.1% of patients in the tirzepatide group discontinuing treatment due to gastrointestinal adverse effects, Packer said.
‘Cornerstone’ therapy for HFpEF with obesity
Discussing the findings, Jennifer E. Ho, MD, cardiologist in the advanced heart failure and transplantation section at Massachusetts General Hospital, and associate professor of medicine at Harvard Medical School, called HFpEF the most serious consequence of obesity-related CVD is HFpEF, noting that the historically difficult-to-treat disease also disproportionately impacts women. The SUMMIT trial, Ho said, builds upon the findings of STEP-HFpEF, presented in 2023 and reported by Healio, that demonstrated semaglutide 2.4 mg (Wegovy, Novo Nordisk), a GLP-1 receptor agonist, significantly reduced HF symptom burden in a similar patient population. However, STEP-HFpEF, and the follow-up trial, STEP-HFpEF Diabetes, were not powered for primary clinical outcomes.
“[SUMMIT] is a practice-changing trial and cements incretin-based therapies as one of the cornerstones of obesity-related HFpEF,” Ho said. “This is not a study that targeted a small subgroup of patients with HFpEF. This is going to affect how we think about the majority of patients with HFpEF who we see.”
Reference:
For more information:
Milton Packer, MD, can be reached at milton.packer@bswhealth.org.
Perspective
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Erin D. Michos, MD, MHS, FACC, FAHA, FASE, FASPC
Patients with the obesity phenotype represent the majority of those with HF with preserved ejection fraction — increased plasma volume and stressed blood volume, more concentric left ventricular remodeling, high prevalence of hypertension, more right ventricular dysfunction, increased epicardial fat thickness, higher total epicardial heart volume, and are more diuretic resistant. This leads to greater symptom burden, poorer functional capacity and more severely impaired quality of life. Overweight and obesity play a causal, if not pivotal, role in the genesis and progression of the HFpEF.
Prior to SGLT2 inhibitors, no effective therapies for HFpEF had been demonstrated. The SUMMIT trial is the first trial in people with HFpEF and obesity that had major HF outcomes as the primary prespecified endpoint. This is the first CV outcome trial reporting out for tirzepatide.
In SUMMIT, notably, 53.8% of participants were women, which reflects that HFpEF has a higher prevalence in women. There was a highly significant 38% reduction in time to first event for CV death or worsening HF. Some had questioned the inclusion of increasing diuretic doses as part of the worsening HF definition; however, when events managed only with intensification of oral diuretic therapy were removed from the primary endpoint analysis, the HR was still highly significant at 0.57.
A statistically significant 6.9 improvement in KCCQ score is a large and meaningful change. Other notable findings were, of course, the 12% weight loss, the 35% reduction in high-sensitivity C-reactive protein and the improvement in 6-minute walk distance by 18 m.
These are impressive clinical benefits and it is very exciting.
Unlike STEP-HFpEF, SUMMIT did not demonstrate a statistically significant reduction in BNP. However, SUMMIT did not require elevated BNP for entry and participants had lower baseline values than in STEP-HFpEF. We know there is an obesity-BNP paradox with lower BNP levels seen in the obesity phenotype of HFpEF. Yet, SUMMIT still demonstrated clear HF clinical benefit. These findings suggest that requiring high levels of BNP to initiate incretin-based therapies might exclude many patients with obesity-related HFpEF who would benefit.
STEP-HFpEF led the way. Now, SUMMIT sealed the deal for incretin therapy (both GLP-1 and dual agonists) to now be considered as a core pillar of therapy for HFpEF for patients with the obesity phenotype of HFpEF, along with SGTL2 inhibitors and nonsteroidal mineralocorticoid receptor antagonists.
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Packer M, et al. LBS.01. Presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2024; Chicago.
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