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Semaglutide and Diuretic Use in HFpEF With Obesity
Quick Takes
- In a prespecified analysis of the STEP-HFpEF program, semaglutide use compared to placebo was associated with improvement in health status, weight loss, BNP levels, and exercise function regardless of baseline diuretic dose.
- The benefit of semaglutide was more pronounced with increasing baseline diuretic dose and semaglutide was associated with higher odds for lowering loop diuretic dose compared to placebo.
- Serious adverse events were similar with semaglutide and placebo.
Study Questions:
Does semaglutide efficacy vary with baseline diuretic use and does semaglutide change diuretic dose in patients with heart failure with preserved ejection fraction (HFpEF)?
Methods:
This was a prespecified analysis of the STEP-HFpEF program with two randomized, placebo-controlled trials. This included the STEP-HFpEF trial that enrolled HFpEF patients with body mass index ≥30 kg/m2 with left ventricular EF ≥45% without type 2 diabetes, and the STEP-HFpEF-DM trial that included patients with type 2 diabetes. All patients were randomized to semaglutide 2.4 mg weekly versus placebo. In this analysis, the effect of semaglutide was assessed across groups of: 1) no diuretics, 2) nonloop diuretics, and 3) loop diuretics at baseline and change in loop diuretic dose over 52 weeks.
Results:
Both trials included 1,145 patients. At baseline, 19% of patients took no diuretics, 19% took nonloop diuretics, and 61% took loop diuretics. The benefits of semaglutide were consistent across all diuretic categories with improved health status, weight loss, improved biomarker, and exercise function compared with placebo. However, improvement in health status with semaglutide was progressively larger from the no diuretic to highest dose loop diuretic subgroup. There were fewer serious adverse events with semaglutide compared to placebo across all diuretic groups. Gastrointestinal (GI) side effects occurred at similar rates in both groups.
From baseline to 52 weeks, loop diuretic dose decreased by 17% in the semaglutide group versus an increase of 2.4% in the placebo group resulting in a difference of 12 mg/day lower furosemide dose with semaglutide. Semaglutide patients had higher odds of reduction in loop diuretic dose (odds ratio [OR], 2.67; 95% confidence interval [CI], 1.70-4.18) and lower odds of needing an increase in loop diuretic dose (OR, 0.35; 95% CI, 0.23-0.53).
Conclusions:
In a post hoc pooled analysis of two randomized trials including obese HFpEF patients and comparing semaglutide to placebo, semaglutide was associated with improved health status and exercise function with weight loss irrespective of baseline diuretic dose. Semaglutide use was associated with higher odds for reduction in loop diuretic dose.
Perspective:
Obesity is among the most common causes of HFpEF and represents one of the toughest groups to treat given limited treatment options. These patients are often deemed too high risk for bariatric interventions. Loop diuretics are typically the first line of treatment used for decongestion in these patients, but these agents are associated with worsening kidney function, electrolyte abnormalities, and hypotension. The dose of loop diuretics needed to achieve successful decongestion also increases with obesity. Data from this study support the addition of glucagon-like peptide-1 receptor agonist agents in HFpEF patients with obesity in addition to sodium-glucose cotransporter-2 inhibitors, mineralocorticoid receptor antagonists, and angiotensin receptor/neprilysin inhibitors.
The benefits of semaglutide were noted regardless of baseline diuretic dose and diuretic dose was also lowered with semaglutide. Notably, the benefits of semaglutide were the largest in individuals with the highest dose of loop diuretics at baseline despite a similar degree of weight loss. In addition, the incidence of serious adverse events including GI side effects was no different between semaglutide and placebo. Once insurance coverage improves and the costs associated with semaglutide decline, these agents hold promise in the treatment of HFpEF with obesity.
Clinical Topics: Heart Failure and Cardiomyopathies, Prevention
Keywords: Diuretics, Glucagon-Like Peptide-1 Receptor, Heart Failure, Preserved Ejection Fraction, Obesity
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