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Disease Research December 2025 9 min read

STEP-HFpEF: Semaglutide Transforms Treatment for the Most Common Heart Failure

Heart failure with preserved ejection fraction affects millions and has had few effective treatments—until now. The STEP-HFpEF trials showed semaglutide dramatically improves symptoms, exercise capacity, and quality of life.

The Bottom Line

In patients with HFpEF and obesity, semaglutide 2.4 mg weekly produced nearly double the improvement in symptoms and quality of life compared to placebo, along with 13% body weight loss. A pooled analysis showed 31% fewer heart failure events. These are the most impressive results ever seen for HFpEF treatment.

Understanding HFpEF: The "Other" Heart Failure

Heart failure with preserved ejection fraction (HFpEF) accounts for about half of all heart failure cases. Unlike heart failure with reduced ejection fraction (HFrEF), where the heart muscle is weakened, HFpEF involves a stiff heart that doesn't relax properly.

The HFpEF Treatment Gap

While multiple drug classes (ACE inhibitors, beta-blockers, SGLT2 inhibitors) have proven benefits in HFrEF, almost nothing has worked convincingly for HFpEF. Obesity is strongly linked to HFpEF, yet weight loss treatments were never formally tested until STEP-HFpEF.

Patients with HFpEF experience severe limitations: breathlessness with minimal activity, fatigue, swelling, and dramatically reduced quality of life. Many can barely walk across a room without symptoms.

The STEP-HFpEF Results

+16.6
Points KCCQ-CSS (Semaglutide)
+8.7
Points KCCQ-CSS (Placebo)
+21.5m
Walk Distance (Semaglutide)
+1.2m
Walk Distance (Placebo)

The Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) is the standard measure of heart failure symptoms and quality of life. A 5-point improvement is considered clinically meaningful. Semaglutide produced 7.8 points more improvement than placebo—a massive effect by cardiology standards.

Quality of Life Improvement (KCCQ-CSS Points)

Semaglutide
+16.6
Placebo
+8.7

Full Results Breakdown

Outcome (52 Weeks) Semaglutide Placebo Difference
KCCQ-CSS change +16.6 points +8.7 points +7.8 points (p<0.001)
Body weight change -13.3% -2.6% -10.7% (p<0.001)
6-minute walk distance +21.5 m +1.2 m +20.3 m (p<0.001)
C-reactive protein (inflammation) -43.5% -7.3% -36.2% (p<0.001)
NT-proBNP (heart strain marker) -20.9% -5.3% -15.6%

STEP-HFpEF DM: Same Results With Diabetes

A companion trial (STEP-HFpEF DM) enrolled patients who had both HFpEF and type 2 diabetes. The results were equally impressive:

Benefits were consistent regardless of baseline HbA1c, suggesting this isn't just about blood sugar control.

Pooled Analysis: Heart Failure Events

The individual STEP-HFpEF trials were powered for symptoms, not clinical events. But a 2024 pooled analysis of 4 trials (SELECT, FLOW, STEP-HFpEF, STEP-HFpEF DM) provided event data:

31%
Fewer HF Events
29%
Fewer CV Death + Worsening HF

Semaglutide reduced the combined endpoint of cardiovascular death or worsening heart failure events by 29%. The effect was driven primarily by fewer worsening HF events (31% reduction).

"These data support the use of semaglutide as an efficacious therapy to reduce the risk of clinical heart failure events in patients with HFpEF, for whom few treatment options are currently available."

— Lancet pooled analysis, September 2024

Why Does It Work?

Weight Loss

13% weight reduction decreases cardiac load, reduces ventricular filling pressures, and improves diastolic function. Benefits were greater with more weight loss.

Reduced Inflammation

43% CRP reduction suggests semaglutide has anti-inflammatory effects beyond weight loss. Chronic inflammation contributes to HFpEF pathophysiology.

Improved Metabolism

Better insulin sensitivity, reduced lipid accumulation, and improved cardiac energetics may all contribute to functional improvements.

Direct Cardiac Effects?

GLP-1 receptors are present in the heart. Some evidence suggests direct effects on cardiac function beyond metabolic improvements.

Importantly, the magnitude of symptom improvement was proportional to weight loss. Every 10% body weight reduction was associated with 6.4 additional points of KCCQ-CSS improvement.

Who Benefits Most?

Prespecified analyses found consistent benefits across:

Safety Profile

Side effects were consistent with other semaglutide trials:

The lower rate of serious adverse events with semaglutide likely reflects reduced heart failure hospitalizations and complications.

Clinical Implications

STEP-HFpEF represents a paradigm shift. For decades, HFpEF has been called "the disease without a treatment." Now there's compelling evidence that aggressive weight management with semaglutide can dramatically improve patients' lives.

"These are landmark findings. The trial was underpowered for clinical events, although reductions in HF were noted. These findings support a larger outcomes trial to study the effect of GLP-1 receptor agonists among patients with HFpEF and obesity."

— American College of Cardiology trial commentary

Questions Remaining

Primary Sources

Medical Disclaimer: This article is for informational purposes only and does not constitute medical advice. Semaglutide is FDA-approved for type 2 diabetes and obesity, but not specifically for heart failure. Treatment decisions for HFpEF should be made with your cardiologist.