Semaglutide and Tirzepatide in Heart Failure With Preserved Ejection Fraction (HFpEF): What Patients Need to Know in 2025

Introduction

Heart failure with preserved ejection fraction (HFpEF) is one of the fastest-growing cardiovascular conditions worldwide. Unlike traditional “weak heart” failure, in HFpEF the heart pumps out blood with normal strength, but the stiffened heart muscle prevents the chambers from filling properly. This leads to symptoms such as shortness of breath, fatigue, swelling, and reduced exercise capacity.

HFpEF is especially common in people who are living with obesity and type 2 diabetes (T2D). These metabolic conditions worsen the stiffness of the heart muscle and increase the risk of fluid buildup and hospitalizations. In fact, many patients with HFpEF have obesity-related complications, and their treatment options have historically been limited.

In recent years, medications originally developed for diabetes and weight loss have shown promise in heart failure. Two of the most talked-about drugs are Semaglutide and Tirzepatide. Both are injectable therapies that help with weight management, blood sugar control, and possibly cardiovascular health.

This article will explore:

• What HFpEF is and why it is linked to obesity and diabetes
• How Semaglutide and Tirzepatide work
• The latest clinical trial evidence and real-world studies
• Whether these drugs reduce hospitalizations and mortality in HFpEF patients
• Practical considerations for patients in the UK and Europe

If you or a loved one is affected by HFpEF and diabetes, understanding the potential role of these treatments could be life-changing.

Understanding Heart Failure With Preserved Ejection Fraction (HFpEF)

What does “preserved ejection fraction” mean?

In heart failure, doctors measure the ejection fraction (EF) – the percentage of blood pumped out of the heart’s main chamber with each beat. In HFpEF, the EF is usually normal (≥50%), meaning the pumping function looks strong. However, the heart muscle is stiff and doesn’t relax properly between beats, which reduces its ability to fill with blood.

The result? Even though the heart squeezes normally, not enough blood enters the chamber, so overall output is reduced. This causes symptoms like breathlessness, fatigue, and fluid retention.

Why is HFpEF linked to obesity and diabetes?

• Obesity adds stress to the heart by increasing blood volume, raising blood pressure, and triggering chronic inflammation.
• Type 2 diabetes damages small blood vessels, stiffens the heart, and worsens metabolic dysfunction.
• Together, obesity and diabetes create a toxic environment for the heart, increasing the likelihood of HFpEF.

Studies suggest that up to 80% of HFpEF patients are overweight or obese, and nearly half also have diabetes. These overlapping conditions create a vicious cycle: obesity and diabetes worsen HFpEF, and HFpEF in turn makes it harder to manage weight and blood sugar.

Current treatment challenges

Unlike heart failure with reduced EF (HFrEF), where therapies like beta-blockers and ACE inhibitors have strong evidence, HFpEF has fewer proven drug options. Treatments mainly focus on:

• Managing symptoms (diuretics for fluid buildup)
• Controlling blood pressure
• Treating diabetes
• Encouraging lifestyle changes (diet, exercise, weight management)

This gap in treatment is why the interest in Semaglutide and Tirzepatide has surged.

What Are Semaglutide and Tirzepatide?

Semaglutide

Semaglutide is a GLP-1 receptor agonist. GLP-1 is a natural hormone that helps regulate blood sugar, slow stomach emptying, and reduce appetite. By mimicking this hormone, semaglutide:

• Improves blood sugar control
• Promotes significant weight loss
• Reduces appetite and food cravings
• May improve cardiovascular outcomes

Semaglutide is available under brand names like Ozempic (for diabetes) and Wegovy (for weight management).

Tirzepatide

Tirzepatide is sometimes called a “dual incretin” drug because it activates both:

• GLP-1 receptors (like semaglutide)
• GIP receptors (glucose-dependent insulinotropic polypeptide)

This dual action provides:

• Even greater weight loss than semaglutide in head-to-head trials
• Improved blood sugar control
• Potential additional metabolic benefits

Tirzepatide is marketed as Mounjaro (for diabetes) and is being rolled out as Zepbound (for weight management) in some countries.

Why might these drugs help in HFpEF?

Both Semaglutide and Tirzepatide reduce body weight, blood sugar, and systemic inflammation – all critical drivers of HFpEF. By lowering obesity-related strain on the heart, these drugs may:

• Reduce fluid overload
• Improve exercise capacity
• Lower the risk of hospital admissions
• Potentially extend life expectancy

Importantly, the benefits seem to apply even in people without diabetes, highlighting their broader cardiovascular impact.

Clinical Trial Evidence

The most reliable way to understand whether a drug works is through randomized controlled trials (RCTs). Both Semaglutide and Tirzepatide have been tested in patients with obesity-related HFpEF, with promising results.

Tirzepatide – The SUMMIT Trial

The SUMMIT trial, published in the New England Journal of Medicine (2025), enrolled 731 patients with obesity and HFpEF. Patients were randomly assigned to tirzepatide or placebo and followed for about two years.

Key findings:

• Primary outcome (CV death or worsening heart failure): Occurred in 9.9% on tirzepatide vs 15.3% on placebo. This translates to a 38% relative risk reduction (HR 0.62, 95% CI 0.41–0.95).
• Heart failure events alone: 46% lower risk with tirzepatide (HR 0.54, 95% CI 0.34–0.85).
• Cardiovascular death: No significant difference, likely due to low event numbers.
• Quality of life: Marked improvements in exercise capacity and symptom scores.
• Weight loss: Significant and sustained over two years.

Importantly, the benefit of tirzepatide was seen both in patients with diabetes and those without. This suggests the drug’s effects are driven largely by weight reduction and metabolic improvement, not just blood sugar control.

Semaglutide – STEP-HFpEF and Pooled Analyses

Semaglutide has been studied in several trials of obesity and diabetes, with a subset of patients who had HFpEF.

• STEP-HFpEF trial: Focused on obese patients with HFpEF, showing major improvements in symptoms, weight, and exercise tolerance after 52 weeks of semaglutide.
• Pooled analysis (Lancet 2024): Combined data from multiple semaglutide trials, including over 3,700 HFpEF patients. Results showed:
  • CV death or first heart failure event: 31% lower risk (HR 0.69, 95% CI 0.53–0.89).
  • Worsening heart failure events: 41% lower risk (HR 0.59, 95% CI 0.41–0.82).
  • Cardiovascular mortality alone: No significant difference.

Taken together, these findings confirm that semaglutide not only helps with weight and blood sugar but may also reduce heart failure hospitalizations in HFpEF patients.

Comparing the Two

Direct head-to-head clinical trials are lacking, but evidence suggests:

• Tirzepatide may produce greater weight loss and possibly stronger HFpEF benefits.
• Semaglutide has a more established track record, with consistent results across multiple studies.

Both appear safe and effective in patients with obesity-related HFpEF and T2D.

Real-World Evidence

While randomized controlled trials provide gold-standard data, real-world studies help us understand how treatments perform outside carefully selected trial populations. In the case of Semaglutide and Tirzepatide, real-world evidence strongly supports their role in reducing heart failure complications.

JAMA Claims Database Study (2025)

Researchers analyzed a large U.S. insurance claims database between 2018 and 2024, focusing on patients with HFpEF and cardiometabolic risk factors (obesity and type 2 diabetes).

Key results:

• Compared with sitagliptin (a neutral diabetes drug), both Semaglutide and Tirzepatide users had fewer hospitalizations and deaths.
• Semaglutide: HR 0.58 (95% CI 0.51–0.65).
• Tirzepatide: HR 0.42 (95% CI 0.31–0.57).
• Head-to-head comparison: No significant difference between the two drugs (HR 0.86, 95% CI 0.70–1.06).

At one year, patients on semaglutide had a hospitalization or death risk of 5.5% vs 8.6% on sitagliptin, while tirzepatide patients had a 3.6% vs 7.5% risk.

This suggests that in routine practice, both drugs meaningfully reduce heart failure complications, and their benefits appear early.

TriNetX EHR Study (2025)

Another large study used the TriNetX electronic health record network, analyzing over 7,000 matched pairs of HFpEF patients.

Findings included:

• Tirzepatide use was linked to a 48% lower risk of the combined outcome of HF exacerbation and all-cause mortality (HR 0.52).
• It also reduced major cardiovascular events (HR 0.64) and renal complications (HR 0.44).
• Benefits were consistent whether or not patients had diabetes.

These results support the idea that the benefits of Semaglutide and Tirzepatide extend beyond glucose lowering, likely tied to weight reduction, anti-inflammatory effects, and improved vascular health.

Do Semaglutide and Tirzepatide Reduce Heart Failure Hospitalizations?

Yes—evidence from both trials and real-world practice suggests they do.

• RCTs: The SUMMIT trial with tirzepatide showed a 46% reduction in worsening HF events. Pooled semaglutide data showed a 41% reduction in hospitalizations.
• Observational studies: Real-world users of semaglutide and tirzepatide had much lower rates of hospitalizations compared with sitagliptin users.

These findings matter because hospitalization is one of the most costly and dangerous complications of HFpEF. Preventing hospital stays improves quality of life, reduces healthcare costs, and lowers risk of death in the long term.

Do They Reduce Mortality in HFpEF?

The evidence on mortality is promising but less conclusive.

• In the SUMMIT trial, tirzepatide reduced CV death or worsening HF events, but CV death alone was not significantly reduced due to low event numbers.
• In the semaglutide pooled analysis, there was a reduction in CV death + HF events, but again, no significant reduction in CV death alone.
• Real-world studies showed lower all-cause mortality rates in tirzepatide users compared with controls, though observational data must be interpreted cautiously.

Bottom line: At present, the strongest evidence supports reducing HF hospitalizations, while effects on mortality are encouraging but need longer follow-up.

Comparing Semaglutide vs Tirzepatide

Although both drugs belong to the same class, they have some differences:

So far, no clear winner has emerged. Tirzepatide may offer slightly more weight loss, but Semaglutide and Tirzepatide appear equally effective for heart failure outcomes in practice.

Safety and Side Effects in HFpEF Patients

Both drugs are generally well tolerated, but side effects need consideration—especially in heart failure patients, who are often older and take multiple medications.

Common Side Effects

• Nausea
• Vomiting
• Diarrhea
• Constipation
• Abdominal pain

These are usually mild to moderate and improve over time.

Serious Risks (rare)

• Pancreatitis
• Gallbladder disease
• Rare risk of thyroid tumors (in animal studies)

Heart Failure Safety

Neither semaglutide nor tirzepatide worsens heart function. In fact, treatment discontinuation due to adverse events was relatively low (6.3% in tirzepatide’s SUMMIT trial vs 1.4% with placebo).

In clinical practice, doctors carefully monitor hydration, kidney function, and drug tolerability, especially in patients already on diuretics.

Practical Implications for Patients and Doctors

For patients with obesity, type 2 diabetes, and HFpEF, the arrival of Semaglutide and Tirzepatide represents a breakthrough.

• Patients benefit through fewer hospitalizations, better symptom control, and weight reduction.
• Doctors benefit from having new tools beyond standard HF medications.
• Healthcare systems benefit because reducing hospital admissions lowers costs.

Who may benefit most?

• Patients with obesity-related HFpEF
• Those with type 2 diabetes and HFpEF
• Patients struggling with weight loss despite lifestyle efforts
• Those frequently hospitalized with fluid overload

Frequently Asked Questions (FAQs)

Q1: Can Semaglutide and Tirzepatide replace standard HF medications?
No. They complement but do not replace treatments like diuretics or blood pressure medications.

Q2: Do you need diabetes to benefit?
No. Both drugs help HFpEF patients with and without diabetes, largely due to weight loss and metabolic improvements.

Q3: Are they safe for older patients?
Yes, but careful monitoring is essential to avoid dehydration or kidney strain.

Q4: How much weight loss is needed for benefits?
Even a 5–10% reduction in body weight improves heart function and symptoms. Tirzepatide often achieves >20% loss.

Q5: How long before results are seen?
Benefits on symptoms and hospitalization risk can appear within months, though full weight loss may take 6–12 months.

Where to Get Semaglutide and Tirzepatide Safely in the UK

Because of rising demand, counterfeit versions of these medications are common online. To ensure safety:

• Only purchase through a licensed UK pharmacy.
• Require a prescription and medical supervision.
• Avoid “black market” sellers or social media promotions.

For reliable access, visit Care Circle Pharmacy, where licensed professionals provide safe dispensing and medical guidance.

Conclusion

Heart failure with preserved ejection fraction has long been one of the most frustrating conditions to treat. But now, Semaglutide and Tirzepatide are rewriting the story.

• They reduce HF hospitalizations.
• They improve symptoms, exercise tolerance, and quality of life.
• They may reduce all-cause mortality, though more data is needed.
• They are safe and effective in both diabetic and non-diabetic patients.

For people living with obesity, diabetes, and HFpEF, these drugs represent a new era of treatment—a chance to breathe easier, live more actively, and spend less time in hospital.

If you’re considering treatment, speak to your GP or heart specialist, and always obtain medications through trusted providers such as Care Circle Pharmacy.