How GLP-1 Drugs Compare in Protecting the Heart and Kidneys of Veterans With Type 2 Diabetes

A new study has taken a close look at three widely used GLP-1 receptor agonists—liraglutide, semaglutide, and dulaglutide—to understand whether their small molecular differences lead to any meaningful differences in health risks. These medications, originally developed for managing type 2 diabetes, have surged in popularity because of their powerful blood-sugar-lowering effects and their well-known impact on weight loss. But as clinicians increasingly prescribe them for broader metabolic benefits, researchers wanted to know if these drugs behave differently when it comes to kidney health, cardiovascular outcomes, and overall mortality.

This new research, based on data from 21,790 U.S. veterans, was conducted to fill a clear evidence gap. Despite the rapid adoption of GLP-1s, there has not been a direct head-to-head comparison of these three major medications focusing on heart and kidney outcomes. Until now, clinicians have assumed they perform similarly because all belong to the same drug class. This study offers the most detailed comparison yet, and the findings are reassuring: across the board, the three drugs showed relatively low and comparable risks.

Why Researchers Needed This Comparison

More than 38 million Americans live with diabetes, and 90–95% of them have type 2 diabetes. Over time, this condition significantly increases the risk of cardiovascular disease and chronic kidney disease. Because cardiovascular disease is one of the leading causes of death among people with diabetes, the medical community has shifted toward treating patients using a cardiovascular-kidney-metabolic (CKM) lens. This approach considers how diabetes, heart disease, and kidney disease influence one another.

GLP-1 receptor agonists have already shown wide-ranging benefits that go beyond controlling blood sugar. They have been linked to improved heart health, reduced cardiovascular risk, and slower kidney disease progression. The U.S. Food and Drug Administration has approved liraglutide, semaglutide, and dulaglutide for preventing cardiovascular events in patients with type 2 diabetes. But when it comes specifically to kidney protection, only semaglutide currently carries FDA approval for slowing chronic kidney disease progression in individuals with diabetes.

Because these drugs are expensive, in high demand, and becoming increasingly available in generic form (especially liraglutide), understanding whether they differ in safety or effectiveness is crucial for clinicians, insurers, and patients.

What the Study Analyzed

The research team used data from the Department of Veterans Affairs health system, which is known for its detailed patient records and long-term tracking. The study compared patients who newly started liraglutide, semaglutide, or dulaglutide and followed them for kidney outcomes, cardiovascular events, hospitalizations, and mortality.

The major finding: the three drugs behaved very similarly in their impact on the kidneys and cardiovascular system. This indicates that patients starting any of the three medications can expect comparable safety levels.

Still, the researchers did identify a few differences:

• Liraglutide showed a lower risk of all-cause mortality compared with dulaglutide.
• Semaglutide was associated with a higher risk of gallstones.
• All three drugs had very low overall rates of these adverse events, so the differences were statistically notable but not considered alarming.

The researchers emphasize that some of these differences—especially the lower mortality risk with liraglutide—require further study. It’s unclear whether liraglutide truly provides a mortality benefit or whether an external factor influenced the results.

Why These Findings Matter

For patients, especially those balancing cost, availability, and insurance coverage, this study provides reassurance. Since the three drugs appear broadly similar in safety and overall effectiveness, choosing between them can focus on practical considerations like:

• Out-of-pocket expense
• Insurance formulary availability
• Dosing convenience (weekly vs. daily injections)
• Personal tolerability and side-effect preference

This is especially relevant because generic liraglutide is entering the market, potentially making it a more accessible option for many.

The study also strengthens the case for expanding GLP-1 use across various stages of CKM syndrome. As clinicians shift toward more holistic metabolic care, drugs that benefit both the heart and kidneys are becoming essential tools.

The Limitations That Must Be Considered

Despite the strong dataset, the study has clear limitations:

• The VA population is mostly older white males, meaning the findings must be replicated in more diverse groups.
• The research was an observational study, not a randomized clinical trial, so it cannot prove cause-and-effect relationships.
• Patients’ underlying health differences, lifestyle factors, or unmeasured variables may have influenced outcomes.

Because of these limitations, experts agree that randomized head-to-head trials comparing GLP-1 drugs directly are still needed to settle lingering questions.

How GLP-1 Drugs Are Evolving

Even as this comparison helps clarify existing treatment options, newer drugs are already expanding the landscape. Emerging GLP-1-based therapies target multiple metabolic pathways at once:

• Tirzepatide activates both GLP-1 and GIP receptors, making it more potent for blood sugar regulation and weight reduction.
• Retratrutide, still in development, targets three receptors—GLP-1, GIP, and glucagon—for potentially even broader metabolic control.

These next-generation medications aim to address diabetes, obesity, and metabolic disease more aggressively, and they may ultimately reshape standard treatment approaches. Future studies will need to compare these newer agents directly with current GLP-1 RAs to determine which provide superior cardiorenal protection.

Understanding GLP-1 RAs Beyond This Study

Since this article aims to be both detailed and informative, here is additional background that expands on the topic beyond the news story:

What GLP-1 Receptor Agonists Do in the Body

GLP-1 is a naturally occurring hormone that helps regulate:

• Insulin secretion
• Blood sugar control
• Appetite and satiety
• Gastric emptying

Medications that mimic GLP-1 improve glucose control by enhancing insulin release when blood sugar is high. They also slow digestion and reduce appetite, which explains their strong impact on weight loss.

Their Impact on the Heart

GLP-1 RAs have been shown to:

• Reduce blood pressure
• Decrease inflammation
• Improve arterial function
• Lower risk of major cardiovascular events

This is why the FDA has approved several of them for cardiovascular protection in patients with type 2 diabetes.

Their Impact on the Kidneys

GLP-1 drugs may protect kidney function by:

• Reducing albuminuria (protein leakage into urine)
• Improving blood vessel health
• Lowering inflammation and oxidative stress
• Enhancing overall metabolic control

These benefits help slow progression toward chronic kidney disease, particularly in individuals with long-standing diabetes.

The Importance of Real-World Data

While clinical trials offer controlled environments, real-world evidence—like what the VA provides—helps show how drugs perform across broader, more complex patient populations. Still, observational studies should be complemented with randomized trials to validate findings.

Reference to the Original Study

Research Paper:
Liraglutide vs Semaglutide vs Dulaglutide in Veterans With Type 2 Diabetes
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2840010