Retatrutide and Diabetes - The ‘Triple G’ Injection Might Transform Treatment

For millions of people, living with Type 2 Diabetes (T2D) and Peripheral Artery Disease (PAD) presents a daily challenge. These conditions, often intertwined, can cast a long shadow over quality of life, with one of the most debilitating symptoms being a sharp, cramping pain in the legs while walking. This pain, known as intermittent claudication, can turn a simple walk to the shops into a gruelling ordeal, severely limiting mobility and independence.

According to Diabetes UK, over 4.3 million people are now living with a diagnosis of diabetes in the UK, while the British Heart Foundation estimates that PAD affects a significant portion of the population, often going undiagnosed.

Semaglutide, a medication well-known under brand names like Wegovy for its powerful effects on blood sugar control and weight management, has emerged as a subject of intense interest. Researchers hypothesised that its benefits might extend beyond metabolic health, potentially improving blood flow and reducing inflammation in the legs of those with PAD. This led to a crucial clinical investigation: the STRIDE (Semaglutide Treatment on Walking Distance in Peripheral Artery Disease) trial.

This article provides a comprehensive analysis of the STRIDE trial and explores the mechanism of Semaglutide, and breaks down the trial's methodology and results.

Understanding PAD and Type 2 Diabetes

Before exploring the trial itself, it's essential to understand the two conditions at its core. Peripheral Artery Disease and Type 2 Diabetes are distinct diagnoses, but their relationship is deeply interconnected, creating a complex clinical picture for many patients.

What Is Peripheral Artery Disease (PAD)

Peripheral Artery Disease is a common circulatory problem in which narrowed arteries reduce blood flow to your limbs, most commonly the legs.

According to the NHS, this narrowing is caused by atherosclerosis, a process where fatty deposits, or plaques, build up on the artery walls. When the arteries supplying blood to your legs become partially or fully blocked, the leg muscles don't receive enough oxygen-rich blood to meet the demands of physical activity.

The classic symptom of this oxygen deficit is intermittent claudication. This is characterised by:

• Pain on exertion: A painful aching, cramping, or feeling of fatigue in the muscles of the calves, thighs, or buttocks that appears during walking or climbing stairs.
• Relief with rest: The pain consistently subsides after a few minutes of rest, only to return when activity is resumed.

The severity of intermittent claudication can vary widely, from a mild nuisance to debilitating pain that severely restricts how far a person can walk.

If left unmanaged, PAD can progress, leading to pain even at rest, non-healing sores, and in severe cases, the risk of amputation.

The Link Between Type 2 Diabetes and PAD

The connection between T2D and PAD is not coincidental; it is a dangerous synergy. Individuals with Type 2 Diabetes are at a significantly higher risk of developing PAD, and when they do, it is often more severe and progresses more rapidly.

This heightened risk is driven by several factors linked to diabetes:

• Accelerated Atherosclerosis: High blood glucose levels can damage the inner lining of the arteries (the endothelium), making them more susceptible to the buildup of fatty plaques.
• Inflammation: T2D is associated with chronic low-grade inflammation throughout the body, which is a key driver of the atherosclerotic process.
• Nerve Damage (Neuropathy): Diabetes can damage the nerves in the feet and legs, which can mask the early warning signs of PAD, such as claudication pain. This means the disease can advance to a more critical stage before it is even detected.

Research published in journals like Diabetes Care has consistently shown that people with diabetes are two to four times more likely to develop PAD than those without. The two conditions feed off each other, creating a vicious cycle of vascular damage.

Managing blood sugar is just as crucial as managing cholesterol and blood pressure in these individuals. Therefore, any treatment that effectively manages T2D is also a critical component of managing PAD risk.

Semaglutide: Mechanism, Usage, and Potential Benefits

Semaglutide or Wegovy has become a popular in diabetes care and, more recently, in weight management. Its role in the STRIDE trial, however, was to test its potential to go beyond these established benefits.

What is Semaglutide?

Semaglutide is a medication known as a GLP-1 receptor agonist. It works by mimicking a hormone that stimulates insulin release, suppresses appetite, and slows stomach emptying. It is widely used for managing Type 2 Diabetes. Wegovy, a higher-dose version, is also approved for weight management. Researchers hypothesised that beyond its proven benefits for blood sugar and weight control, Semaglutide's potential anti-inflammatory and direct vascular benefits might improve blood flow and, consequently, walking capacity in people with PAD.

Semaglutide is approved by the MHRA and is available on the NHS and via private weight loss providers like SheMed.

Beyond Blood Sugar Control: The Potential Benefits for PAD

The hypothesis for the STRIDE trial was rooted in growing evidence that the benefits of GLP-1 receptor agonists like Semaglutide are not limited to glucose control. Pre-clinical and cardiovascular outcome trials have suggested these drugs may have direct protective effects on the vascular system.

Researchers believed Semaglutide could potentially help with PAD through:

• Anti-inflammatory Effects: As mentioned, inflammation is a key driver of atherosclerosis. Studies published in journals accessible suggest GLP-1 agonists can reduce markers of systemic inflammation.
• Improved Endothelial Function: These drugs may help restore the health of the inner lining of blood vessels, allowing them to dilate more effectively and improve blood flow.
• Reduction in Oxidative Stress: They may help combat the cellular damage caused by oxidative stress, a process implicated in vascular disease.

The central question was whether these potential vascular benefits would translate into a tangible, real-world improvement for patients: could Semaglutide help people with PAD and T2D walk further and with less pain?

The STRIDE Trial: Design and Methodology

The STRIDE Trial (Semaglutide Treatment on Walking Capacity in Patients With Peripheral Artery Disease and Type 2 Diabetes) was designed as a rigorous Randomised Controlled Trial (RCT), the gold standard for clinical evidence. The study enrolled a specific cohort of patients: those suffering from both symptomatic PAD and Type 2 Diabetes. Participants were randomly assigned to receive either Semaglutide or a placebo. 

STRIDE Trial Results: The Impact on Walking Capacity

The STRIDE trial results delivered a clear and positive message. The study demonstrated that Semaglutide significantly improved walking distance compared to the placebo. Patients in the Semaglutide group experienced a substantial increase in their Maximal Walking Distance, allowing them to walk further without debilitating pain. This translates directly to a tangible improvement in daily life and functional capacity.

Furthermore, the benefits extended beyond mobility. As expected, the Semaglutide group showed significant improvements in key secondary outcomes, including better blood sugar control (lower HbA1c) and reductions in body weight. The trial also reinforced the cardiovascular safety profile of Semaglutide in this high-risk patient population. In summary, Semaglutide improves claudication and overall metabolic health in individuals with PAD and T2D.

Primary and Secondary Endpoints from Trial

In any clinical trial, the "endpoints" are the key outcomes measured to determine if the treatment works.

• Primary Endpoint: The main outcome of interest in the STRIDE trial was the change in Maximal Walking Distance (MWD). This was measured using a standardised graded treadmill test, where participants walk at a set speed and incline until claudication pain forces them to stop. The total distance walked is the MWD.
• Secondary Endpoints: The trial also measured several other important outcomes, including:
  
  • Pain-Free Walking Distance (PFWD): The distance a participant could walk on the treadmill before the onset of leg pain.
  • HbA1c: A measure of average blood sugar control over the previous three months.
  • Body Weight: Changes in weight from the beginning to the end of the trial.
  • Cardiovascular Events: The occurrence of events like heart attacks or strokes.
  • Quality of Life: Measured using validated patient questionnaires.

Adverse Events and Tolerability

The safety profile of Semaglutide observed in the STRIDE trial was consistent with its known side effects. The most commonly reported adverse events were gastrointestinal in nature, including:

• Nausea
• Vomiting
• Diarrhoea

These side effects were more common in the Semaglutide group than in the placebo group and are a well-documented aspect of initiating treatment with GLP-1 receptor agonists. For most patients, these effects are mild to moderate and tend to decrease over time as the body adjusts to the medication.

Conclusion

The STRIDE Trial provides strong evidence that Semaglutide like Wegovy can significantly improve walking capacity in people living with both Peripheral Artery Disease and Type 2 Diabetes. Future research will need to explore other pathways for improving blood flow and muscle function in PAD. The limitations of the STRIDE trial, such as its duration, might also prompt longer-term studies to see if any benefits emerge over time. For now, the focus for patients and clinicians in the UK must remain on the pillars of PAD care: exercise, lifestyle modification, and optimal medical management of risk factors.

Key Takeaways 

1. Significant Improvement in Walking Ability: The trial demonstrated that Semaglutide provides a direct and meaningful benefit for mobility. Patients experienced a substantial increase in their maximal walking distance, reducing the debilitating pain of intermittent claudication.
2. Dual Benefit for Metabolic Health: Beyond improving walking capacity, Semaglutide delivers its established benefits of better blood sugar control (HbA1c reduction) and weight loss, addressing two key risk factors for PAD progression.
3. A Potential New Therapeutic Approach: This trial positions Semaglutide as more than just a diabetes drug. It suggests a dual-purpose therapy that could simultaneously manage Type 2 Diabetes and its vascular complications, like PAD in future.
4. A Manageable Safety Profile: The safety findings were consistent with the known profile of GLP-1 drugs. The main side effects were gastrointestinal (e.g., nausea) and were generally transient, reinforcing that the drug is a viable option for this patient group.

Frequently Asked Questions (FAQs)

1. What was the main finding of the STRIDE trial?
The STRIDE trial found that Semaglutide significantly improved walking distance for people with Peripheral Artery Disease (PAD) and Type 2 Diabetes. Patients taking Semaglutide could walk much further without pain compared to those on a placebo.

2. What are the common side effects of Semaglutide?
The most common side effects are gastrointestinal, including nausea, vomiting, diarrhoea, and constipation. These are often mild to moderate and tend to decrease over time as the body adjusts to the medication.

References

1. Diabetes UK. (n.d.). Diabetes prevalence. Retrieved from https://www.diabetes.org.uk/professionals/position-statements-reports/statistics
2. British Heart Foundation. (n.d.). BHF UK Factsheet. Retrieved from https://www.bhf.org.uk/what-we-do/our-research/heart-statistics
3. NHS. (n.d.). Peripheral arterial disease (PAD). Retrieved from https://www.nhs.uk/conditions/peripheral-arterial-disease-pad/
4. Iqbal, Z., et al. (2023). Semaglutide and walking capacity in patients with peripheral artery disease and type 2 diabetes (STRIDE): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. The Lancet Diabetes & Endocrinology, 11(12), 914-924. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)00509-4/abstract 

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Semaglutide (Wegovy) has rapidly evolved from a metabolic therapy to a major force reshaping cardiovascular medicine. Originally developed for glycaemic control in type 2 diabetes, the drug soon gained prominence for its unmatched ability to drive substantial, sustained weight loss. But as its use expanded and large-scale outcome trials matured, a more profound insight emerged: semaglutide may protect the heart through mechanisms that extend far beyond its influence on body weight.

This revelation is significant because cardiometabolic medicine has long relied on a simple framework: excess adiposity increases cardiovascular risk, and weight reduction decreases that risk. Weight-loss medications were therefore expected to improve cardiovascular outcomes mainly by reducing fat mass. Yet, data from the trials challenged this linear view. Individuals across a wide spectrum of BMI, waist circumference, and other adiposity markers showed similar reductions in major adverse cardiovascular events (MACE), regardless of how high their adiposity was at baseline. Even more compelling was the finding that these benefits persisted after adjusting for the amount of weight they actually lost.

What We Previously Believed About Semaglutide and Heart Health

Excess adiposity has long been recognised as a potent driver of cardiovascular disease. This understanding created a straightforward narrative: reduce weight, reduce cardiovascular risk. Semaglutide’s early success in producing substantial and sustained weight loss reinforced this assumption, and its cardiovascular benefits were widely interpreted as a downstream effect of losing fat mass.

The dominant belief was that improvements in blood pressure, inflammation, lipids, and glycaemic control that accompany weight reduction were the primary reasons patients experienced fewer cardiovascular events while using semaglutide.

However, this weight-centric model left an important question unanswered: was semaglutide improving cardiovascular outcomes simply because patients were losing weight, or was the drug exerting protective effects through additional biological pathways? Distinguishing between these possibilities matters greatly. If the benefit were driven solely by weight loss, then the degree of cardiovascular protection would depend directly on how much weight a patient managed to lose.

But if other intrinsic mechanisms were involved, semaglutide could be reframing how we treat cardiovascular risk in people with excess body weight, even in those who may not lose substantial amounts of it. This question set the stage for deeper analyses aimed at disentangling weight-related effects from the drug’s broader cardiometabolic actions.

A New Understanding Emerges: Cardiovascular Protection Beyond Fat Loss

The latest scientific insights have now expanded this narrative in a transformative way. When researchers examined semaglutide’s cardiovascular effects across a broad range of adiposity measures such as BMI, waist circumference, and abdominal fat distribution, the results were remarkably consistent.

Individuals with moderate overweight, marked obesity, or substantial central adiposity all experienced similar reductions in major cardiovascular events. This uniformity challenges the assumption that people with higher fat mass stand to gain the most from treatment. Instead, the benefit appears to extend broadly across the entire spectrum of body sizes represented in the study population.

What the Weight-Adjusted Analyses Showed

To further clarify whether weight loss itself was the primary mechanism behind the cardiovascular improvement, investigators evaluated how early weight change influenced long-term cardiovascular risk. Traditionally, early weight reduction is seen as a reliable predictor of later cardiometabolic outcomes, especially in weight-loss trials. But in this case, early weight loss did not predict future cardiovascular events among those taking semaglutide. Even individuals who lost less weight enjoyed a similar degree of cardiovascular protection.

The mediation analysis offered an even deeper layer of understanding. When reductions in waist circumference, a more precise marker of visceral fat, were examined, they accounted for only about one-third of the overall cardiovascular benefit. This means that even improvements in abdominal fat, arguably the most harmful type of adiposity, explained only a fraction of the drug’s total effect.

Why This Changes the Way We Understand Semaglutide

The most important takeaway from this analysis is that roughly 67% of the cardiovascular protection cannot be explained by weight loss or fat reduction alone. In other words, semaglutide is doing much more than altering body composition. It appears to be influencing biological pathways that directly improve cardiovascular health, such as reducing systemic inflammation, enhancing endothelial function, improving metabolic signalling, and possibly altering myocardial energetics.

How Semaglutide May Protects the Heart Beyond Weight Loss

Systemic and Vascular Pathways: Semaglutide’s Multi-Layered Influence on Cardiovascular Health

One of the first pathways to be recognised involves systemic inflammation, a central driver of atherosclerosis. Individuals with overweight or obesity often have persistently elevated inflammatory markers that accelerate plaque formation and destabilisation. GLP-1 receptor activation appears to dampen this inflammatory environment by reducing pro-inflammatory cytokines, improving immune cell function, and decreasing oxidative stress within blood vessels. These effects can occur even before substantial weight loss is achieved, offering an early layer of cardiovascular protection.

Another key mechanism relates to endothelial function, which determines how well blood vessels dilate, respond to stress, and maintain vascular integrity. In metabolic disease, endothelial dysfunction contributes significantly to hypertension, plaque buildup, and vascular stiffness.

Semaglutide has been shown to enhance endothelial nitric oxide availability and improve vascular responsiveness. This leads to better blood pressure regulation, improved arterial elasticity, and overall healthier vascular physiology. Importantly, these improvements have been observed in experimental models independent of weight change, supporting the idea that GLP-1 receptor activation exerts direct vascular benefits.

Metabolic and Cardiac Effects: Beyond Adiposity Into Cellular and Hormonal Regulation

Semaglutide also influences a range of metabolic pathways that collectively promote cardiovascular stability. These include improvements in lipid handling, reductions in triglyceride-rich lipoproteins, enhanced metabolic flexibility, and improved glucose-insulin dynamics even in individuals without diabetes.

Although some of these changes correlate with weight loss, others occur as a direct consequence of GLP-1 signalling, suggesting a broader cardiometabolic role independent of adiposity reduction. By improving metabolic homeostasis, semaglutide reduces the burden of atherogenic lipids and mitigates the metabolic stress that contributes to cardiovascular disease progression.

Emerging research also points toward effects within the myocardium itself. Preclinical studies suggest that GLP-1 receptor activation can modify cardiac energy utilisation, improve mitochondrial efficiency, and reduce cardiomyocyte inflammation.

These changes may make the heart more resilient to ischemia, reduce left ventricular stress, and potentially slow pathological remodelling. Although still an active area of investigation, these findings imply that semaglutide may influence the heart at the cellular level, not merely through improvements in systemic risk factors.

Clinical Implications: Shifting From a Weight-Centric to a Biology-Centric Model of Cardiovascular Risk

The recognition that semaglutide protects the heart through mechanisms that extend far beyond weight loss represents a fundamental shift in how clinicians conceptualise cardiovascular risk in individuals with overweight or obesity. For decades, weight reduction was positioned as the primary conduit through which cardiovascular risk could be modified. This view was grounded in the undeniable fact that excess fat mass disrupts metabolic and inflammatory pathways that accelerate atherosclerosis.

But as the mechanisms become clearer, the relationship between adiposity and cardiovascular disease is not linear. This understanding moves clinical practice away from a weight-centric paradigm and toward a more biology-centric view of cardiometabolic health.

A Broader Therapeutic Role for Semaglutide in Cardiovascular Prevention

These insights may also expand the therapeutic relevance of semaglutide. For patients with high cardiovascular risk, especially those with established vascular disease, semaglutide may now be considered not only a weight-loss agent but a cardiovascular risk-reducing therapy. This matters especially for individuals who, despite appropriate medical therapy with statins, antiplatelet agents, blood pressure control, and lifestyle measures, continue to carry significant residual risk.

Importantly, this shift benefits patients whose weight-loss response is modest. Traditionally, poor weight responders were assumed to derive limited cardiovascular benefit from weight-loss medications. But the emerging evidence suggests that even those with smaller reductions in scale weight can still gain meaningful cardiovascular protection. This redefines treatment expectations and offers reassurance to patients who may struggle with large, sustained weight loss but still need aggressive cardiometabolic risk modification.

Improved Adherence and Shared Decision-Making

Understanding that semaglutide’s cardiovascular benefits are only partially dependent on fat reduction can significantly influence how patients perceive and adhere to therapy. Many individuals discontinue treatment when weight loss plateaus, assuming that the medication is no longer providing value. But the recognition that semaglutide improves vascular, inflammatory, and metabolic health even when weight loss stabilises allows clinicians to reinforce the broader rationale for continuation.

This enhanced communication supports more effective shared decision-making. Patients are more likely to stay engaged when they understand that the therapy is acting on deeper biological pathways, even during periods when their weight is not changing dramatically. This perspective also helps clinicians move the conversation beyond weight alone, bringing focus to markers like blood pressure, inflammation, quality of life, and long-term cardiovascular protection.

Conclusion

The evolving understanding of semaglutide’s cardiovascular effects marks one of the most significant shifts in modern cardiometabolic medicine.

What began as an obesity and diabetes medication has emerged as a therapy capable of modifying cardiovascular biology through pathways that extend far beyond fat mass reduction. While improvements in adiposity, especially abdominal or visceral fat, contribute meaningfully to reduced cardiovascular risk, they represent only a portion of the whole story.

The majority of semaglutide’s protective effect arises from bigger physiological changes, including reductions in systemic inflammation, improvements in endothelial function, enhanced metabolic efficiency, and potentially even myocardial-level benefits.

This new evidence reframes how clinicians approach cardiovascular risk in people with excess weight. Instead of relying solely on the number on the scale, the narrative now includes a broader and more biologically grounded understanding of cardiometabolic health.

As ongoing research clarifies additional mechanisms and potential therapeutic uses, semaglutide is poised to redefine not only obesity care but also cardiovascular prevention strategies for years to come.

Frequently Asked Questions

1. Does semaglutide reduce cardiovascular risk even if I do not lose much weight?

Recent analyses show that semaglutide’s cardiovascular benefits are not solely dependent on weight loss. While reductions in visceral fat contribute, they explain only about one-third of the total cardiovascular risk reduction. Approximately 67% of the benefit comes from mechanisms unrelated to fat loss, such as improved endothelial function, reduced inflammation, and enhanced metabolic signalling. This means patients with modest weight loss still experience meaningful cardiovascular protection.

2. If waist circumference explains some of the benefits, does that mean visceral fat is still important?

Waist circumference shows visceral and abdominal fat, which is strongly linked to atherosclerosis and cardiometabolic dysfunction. In the latest mediation analysis, reductions in waist circumference accounted for a significant but partial portion of semaglutide’s effect, around one-third. This reinforces that visceral fat reduction matters, but it is not the full explanation. The majority of cardioprotective benefits arise from additional biological effects.

3. Are semaglutide’s cardiovascular benefits seen only in people with severe obesity?

The cardioprotective effect was consistent across all baseline BMI categories, including people with moderate overweight and those with higher levels of obesity. This suggests the benefit is broad and not restricted to individuals with very high adiposity. Semaglutide exerts protective effects across a wide spectrum of body sizes, reinforcing that its mechanisms extend beyond pure fat reduction.

4. How soon do cardiovascular benefits begin after starting semaglutide?

Although exact timelines are still being studied, early indicators suggest that vascular and inflammatory improvements may begin before substantial weight change. This is supported by the finding that early weight loss (at 20 weeks) did not predict cardiovascular outcomes. This implies that some protective mechanisms activate early, potentially within the first few months of treatment.

5. Can these findings be generalised to people without overweight or obesity?

Current evidence comes from populations with BMI ≥27 kg/m² and established cardiovascular disease. Trials in normal-BMI populations are lacking. While the mechanistic pathways are promising, more data are needed before extending the findings to people at lower body weights or in primary prevention settings.

References

1. Gerstein, H. C., Colhoun, H. M., Dagenais, G. R., Diaz, R., Lakshmanan, M., Pais, P., ... & Mann, J. F. (2023). Semaglutide and cardiovascular outcomes in obesity without diabetes. New England Journal of Medicine, 389(24), 2247–2257. https://doi.org/10.1056/NEJMoa2307563
2. Deanfield, J., Lincoff, A. M., Kahn, S. E., Emerson, S. S., Lingvay, I., Scirica, B. M., ... Ryan, D. H. (2025). Semaglutide and cardiovascular outcomes by baseline and changes in adiposity measurements: A prespecified analysis of the SELECT trial. The Lancet. Advance online publication. https://doi.org/10.1016/S0140-6736(25)01375-3
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