Feeling constantly hungry, battling random cravings, or feeling like your body is “working against you” is not a personal failing. GLP-1, a key hormone that regulates appetite, fullness, and blood sugar, plays an important role in these experiences.
It is released from intestinal L-cells after eating and helps stimulate insulin, reduce glucagon, slow stomach emptying, and promote satiety, making it central to metabolic health and a major target in obesity and type 2 diabetes care.
Medications like semaglutide and tirzepatide are designed to mimic or enhance GLP-1 activity, but everyday dietary choices can also help support your body’s own GLP-1 response.
Research suggests that people with higher natural GLP-1 responses may eat around 20–30% fewer calories after a meal, highlighting how powerful this hormone can be in shaping appetite. The following article focuses on six food categories rich in specific nutrients that may naturally stimulate GLP-1 release and help you feel more satisfied throughout the day.
Supporting your body’s natural GLP-1 response may be simpler than many people expect. Below are six food categories that research has linked with GLP-1 activity, along with practical ways they are commonly included in everyday diets.
Starting the day with eggs is a common dietary choice in many balanced eating patterns. Eggs provide a source of high-quality protein and fats, nutrients that have been studied for their potential role in supporting feelings of fullness after meals.
Some research suggests that meals higher in protein, including those containing eggs, may be associated with improved post-meal blood sugar responses and increased satiety when compared with higher-carbohydrate breakfasts. These effects are thought to involve appetite-regulating hormones such as GLP-1 and peptide YY (PYY), which play a role in signalling fullness.
Including eggs as part of breakfast may help some people feel more satisfied for longer and support overall dietary balance. As with all foods, individual responses can vary, and eggs are best consumed as part of a varied, nutritious diet.
Nuts such as almonds, pistachios, and peanuts provide a combination of protein, unsaturated fats, and dietary fibre that slows gastric emptying, supports insulin sensitivity, and is associated with increased GLP-1 release and satiety.
Regular nut intake has been linked with improved glycaemic control, greater fullness, and reduced risk markers for type 2 diabetes and cardiovascular disease in clinical and epidemiological studies.
Fermentation of nut fibre by gut bacteria produces short-chain fatty acids, which can stimulate GLP-1 secretion from intestinal L-cells through dedicated receptors and related metabolic pathways.
If you are not allergic to nuts, include a small handful of nuts as a snack or add them to meals like yoghurt, salads, or porridge as a practical way to support natural GLP-1 activity and promote fullness. Evidence suggests that nut-based snacks can enhance satiety and modulate appetite-regulating hormones, including GLP-1, compared with refined-carbohydrate options.
Whole grains such as oats, barley, and whole wheat are rich in soluble fibre, which helps smooth out post-meal rises in blood glucose and is associated with increased GLP-1 secretion and improved satiety. Soluble fibre forms a gel-like texture in the gut that slows digestion and glucose absorption, providing a more gradual stimulus for appetite-regulating hormones like GLP-1 and PYY.
A key part of this effect comes from fermentation of fibre by gut bacteria into short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate, which can activate receptors on intestinal L-cells and promote GLP-1 release. Randomised controlled trials have shown that high-fibre, oat-based meals can increase GLP-1 and PYY levels, enhance fullness, and reduce subsequent energy intake compared with low-fibre cereals.
Choosing high-fibre grains like oats and barley in place of refined grains (for example, white bread or sugary cereals) is a practical, research-supported way to support natural GLP-1 activity and appetite regulation. People with coeliac disease or gluten intolerance should select certified gluten-free whole-grain options and seek personalised dietary advice where needed.
Avocado is a source of monounsaturated fats and soluble fibre, nutrients that are commonly associated with supporting satiety and digestive comfort. Soluble fibre can contribute to slower digestion and more gradual nutrient absorption, while unsaturated fats are often included in dietary patterns linked with metabolic health.
Some research has explored the relationship between avocado consumption and post-meal hormonal responses, including appetite-regulating hormones such as GLP-1 and peptide YY (PYY). These studies suggest that meals containing avocado may be associated with greater feelings of fullness and more stable post-meal insulin responses in some individuals.
Including avocado in meals such as salads or sandwiches may help support satiety as part of a balanced diet. Individual responses can vary, and avocado is best consumed alongside a variety of other nutrient-rich foods.
Olive oil is a key component of Mediterranean-style eating patterns and is a source of monounsaturated and polyunsaturated fats. Diets that include higher proportions of unsaturated fats are commonly associated with cardiometabolic health and may influence post-meal satiety responses.
Research examining Mediterranean dietary patterns has explored their relationship with appetite-regulating hormones, including GLP-1. Some studies suggest that meals rich in unsaturated fats, such as those containing olive oil, may be associated with differences in post-meal hormonal responses and markers of glycaemic control when compared with lower-fat dietary approaches. These effects are thought to involve interactions between dietary fats and gut-derived hormones, although the exact mechanisms are still being studied.
Using olive oil in cooking or as a salad dressing can be a practical way to include unsaturated fats as part of a balanced diet. As with all dietary choices, individual responses may vary, and olive oil is best consumed in moderation alongside a variety of nutrient-rich foods.
Non-starchy vegetables such as Brussels sprouts, broccoli, and carrots provide dietary fibre, vitamins, and a range of plant compounds that support overall nutritional quality. Fibre-rich foods are commonly associated with digestive health and may influence feelings of fullness after meals.
Some research has examined how the order in which foods are consumed -such as eating vegetables before carbohydrate-rich foods-may affect post-meal glucose responses and appetite-related hormones, including GLP-1. These studies suggest that prioritising vegetables earlier in a meal may be associated with more gradual rises in blood glucose and differences in satiety signals, particularly in certain populations. The underlying mechanisms are still being explored and may involve interactions between dietary fibre, digestion, and gut-derived signals.
Including non-starchy vegetables as part of the first course of a meal can be a practical way to increase fibre intake and support balanced blood sugar responses as part of an overall healthy eating pattern. Individual responses may vary.
The secretion of GLP-1 is closely linked to nutrient sensing by L-cells in the distal small intestine and colon. Specific nutrients, including proteins, peptides, fatty acids, and monosaccharides, interact with G-protein coupled receptors and transporters on L-cells, triggering intracellular signalling cascades that culminate in GLP-1 exocytosis.
Protein ingestion, for example, leads to the generation of peptides and amino acids that bind to calcium-sensing receptors and other nutrient sensors on L-cells, directly stimulating GLP-1 release. Similarly, mono- and polyunsaturated fats activate free fatty acid receptors (FFAR1 and FFAR4), while fibre-derived SCFAs interact with FFAR2 and FFAR3 to promote GLP-1 secretion.
Overall, protein, healthy fats, and dietary fibre represent the three main dietary triggers for endogenous GLP-1 release. Their combined presence in whole, minimally processed foods accounts for the satiety-enhancing and glucose-lowering effects observed in dietary intervention studies.
The interplay between dietary fibre, gut microbiota, and GLP-1 secretion exemplifies the complex synergy underlying metabolic health. Fibre that escapes digestion in the upper gastrointestinal tract is fermented by colonic bacteria, resulting in the production of SCFAs such as acetate, propionate, and butyrate. These SCFAs serve as signalling molecules that activate FFAR2 and FFAR3 on L-cells, directly inducing GLP-1 release.
This gut microbiota-mediated mechanism not only enhances GLP-1 secretion but also confers additional metabolic benefits, including improved insulin sensitivity, reduced inflammation, and maintenance of gut barrier integrity. The inclusion of high-fibre foods such as whole grains, nuts, vegetables, and legumes thus represents a cornerstone of dietary strategies aimed at boosting GLP-1 and supporting overall metabolic health.
Dietary patterns that include adequate protein, fibre, and unsaturated fats are commonly associated with satiety, balanced blood sugar responses, and overall metabolic health. Foods such as eggs, nuts, high-fibre grains, avocado, olive oil, and non-starchy vegetables provide a range of nutrients that have been studied for their potential association with appetite-regulating hormones, including GLP-1. These foods contribute to feelings of fullness and may support steadier post-meal glucose responses as part of a balanced diet.
Research exploring GLP-1 has primarily focused on its role in appetite regulation and glucose metabolism. While diet alone is not a treatment for metabolic conditions, nutritional approaches that prioritise whole, fibre-rich, and protein-containing foods are widely recommended to support long-term health. Individual responses can vary, and dietary strategies are most effective when tailored to personal needs, preferences, and medical guidance.For those exploring structured weight-management support, clinically supervised programmes can help integrate nutrition, lifestyle, and medical considerations in a safe and evidence-informed way.
If you would like to learn more about medically supported weight-management options, SheMed offers personalised programmes designed to align with individual health goals. Eligibility assessment is available online to help determine whether a programme may be suitable.
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as semaglutide (Wegovy) and liraglutide, are transforming the management of type 2 diabetes mellitus (T2DM) and obesity. Everyone is well-versed in their effects on blood sugar, weight, and the cardiovascular system.
One area of growing clinical interest is the impact of GLP-1 RAs on eye health, specifically their relationship with glaucoma, a progressive optic neuropathy that can lead to irreversible vision loss.
According to the National Health Service (NHS), glaucoma is a significant public health concern, with chronic open-angle glaucoma affecting approximately 480,000 people across the country.
Recent research supported by large-scale retrospective studies suggests that GLP-1 RAs are associated with a reduced risk of glaucoma incidence, particularly primary open-angle glaucoma (POAG), compared with other antidiabetic agents. This article provides a comprehensive, evidence-based analysis of the current state of knowledge regarding GLP-1 RAs and glaucoma risk.
GLP-1 RAs, also known as incretin mimetics, are a class of drugs that enhance glucose-dependent insulin secretion, suppress glucagon release, delay gastric emptying, and promote satiety, making them effective treatments for T2DM and obesity. Semaglutide, in particular, has gained widespread attention due to its efficacy in both glycaemic control and weight reduction.
Glaucoma is an umbrella term for a group of optic neuropathies characterised by progressive loss of retinal ganglion cells (RGCs) and corresponding visual field defects, frequently but not exclusively associated with elevated intraocular pressure (IOP). The most common subtype, primary open-angle glaucoma (POAG), is a leading cause of irreversible blindness worldwide. Diabetes is a well-recognised risk factor for glaucoma, likely due to shared pathways involving vascular dysregulation, oxidative stress, and neurodegeneration.
Several robust observational studies have investigated the association between GLP-1 RA use and glaucoma risk. Population-based registry analyses from Denmark and large US cohort studies consistently demonstrate a protective signal. Research, like a Danish nationwide case control study, found that patients with T2DM initiating GLP-1 RA therapy had a 19–29% lower risk of developing POAG compared to those prescribed other anti-diabetic agents. These findings further suggest that the magnitude of risk reduction increases with the duration of GLP-1 RA exposure; patients using these agents for more than three years experienced the most pronounced benefits.
Importantly, emerging data indicate that the glaucoma-protective effect of GLP-1 RAs may extend beyond patients with diabetes. Observational analyses in obese, non-diabetic individuals prescribed GLP-1 RAs for weight management also show a reduced risk of incident glaucoma.
This suggests the benefit may not solely be attributabled to improved glycaemic control and may instead reflect a direct neuroprotective action. While these findings are compelling, it is crucial to acknowledge the limitations inherent in observational research, including residual confounding and potential selection bias.
Nevertheless, the consistency and magnitude of the association, alongside plausible biological mechanisms, strengthen the case for a genuine effect.
The mechanisms underlying the glaucoma-protective effects of GLP-1 RAs are under active investigation. The following pathways are most frequently proposed:
Collectively, these mechanisms align with contemporary theories of glaucoma pathogenesis as a neurodegenerative disease with vascular and inflammatory components, not simply one of elevated IOP.
While the evidence for a glaucoma-protective effect is encouraging, clinicians should balance this against specific ocular safety considerations associated with GLP-1 RAs. These include the potential for diabetic retinopathy progression and the rare but serious risk of non-arteritic anterior ischemic optic neuropathy (NAION).
A paradox exists in the relationship among GLP-1 RAs, glycaemic control, and progression of diabetic retinopathy (DR). Long-term glycaemic improvement is unequivocally beneficial for retinopathy risk, yet rapid reductions in glycated haemoglobin (HbA1c), particularly greater than 2% over a short period, can transiently worsen pre-existing, advanced DR. This phenomenon was highlighted in the SUSTAIN-6 trial, where patients with advanced baseline DR who experienced rapid HbA1c declines on semaglutide had higher rates of retinopathy progression compared to controls.
Key clinical implications include:
This emphasises the need for careful patient selection and counselling, as well as integrated care between diabetologists, general practitioners, and ophthalmologists.
NAION is characterised by sudden, painless visual loss due to infarction of the optic nerve head in the absence of giant cell arteritis. While rare, several post-marketing reports and some large database studies suggest a possible increased risk of NAION associated with certain GLP-1 RAs, including semaglutide.
The proposed mechanism involves systemic fluctuations in blood pressure and glucose, which, when superimposed on a “disc at risk” (an anatomically crowded optic nerve head), may precipitate ischemic events. Patients with diabetes, hypertension, hyperlipidaemia, and established small vessel disease are particularly susceptible.
Clinical recommendations include:
The neuroprotective properties of GLP-1 RAs in glaucoma reflect a broader paradigm shift in the management of neurodegenerative diseases, emphasising multi-modal strategies that target not only acute injury but also the chronic processes underpinning neuronal loss. Lessons from preclinical and translational research in cerebral ischemia and stroke illuminate both the promise and challenges of neuroprotective therapy.
Amato and Arnold (2020) provided additional mechanistic clarity, modelling the activation of microglia and the balance between pro- and anti-inflammatory phenotypes (M1 and M2) in ischemic stroke. Their results suggest that early inhibition of M1 (pro-inflammatory) activation and support of M2 (anti-inflammatory) activation can shift the neuroinflammatory milieu towards tissue repair and recovery. By extension, GLP-1 RAs through their modulation of microglial activation may replicate these neuroprotective dynamics in the optic nerve, offering a biological rationale for the observed reduction in glaucoma risk.
Current research has examined a possible association between GLP-1 receptor agonist use and glaucoma-related outcomes, but the evidence remains limited and observational. Proposed neurobiological mechanisms have not been conclusively established, and no protective effect has been confirmed.
Existing literature highlights the importance of clinical awareness of ocular changes, particularly in people with diabetes, including transient changes in diabetic retinopathy and rare optic nerve events. Clinical decisions should continue to follow approved indications, individual patient factors, and established guidelines.
Further prospective and randomised studies are needed to clarify any relationship between GLP-1 receptor agonists and glaucoma, as well as their long-term ocular safety.
For most of my life, I knew something wasn’t right. I had every resource at my fingertips – access to specialists, a degree in nutrition, and a family with a background in healthcare, yet I was trapped in a body that didn’t make sense to me.
For years, I lived with excruciating pain, bloating, and cysts that would send me to the hospital time and time again. I had surgeries, ultrasounds, endless blood tests and still, no one could tell me why this was happening. It took nearly a decade before I finally received the diagnosis that explained everything: Polycystic Ovary Syndrome (PCOS).
Getting that diagnosis was both disheartening and liberating. Disheartening because I’d spent ten years fighting for an answer but liberating because, at last, I knew what I was up against. For the first time, I could treat the root cause instead of just the symptoms.
This is when my GLP-1 journey began and I was able to experience SheMed through a completely new lens; a member. It’s hard to put into words how much it changed my life. Within months, the chronic pain that had defined my every day; the sharp pelvic aches, the fatigue, the inflammation began to fade. For the first time in my adult life, I felt normal.
As someone who studied nutrition, played three sports, and still to this day works out five days a week, I’ve always lived an active and healthy lifestyle. Yet despite doing “everything right,” I couldn’t lose the extra weight brought on by my PCOS. On GLP-1s, my body finally responded. I shed 30 pounds in a healthy, steady way. But more importantly, I finally felt like my body was working with me instead of against me.
This medication has given me my life back. That’s why I plan to continue taking it for the foreseeable future, because for me it’s not about vanity or temporary results. It’s about treating a chronic condition that has caused years of pain and frustration. Stopping it would mean stopping the only treatment that has ever truly worked for me.
I know for many, GLP-1s are part of a weight loss journey, and that’s wonderful. But for me, and for so many others, this is about much more than the number on a scale. It’s about healing from the inside out. PCOS, endometriosis, and obesity are all examples of chronic conditions, and they all deserve compassion, understanding, and long-term care.
So wherever you are on your journey, listen to your body – really listen.
Not just to the number on the scale, but to your blood work, your hormones, your energy, and always your clinicians.
Do your research. Stay consistent. Keep taking your meds.
Because the most powerful transformation isn’t what people see, it’s what’s happening within.
💗 OliviaCo-Founder, SheMed
In recent years, medications like Wegovy (Semaglutide) and Mounjaro (Tirzepatide) have taken the world by storm, revolutionising the management of Type 2 diabetes and obesity. Their profound impact on blood sugar control and weight loss has generated headlines and offered new hope to millions. But what if this was just the beginning? What if the next generation of metabolic medicine could deliver even more powerful results?
Enter Retatrutide, an investigational medicine that is rapidly becoming one of the most talked-about drugs in development.
Nicknamed the "Triple G" drug, Retatrutide is currently undergoing extensive Phase 3 clinical trials and is not yet available to the public.
Its unique power lies in its ability to target not one, not two, but three key metabolic hormone receptors, a triple-action mechanism that promises to push the boundaries of what's possible in diabetes and weight management.
This article will delve into the ground-breaking science to discover how Retatrutide could revolutionise diabetes and weight loss management with its triple-agonist action.
The excitement surrounding Retatrutide stems from its sophisticated and unprecedented mechanism of action. While older drugs target a single hormone pathway, Retatrutide is a triple receptor agonist, engaging with three distinct hormones that play a crucial role in regulating our metabolism, appetite, and blood sugar. This multi-pronged attack is what sets it apart and gives it a potential clinical edge.
To understand its power, we need to break down each component of its "Triple G" action:
This triple-action mechanism results in a powerful synergy. The GLP-1 and GIP components work together to control blood sugar and suppress appetite, while the glucagon component accelerates fat burning and energy use. For a person with Type 2 diabetes, this combination is revolutionary. It not only addresses high blood sugar (hyperglycaemia) but also tackles one of the primary drivers of the condition: excess body weight, particularly visceral fat. The strong link between weight loss and improved diabetes outcomes is well-established, with bodies like the American Diabetes Association (ADA) highlighting that significant weight reduction can even lead to remission in some cases.
The theoretical promise of Retatrutide's triple-action mechanism has been powerfully validated by its clinical trial results. The data from the Phase 2 trial, published in The Lancet, has sent waves of excitement through the medical community. The study evaluated the drug's effects on individuals with Type 2 diabetes over 36 weeks, revealing unprecedented efficacy in both blood sugar control and weight loss.
A key measure for diabetes management is HbA1c, which reflects average blood glucose levels over the preceding two to three months. According to NICE guidelines in the UK, a target HbA1c for adults with Type 2 diabetes is typically 48 mmol/mol (6.5%) or lower.
In the Phase 2 trial, participants receiving the highest doses of Retatrutide saw their HbA1c levels fall by a staggering average of 2.02% (22.1 mmol/mol). This reduction is significantly greater than that seen with many existing diabetes medications. To put this into perspective, a large number of participants achieved levels that are considered non-diabetic:
These results suggest that Retatrutide has the potential not just to manage Type 2 diabetes, but to normalise blood sugar
While glucose control was impressive, the weight-loss results were truly groundbreaking.
Obesity is a major risk factor and complicating factor for Type 2 diabetes, and achieving substantial weight loss is critical for improving insulin sensitivity and overall health.
The trial participants on the highest dose of Retatrutide lost an average of 16.9% of their body weight (around 17.5 kg or 38.6 lbs) in just 36 weeks. A separate Phase 2 trial focusing on obesity, published in The New England Journal of Medicine, showed even more profound results over a longer period, with participants losing up to 24.2% of their body weight at 48 weeks.
This level of weight loss, achieved without intensive surgical intervention, was previously unimaginable for a pharmaceutical drug. Crucially, a substudy using advanced imaging techniques revealed that this weight loss was primarily due to a reduction in fat mass, not muscle.
Participants lost up to 26.1% of their total fat mass while largely preserving lean muscle tissue, which is vital for maintaining metabolic health and physical strength. This targeted fat reduction directly contributes to improved insulin sensitivity and can significantly ease the metabolic burden of Type 2 diabetes.
The research data strongly suggest that adding glucagon receptor agonism provides a significant clinical advantage. While Mounjaro's dual action demonstrated the benefit of targeting more than one pathway, Retatrutide's third mechanism appears to unlock a new level of efficacy. The glucagon action's ability to increase energy expenditure and burn fat on top of the appetite suppression and insulin regulation from GLP-1 and GIP creates a comprehensive metabolic treatment that tackles the problem from three different angles. This is why experts believe Retatrutide could offer superior and more durable results for both diabetes control and weight reduction.
While the clinical trial results for Retatrutide are incredibly promising, it is absolutely vital for the public to understand its current status.
Retatrutide is an investigational drug and is NOT approved for public use anywhere in the world yet ( 12 December 2025), including the United Kingdom.
If you see advertisements for Retatrutide or its compounded form on social media like TikTok or Instagram, you should not purchase it, as this substance is currently an investigational drug, has not been approved by the MHRA or other regulatory bodies for prescription or sale, and is only legally available to participants in clinical trials, which are not expected to conclude until 2026 at the earliest; consequently, any website or seller offering it is doing so illegally, and buying unregulated, non-pharmacy grade compounds carries serious health risks, including potential contamination, incorrect dosages, and severe adverse effects.
The extraordinary public appetite for these groundbreaking new metabolic drugs has, regrettably, given rise to a perilous unregulated trade for unapproved substances. Unscrupulous sellers are frequently peddling these products online, often marketing them dishonestly as "research peptides" in an attempt to sidestep crucial regulations. It is absolutely vital that the public understands the serious risks associated with buying these illicit products:
Regulatory bodies are actively cracking down on this illegal trade. The MHRA recently announced a raid on an illegal manufacturing facility, seizing thousands of doses of unapproved products. This highlights the very real and present danger of the unregulated market.
Retatrutide represents a potential paradigm shift in the treatment of Type 2 diabetes and obesity. Its unique triple-action mechanism has delivered unprecedented results in clinical trials, offering the possibility of not just managing these chronic conditions, but of normalising key metabolic markers to a degree previously thought impossible with medication alone.
The significant reductions in HbA1c and body weight point to a future where medicine moves beyond simple glucose control and towards a more comprehensive and holistic approach to metabolic health. However, excitement must be tempered with patience and caution.
The global medical community now awaits the results of the large-scale Phase 3 trials to confirm these promising findings and, most importantly, to establish a long-term safety profile. Retatrutide is a beacon of hope and a testament to the incredible pace of medical innovation. While it is not a solution for today, it provides a tantalising glimpse into the future of metabolic medicine, a future that looks brighter and more hopeful than ever before.
You do not have to wait for Retatrutide to be approved.
You can start transforming your life and health today with currently approved, effective treatments like Wegovy or Mounjaro (where clinically appropriate).
Looking for effective and weight management solutions? Discover our evidence-based weight loss programme at SheMed, designed for lasting results and delivered with clinical excellence.
Frequently Asked Questions (FAQs)
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.
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.
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:
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 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:
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 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.
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.
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:
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 (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.
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.
In any clinical trial, the "endpoints" are the key outcomes measured to determine if the treatment works.
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:
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
