A study using semaglutide confirms that weight loss in people (predominantly men) with obesity and pre-existing cardiovascular, peripheral vascular or cerebral vascular disease prevents adverse cardiovascular events, death from adverse cardiovascular events and all-cause mortality.

The study population did not include people with type 2 diabetes. The dose of semaglutide that was used was 2.4 mg/week which is a significantly higher dose than that used to treat people with type 2 diabetes.

Just over 17,500 participants were enrolled in the study half receiving semaglutide and half receive 04 in duration of 34 months with a mean duration of follow-up of 39 months. The primary cardiovascular end point was a composite risk of death from cardiovascular causes, nonfatal heart attack or nonfatal stroke in the time to event analysis. The primary endpoint occurred in 6.5% of people administering semaglutide and 8% of people in the placebo group.16.6% of people in the treatment group discontinue treatment due to adverse effects compared to 8% in the placebo group.

There are 2 important points to note about this study. Firstly this group of participants were were comprised of mostly men (72.2%) with an average age of 61, secondly the participants mostly had complicated obesity with pre-existing cardiovascular disease. For example 68% had had a prior myocardial infarction 18% / 4% peripheral vascular disease 8% to a more of these. There was a significant proportion with elevated risk factors including the typical dyslipidaemia of the metabolic syndrome with a low good cholesterol and elevated triglycerides, elevated blood pressure.

Essentially the study confirms the benefit of weight loss to reduce residual risk in people at high risk of cardiovascular events.

The mean change in weight after 104 weeks after randomisation with 9.39% in the semaglutide treated group and 0.88% on the placebo treated group. Weight circumference decreased just over 7.5 cm in the semaglutide group and 1 cm in the placebo group there were also greater reductions in glycated haemoglobin systolic and diastolic blood pressure, a marker of inflammation, an increase in the good cholesterol HDL and a a very striking decrease in triglyceride concentration.

The participants in the study were all enrolled in a lifestyle programme that involved healthy eating and physical activity and control of alcohol intake.

Apart from confirming the benefit of using semaglutide to induce significant weight loss over the time, this study serves to remind us that management of weight has substantial benefits to reduce in people (in this case particularly men) at high risk residual risk of cardiovascular disease. It is likely that for ongoing benefit use of the drug will need to be sustained.

This study's findings carry significant implications, especially considering the alarming projection that more than half the global population will grapple with overweight or obesity by 2035. The trial, involving over 17,000 overweight/obese patients showed that once-weekly injections of semaglutide, notably at a substantial dose of 2.4 mg, for nearly 40 months, proved superior to a placebo in mitigating the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.
 
The study takes on heightened significance when contextualized against the backdrop of high BMI contributing to a staggering 4 million global deaths in 2015, with cardiovascular diseases being the primary driver of over two-thirds of these fatalities. In a landscape where therapeutic options are basically non-existent, this research introduces a vital avenue for intervention.
 
While the findings are exciting, caution must be exercised in interpreting them. The observed effects, while statistically significant, are relatively modest, emphasizing the need to avoid overinterpretation. The study reveals that cardiovascular-related deaths occurred in 6.5% of the semaglutide group compared to 8.0% in the placebo group, translating to a difference of merely 1.5%.

The mechanism through which semaglutide protects against cardiovascular-related death remains unclear, with questions arising about whether the observed benefits are solely attributed to weight loss, given the 8.5% greater reduction in body weight in the semaglutide-treated group.

Furthermore, the study's focus on patients with mild or stage 1 obesity (average BMI around 33) prompts scrutiny regarding the potential applicability of these effects in severely obese patients, who arguably face the highest risk of cardiovascular death. Notably, the study's authors and funders hail from Novo Nordisk, the pharmaceutical giant behind the development and global trade of Semaglutide.
 
While these results offer encouragement, they signify just the beginning. Effective treatments for promoting the remission of metabolic diseases, encompassing obesity, cardiovascular disease, and type-2 diabetes, are currently non-existent. Given the projected exponential rise in the incidence of metabolic diseases over the next decade, global health organizations, including the Australian Government, must escalate funding for research to confront what is the greatest health challenge of our lifetimes.

This randomised controlled trial of >17,000 participants found that, in patients with pre-existing cardiovascular disease and overweight or obesity but without diabetes, use of semaglutide reduced the incidence of cardiovascular events (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) at a mean follow-up of 40 months. 

Although some GLP-1 receptor agonist medications (including semaglutide) have previously been shown to reduce the risk of cardiovascular events in people with diabetes, it wasn't clear until now if the reduced risk was mainly due to the improvement in blood glucose control. This study is important because it is the first clinical trial to show that this type of medication can reduce the risk of cardiovascular events not only when used for diabetes management, but also weight management.

This NEJM study shows that higher weekly doses of semaglutide (2.4mg (Australian trade-name; wegovy)) reduced the risk of cardiac events by ~20%, and reduced death from any cause by ~19% (Hazard ratio 0.81). 8% of people in the placebo arm died over the course of the study compared to 6.5% with semaglutide. 

The people recruited for the study were mostly male (>72%), had pre-existing known cardiac disease, and were, on average, obese with BMI >33, and body weight of >95kg, and none had diabetes. People who received semaglutide lost significant amounts of weight, and had improvements in their blood pressure, and cholesterol. Quality of life scores also improved.

The side effects in this study were similar to other studies with this agent, including gastrointestinal side-effects and local injection reactions.

Glucagon Like Peptide-1 agonists (GLP-1 agonists) such as Wegovy (Semaglutide) mimic hormones that link the absorption of nutrients from the gastrointestinal tract with pancreatic hormone secretion and help regulate insulin release after eating. They are a useful add-on therapy for type 2 diabetes. As well as lowering blood glucose, they also have other favourable effects such as reducing blood pressure and providing protection for the heart and kidneys.

As they have multiple effects such as increased satiety, decreased appetite and decreased gastric motility that results in weight loss, off-label prescription of these drugs for weight loss has increased. However, it is unclear if the heart and circulatory system benefits in people with type-II diabetes extends to overweight or obese people without diabetes.

This paper clarifies the effects of semaglutide on the heart and circulatory system in overweight or obese people without diabetes. This was a multicentre, double-blind, randomized, placebo-controlled trial. The subjects were overweight or obese people 45 years of age or older who had pre-existing heart and circulatory system disease and 17,604 patients were enrolled. This trial is big enough to be reasonably confident of the results.

After 39.8 months of weekly subcutaneous semaglutide at a dose of 2.4 mg, semaglutide was better than placebo in reducing the incidence of death from cardiovascular causes, as well as reducing nonfatal myocardial infarction, or nonfatal stroke. These effects were relatively modest roughly 6.5 per cent of patients experienced any heart or circulatory event, while 8% of patients on placebo experienced such an event. While modest these are clinically meaningful reductions. Body weight fell by a modest 9%.

After the recent reports of side effects in overweight or obese people without diabetes using semaglutide for weight loss, the reported incidence of serious adverse events was lower among patients with heart and circulatory system disease taking semaglutide than among those who received placebo. Interestingly pancreatitis, a concern in the weight loss study, was not more common in treated people vs placebo consumers.

Overall, as well as reducing weight, patients on semaglutide had a modest overall benefit in terms of the heart and circulatory system, consistent with previous studies in people with type-II diabetes.