Is Semaglutide the ‘New Statin’? Not So Fast

There has been a lot of hyperbole since the presentation of results from the SELECT cardiovascular outcomes trial (CVOT) at this year’s European Congress on Obesity, leading many to declare semaglutide the “new statin.”

In SELECT CVOT, participants with overweight or obesity (body mass index [BMI] ≥ 27), established cardiovascular disease (CVD), and no history of type 2 diabetes were administered the injectable glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide (Wegovy) at a dose of 2.4-mg weekly. The treatment resulted in a significant 20% reduction in the risk associated with major adverse CV events (a composite outcome including CV death, infatal myocardial infarction, or nonfatal stroke). Importantly, SELECT was a trial of secondary prevention of CVD.

The CV benefit of semaglutide was largely independent of baseline weight or weight loss. This suggests that the main driver of improved CV outcomes with semaglutide goes beyond a simple reduction in obesity and probably reflects a direct effect on the vasculature and the reduction of atherosclerosis, although this still not confirmed.

Not All Risk Reduction Is Equal

Most of the sensational news in the press focused on the 20% injury reduction figure. These outcomes are often more interesting and headline-grabbing than absolute risk reduction, which provides a clearer picture of the real-world effect of a treatment.

In SELECT, the absolute risk reduction was 1.5 percent, which translated into a number needed to treat (NNT) of 67 over 34 months to prevent at least one major adverse CV event .

Low NNTs suggest effective treatments because fewer people need to be treated to prevent a single medical event, such as the major adverse CV events used in SELECT.

Semaglutide vs Statins

How does the clinical success observed in the SELECT trial compare with that seen in statin trials when it comes to secondary prevention of CVD?

The seminal 4S study published in 1994 evaluated the effect of simvastatin on all-cause mortality among people with previous myocardial infarction or angina and hyperlipidemia (mean baseline BMI, 26). After 5.4 years of follow-up, the trial was stopped early because of an absolute risk reduction of 3.3 percent in all-cause mortality (NNT, 30; relative risk reduction, 28%). The NNT for preventing one CV death was 31, and the NNT for preventing one major cardiovascular event was lower, at 15.

Other statin secondary prevention trials, such as the LIPID and MIRACL studies, have shown similarly low NNTs.

So, you can see that the NNTs for the dual inhibitor statins are much lower than with semaglutide in SELECT. Furthermore, the benefits of semaglutide in preventing CVD in people living with overweight/obesity have not been clarified.

On the other hand, we have published evidence showing the benefits of statins in the primary prevention of CVD, although there are higher and different NNTs than in secondary statin prevention studies.

The benefits of statins are also expected to extend beyond their effect on lowering low-density lipoprotein cholesterol. Statins have been suggested to have anti-inflammatory and plaque-stabilizing effects, among other pleiotropic benefits.

We also currently have no evidence for the cost-effectiveness of semaglutide for CV risk reduction. Evaluating cost-effectiveness and utility in healthcare settings, such as the UK’s National Health Service, including comparing semaglutide costs versus healthcare savings from events restricted CVs. Health economic studies are important to determine whether the benefits justify the costs. On the other hand, the cost-effectiveness of statins is well established, especially in high-risk populations.

The benefits of GLP-1s should not be overlooked

Of course, statins do not provide the significant weight loss benefits of semaglutide.

Additional data from SELECT presented at the 2024 European Congress on Obesity showed that participants lost 10.2% of body weight and 7.7 cm from their waistline after 4 years. Furthermore, after at 2 years, 12% of semaglutide-naïve subjects had returned to normal BMI, and nearly half were no longer obese.

Although the CV benefits of semaglutide were independent of weight loss, this level of weight loss is clinically meaningful and will reduce the risk of many other cardiovascular conditions. including type 2 diabetes, metabolic syndrome associated with steatotic liver disease, and obstructive sleep apnea/hypopnea syndrome. , as well as improving low mood, depression, and overall quality of life. In addition, obesity is already a risk factor for 13 different types of cancer, including colon, breast and pancreatic cancer, so helping to return to a healthy weight will reduce the risk. of cancer in the future.

Sticking to Our Cornerstone Therapy, Now

Finally, I do not believe that semaglutide is the “new statin.” Statins are the cornerstone of primary and secondary prevention of CVD in a wide range of comorbidities, as evidenced in many large and high-quality trials spanning more than 30 years.

However, there is no doubt that the GLP-1 receptor agonist class is the most important therapeutic advance for the management of obesity and its comorbidities to date.

The SELECT CVOT data uniquely place semaglutide as a second-line CVD prevention agent above the guideline-directed regimen for people living with overweight/obesity and developing CVD. In addition, weight loss achieved with semaglutide will affect the risk of many other cardiometabolic conditions, as well as improve mental health and overall quality of life.

Dr Kevin Fernando makes a brief clinical cheat sheet for primary and secondary care to make life easier for health care professionals and improve the lives of patients. He is very active on social media (X handle @drkevinfernando), where he writes hot topics about type 2 diabetes and CVRM. He recently joined YouTube (@DrKevinFernando) and TikTok (@drkevinfernando) with patient-oriented video content. Kevin has been appointed to the Fellowship of the Royal College of General Practitioners, the Royal College of Physicians of Edinburgh, and the Academy of Medical Educators for his work in diabetes and medical education.