Semaglutide and Cardiovascular Outcomes in Patients With Obesity Without Diabetes

The long-awaited SELECT trial results are now published. The GLP-1 receptor agonists (GLP-1 RA) have been shown to reduce MACE in high-risk individuals with type 2 diabetes. Two of these, liraglutide and semaglutide (along with the dual GLP-1/GIP co-agonist tirzepatide), are also approved in the US as weight-loss agents for those with obesity who do not necessarily have diabetes. The natural research question is whether they also improve cardiovascular outcomes when diabetes is not present.

SELECT studied 17,000 patients who were 45 years old with a BMI of 27 kg/m² and established CVD. They were randomized to weekly subcutaneous injections of semaglutide 2.8 mg versus matching placebo. Mean follow-up extended to more than 3 years. The primary outcome was the classical MACE composite used in cardiovascular outcome trials (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death). This occurred in 6.5% of the group randomized to active therapy and 8.0% of those on placebo, calculating to a hazard ratio of 0.80 (95% CI, 0.72–0.90; P < .001). This relative risk reduction of 20% is numerically larger than what has been observed in most prior GLP-1 RA cardiovascular outcome trials in type 2 diabetes. However it falls within the lower bound of the confidence interval for MACE reported in the largest meta-analysis of GLP-1 RA therapy in type 2 diabetes by Sattar et al (HR, 0.86; 95% CI, 0.80–0.93), suggesting a similar effect in the SELECT cohort. Key secondary outcomes, including components of the primary and major prespecified subgroups, revealed results that were directionally concordant with the main findings. Other outcomes included more weight loss (−8.5 kg), and greater reductions in HbA1c (−0.32% [absolute]) and CRP (−38%) in the semaglutide group versus placebo.

SELECT is therefore the first study of its kind to show that a pharmacological therapy directed at weight loss in a large group of overweight or obese patients with CVD results in reduced cardiovascular events. Such a strategy must now be considered standard of care, increasing the therapeutic armamentarium for clinicians treating patients with CVD and high BMI.

The results of the SELECT trial, which demonstrated that the glucagon-like peptide-1 receptor agonist (GLP1RA) semaglutide 2.4 mg reduced the risk of cardiovascular events compared with placebo, should change the paradigm of how we reduce cardiovascular risk in patients with obesity. This is the first time any therapy targeting weight reduction has demonstrated clear evidence of a reduction in the risk of cardiac events.

In 17,604 patients with overweight and obesity as well as established atherosclerotic cardiovascular disease but without diabetes, semaglutide reduced the risk of major adverse cardiovascular events (cardiovascular death, myocardial infarction, or stroke) by 20% (HR, 0.80; 95% CI, 0.72–0.90; P < .001), myocardial infarction alone by 28% (HR, 0.72; 95% CI, 0.61–0.85), and all-cause mortality by 19% (HR, 0.81; 95% CI, 0.71–0.93) over a mean follow-up period of 3.3 years. On average, semaglutide resulted in an 8.5-kg weight loss compared with placebo, with favorable reductions in the levels of cardiovascular risk factors like systolic blood pressure, diastolic blood pressure, LDL-C, triglycerides, and hs-CRP. There were no important safety concerns such as pancreatitis or cancer, and over 75% of the subjects reached the highest semaglutide dose (2.4 mg).

There is over a decade of experience with GLP1RAs in patients with diabetes where they are now first-line agents for glucose control and, after a series of cardiovascular outcomes trials, with several different GLP1RAs proven to reduce cardiovascular events. The more potent GLP1RAs like semaglutide 2.4 mg have been shown to reduce weight by over 15% in healthier patients with obesity. The SELECT trial, the largest completed randomized controlled trial in diabetes or obesity, is the first to show the benefit of this class of drugs in patients with obesity without diabetes.

The implications of these results are enormous. A large proportion of patients with atherosclerotic cardiovascular disease are obese or overweight (BMI, ≥27 kg/m²) and are, thus, potentially eligible for treatment. The implementation barriers — such as whether cardiologists are going to “own” GLP1RAs, like statins, for cardiovascular risk reduction — and the costs of GLP1RAs, which are already straining budgets, may slow the adoption of GLP1RAs. Obesity should be considered a modifiable cardiovascular risk factor. Amidst all the debates, it should not be forgotten that this is the first therapy for obesity ever proven to make people live longer and have fewer cardiovascular events.

SELECT trial – Semaglutide reduces major adverse cardiovascular events in obese patients who do not have diabetes

We have always thought that obesity drives cardiovascular disease, but we have never been able to show that reducing weight would reduce the risk of cardiovascular (CV) events. That is why the SELECT study was received with such enthusiasm when it was presented at the American Heart Association meeting this year.

For the first time, a treatment that leads to weight loss, semaglutide, was able to show a 20.0% reduction in major adverse cardiovascular events (MACE; HR, 0.80; 95% CI, 0.72–0.90; P < .001). The authors of the study enrolled 17,604 patients who had pre-existing CV disease and a BMI that was greater than 27 kg/m². The enrolled patients did not have diabetes. Half of the group was given semaglutide 2.4 mg subcutaneously every week. The MACE outcome (CV death, nonfatal MI, and nonfatal stroke) occurred in 8% and 6.5 % of the placebo and semaglutide groups, respectively, translating to a 20% relative risk reduction. The absolute risk reduction was 1.5% and if you divide that into 100 then the number needed to treat was 67.

The discontinuation rate due to adverse events was higher in the semaglutide group at 16.6% compared with 8.2% in the placebo group. Most of the adverse events were gastrointestinal-related. Now, I look at this and think that the beneficial effect of semaglutide must has been quite significant, considering you have fewer people taking the medication. Yet, it was still able to lead to a 20.0% risk reduction in MACE.

The other interesting thing is that the curves diverge early on. This means that there is an effect of semaglutide that is immediate; hence, there is no need to wait for weight reductions. Perhaps some of the benefits of semaglutide are not just coming from weight reduction.

This then leads us to think about what semaglutide is really doing in the body. Well, the intestine needs a way to tell the rest of the body that food is coming in. That way all the organs will know what to do to help process that food. So think of glucagon-like peptide 1 (GLP-1) as a text message that the intestine sends out when food is in the intestine. The L cells within the terminal ileum send out GLP-1 whenever they detect food. Therefore, GLP-1 is a text message that food is in the terminal ileum. All the organs that need this information have receptors that can bind to GLP-1 in the bloodstream. This is a perfect messaging system. The intestine just has to release the GLP-1 into the bloodstream, and other organs that need this information will get the message.

The brain also has GLP-1 receptors, so when the brain gets the message that there is food, then the brain will say now we do not have to eat as much. When the beta cells in the pancreas get the text message that food is coming, they will make more insulin. When the alpha cells get the message, then they know not to make glucagon. Glucagon tells the liver to release glucose into the bloodstream. However, when the alpha cells get the text message saying there is a lot of food, then the liver does not need to release glucose into the bloodstream.

In patients with type 2 diabetes, GLP-1 activity is reduced so we need to boost it back up. Perhaps patients with obesity without diabetes may have a GLP-1 issue too.

In this study, the patients were given semaglutide 2.4 mg weekly by injections and the authors observed a reduction in MACE reduction in these patients. However, interestingly, the reduction in MACE started before the substantial weight loss had kicked in. In other words, the reduction in MACE may not be completely from weight reduction. Other organs that have GLP-1 receptors may be helping in reducing the MACE outcome.

Weight reduction is very important but these other organs that use the GLP-1 signaling might also be important. We are now entering an era where we are hacking into the communication systems in the body and trying to control the system by giving the body the right messages. This could be revolutionary.