Semaglutide 'A New Pathway' to CVD Risk Reduction: SELECT

Final results of the SELECT trial have shown that the anti-obesity drug semaglutide (Wegovy) produced a consistent reduction of around 20% vs placebo across major cardiovascular event endpoints over the approximately 3-year follow-up in patients with overweight or obesity and cardiovascular disease but not diabetes.

"This is a very exciting set of results. I think it is going to have a big impact on a large number of people," lead investigator A. Michael Lincoff, MD, vice chair for research in the department of cardiovascular medicine at the Cleveland Clinic, Cleveland, Ohio, told theheart.org | Medscape Cardiology. 

"And from a scientific standpoint, these data show that we now have a new pathway or a new modifiable risk factor for cardiovascular disease that we can use in our patients who have overweight or obesity," he added.

The trial involved 17,604 patients with a history of cardiovascular disease and a BMI of 27 or above (mean BMI was 33), who were randomly assigned to the glucagon-like peptide 1 (GLP-1) agonist semaglutide, given by subcutaneous injection once weekly at a gradually escalating dose up to 2.4 mg daily by week 16, or placebo. The mean baseline glycated hemoglobin level was 5.8% and 66.4% of patients met the criteria for prediabetes.

Patients lost a mean of 9.4% of body weight over the first 2 years with semaglutide versus 0.88% with placebo.

The primary cardiovascular endpoint — a composite of death from cardiovascular causes, nonfatal myocardial infarction (MI), or nonfatal stroke — was reduced significantly, with a hazard ratio of 0.80 (95% CI, 0.72 - 0.90; P < .001).  

Death from cardiovascular causes, the first confirmatory secondary endpoint, showed a 15% reduction (HR, 0.85; P = .07) but this missed meeting criteria for statistical significance, and because of the hierarchical design of the trial, this meant that superiority testing was not performed for the remaining confirmatory secondary endpoints.

However, results showed reductions of around 20% for the heart failure composite endpoint and for all-cause mortality, with confidence intervals that did not cross 1.0, and directionally consistent effects were observed for all supportive secondary endpoints.

The hazard ratio for the heart failure composite endpoint was 0.82 (95% CI, 0.71 - 0.96), and the HR for death from any cause was 0.81 (0.71 - 0.93). Nonfatal MI was reduced by 28%, hazard ratio 0.72 (95% CI, 0.61 - 0.85).

The effects of semaglutide on the primary endpoint appeared to be similar across all prespecified subgroups.

Adverse events leading to discontinuation of treatment occurred in 16.6% in the semaglutide group, mostly gastrointestinal (GI) effects, and in 8.2% in the placebo group.

The trial results were presented by Lincoff today at the 2023 American Heart Association (AHA) Scientific Sessions, being held in Philadelphia. They were also simultaneously published online in the New England Journal of Medicine.

Lincoff explained that there is a growing pandemic of overweight and obesity worldwide with clear evidence for years that these conditions increase the risk of cardiovascular events — and yet there has been no evidence, until now, that any pharmacologic or lifestyle therapy can reduce the increased risk conferred by overweight/obesity. 

"Patients in the trial were already taking standard-of-care therapies for other risk factors, such as hypertension and cholesterol, so this drug is giving additional benefit," he said.

Lincoff believes these data will lead to a large increase in use of semaglutide, which is already available for the treatment of obesity and diabetes but can be difficult to get reimbursed.

"There is a lot of difficulty getting payors to pay for this drug for weight management. But with this new data from the SELECT trial there should be more willingness — at least in the population with a history of cardiovascular disease," he commented. In diabetes, where it is already established that there is a cardiovascular risk reduction, it is easier to get these drugs reimbursed, he noted.

On the outcome data, Lincoff said he could not explain why cardiovascular death was not significantly reduced while all-cause mortality appeared to be cut more definitively.

"The cardiovascular death curves separated, then merged, then separated again. We don't really know what is going on there. It may be that some deaths were misclassified. This trial was conducted through the COVID era and there may have been less information available on some patients because of that."

But he added: "The all-cause mortality is more reassuring, as it doesn't depend on classifying cause of death. Because of the design of the trial, we can't formally claim a reduction in all-cause mortality, but the results do suggest there is an effect on this endpoint. And all the different types of cardiovascular events were similarly reduced in a consistent way, with similar effects seen across all subgroups. That is very reassuring."

"A New Era" for Patients With Obesity

Outside experts in the field were also impressed with the data.

Designated discussant of the trial at the AHA meeting, Ania Jastreboff, MD, associate professor medicine (endocrinology) at Yale School of Medicine, New Haven, Connecticut, said the SELECT trial was "a turning point in the treatment of obesity and a call to action.

"Now is the time to treat obesity to improve health outcomes in people with cardiovascular disease," she said.

Jastreboff noted that high BMI was estimated to have accounted for 4 million deaths worldwide in 2015, two thirds of which were caused by cardiovascular disease. And she presented data showing that US individuals meeting the SELECT criteria increased from 4.3 million in 2011-12 to 6.6 million in 2017-18.

She highlighted one major limitation of the SELECT trial: it enrolled a low number of women (38%) and ethnic minorities, with only 12% of the trial population being Black.

Deepak Bhatt, MD, director of Mount Sinai Fuster Heart Hospital, New York City, described the SELECT results as "altogether a compelling package of data."

"These results are even better than I had expected," Bhatt told theheart.org | Medscape Cardiology. "There is a significant reduction in MI as I had anticipated, but additionally, there is a reduction in all-cause death. One can debate the statistics, though on a common-sense level, I think it is a real finding," he noted.

"Given that MI, heart failure, nephropathy, and revascularization are all reduced, and even stroke is numerically lower, it makes sense that all-cause mortality would be reduced," he said. "To me, apart from the GI side-effects, this counts as a home run."

Steve Nissen, MD, chief academic officer at the Cleveland Clinic's Heart, Vascular and Thoracic Institute, was similarly upbeat.

"These data prove what many of us have long suspected — that losing weight can reduce cardiovascular morbidity and mortality. This is great news for patients living with obesity. The obesity epidemic is out of control," he added. "We need to have therapies that improve cardiovascular outcomes caused by obesity and this shows that semaglutide can do that. I think this is the beginning of a whole new era for patients with obesity."

Michelle O'Donoghue, MD, associate professor of medicine, Harvard Medical School, Boston, called the results of SELECT "both intriguing and compelling. Certainly, these findings lend further support to the use of semaglutide in a much broader secondary prevention population of individuals with obesity."

Christie Ballantyne, MD, director of the center for cardiometabolic disease prevention at Baylor College of Medicine, Houston, Texas, described the SELECT study as "a landmark trial which will change the practice of medicine in regard to how we treat obesity."

He compared it to the landmark 4S trial in 1994, the first study in the area of cholesterol lowering therapy to show a clear benefit in reducing cardiovascular events and total mortality, and "began a drastic change in the way that physicians approached treatment of cholesterol."

On the more robust reduction in all cause death compared with cardiovascular death,

Ballantyne pointed out: "Adjudication of dead or alive is something that everyone gets right. In contrast, the cause of death is sometime difficult to ascertain. Most importantly, the benefit on total mortality also provides assurance that this therapy does not have some adverse effect on increasing noncardiovascular deaths."

Gastrointestinal Adverse Effects

On the side effects seen with semaglutide, Lincoff reported that 10% of patients in the semaglutide group discontinued treatment because of GI side effects vs 2% in the placebo arm. He said this was "an expected issue."

"GI effects, such as nausea, vomiting and diarrhea, are known side effects of this whole class of drugs. The dose is slowly escalated to manage these adverse effects but there will be a proportion of patients who can't tolerate it, although the vast majority are able to continue."

He noted that while dose reduction was allowed, of the patients who were still on the drug at 2 years, 77% were on the full dose, and 23% were on a reduced dose.

Lincoff pointed out that there were no serious adverse events with semaglutide. "This is the largest database by far now on the drug with a long-term follow up and we didn't see the emergence of any new safety signals, which is very reassuring."  

Nissen said the 16% rate of patients stopping the drug because of tolerability "is not a trivial number."

He noted that the semaglutide dose used in this study was larger than that used in diabetes.

"They did this to try to achieve more weight loss but then you get more issues with tolerability. It's a tradeoff. If patients are experiencing adverse effects, the dose can be reduced, but then you will lose some effect. All the GLP-1 agonists have GI side effects — it's part of the way that they work."

Just Weight Loss or Other Actions Too?

Speculating on the mechanism behind the reduction in cardiovascular events with semaglutide, Lincoff does not think it is just weight reduction.

"The event curves start to diverge very soon after the start of the trial and yet the maximum weight loss doesn't occur until about 65 weeks. I think something else is going on."

In the paper, the researchers note that GLP-1 agonists have been shown in animal studies to reduce inflammation, improve endothelial and left ventricular function, promote plaque stability, and decrease platelet aggregation. In this trial, semaglutide was associated with changes in multiple biomarkers of cardiovascular risk, including blood pressure, waist circumference, glycemic control, nephropathy, and levels of lipids and C-reactive protein.

Lincoff also pointed out that similar benefits were seen in patients with different levels of overweight, and in those who were prediabetic and those who weren't, so benefit was not dependent on baseline BMI or glycated hemoglobin levels.

O'Donoghue agreed that other effects, as well as weight loss, could be involved. "The reduction in events with semaglutide appeared very early after initiation and far preceded the drug's maximal effects on weight reduction. This might suggest that the drug offers other cardioprotective effects through pathways independent of weight loss. Certainly, semaglutide and the other GLP-1 agonists appear to attenuate inflammation, and the patterns of redistribution of adipose tissue may also be of interest."

She also pointed out that the reduction in cardiovascular events appeared even earlier in this population of obese nondiabetic patients with cardiovascular disease than in prior studies of patients with diabetes. "It may suggest that there is particular benefit for this type of therapy in patients with an inflammatory milieu. I look forward to seeing further analyses to help tease apart the correlation between changes in inflammation, observed weight loss and cardiovascular benefit."

Effect on Clinical Practice

With the majority of patients with cardiovascular disease being overweight, these results are obviously going to increase demand for semaglutide, but cost and availability are going to be an issue.

Bhatt notes that semaglutide is already very popular. "Weight loss drugs are somewhat different from other medications. I can spend 30 minutes trying to convince a patient to take a statin, but here people realize it's going to cause weight loss and they come in asking for it even if they don't strictly need it. I think it's good to have cardiovascular outcome data because now at least for this population of patients, we have evidence to prescribe it."

He agrees with Lincoff that these new data should encourage insurance companies to cover the drug, because in reducing cardiovascular events it should also improve downstream healthcare costs.

"It is providing clear cardiovascular and kidney benefit, so it is in the best interest to the healthcare system to fund this drug," he said. "I hope insurers look at it rationally in this way, but they may also be frightened of the explosion of patients wanting this drug and now doctors wanting to prescribe it and how that would affect their shorter-term costs."

Lincoff said it would not be easy to prioritize certain groups. "We couldn't identify any subgroup who showed particularly more benefit than any others. But in the evolution of any therapy, there is a time period where it is in short supply and prohibitively expensive, then over time when there is some competition and pricing deals occur as more people are advocating for it, they become more available."

"A Welcome Treatment Option"

In an editorial accompanying publication of the trial, Amit Khera, MD, University of Texas Southwestern Medical Center, Dallas, and Tiffany Powell‑Wiley, MD, MPH, National Institutes of Health, Bethesda, note that baseline risk factors such as LDL-cholesterol (78 mg/dL) and systolic blood pressure (131 mm Hg) were not ideal in the semaglutide group in this trial, and they suggest that  the benefits of semaglutide may be attenuated when these measures are better controlled.

But given that more than 20 million people in the United States have coronary artery disease, with the majority having overweight or obesity and only approximately 30% having concomitant diabetes, they say that even in the context of well-controlled risk factors and very low LDL levels, the residual risk of atherosclerotic cardiovascular disease in these persons is unacceptably high. "Thus, the SELECT trial provides a welcome treatment option that can be extended to millions of additional patients."

However, the editorialists caution that semaglutide at current pricing comes with a significant cost to both patients and society, which makes this treatment inaccessible for many. 

They add that intensive lifestyle interventions and bariatric surgery remain effective but underutilized options for obesity, and that the prevention of obesity before it develops should be the primary goal.

The SELECT trial was supported by Novo Nordisk, and several co-authors are employees of the company. Lincoff is a consultant for Novo Nordisk. Bhatt and Nissen are involved in a cardiovascular outcomes trial with a new investigational weight loss drug from Lilly. Bhatt and Ballantyne are also investigators in a Novo Nordisk trial of a new anti-inflammatory drug.