A Skeptical Take of Semaglutide for Cardiac Protection

A preventive cardiologist offers a critical appraisal of the SELECT trial of Semaglutide (Wegovy)

When the New England Journal of Medicine published the placebo-controlled SELECT trial of semaglutide in patients with established vascular disease, I had thought cardiology had discovered another disease-modifying drug. SELECT found a statistically significant and clinically meaningful lowering of a composite endpoint with semaglutide. My former partner, who writes under the pseudonym, the Skeptical Cardiologist, has a different take. His argument made me rethink my embrace of semaglutide as a disease-modifier for vascular disease. JMM

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You probably have heard a lot about semaglutide, the injectable drug from Danish Pharma Novo Nordisk which is known as Ozempic* when given to treat diabetes and Wegovy when used for weight loss.

GLP-1 receptor agonists (GLP-1RAs or GLP1s) like semaglutide have been proven to reduce body weight and lessen cardiovascular (CV) risk in patients with type 2 diabetes, but—until SELECT was published—they had not been shown to improve cardiovascular outcomes in patients with a high BMI (aka the obese and overweight**) without diabetes.

GLP-1 RAs reduce caloric intake by slowing gastric emptying, increasing satiety, and reducing appetite. Fewer calories coming in, given no reduction of calories going out, results in weight loss.

The skeptical cardiologist, like most physicians, has always assumed that weight loss, whether accomplished by diet/exercise, bariatric surgery, or drugs would benefit obese patients since it lowers blood pressure, cholesterol and blood sugar levels. Yet those are just markers of health. Until the SELECT trial was published we lacked evidence that the drugs would lower the risk of heart attack, stroke, and cardiovascular death.

What Did SELECT Show?

SELECT showed that in obese (BMI>27) non-diabetic individuals with established cardiovascular disease (MI, peripheral artery disease, or stroke) semaglutide lowered major adverse cardiovascular events by 20% compared to placebo over about 3 years of treatment. Death from CV cause, nonfatal MI or stroke occurred in 8% of the placebo group and 6.5 % of the treatment group—so the absolute risk of events was reduced by 1.5%.

Semaglutide (aka Ozempic or Wegovy) has become ubiquitous because of established benefits in diabetes and obesity but SELECT showed that the drug should be considered in those who are obese with established atherosclerotic CV disease (ASCVD.)

In March of 2024 the FDA approved a new indication for Wegovy based on the SELECT trial to reduce the risk of CV death, stroke, and heart attack in adults with “cardiovascular disease” and either “obese or overweight”

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My Thoughts on Semaglutide for Secondary Prevention

After looking in detail at SELECT I realized that it does not apply to most patients in my practice.

I consider the majority of the enrollees in SELECT to represent a failure of appropriate use of currently available therapy to be applied in reducing the residual risk of cardiovascular events.

Given that all these patients had established ASCVD, I would deem them under-treated with standard lipid-lowering therapy because the average LDL-C was 78 (goal LDL-C in this population is at least <70 mg/dl and the average hs-CRP (a measure of coronary inflammation) was elevated at 1.8.

If we are talking solely about CV risk reduction we get more bang for our buck by adding the cheap and well-tolerated generic ezetimibe (to drop the LDL < 70). Although 88% of SELECT participants were on statin therapy, only 13% were taking ezetimibe. Even less were on PCSK9 inhibitors.

Similarly, these patients had evidence of ongoing significant inflammation based on the hs-CRP average level of 1.8. We have had an approved drug, colchicine, which targets the residual risk related to inflammation since 2023.

Colchicine, which is available as a cheap generic and has been used for centuries for gout has been shown in recent studies to reduce ASCVD events by 25-30% when used in secondary prevention. Most of this SELECT population would now be treated with colchicine.

Finally, the systolic blood pressure averaged 130 mm Hg prior to study entry. We know from the SPRINT trial that a goal of 120 mm Hg results in a significant lowering of CV events compared to routine management. In SPRINT, the primary outcome, myocardial infarction (MI), acute coronary syndrome (ACS), stroke, congestive heart failure (CHF), or cardiovascular (CV) death, was significantly lower in the intensive BP management arm compared with the routine management arm ((5.2% vs. 6.8%, hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.64–0.89; p < 0.0001).)

There are plenty of generic options for achieving SPRINT-level BP goals which apparently weren’t used in SELECT enrollees.

Current Practice of Secondary Prevention by Cardiologists

Few cardiologists are prescribing semaglutide. One study found 1% of cardiologists prescribed it for patients with T2DM and obesity.

To be honest, most cardiologists are too busy to do the work necessary to eliminate residual risk in secondary prevention CAD patients.

The vast majority of patients I inherited from prior cardiologists in the last 4 years who were post-MI and/or had prior coronary stenting had LDL-C > 70 and had never had apo B. Lp(a) or hs-CRP levels checked.

Even for preventive cardiologists like myself who take the time to delve into a patient’s diet, exercise and lifestyle and discuss weight management, there are substantial barriers to starting semaglutide.

Cost, availability, insurance coverage, prior authorization and side effects all make semaglutide unattractive to me. It is infuriating that the cost is $16,000 per year, 4-5 times higher than in Germany and most other countries.

As a preventive cardiologist, I would rather spend my effort driving apo B/LDL-C down to levels where ASCVD regresses, carefully lowering BP into SPRINT goal territory, and, in appropriate patients, lowering CRP levels to <1 rather than be on the phone with insurance people trying to get authorization for a drug that costs 16K per year and has substantial GI side effects.

In addition, I will continue to work diligently with patients on dietary modification and advancement of their aerobic and resistance exercises to improve weight parameters. 

I recognize that loss of visceral fat has multiple other benefits beyond the cardiovascular system, and I think semaglutide would be useful in many of my obese patients for these benefits.

However, I can’t help but view the SELECT trial as cynically engineered to achieve an indication for preventing CV disease in a population that was not being appropriately treated with currently available and much more accessible therapy.

Semi-skeptically Yours,

-ACP

*Ozempic commercials are single-handedly responsible for destroying any magic that the song “Magic” ever possessed. 

**BMI (body mass index) has become the parameter doctors use to diagnose obesity. It is weight in kilograms (kg) divided by height in meters squared (m²) or (weight (lbs)/ inches squared) * 703. It is imperfect because it doesn’t differentiate between fat and muscle but if your BMI is between 25 and 30 you are classified as overweight and if over 30, as obese.