If You Are Overweight and Have Had a Cardiovascular Event Should You Take the Obesity Drug Wegovy?

Semaglutide lowered cardic events but enrollees weren't treated with currently available generic medications to achieve appropriate cholesterol, blood pressure, and inflammation goals

Amongst all the meaningless observational studies grabbing media headlines in the last year and the constant noise and misinformation emanating from the nutraceutical industry and wellness industries it likely has been difficult for readers to note that a very important and potentially cardiology practice-changing randomized trial, the SELECT trial, was published a year ago.

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**) but no 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 results in lower blood pressure, improved cholesterol, and less diabetes but until the SELECT RCT was published we lacked solid evidence that any weight reduction therapy would lower the risk of heart attack, stroke, and cardiovascular death.

What Did SELECT Show?

SELECT showed that in obese (BMI>27) individuals with established cardiovascular disease (MI, PAD, or stroke) and no diabetes semaglutide lowered major adverse cardiovascular events by 20% compared to placebo over about 3 years of treatment.

Semaglutide (aka Ozempic or Wegovy) has become ubiquitous because of established benefits in diabetes and obesity but SELECT showed that the wonder 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”

Let’s take a look at the group SELECT enrolled to see if you or the patient in front of you is similar to those enrolled.

Of the roughly 17K participants with an average of 62 years, 84% were white, 72% male and 2/3 had HbA1C>= 5.7% (making them pre-diabetic), 3/4 had a prior myocardial infarction and 1/4 had heart failure.***

Death from CV cause, nonfatal MI or stroke occurred in 6.5% of the treatment group and 8.0% of the placebo group so the absolute risk of events was reduced by 1.5%.

One subsequent analysis has estimated that 7.9 million individuals meet the SELECT trial criteria in the US:

“Among these individuals, treatment with semaglutide could prevent about 190 000 cardiovascular events in 5 years.”

“If each eligible patient received semaglutide at a retail price of $16 188 per year, the total cost would amount to $127 billion per year.”

The authors of SELECT noted that:

Potentially less costly alternatives for reducing obesity and CVD risk include lifestyle counseling, dietary fasting, and alternative pharmacological weight loss approaches. However, evidence supporting these measures is mixed, and long-term studies are needed to clarify their efficacy.

My Thoughts on Semaglutide for Secondary Prevention

My eldest daughter is an internist with a great interest in obesity treatment and invited me to attend the quarterly meeting of the STL Obesity Society recently. She asked me to provide comments from a cardiologist’s perspective on the SELECT trial after a presentation on the trial.***

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 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 much 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 fewer were on PCK9 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 managementThe 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 that weren’t utilized in SELECT enrolees.

Current Practice of Secondary Prevention by Cardiologists

Very 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>>70 and had never had apo B. Lipo a or hs-CRP checked. The 2013 ACC/AHA approach of starting a high-intensity statin and not treating to 2023 target LDL/apo B levels seemed to be the approach.

Even for preventive cardiologists like myself who take the time to delve deeply into patient diet, exercise, and lifestyle and discuss weight management with every patient, there are huge 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 time 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 on the phone with insurance people trying to get authorization for a drug that costs 16K per year, requires prior authorization, 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.

Semaskeptically 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.

*** Normally, I scrupulously avoid drug-sponsored “educational” dinners. Physician speakers are paid thousands of dollars to convince attendees to write more prescriptions for the drug they are discussing. In this case, although the 3-hour meeting was funded by an unrestricted educational grant from Novo Nordisk it had many other educational components related to obesity management and the slide presentation on SELECT was brief. Attending this meeting actually resulted in me being less likely to prescribe semaglutide to my patients.