SELECT: The Study That Changed Understanding of Ozempic's Cardiovascular Impact

When a weight loss medication receives the first cardiovascular protection indication in medical history, it's not just news. It's a paradigm shift. In November 2023, The New England Journal of Medicine published SELECT results, and cardiologists worldwide began reviewing their protocols.

How did semaglutide, known to most as Ozempic or Wegovy, demonstrate what no weight loss drug had achieved before? And what does this mean for people with excess weight and heart problems?

SELECT: What is this study and when was it conducted?

SELECT stands for Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity. This is a large-scale clinical trial organized by Novo Nordisk [3]. The study started on October 24, 2018, and primary results were obtained on June 21, 2023 [3].

The scale of the study is impressive. 804 clinical centers in 41 countries worldwide, including Germany, France, Canada, Australia, Japan, and Israel [3]. In total, 17,604 patients participated in the study, making SELECT one of the largest trials in its class [15].

Why is this study so important? Before SELECT, no obesity treatment drug had demonstrated the ability to protect the heart. Previous attempts ended in failure or even revealed harmful effects on the cardiovascular system [11]. SELECT had to answer a fundamental question: can a weight loss drug not only reduce weight but also save lives?

Methodology: placebo-controlled randomized trial

SELECT was a multicenter, double-blind, randomized, placebo-controlled study [14]. This means that neither patients nor doctors knew who received the drug and who received placebo. Such design is considered the gold standard in clinical trials.

Participants were randomly assigned in a 1:1 ratio to two groups. One group received semaglutide 2.4 mg subcutaneously once weekly, the other received placebo [14]. Dosing was titrated gradually, starting with 0.24 mg weekly for the first 4 weeks, then increasing to 0.5 mg, 1.0 mg, 1.7 mg, and finally to 2.4 mg every 4 weeks [14].

Crucially, all participants continued to receive standard therapy for cardiovascular diseases. Semaglutide or placebo was added to existing treatment, not replacing it [3]. This allowed assessment of the drug's additional effect.

Who participated: inclusion criteria BMI≥27 and cardiovascular history

SELECT studied a specific patient population. To enter the study, a participant had to meet several criteria simultaneously [32]:

• Age 45 years and older
• Body mass index (BMI) 27 kg/m² and above
• Established cardiovascular disease: prior myocardial infarction, prior stroke, or symptomatic peripheral artery disease
• Absence of diabetes mellitus

The last criterion is key. Before SELECT, semaglutide was already approved for type 2 diabetes patients, and its cardioprotective effect in this population was well documented. But SELECT posed a different question: does heart protection work without diabetes, solely through effects on obesity and inflammation?

Who was not included in the study? Patients with type 1 or 2 diabetes, people with glycated hemoglobin levels of 6.5% and above at screening [32]. This allowed isolation of the effect specifically in people with excess weight and cardiovascular problems, but without carbohydrate metabolism disorders.

The average BMI of participants was 33.3 kg/m² [33]. This corresponds to grade 1 obesity. The average age was about 60 years, most had a history of prior heart attack or stroke.

Primary endpoint: what is MACE and why is it important?

The main efficacy endpoint in SELECT was MACE, or Major Adverse Cardiovascular Events. This is a composite endpoint that includes three components [37]:

• Death from cardiovascular causes
• Non-fatal myocardial infarction
• Non-fatal stroke

Why these three events? Because they are the most severe consequences of cardiovascular diseases. Heart attack can lead to heart failure or sudden death. Stroke threatens disability or loss of life. Death from cardiovascular causes is the worst outcome.

SELECT was a superiority trial, not just non-inferiority. The goal was not to show that semaglutide was no worse than placebo. The task was to prove it was significantly better [3].

The study used hierarchical testing. First, they tested the primary endpoint MACE. If achieved, they moved to the first confirmatory secondary endpoints. This strategy protects against false conclusions in multiple comparisons [7].

Result: -20% MACE with hazard ratio 0.80

SELECT's main result exceeded expectations. A primary cardiovascular event occurred in 569 of 8,803 patients (6.5%) in the semaglutide group and in 701 of 8,801 patients (8.0%) in the placebo group [37].

The hazard ratio was 0.80 with 95% confidence interval from 0.72 to 0.90 and p<0.001 [15]. What does this mean in simple terms? For every 100 serious cardiovascular events in the placebo group, there were only 80 in the semaglutide group. Statistical significance is extremely high, virtually excluding randomness of the result.

How it looked for individual MACE components [9]:

• Non-fatal myocardial infarction: 28% reduction
• Death from cardiovascular causes: 15% reduction
• Non-fatal stroke: 7% reduction

The reduction in cardiovascular death (hazard ratio 0.85, p=0.07) did not reach statistical significance due to the hierarchical testing structure [37]. This doesn't mean there's no effect, just that it wasn't formally confirmed within this specific analysis.

Population-level modeling shows the scale of potential impact. Among more than 6 million Americans who meet SELECT criteria, semaglutide treatment could prevent approximately 496,400 cardiovascular events over 10 years [1]. That's nearly half a million heart attacks, strokes, and deaths.

Secondary endpoints: heart failure, mortality, revascularization

Beyond the main result, SELECT showed positive impact on a number of secondary endpoints [24]:

• Heart failure: 18% reduction (3.4% vs 4.1%, hazard ratio 0.82)
• Death from all causes: 19% reduction (4.3% vs 5.2%, hazard ratio 0.81)
• Coronary revascularization: 23% reduction (5.4% vs 6.9%, hazard ratio 0.77)

Additionally, semaglutide significantly reduced progression to diabetes. Among participants receiving the drug, only 3.5% developed type 2 diabetes (defined as glycated hemoglobin 6.5% and above) compared to 12.0% in the placebo group [24]. Hazard ratio 0.27 means 73% reduction in new diabetes risk.

Among expanded MACE-5 (including revascularization and unstable angina), semaglutide also showed convincing results. A recent analysis presented at ACC 2025 showed reduction in both first MACE-5 events (hazard ratio 0.80) and total number of events (mean ratio 0.78) [23].

DOZA offers original Mounjaro with tirzepatide, which works through a dual GLP-1 and GIP mechanism. Although SELECT studied semaglutide specifically, both drugs belong to the GLP-1 agonist class with proven cardiometabolic benefits.

Weight loss as secondary outcome: -9.4%

Although SELECT was not a specialized weight loss study, weight reduction was recorded as a secondary endpoint [38].

Average body weight reduction in the semaglutide group was 9.4% compared to 0.9% in the placebo group [31]. The 8.5 percentage point difference is clinically significant.

Importantly, weight loss lasted through 65 weeks and was maintained up to 4 years of follow-up [38]. At week 208, semaglutide showed:

• Weight reduction: -10.2% vs -1.5%
• Waist circumference reduction: -7.7 cm vs -1.3 cm
• Waist-to-height ratio reduction: -6.9% vs -1.0%

All comparisons were statistically significant (p<0.0001) [38].

But the most interesting thing is different. Analysis showed that semaglutide's cardioprotective effect did not depend on the degree of weight loss [17]. This means the drug protects the heart through mechanisms that go beyond simple weight loss.

Why SELECT is historic: paradigm shift in obesity treatment

SELECT became the first randomized controlled trial to test semaglutide in patients with obesity or overweight WITHOUT diabetes [7]. And it won.

Before this, the anti-obesity drug industry had a sad history. Fenfluramine was withdrawn from the market due to heart valve damage. Sibutramine showed increased cardiovascular risk. Other drugs simply did not demonstrate cardiovascular benefits [12].

As noted by Dr. Michael Lincoff, lead author of the study and vice-chair of research at Cleveland Clinic: "For the first time, we have evidence that semaglutide 2.4 mg improves cardiovascular outcomes in at-risk patients with BMI 27 and above and established cardiovascular disease, without diabetes" [9].

Mechanisms of semaglutide's cardioprotective effect remain a subject of research. Scientists suggest it acts through several pathways [27]:

• Weight and visceral fat reduction
• Improved glycemic control
• Reduced systemic inflammation
• Possible direct effects on cardiomyocytes and vascular wall
• Impact on platelet function

SELECT also demonstrated improvement in a number of cardiometabolic markers: blood pressure, high-sensitivity C-reactive protein, and lipid profile [24].

FDA approval of cardiovascular indication in 2024

On March 8, 2024, FDA made a historic step. The agency approved a new indication for Wegovy (semaglutide 2.4 mg): reducing the risk of cardiovascular death, non-fatal heart attack, and non-fatal stroke in adults with cardiovascular disease and obesity or overweight [39].

"Wegovy is now the first weight reduction drug that is also approved to help prevent life-threatening cardiovascular events in adults with cardiovascular disease and obesity or overweight," said John Sharretts from FDA's Center for Drug Evaluation and Research [35].

This approval created a separate insurance pathway in the US. Now even plans that exclude weight loss drugs can cover Wegovy for the cardioprotective indication [21].

To receive the drug for the new indication, a patient must [21]:

• Have established cardiovascular disease
• Have BMI 27 or higher
• Not necessarily have diabetes

Further research: SELECT-2 and extended analyses

SELECT results opened new research directions. The team continues analyzing data, and new findings are regularly published.

In August 2024, The Lancet published a pre-planned analysis of patients with heart failure with preserved ejection fraction [10]. Semaglutide showed substantial benefits in this subgroup as well.

In 2025, real-world studies began confirming SELECT results. Truveta data analysis showed that GLP-1 agonist prescribing to patients with cardiovascular diseases increased significantly after FDA approval [30].

A Harvard study demonstrated that GLP-1 drugs, including semaglutide, are associated with over 40% reduction in heart failure hospitalizations or death compared to control [13].

However, cautionary data also emerged. A University of Washington study showed that discontinuing GLP-1 drugs can quickly negate cardiovascular benefits [19]. After 1-2 years break without resuming therapy, the risk of heart attack, stroke, and death increased by 14%. This emphasizes the importance of long-term treatment.

UC Irvine researchers also projected that another drug in this class, tirzepatide (Mounjaro), could reduce cardiovascular events by 24% in people with overweight or obesity WITHOUT existing cardiovascular diseases [18]. This expands the potential audience for preventive therapy.

Critical view: limitations and caveats

No study is perfect, and SELECT has its limitations.

Cardiovascular death as a separate endpoint did not reach statistical significance (p=0.07) due to the pre-defined hierarchical testing structure [37]. This means we cannot formally claim cardiovascular mortality reduction, although the trend was positive (hazard ratio 0.85).

The study was funded by Novo Nordisk, the manufacturer of semaglutide [7]. While this is standard practice for phase 3 trials, potential conflict of interest should be considered.

The most common side effects remained gastrointestinal symptoms: nausea, diarrhea, vomiting, constipation [39]. They were usually mild to moderate and resolved over time, but some patients discontinued therapy due to these symptoms.

Treatment duration is a critical factor. As subsequent analyses showed, discontinuing therapy leads to loss of both weight and cardioprotective effect [19]. This raises questions about the need for lifelong therapy to maintain results.

It should also be remembered that SELECT studied a specific population: people with existing cardiovascular diseases. Will results be the same in people without cardiac history? Research in this direction continues.

What this means for you?

SELECT changed our understanding of what weight management drugs can do. Semaglutide showed that cardiovascular risk reduction is possible even in people without diabetes, if they have excess weight and cardiac history [15].

Key conclusions for patients:

1. If you have BMI 27+ and have had a heart attack, stroke, or peripheral artery disease — semaglutide (Wegovy) now has an official indication for reducing your cardiovascular risk.
2. The cardioprotective effect doesn't depend only on weight loss — the drug protects the heart through additional mechanisms.
3. Therapy must be long-term — discontinuing treatment is associated with risk return.
4. The GLP-1 agonist class as a whole shows benefits — both Ozempic and Mounjaro belong to drugs with proven cardiometabolic advantages.

For a more detailed comparison of Ozempic and Mounjaro, we recommend reviewing our comparative overview.

If you're considering weight management using GLP-1 agonists, DOZA specialists will help select the optimal program considering your health status and goals.

Where to order DOZA products

DOZA supplies all products mentioned in the article with official cold chain and 24/7 specialist support. Choose what you need:

• Buy Mounjaro in Ukraine — DOZA catalog with all 6 doses (2.5, 5, 7.5, 10, 12.5, 15 mg) and official thermal delivery in 24 hours. Current Mounjaro prices 2026 — from 1,000 ₴ for test dose.
• Buy Ozempic in Ukraine — original semaglutide from Novo Nordisk with thermal delivery. Current Ozempic prices 2026 — from 1,600 ₴ for starting dose.

FAQ: Frequently asked questions about the SELECT study