In a large study published in the New England Journal of Medicine, overweight or obese people with existing heart disease but no diabetes received weekly semaglutide injections (or placebo). Those on semaglutide had a 20% lower risk of heart attack, stroke, or heart-related death, mainly driven by stroke prevention. However, more experienced side effects like nausea and vomiting. Overall, semaglutide shows promise for reducing cardiovascular risk beyond diabetes, but its use needs careful consideration due to side effects.

Key Points

Background: Semaglutide, a drug that mimics a natural gut hormone, has been shown to reduce cardiovascular risks in patients with diabetes. This study examined whether it could also benefit people with overweight or obesity and existing heart disease, but not diabetes.

Methods: Over 17,000 adults with both conditions were randomly assigned to receive weekly semaglutide injections or placebo for an average of 34 months. The primary outcome was a combined measure of heart-related death, non-fatal heart attack, or stroke (cardiovascular events). Safety was also evaluated.

Results:

• Overall, 6.5% of the semaglutide group and 8.0% of the placebo group experienced a cardiovascular event, representing a 20% risk reduction with semaglutide.

• This benefit was driven mainly by a 39% reduction in non-fatal stroke, while non-fatal heart attack reduction was 26% but not statistically significant.

• Cardiovascular death rates were similar in both groups.

• Side effects leading to stopping the study were more common in the semaglutide group (16.6% vs. 8.2% in placebo), mainly consisting of gastrointestinal issues like nausea and vomiting.

Conclusions: Weekly semaglutide injections significantly reduced the risk of major cardiovascular events in overweight or obese patients with existing heart disease but no diabetes. However, its use comes with a higher risk of side effects.

Additional key points:

• This study adds to the growing evidence suggesting semaglutide's potential to improve cardiovascular health beyond its established role in diabetes treatment.

• While the results are promising, further research is needed to understand the mechanisms behind semaglutide's benefits and refine its use in different patient populations.

• The increased side effects of semaglutide require careful consideration, and treatment decisions should be individualized based on patient risk factors and preferences.

Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist. GLP-1 is a natural hormone in the body that plays a crucial role in regulating blood sugar levels. Semaglutide mimics the action of GLP-1, leading to improved glucose control in individuals with type 2 diabetes. Semaglutide is primarily indicated for the treatment of type 2 diabetes mellitus. It is used to help lower blood sugar levels in adults with this condition. The medication is typically administered as a once-weekly subcutaneous injection. The dosage may vary, and healthcare providers will determine the appropriate dose for each individual based on factors such as the patient's response, overall health, and other medications they may be taking. Semaglutide helps control blood sugar levels by stimulating the release of insulin from the pancreas and reducing the amount of glucagon produced by the liver. These actions work together to decrease glucose production in the liver and increase the uptake of glucose by the cells. Common side effects of semaglutide may include nausea, vomiting, diarrhoea, and decreased appetite. Serious but rare side effects can include pancreatitis and changes in kidney function. Patients must report any unusual or severe side effects to their healthcare provider.

Unveiling the Triumph: SELECT Cardiovascular Outcomes Trial

Novo Nordisk's SELECT trial sought to redefine preventive measures against MACE in individuals aged 45 years or older with overweight or obesity and established cardiovascular disease, excluding any prior history of diabetes. The trial's canvas extended over five years, involving 17,604 participants, and employed a double-blinded design comparing subcutaneous, once-weekly semaglutide 2.4 mg with placebo as an adjunct to standard care. Semaglutide vs. Placebo in Overweight or Obese Patients With Pre-Existing CVD, But Without Diabetes

Key Findings:

• In a large clinical trial (SELECT) published in the journal New England Journal of Medicine,once-weekly subcutaneous semaglutide 2.4mg significantly reduced the risk of heart attack, stroke, or cardiovascular death by 20% compared to placebo in patients with overweight or obesity and established cardiovascular disease (CVD) but no diabetes.

• These benefits were observed early and consistently across different subgroups and cardiovascular endpoints.

• Semaglutide also led to weight loss, reduced waist circumference, improved cholesterol and triglyceride levels, and lower blood pressure.

Trial Details:

• Type: Randomized, double-blind, placebo-controlled

• Participants: 17,604 adults aged ≥45 years with BMI ≥27 kg/m2 and pre-existing CVD but no diabetes

• Duration: Average follow-up of 39.8 months

• Intervention: Subcutaneous semaglutide 2.4mg vs. placebo, both alongside standard CVD care

• Primary Endpoint: Composite of cardiovascular death, nonfatal myocardial infarction, or non-fatal stroke

Significance:

• This is the first study to show a weight-management medication effectively reduces cardiovascular risk in non-diabetic patients with obesity and CVD.

• These findings could significantly change how these conditions are managed, offering a new approach to prevention and treatment.

• Novo Nordisk plans to seek regulatory approval for this expanded indication for semaglutide (Wegovy®) in 2023.

Additional Notes:

• SELECT is one of the largest cardiovascular outcome trials in people with obesity.

• While semaglutide was well-tolerated, more patients discontinued it due to gastrointestinal side effects compared to placebo.

Implications:

These results suggest that semaglutide 2.4mg may be a valuable tool for reducing cardiovascular risk in a large population at risk—people with obesity and existing CVD. This could lead to improved patient outcomes and potentially change the paradigm for managing these conditions.

A Resounding Victory: 20% Reduction in MACE

The cornerstone of this medical saga lies in the statistically significant and superior reduction of MACE by 20% in those treated with semaglutide 2.4 mg compared to the placebo. The primary endpoint, a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, witnessed a resounding success, with all three components contributing to the substantial MACE reduction—a triumphant feat backed by the accrual of 1,270 first MACEs.

Safety at the Helm: Semaglutide 2.4 mg's Profile

Beyond its efficacy, semaglutide 2.4 mg exhibited a commendable safety profile throughout the trial, aligning seamlessly with the precedent set by previous trials involving this dosage. This safety and tolerability further amplify the potential impact of semaglutide 2.4 mg in a population where effective weight management intersects with the daunting risk of heart attack, stroke, or cardiovascular death.

Shaping the Future: Regulatory Approvals and Beyond

The momentum generated by the SELECT trial propels Novo Nordisk into an anticipatory phase, with expectations of filing for regulatory approvals for semaglutide 2.4 mg (branded as Wegovy®) expansion in the US and the EU in 2023. The prospect of this groundbreaking medication-shifting paradigm in the treatment and perception of obesity is underscored by the colossal potential outlined in the SELECT trial.

Decoding SELECT: A Closer Look at the Trial

The SELECT trial, spanning 41 countries and over 800 investigator sites since its initiation in 2018, adopts a comprehensive approach. This randomized, double-blind, parallel-group, placebo-controlled venture not only scrutinizes the efficacy of semaglutide 2.4 mg in reducing MACE but also delves into key secondary objectives.

Beyond MACE: Secondary Objectives Explored

While the primary objective focuses on the superiority of semaglutide 2.4 mg in reducing the incidence of three-point MACE, the SELECT trial branches into mortality, cardiovascular risk factors, glucose metabolism, body weight, and renal function as key secondary objectives. This expansive lens ensures a holistic understanding of semaglutide 2.4 mg's impact on multifaceted aspects of health.

Conclusion:

As per the SELECT trial, Novo Nordisk's semaglutide 2.4 mg stands at the forefront, poised to usher in a new era at the intersection of obesity, cardiovascular health, and diabetes. The SELECT trial marks not just a milestone but a paradigm shift.

Reference Articles

Lincoff, A. M., Brown-Frandsen, K., Colhoun, H. M., Deanfield, J., Emerson, S. S., Esbjerg, S., Hardt-Lindberg, S., Hovingh, G. K., Kahn, S. E., Kushner, R. F., Lingvay, I., Oral, T. K., Michelsen, M. M., Plutzky, J., Tornøe, C. W., & Ryan, D. H. (2023, December 14). Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. New England Journal of Medicine, 389(24), 2221–2232. https://doi.org/10.1056/nejmoa2307563

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