Semaglutide improves heart health and reduces weight in obese patients, but with side effects

Study shows that semaglutide not only aids in weight loss but also slashes heart failure risk by 76% in overweight patients—though higher doses bring notable side effects.

Semaglutide is among the newer anti-diabetes agents that have also proved unexpectedly helpful in weight management. However, research on its long-term risks and its effects on cardiovascular risk in obese and overweight people who do not have diabetes remains limited. A recent study published in the International Journal of Obesity addressed these aspects.

Semaglutide’s cardiovascular benefits extend beyond reducing heart failure and stroke risk; it also improves blood pressure, cholesterol levels, and atherosclerotic plaque stability, contributing to better overall heart health.

In 2020, there were 2.6 billion obese or overweight people worldwide, with the number predicted to hit four billion by 2035. Cardiovascular disease (CVD) is the major cause of death in this population. GLP-1 receptor agonists, including semaglutide, are increasingly used for this population due to their potential to reduce both weight and cardiovascular events.

The glucagon-like peptide-1 receptor (GLP1R) is a glucose-regulating G protein-coupled receptor (GPCR) found on pancreatic beta cells and brain neurons. Semaglutide is a GLP-1 receptor agonist, providing glycemic control and also promoting cardiovascular health in diabetes patients. However, it has a longer duration of action than natural GLP-1.

By binding to and stimulating the GLP-1 receptor, it increases insulin release, pushing glucose out of the blood while reducing the secretion of glucagon (glucagon has the opposite effect). In addition, it slows gastric emptying and enhances the feeling of fullness, prolonging the period of satiety. It reduces food intake and restores insulin secretion patterns to normal during both fasting and postprandial timings.

Semaglutide also reduces weight, which has led to its use in overweight and obese patients to modulate their cardiovascular disease (CVD) risk. It has been shown to lower triglyceride and low-density (‘bad’) cholesterol levels. Overall, it reduces glycated hemoglobin (HbA1c) levels and body weight.

Previous research indicated a 22% improvement in cardiovascular outcomes, suggesting other modes of action of GLP-1 agonists. Among these, semaglutide stands out as the most extensively studied. The current study aimed to understand how far it improves cardiovascular outcomes and its adverse effects (AEs).

About the study

The researchers included 38 studies in the systematic review for AE analysis, vs. five of them for cardiovascular outcome analysis. The pooled number of participants included 50,859.

In 23 studies, subcutaneous semaglutide was used at doses ranging from 0.5 mg through 1 mg, 2 mg, and 2.4 mg to 3 mg, vs. oral (from 3 mg through 4 mg, 7 mg, and 14 mg, to a maximum of 50 mg) in nine studies, and both routes in seven. The control groups used a placebo, a GLP-1 agonist, or an insulin analog, along with other oral medications, including sitagliptin.

The participants had body mass indices (BMI) between 24.7 kg/m2 and 38.8 kg/m2. The HbA1c values were between 5.4% and 9%. Most studies (92%) had a low risk of bias.

Improved cardiovascular outcomes

The results showed that patients on semaglutide were 76% less likely to be hospitalized for heart failure than controls. However, this effect was primarily observed in patients without diabetes. The risk of death from CVD fell by 17%.

Semaglutide’s anti-inflammatory effects contribute to its cardiovascular benefits, including improved coronary blood flow and reduced hepatic steatosis, helping to prevent fatty liver disease.

Similarly, death from any cause was reduced by 20%, with the oral route being superior to the subcutaneous. The risk of requiring coronary revascularization was 24% lower among semaglutide users, with non-fatal heart attacks being 24% less likely.

Among patients with diabetes, stroke risk was cut by 35%.

The improved outcomes are likely due to the action of GLP-1 receptor agonists on multiple organs, including the cardiovascular and central nervous systems, as well as their role in reducing inflammation and improving lipid profiles.

Subcutaneous administration was associated with a somewhat better outcome compared to oral semaglutide. However, no significant differences in dosage-related outcomes were found between administration routes.

Adverse effects analysis

Treatment discontinuation was twice as likely with both subcutaneous and oral semaglutide vs. controls.

For other AEs, similar incidences were observed irrespective of the route of administration. Nausea was increased approximately fourfold with semaglutide vs. controls, while vomiting increased 5.5-fold and 8.4-fold, respectively, vs. 4% on placebo. Diarrhea and constipation risk were doubled with semaglutide.

Further analysis showed that nausea, vomiting, diarrhea, and constipation occurred at similar rates with subcutaneous and oral semaglutide users.

The AE frequency increased in a dose-dependent fashion except for rates of treatment discontinuation and constipation. Between 0.5 mg and 2.4 mg subcutaneous semaglutide, 9% to 11% of users discontinued treatment because of AEs. Nausea incidence rose from 23% with 0.5 mg to 68% with 2.4 mg, and vomiting incidence increased from 9% to 45%, respectively.

With oral semaglutide, treatment discontinuation due to AEs increased steeply from 3 mg to 25 mg before decreasing at 50 mg. Nausea, vomiting, and diarrhea also increased sharply from 3 mg to 50 mg.

Conclusions

This is the first systematic review and meta-analysis to shed light on how semaglutide in patients with overweight or obesity affects cardiovascular outcomes and its associated AEs. Compared to previous research based on other GLP-1 agonists, the data from this review underscore the superiority of semaglutide in reducing cardiovascular outcomes.

However, oral administration appeared to be easier on the digestive tract. As expected from extant literature, lower doses were less likely to cause AEs.

These results could potentially change practice guidelines due to the significant effect on hospitalization due to decompensated heart failure, mortality due to cardiovascular as well as other causes, and non-fatal heart attacks.

Journal reference:

• Cleto, A. S., Schirlo, J. M., Beltrame, M., Gomes, V. H., Acras, I. H., Neiverth, G. S., Silva, B. B., Juliatto, B. M., Machozeki, J., & Martins, C. M. (2024). Semaglutide effects on safety and cardiovascular outcomes in patients with overweight or obesity: A systematic review and meta-analysis. International Journal of Obesity, 1-10. https://www.nature.com/articles/s41366-024-01646-9