Overweight and obesity affect the world population in epidemic proportions, with more than 70% of US adults and more than 50% of the global population included in these diagnoses.

Khera A, Powell-Wiley TM. SELECTing treatments for cardiovascular disease—obesity in the spotlight. N Engl J Med. 2023;389:2287–2288.

Until recently, however, few pharmacologic agents were available for the safe and effective treatment of excess body weight.

 

Various weight-loss drugs have seen a significant uptick in approvals, uses, and new indications recently, largely due to favorable clinical data.

 

Obesity has been associated with several forms of cardiovascular disease (CVD), including hypertension, heart failure, atherosclerotic CVD, and atrial fibrillation, as well as CVD risk factors like dyslipidemia, type 2 diabetes mellitus, and obstructive sleep apnea.

Gaine SP, Grandhi G, Blumenthal RS, et al. Challenges in the cardiovascular evaluation and management of patients with obesity. American College of Cardiology Expert Analysis. January 8, 2024.

 

Until recently, however, few pharmacologic agents were available for the safe and effective treatment of excess body weight.

Some of the most promising new agents are those that were originally developed for the treatment of type 2 diabetes.

 

Semaglutide

 

Semaglutide, which has the distinction of being the first oral glucagon-like peptide 1 (GLP-1) agonist, was initially approved for treatment of type 2 diabetes. It is also one of the agents that has recently shown favorable results in clinical trials examining CVD outcomes.

In the SELECT trial, semaglutide was found to be superior to placebo in reducing the incidence of death from CVD, nonfatal myocardial infarction (MI), or nonfatal stroke at a mean follow-up of 39.8 months in patients with pre-existing CVD and overweight or obesity who did not have diabetes.

Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389:2221–2232.

 

In June 2023, for example, the American Society of Anesthesiologists released new recommendations for patients to stop taking GLP-1 agonists before elective surgery due to the potential for vomiting while under anesthesia.

American Society of Anesthesiologists. Patients taking popular medications for diabetes and weight loss should stop before elective surgery, ASA suggests. June 28, 2023.

 

When treating millions of people with medications like semaglutide, even relatively rare side effects will occur in a large number of people.

In October 2023, researchers reported dangerous gastrointestinal complications, such as pancreatitis and bowel obstruction, as well as gastroparesis, in patients with obesity who were taking GLP-1 agonists.

Sodhi M, Rezaeianzadeh R, Kezouh A, et al. Risk of gastrointestinal adverse effects associated with glucagon-like peptide-1 receptor agonists for weight loss. JAMA. 2023;330(18):1795–1797.

As Susan Yanovski, MD, senior scientific advisor for clinical obesity research and co-director of the Office of Obesity Research at the National Institute of Diabetes and Digestive and Kidney Diseases, told JAMA, “When treating millions of people with medications like semaglutide, even relatively rare side effects will occur in a large number of people.”

Ruder K. As semaglutide’s popularity soars, rare but serious adverse effects are emerging. JAMA. 2023;330(22):2140–2142.

 

 

Liraglutide

 

Another GLP-1 agonist originally approved for type 2 diabetes, liraglutide, has been found to have cardiovascular benefits as well. In the LEADER trial, patients randomized to liraglutide had a significant reduction in major adverse cardiovascular events after a median follow-up of 3.8 years. 

Despite a known side effect of an increased heart rate, a subsequent analysis found that there was no increased risk of heart failure hospitalization with liraglutide.

Marso SP, Baeres FMM, Bain SC, et al. Effects of liraglutide on cardiovascular outcomes in patients with diabetes with or without heart failure. J Am Coll Cardiol. 2020;75(10):1128–1141.

 

 

Tirzepatide

 

In the SURMOUNT-1 trial, treatment with tirzepatide, a novel GLP-1 agonist and glucose-dependent insulinotropic polypeptide, resulted in improvements in all prespecified cardiometabolic measures. However, as with other GLP-1 agonists, the most common adverse events were gastrointestinal and occurred primarily during dose escalation.

Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205–216.

 

 

Longer-term, real-world safety data needed

 

Given how recently these drugs have been introduced to the broader, real-world market, post-market surveillance and adverse event reporting will be followed closely to determine how safe they really are in the general patient population for whom they are intended. Obesity and lifestyle medicine experts also continue to remind the public and our colleagues that we must not abandon efforts to encourage healthy lifestyle changes and systemic obesity-prevention measures.