Cardiovascular effects of anti-obesity medications: the perils and promise

Anti-obesity medications have gone through a tumultuous course of approvals and withdrawals, often triggered by serious cardiovascular complications. Early agents, including amphetamines and fenfluramine–phentermine, were once widely used but ultimately banned or voluntarily withdrawn due to cardiovascular complications. Sibutramine followed a similar trajectory when clinical trials revealed increased cardiovascular event rates, prompting its market withdrawal. Lorcaserin, initially promising for weight management without significant cardiovascular risks, was withdrawn after postmarketing surveillance revealed a potential link to increased cancer incidence. Although more recent medications, including orlistat, phentermine–topiramate, and naltrexone–bupropion, remain available, their cardiometabolic benefits are modest, and long-term cardiovascular outcome data remain inconclusive or still lacking. The emergence of glucagon-like peptide 1 (GLP-1) receptor agonists or co-agonists has transformed obesity management. Liraglutide, semaglutide, and tirzepatide, originally developed for type 2 diabetes, have demonstrated substantial and sustained weight loss along with notable improvements in cardiometabolic markers. In high-risk populations, randomized trials with liraglutide and semaglutide have also shown reductions in major adverse cardiovascular events. Moreover, semaglutide and tirzepatide have exhibited benefits in patients with heart failure with preserved ejection fraction and obesity. Overall, GLP-1 receptor agonists or co-agonists hold substantial promise, however, questions remain regarding their long-term safety and effects in broader populations. The history of approval and withdrawal of anti-obesity medications underscores the importance of postmarketing surveillance. As evidence continues to accumulate, the balance between efficacy and safety will guide the optimal use of GLP-1 receptor agonists or co-agonists in both obesity management and cardiovascular risk reduction.