Injectable glucagon-like peptide-1 (GLP-1) receptor agonists, such as semaglutide, are increasingly recognized for their potential to improve cardiovascular health beyond their well-established role in weight loss and diabetes management. These medications are now capturing the attention of cardiologists, driven by their ability to address key cardiometabolic risk factors.
Clinical Success and Patient Impact
Dr. Michael Blaha from John Hopkins Medicine shared a compelling case of a patient with a history of myocardial infarction (MI), diabetes, sleep apnea, and atrial fibrillation. The patient, who also had a BMI close to 40, experienced significant improvements after starting on semaglutide (Ozempic). "She lost 26 pounds, which for her was about 12% of her body weight. Her triglycerides had come down from 700 to 300, her LDL dropped 15 to 20 points, and her blood pressure looked good for the first time in a long time," Dr. Blaha noted. The patient also reported improved mobility and overall well-being.
The Rise of GLP-1 Agonists
The surge in popularity of GLP-1 receptor agonists is attributed to their demonstrated efficacy in reducing atherosclerotic cardiovascular disease (ASCVD) risk by improving vasculature endothelium, reducing oxidative stress, and increasing nitric oxide production, in addition to lowering blood glucose. Semaglutide, in particular, has garnered significant research support. The SUSTAIN-6 trial demonstrated noninferiority to placebo for major adverse cardiovascular events (MACE) with once-weekly semaglutide in patients with type 2 diabetes. Furthermore, the PIONEER 6 study showed a 51% relative reduction in cardiovascular death risk and a 49% relative reduction in all-cause death with oral semaglutide in similar patients.
Ongoing Trials and Future Directions
Several ongoing trials are poised to further define the cardiovascular benefits of GLP-1 agonists. The SELECT trial is evaluating CV event reduction in 17,500 overweight or obese patients receiving once-weekly semaglutide or placebo over 5 years. Dr. Blaha considers SELECT one of the most important preventive cardiology trials in decades, anticipating that secondary analyses may reveal broader benefits beyond ASCVD outcomes. SURMOUNT MMO is another key trial, assessing tirzepatide, a dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) agonist, in 15,000 patients with established CVD but without diabetes or recent CV events. The primary endpoint is the time to first MACE occurrence.
Integrating GLP-1 Agonists into Practice
Experts emphasize that GLP-1 agonists should be integrated into a comprehensive approach to cardiovascular risk management, including lifestyle modifications. Dr. Sean Heffron from NYU Langone Health advocates for a "three-legged stool" approach, comprising good diet, exercise, and medication. He also noted that the weight-loss indications extend down to a BMI of about 27.5, making these medications relevant for a large proportion of patients.
Addressing Side Effects and Education
Gastrointestinal side effects, such as nausea, constipation, and diarrhea, are commonly reported with GLP-1 agonists. These can be mitigated by starting with low doses and gradually titrating upwards. Dr. Maria Hurtado Andrade from Mayo Clinic also highlighted the importance of managing patient expectations, as real-world outcomes may differ from those observed in clinical trials due to variations in access to resources and behavioral support.
The Future of Cardiometabolic Medicine
The increasing use of GLP-1 agonists underscores the need for enhanced cardiometabolic education among cardiologists. Dr. Blaha envisions the development of a dedicated training program in cardiometabolic medicine to bridge the gap in expertise and address the complex interplay between the heart, brain, and gastrointestinal tract. He also speculated that future weight-loss plans might incorporate an induction phase with semaglutide followed by a maintenance phase involving exercise, diet, or intermittent fasting.
Emerging Therapies
Looking ahead, there is optimism that current GLP-1 agonists are just the beginning. Dual and triple-ingredient agonists with potentially greater efficacy for weight loss are in the pipeline. However, as newer versions of these medications are developed, careful monitoring of their safety profiles will be essential, given the history of challenges with earlier agents like taspoglutide.
