New 5-Year Study Reveals Surprising Long-Term Effects of GLP-1 Medications

A landmark five-year longitudinal study published in the New England Journal of Medicine has provided the most comprehensive picture yet of what happens to patients who take GLP-1 receptor agonists like semaglutide (Ozempic, Wegovy) over extended periods. The findings are reshaping clinical practice and raising important questions about long-term use of these medications.

The Study Design

The research followed 12,400 participants across 23 countries who were prescribed semaglutide for either type 2 diabetes management or weight loss. Participants were matched with a control group of similar demographics and health profiles who did not receive GLP-1 medications. The study tracked a comprehensive array of outcomes including cardiovascular events, kidney function, mental health indicators, bone density, and quality of life measures.

Cardiovascular Benefits Exceed Expectations

The most striking finding was the magnitude of cardiovascular protection. Participants taking semaglutide experienced a 28% reduction in major adverse cardiovascular events (MACE), including heart attacks and strokes, compared to the control group. This exceeded the 20% reduction observed in earlier shorter-term studies and suggests that the cardiovascular benefits compound over time.

Particularly notable was the reduction in heart failure hospitalizations, which fell by 41% in the treatment group. Researchers believe this reflects multiple mechanisms including weight reduction, improved glycemic control, direct cardioprotective effects of the drug, and reduction in systemic inflammation.

Kidney Function Improvements

Nephrology was one of the most significant areas of benefit. Participants with pre-existing chronic kidney disease showed a 24% slower rate of kidney function decline compared to controls. In a subset of patients with diabetic nephropathy, the drug appeared to halt progression in approximately 18% of cases, an outcome that would previously have been considered exceptional.

Mental Health Considerations

The mental health findings were more nuanced. While many participants reported improvements in depression scores and quality of life measures, a subset — approximately 8% — experienced increased anxiety, particularly around food and eating behaviors. Clinicians are now advised to screen for eating disorder history before initiating GLP-1 therapy and to monitor mental health closely during the first year of treatment.

Bone Density Concerns

One area of concern that emerged from the long-term data was bone density. Participants who lost more than 15% of their body weight showed a statistically significant reduction in bone mineral density, particularly in the hip and spine. Researchers recommend calcium and vitamin D supplementation, weight-bearing exercise, and regular bone density monitoring for patients on long-term GLP-1 therapy.

Clinical Implications

The study's findings are already influencing prescribing guidelines. Several major medical associations are updating their recommendations to reflect the expanded evidence base for cardiovascular and kidney benefits, potentially broadening the eligible patient population beyond those with diabetes or obesity.