Are GLP-1 Drugs Linked to Erectile Dysfunction?

GLP-1 receptor agonist use may be associated with a modest increase in erectile dysfunction (ED) risk in men with type 2 diabetes, a target trial emulation suggested.

Using U.S. electronic health record data, the incidence of an ED diagnosis over nearly 3 years of follow-up was 26% higher among new users of GLP-1 medications versus DPP-4 inhibitor initiators (35.2 vs 28 per 1,000 person-years; HR 1.26, 95% CI 1.08-1.46, P=0.004), reported Yong Chen, PhD, of the University of Pennsylvania in Philadelphia, and colleagues.

The association was generally consistent across demographic and clinical subgroups, but lost significance in a sensitivity analysis that aimed to capture unmeasured confounding or systematic biases (HR 1.23, 95% CI 0.86-1.75), according to the study in eClinicalMedicine.

Furthermore, the results contrast with earlier data and should be considered hypothesis-generating as they “may reflect residual or selection bias,” wrote Chen and colleagues. “Future randomized controlled trials with standardized assessment of erectile function and comprehensive longitudinal measurement of treatment exposure are needed to confirm these findings and elucidate the underlying mechanisms.”

ED affects nearly 50% of men with type 2 diabetes at some point in their lifetime. The pathophysiology is multifactorial, the researchers explained, “primarily attributed to endothelial dysfunction, impaired nitric oxide signaling, and autonomic neuropathy, which collectively contribute to vascular and neurogenic deficits.”

The relationship between use of GLP-1 agonists and ED is “complex,” they noted, with some preclinical and clinical data suggesting possible erectile health benefits.

For example, an exploratory analysis of the randomized REWIND trial found that slightly fewer men developed erectile dysfunction in the group assigned to dulaglutide (Trulicity) than in the placebo group over more than 5 years of median follow-up (HR 0.92, 95% CI 0.85-0.99, P=0.021).

Meanwhile, a cohort study using the TriNetX database reported higher ED risk and increased use of PDE5 inhibitors such as sildenafil (Viagra) among nondiabetic men with obesity prescribed semaglutide (Ozempic, Wegovy), compared with nonusers.

“These conflicting findings between real-world evidence and trial-based data underscore the need for further mechanistic and prospective studies to clarify the net effect of GLP-1 receptor agonists on sexual health,” Chen and colleagues noted.

Their target trial emulation used electronic health records from the University of Pennsylvania Health System from January 2019 to September 2024. Adult men with type 2 diabetes, identified by diagnostic codes, were included. Men with a prior ED diagnosis or end-stage renal disease were excluded.

After stabilized inverse probability of treatment weighting, the analysis included 4,910 patients who initiated a GLP-1 drug and 5,524 who initiated a DPP-4 inhibitor. Mean age was 63, body mass index was 32.8, 55% were white, and 23% were Black. Before weighting, GLP-1 drug users tended to be younger, have a higher prevalence of obesity, and a higher estimated glomerular filtration rate.

Analyses stratified by specific GLP-1 agent suggested a higher ED risk among men prescribed dulaglutide (HR 1.44, 95% CI 1.20-1.73). Estimates for other agents — semaglutide, tirzepatide (Mounjaro, Zepbound), and liraglutide (Victoza, Saxenda) — were modest or imprecise due to small sample sizes.

Chen and co-authors also used U.S. electronic health record data from the TriNetX database to validate their findings. In this analysis, men on GLP-1 drugs had a 13% increased ED risk compared with DPP-4 inhibitor users over nearly 3 years (HR 1.13, 95% CI 1.10-1.17, P<0.001).

The researchers acknowledged a few limitations, including a lack of data on changes in body weight and glycemic control after starting treatment, as well as pre-baseline medication history and diabetes duration. Also, ED was identified using diagnosis codes, which may not capture milder cases and could introduce misclassification.