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TOPLINE:

Men with type 2 diabetes (T2D) who initiated SGLT2 inhibitors showed nearly double the risk for phimosis after 1 year of treatment than those who initiated GLP-1 receptor agonists (GLP-1 RAs). This elevated risk persisted for over 8 years of follow-up.

METHODOLOGY:

• SGLT2 inhibitors decrease hyperglycaemia by promoting glucose excretion through the kidneys, causing glucosuria, but raise concerns about an approximately threefold elevated risk for genital infections.
• Researchers in Denmark emulated a target trial to compare the risk for phimosis between male metformin users with T2D who initiated SGLT2 inhibitors (n = 32,543; median age, 62.8 years) and those who initiated GLP-1 RAs (n = 14,730; median age, 63.1 years) from January 2016 to December 2021.
• The primary outcome was a first-time inpatient or outpatient diagnosis of phimosis, with penile cancer being included as a prespecified secondary outcome.
• Participants were followed up for a median duration of 4 years, with a maximum follow-up duration being 8 years.

TAKEAWAY:

• The use of SGLT2 inhibitors was associated with a nearly twofold higher risk for phimosis than the use of GLP-1 RAs at 1 year (risk ratio [RR], 1.88; 95% CI, 1.43-2.47).
• The elevated risk for phimosis with the use of SGLT2 inhibitors vs GLP-1 RAs persisted even after 8 years of follow-up (RR, 1.36; 95% CI, 1.14-1.61).
• Although the absolute risk for penile cancer was low, the results suggested that men initiating SGLT2 inhibitors had a higher 8-year cumulative risk for penile cancer than those initiating GLP-1 RAs, corresponding to an RR of 6.34 (95% CI, 1.16-34.52).

IN PRACTICE:

"Increased genital infections due to glucosuria in SGLT2i [SGLT2 inhibitor] users might therefore contribute to the elevated risks of both phimosis and penile cancer. Of note, any such risk must be weighed against the clear beneficial effects of SGLT2i on cardiovascular risk and overall mortality," the authors wrote.

SOURCE:

This study was led by Christine Ljungberg, Aarhus University and Aarhus University Hospital, Aarhus, Denmark. It was published online on July 30, 2025, in Diabetes Care.

LIMITATIONS:

Detection bias may have affected the findings as SGLT2 inhibitor users are more likely to develop urogenital symptoms, potentially resulting in more frequent urologic assessments. This study identified few cases of penile cancer, limiting statistical precision for this outcome, and the median follow-up duration of 4 years may have been insufficient for thoroughly assessing the risk for penile cancer. This study lacked information on covariates such as BMI, circumcision status, ethnic diversity, socioeconomic factors, and lifestyle behaviours.

DISCLOSURES:

This study was supported by Aarhus University. Some authors reported giving presentations and lectures on medical research (with or without compensation), receiving research support, teaching healthcare professionals, and having other ties with various pharmaceutical companies.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.