How significant are urinary tract infections (UTIs) associated with sodium‑glucose cotransporter‑2 (SGLT2) inhibitor therapy?

UTI Risk with SGLT2 Inhibitors is Not Clinically Significant

SGLT2 inhibitors do not increase the risk of urinary tract infections compared to placebo or other antidiabetic agents, despite theoretical concerns about glycosuria creating a favorable environment for bacterial growth. 1

Evidence from Major Clinical Trials

The EMPA-REG OUTCOME, CANVAS, and CANVAS-R trials demonstrated no difference in rates of any urinary tract infections or serious urinary tract infections between SGLT2 inhibitors and placebo, despite millions of patient-years of exposure. 1 This finding is supported by large-scale population-based cohort studies showing SGLT2 inhibitor use is not associated with increased UTI risk compared with DPP-4 inhibitors, sulfonylureas, GLP-1 receptor agonists, or thiazolidinediones. 2 In fact, UTI risk was lower compared with insulin (pooled HR 0.74,95% CI 0.63-0.87). 2

More recent comparative effectiveness data confirms that SGLT2 inhibitor exposure is associated with a lower risk of noncandida UTI compared to GLP-1 receptor agonists (all HRs ≤0.91, p < 0.001). 3

The Real Genitourinary Concern: Genital Mycotic Infections

Genital mycotic infections—not UTIs—represent the primary genitourinary adverse event with SGLT2 inhibitors, occurring in approximately 6% of users versus 1% on placebo. 4, 1 SGLT2 inhibitor exposure is associated with a greater risk of candida UTI compared to GLP-1 receptor agonists (all HRs ≥2.42, p < 0.001). 3

These genital infections are typically mild, respond to brief antifungal courses (oral fluconazole 150 mg single dose or topical azoles for 3-7 days), and rarely recur. 4, 1

Risk Stratification for UTI

Patients Without Genitourinary Abnormalities

• Initiate SGLT2 inhibitors without additional UTI-specific precautions. 1
• No increased risk of noncandida UTI exists in the general population. 3

Patients With Genitourinary Abnormalities

• Prior GU abnormalities (prior UTI, prior genital infection, GU malignancy, indwelling Foley, or other GU pathology) are associated with greater baseline risk of UTI (all adjusted HRs ≥1.26, p ≤ 0.002). 3
• However, no additive risk of noncandida UTI occurs when SGLT2 inhibitors are added in these high-risk populations. 3
• An additive effect between SGLT2 inhibitor exposure and several GU abnormalities does exist for candida UTI (all adjusted HRs ≥2.37, p < 0.001). 3
• Use SGLT2 inhibitors cautiously in patients with recurrent or severe UTI history, though cardiovascular and renal benefits may still outweigh risks. 1

Clinical Management Algorithm

For Patients Initiating SGLT2 Inhibitors

• Counsel patients on proper genital hygiene and adequate hydration to lower the risk of genital infections. 4
• Educate patients about early symptoms of genitourinary infections (genital itching, discharge, dysuria) to facilitate prompt treatment. 4
• Older age is consistently associated with increased susceptibility to UTIs in SGLT2 inhibitor users, warranting closer monitoring. 1

When Infections Occur

• Genital mycotic infections: Treat with standard antifungal therapy and continue SGLT2 inhibitor during treatment of mild to moderate infections. 4
• Mild to moderate UTIs: Continue SGLT2 inhibitor therapy during standard antibiotic treatment. 4
• Severe or recurrent UTIs: Consider temporary discontinuation of SGLT2 inhibitor. 4
• Fournier's gangrene: Discontinue SGLT2 inhibitor immediately and provide urgent surgical debridement and broad-spectrum antibiotics. 4

Post-UTI Management

• In patients with type 2 diabetes recovering from UTI, SGLT2 inhibitor use is associated with lower risks of mortality (HR 0.59,95% CI 0.45-0.77), major adverse kidney events (HR 0.78), and sepsis (HR 0.75) compared with DPP-4 inhibitors. 5
• Resume or continue SGLT2 inhibitor after UTI resolution, as the safety and clinical benefit support use during the post-infectious phase. 5

Guideline Recommendations Across CKD Risk Strata

The 2024 BMJ guidelines provide risk-stratified recommendations for SGLT2 inhibitor use in adults with chronic kidney disease, acknowledging that moderate certainty evidence shows no important increase in the risk of harms across all risk strata. 6

• Very high risk: Strong recommendation in favor (high certainty of survival benefit and reduced kidney failure). 6
• High risk: Weak recommendation in favor (moderate certainty of reductions in mortality and cardiovascular outcomes). 6
• Moderate risk: Weak recommendation in favor (moderate certainty of reductions in all-cause mortality and non-fatal stroke). 6
• Low risk: Weak recommendation in favor (moderate certainty of small but important reductions in mortality and stroke). 6

The panel acknowledged that adverse events remain plausible at the individual patient level, but the benefits of SGLT2 inhibitors on kidney and cardiovascular outcomes generally outweigh the risk of genitourinary infections in most patients. 6, 4

Common Pitfalls

• Do not confuse euglycemic ketoacidosis with symptoms of genitourinary infection—both can present with malaise and abdominal discomfort. 4
• Do not withhold SGLT2 inhibitors solely due to theoretical UTI concerns—the evidence does not support increased noncandida UTI risk. 1, 2
• Do not ignore the real risk of genital mycotic infections—counsel patients proactively about this more common adverse event. 4
• Withhold SGLT2 inhibitors during periods of acute illness, prolonged fasting, or before surgical procedures to reduce the likelihood of ketoacidosis and other complications. 4