What is the association between Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors and the risk of urinary tract infections?

Systematic Reviews and Meta-Analyses on SGLT2 Inhibitors and Urinary Tract Infections

Key Systematic Reviews and Meta-Analyses

1. Systematic Review by Revista da Associação Médica Brasileira (2019)

Study Design: Systematic review of 23 randomized clinical trials evaluating UTI risk with SGLT2 inhibitors in type 2 diabetes patients 1

Key Results:

• Increased UTI risk was demonstrated across SGLT2 inhibitor groups compared to placebo or other oral antidiabetic agents 1
• The increased risk was found predominantly with dapagliflozin, canagliflozin, and tofogliflozin, regardless of dosing 1
• UTI incidence was analyzed in multiple subgroups: monotherapy versus combination therapy, and according to specific comorbidities 1
• The authors concluded that the precise magnitude of UTI risk in type 2 diabetes patients using SGLT2 inhibitors remains to be more strictly determined 1

Important Caveat: This systematic review contradicts findings from large randomized controlled trials like EMPA-REG OUTCOME and CANVAS, which showed no difference in UTI rates between SGLT2 inhibitors and placebo 2, 3

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2. Meta-Analysis in Archivio Italiano di Urologia (2023) - Non-Diabetic Populations

Study Design: Systematic review and meta-analysis of 12 randomized controlled trials examining urogenital infections in non-diabetic patients treated with SGLT2 inhibitors 4

Key Results:

• SGLT2 inhibitors were associated with increased odds of urinary tract infections (OR 1.33,95% CI: 1.13-1.57, p < 0.0001, I² = 0%) in non-diabetic patients 4
• Genital infections showed even higher odds (OR 3.01,95% CI: 1.93-4.68, p < 0.0001, I² = 0%) 4
• When comparing diabetic versus non-diabetic patients in four trials with mixed populations, diabetic patients had significantly higher odds of genital infections but not UTIs compared to non-diabetic patients 4
• Patients taking placebo had significantly increased odds of UTIs if they were diabetic compared to non-diabetic 4

Clinical Implications: The risk of genital infections is increased in non-diabetic patients taking SGLT2 inhibitors, although to a lesser extent than in diabetics 4. A careful assessment of local anatomical conditions and history of previous urogenital infections is recommended to identify patients requiring more intense follow-up 4

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Reconciling Contradictory Evidence

Major Clinical Trials Show No Increased UTI Risk

The most robust evidence from large randomized controlled trials demonstrates no difference in UTI rates between SGLT2 inhibitors and placebo:

• The EMPA-REG OUTCOME, CANVAS, and CANVAS-R trials showed 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 2, 3
• The American College of Cardiology states that large clinical trials have shown no difference in the rates of any urinary tract infections or serious urinary tract infections between SGLT2 inhibitors and placebo, despite spontaneous postmarketing reports of pyelonephritis and urosepsis 2

Real-World Observational Studies Show Mixed Results

Some observational studies suggest increased UTI risk:

• A 2022 Thai observational study found an overall UTI incidence of 33.49% in the SGLT2 inhibitor group versus 11.72% in the non-SGLT2 inhibitor group 5
• Patients treated with SGLT2 inhibitors had a 3.70 times higher risk of UTI (95% CI: 2.60-5.29) compared to non-SGLT2 inhibitors 5
• Significant risk factors included female gender, older age, and occupation 5

However, a 2024 cross-sectional study contradicted these findings:

• A study of 328 type 2 diabetes patients found no statistical difference in UTI presence between patients taking SGLT2 inhibitors and those taking other glucose-lowering medications 6
• Higher HbA1c, higher BMI, female gender, and longer duration of type 2 diabetes were associated with increased UTI risk, but SGLT2 inhibitor use itself did not increase UTI likelihood 6

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Risk Factors for UTI in SGLT2 Inhibitor Users

When UTIs do occur in patients on SGLT2 inhibitors, the following risk factors are consistently identified:

• Older age is associated with increased susceptibility to UTIs 2, 5
• Female gender shows significantly higher UTI risk 6, 5
• History of recurrent or severe UTIs warrants cautious use 2, 7
• Higher HbA1c and BMI predict increased UTI likelihood 6
• Longer duration of type 2 diabetes is a predisposing factor 6

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Contrast with Genital Mycotic Infections

All evidence consistently demonstrates that genital mycotic infections, not UTIs, are the primary genitourinary concern with SGLT2 inhibitors:

• Genital mycotic infections occur in approximately 6% of SGLT2 inhibitor users versus 1% on placebo 2, 3, 8
• These infections are typically mild, respond to brief antifungal courses, and rarely recur 2, 3
• Women experience significantly higher incidence of genital yeast infections compared to men 2

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FDA Drug Label Warnings

Both dapagliflozin and empagliflozin FDA labels include warnings about serious urinary tract infections:

• Urosepsis and pyelonephritis requiring hospitalization have been reported in postmarketing surveillance 7, 9
• Treatment with SGLT2 inhibitors increases the risk for urinary tract infections 7, 9
• Patients should be evaluated for signs and symptoms of UTIs and treated promptly 7, 9

However, these warnings are based on postmarketing reports, not randomized controlled trial data 2

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Clinical Management Algorithm

For patients WITHOUT recurrent UTI history:

• The American College of Cardiology recommends initiating SGLT2 inhibitors without additional UTI-specific precautions, as large trials show no increased UTI risk 2, 3

For patients WITH recurrent or severe UTI history:

• The American Diabetes Association suggests using SGLT2 inhibitors cautiously, as cardiovascular and renal benefits may still outweigh risks 2, 3
• Consider more frequent monitoring for UTI symptoms 2

For older adults:

• Use SGLT2 inhibitors cautiously in frail elderly or those prone to orthostasis due to volume depletion risk 2
• UTI risk alone should not preclude use in older adults 2

If UTI develops during SGLT2 inhibitor therapy:

• Treat promptly with appropriate antibiotics 7, 9
• Consider temporary discontinuation in severe or recurrent UTIs 8
• Resume SGLT2 inhibitor after complete resolution of infection 8

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Common Pitfalls to Avoid

• Do not confuse postmarketing reports with randomized trial evidence: The highest quality evidence from large RCTs shows no increased UTI risk 2, 3
• Do not discontinue SGLT2 inhibitors solely due to theoretical UTI concerns: The cardiovascular and renal benefits generally outweigh infection risks 2, 3, 8
• Do not overlook genital mycotic infections: These are far more common than UTIs and represent the primary genitourinary adverse effect 2, 3, 8
• Do not ignore volume depletion as a confounding factor: Acute kidney injury from volume depletion may be mistaken for UTI-related complications 2, 7, 9