Increased risk of urinary tract infection and pyelonephritis under concomitant use of sodium‐dependent glucose cotransporter 2 inhibitors with antidiabetic, antidyslipidemic, and antihypertensive drugs: An observational study

Abstract

Urinary tract infection (UTI) and pyelonephritis cause urosepsis, which can become life threating. Sodium‐dependent glucose cotransporter 2 (SGLT2) inhibitors, a class of oral anti‐diabetic drugs, may increase the risk of UTI and pyelonephritis, as observed from their mechanism of action. Patients with diabetes receiving SGLT2 inhibitors are often concomitantly administered other antidiabetic, antidyslipidemic, or antihypertensive drugs. To determine if drug–drug interactions (DDIs) between SGLT2 inhibitors and these medications increased the risk of UTI and pyelonephritis, we analyzed the Food and Drug Administration Adverse Event Reporting System (FAERS) database. We applied Norén's and Gosho's methods for detecting DDIs. FAERS contains records describing 14 526 398 patient characteristics, 54 290 663 drug properties, and 47 252 416 reactions/events. We found 23 drug combinations that could induce UTI and pyelonephritis, such as SGLT2 inhibitors administered with dipeptidyl peptidase‐4 inhibitors, thiazolidinediones, glinides, statins, angiotensin II receptor blockers, and calcium channel blockers. Combination therapy with the drugs detected in our analyses would show potential interactions that could result in UTI and pyelonephritis in patients with diabetes mellitus. However, owing to various limitations, these results must be confirmed by additional analyses.

Multivariate generalized mixed-effects models for screening multiple adverse drug reactions in spontaneous reporting systems

“…For example, only observed ADRs are registered in spontaneous reporting systems databases, resulting in underreporting bias ( Noguchi et al, 2021 ). Furthermore, the incidence rate for ADRs cannot be calculated because databases collect only patient information with the ADR ( Tada and Gosho, 2022 ). Moreover, even if the patients are actually taking multiple drugs, some drug information might be missing.…”

Drug Safety Evaluation of Sodium-Glucose Cotransporter 2 Inhibitors in Diabetic Comorbid Patients by Review of Systemic Extraglycemic Effects

“… 139 Also, two observational studies show an increase in the incidence of UTI in the SGLT2 inhibitor group compared to other antidiabetic drugs. 140 , 141 …”

“…139 Also, two observational studies show an increase in the incidence of UTI in the SGLT2 inhibitor group compared to other antidiabetic drugs. 140,141 Lower limb amputation is another side effect of this drug. Several meta-analyses suggest the causative role of canagliflozin in lower extremity amputations, [142][143][144] but the definitive role of other agents (such as dapagliflozin and empagliflozin) in this regard is not clear.…”

Sodium‐glucose cotransporter 2 inhibitors: A comprehensive review from cells to bedside

“…The American Diabetes Association (ADA) described SGLT2is as a class with moderate efficacy compared with other antidiabetic classes with beneficial effects on the both cardiovascular and renal systems without inducing the risk of hypoglycemia 37 ; however, it is associated with adverse events such as urinary tract infection. 38 SGLT2is efficacy in improving glycemic control in patients with T2DM has been demonstrated in different clinical trials. 39 SGLT2is decrease the circulating level of glucose through its glycosuric effect and draw back to normal the glycemic values including the fasting and postprandial plasma glucose levels and glycated hemoglobin (HbA1c) level.…”

“…Similar beneficial effects were reported by other SGLT2is; dapagliflozin was associated with a lower rate of hospitalization due to HF exacerbation in DECLARE–TIMI 58 trial 34 and canagliflozin with a lower rate of a major cardiovascular event in both CANVAS 35 and CREDENCE 36 trials, which all were conducted on patients with T2DM. The American Diabetes Association (ADA) described SGLT2is as a class with moderate efficacy compared with other antidiabetic classes with beneficial effects on the both cardiovascular and renal systems without inducing the risk of hypoglycemia 37 ; however, it is associated with adverse events such as urinary tract infection 38 …”