Sodium glucose cotransporter 2 (SGLT2) inhibitors provide better glycemic control in patients with type 2 diabetes and reduce the risks for cardiovascular events, kidney disease progression, and early mortality. Although development of acute kidney injury (AKI) with the use of SGLT2 inhibitors has been a concern, recent studies suggest that these agents may actually lower the risk for AKI.
The drugs have potential adverse effects, however. For example, observational studies have revealed increased risks for urinary tract infections (UTIs) and genital infections with SGLT2 inhibitors compared with other antidiabetes agents.
Acute Kidney Injury
A meta-analysis of 30 randomized trials published in PLOS Medicine demonstrated that use of an SGLT2 inhibitor (mostly for type 2 diabetes) significantly decreased the odds of AKI requiring hospitalization by 36% compared with placebo or another oral hypoglycemic agent, Jan Menne, MD, of Hannover Medical School in Hannover, Germany, and colleagues reported. The odds of adverse events related to hypovolemia were significantly increased 20%, however.
“Our findings indicate that fear of causing acute kidney injury should not stop practitioners prescribing SGLT2is,” the authors wrote.
Recent research published in the American Journal of Kidney Disease examined AKI among “high-risk” patients who were older than 65 years with multiple comorbidities and polypharmacy. Using Medicare data, investigators propensity-score matched 68,130 and 71,477 new users of a dipeptidyl peptidase-4 (DPP-4) inhibitor or glucagon-like peptide-1 (GLP-1) receptor agonist, respectively, with the same number of new users of SGLT2 inhibitors. Initiation of an SGLT2 inhibitor was significantly associated with a 29% and 19% lower risk of AKI hospitalization and a 61% and 44% lower risk of AKI requiring dialysis compared with initiation of a DPP-4 inhibitor or GLP-1 receptor agonist, respectively, Elisabetta Patorno, MD, DrPH, of Brigham and Women’s Hospital and Harvard Medical School in Boston, Massachusetts, and colleagues reported. Reduced AKI risk was found among patients with and without prior metformin use, heart failure, and chronic kidney disease. Patients with a history of AKI were an exception.
“Our study, which is based on a large population of routine care patients older than 65 years, provides reassurance on the safety of SGLT-2i with respect to the risk of AKI, and suggests SGLT-2i may actually prevent AKI events compared to alternative diabetes treatments,” Dr Patorno’s team wrote.
Another team of investigators probed US and Japanese postmarketing safety reports to examine if SGLT2 inhibitors could decrease AKI risk from common drugs. An analysis of data from the US FDA’s Adverse Event Reporting System demonstrated that the odds of AKI significantly decreased 35% and 22% among users of SGLT2 vs DPP-4 inhibitors who concomitantly received nonsteroidal anti-inflammatory drugs (NSAIDs) and thiazide diuretics, respectively, Mitsuboshi Satoru, PhD, of Kaetsu Hospital in Niigata, Japan, and colleagues reported in the Journal of Clinical Pharmacology.
Analyses of Japan’s Medical Data Vision showed that SGLT2 inhibitor users administered NSAIDs, thiazide diuretics, loop diuretics, and anti-herpes simplex virus drugs had significant 54%, 50%, 29%, and 80% decreased odds of AKI, respectively, compared with DPP-4 inhibitor users receiving the same drugs. No differences were observed in AKI risk after concomitant cisplatin or intravenous vancomycin.
“These results suggest that the use of SGLT-2 inhibitors might decrease the risk of drug-induced AKI caused by some drugs,” Dr Satoru’s team wrote.
Urinary Tract and Genital Infections
Among 107,131 new users of metformin older than 18 years from the Korean National Health Insurance Service, 7741 also received an SGLT2 inhibitor (dapagliflozin, empagliflozin, or ipragliflozin) and 99,390 received another second-line antidiabetic drug. After propensity-score matching, the risk for genital infections was a significant 2.4-, 3.2-, and 3.2-fold higher with concomitant use of SGLT2 inhibitors compared with use of DPP-4 inhibitors, sulfonylurea, and thiazolidinedione, respectively, Bonggi Kim, PhD, of the Korea Institute of Drug Safety and Risk Management, and colleagues reported in Pharmacology Research & Perspectives. Genital infections included Candida infections, vaginitis, vulvitis, gonococcal infections, and inflammatory disease of the uterus in women and candidal balanitis, orchitis, epididymitis, and balanoposthitis in men.
SGLT2 inhibitor use was also significantly associated with a 1.6-, 1.7-, and 1.7-fold increased risk of UTIs compared with DPP-4 inhibitors, sulfonylurea, and thiazolidinedione, respectively, the investigators reported. UTIs included pyelonephritis, cystitis, urethritis, urethral syndrome in women, and inflammatory prostate diseases in men.
Women taking SGLT2 inhibitors had slightly higher risks for genital infections and UTIs compared with men. Patients older vs younger than 60 years taking SGLT2 inhibitors also had increased risks. Monitoring is crucial, according to the investigators. Dr Kim’s team noted that for “patients with a very high risk of genital infections and UTIs, such as perineal gangrene, recurrent and neurological bladder patients, it is probably recommended not to administer SGLT2 inhibitors.”
In a separate study, researchers offered some practical ways to manage SGLT2 inhibitor-associated genital mycotic infections.
Potential Risks vs Benefits
The benefits of SLGT2 inhibitors may outweigh the risks of adverse events, according to investigators of a study published in the International Journal of Cardiology. Brian Chiang, MBBS, of Flinders Medical Centre in Australia, and colleagues compiled trial data from 71,545 patients, of whom 53,144 had type 2 diabetes, 8705 chronic kidney disease (CKD), and 9696 heart failure with reduced ejection fraction.
For the type 2 diabetes cohort, the investigators calculated that 558, 139, 851, and 601 patients would need to be treated with an SGLT2 inhibitor to prevent 1 renal deterioration, heart failure hospitalization, cardiovascular death, and death from any cause, respectively. However, 1 episode of diabetic ketoacidosis, UTI, mycotic genital infection, hypotension, hypoglycemia, amputation, and fracture might occur among 1525, 239, 69, 325, 472, 1578, and 9569 treated patients, respectively.
In the CKD cohort, the number of patients who would need to be treated to prevent 1 renal deterioration, heart failure hospitalization, cardiovascular death, and death from any cause was 63, 116, 245, and 138, respectively. For 1 episode of diabetic ketoacidosis, UTI, mycotic genital infection, hypotension, hypoglycemia, amputation, and fracture to occur, 1458, 309, 291, 165, 374, 4450, and 696 patients would need to be treated, respectively.
For the cohort with heart failure with reduced ejection fraction, the number of patients who would need to be treated to prevent 1 renal deterioration, heart failure hospitalization, cardiovascular death, death from any cause, and diabetic ketoacidosis was 143, 18, 93, 76, and 6224, respectively. By comparison, 1 instance of UTI, mycotic genital infection, hypotension, hypoglycemia, amputation, and fracture might develop among 557, 356, 120, 574, 707, and 858 treated patients, respectively. The study did not examine AKI.
“Based on a large pool of data from several rigorous placebo-controlled trials, our results suggest that the benefits outweigh the risks when treating patients with SGLT2 inhibitors,” Dr Chiang’s team stated. “Catastrophic adverse effects are rare while those less severe, although increased, are generally manageable with clinical acumen and patient education.”
Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original references for a full list of authors’ disclosures.
Yang H, Choi E, Park E, et al. Risk of genital and urinary tract infections associated with SGLT-2 inhibitors as an add-on therapy to metformin in patients with type 2 diabetes mellitus: A retrospective cohort study in Korea. Pharmacol Res Perspect. Published online January 10, 2022. doi:10.1002/prp2.910
Menne J, Dumann E, Haller H, Schmidt BMW. Acute kidney injury and adverse renal events in patients receiving SGLT2-inhibitors: A systematic review and meta-analysis. Published online December 9, 2019. PLOS Med. doi:10.1371/journal.pmed.1002983
Zhuo M, Paik JM, Wexler DJ, Bonventre JV, Kim SC, Patorno E. SGLT2 inhibitors and the risk of acute kidney injury in older adults with type 2 diabetes. Am J Kidney Dis. Published online November 8, 2021. doi:10.1053/j.ajkd.2021.09.015
Satoru M, Kaseda R, Narita I, et al. Association between the use of sodium-glucose cotransporter-2 inhibitors and drug-induced acute kidney injury: Analysis of 2 databases. J Clinical Pharmacol. Published online November 11, 2021. doi:10.1002/jcph.1998
Chiang B, Chew DP, De Pasquale CG. Outcome trial data on sodium glucose cotransporter-2 inhibitors: Putting clinical benefits and risks in perspective. Int J Cardiol. 2022 Feb 15;349:96-98. doi:10.1016/j.ijcard.2021.12.015