A hypothesis for why sodium glucose co‐transporter 2 inhibitors have been found to cause genital infection, but not urinary tract infection

Sodium glucose co-transporter 2 (SGLT2) inhibitors are an effective class of medications for adults with type 2 diabetes. In this population, they reduce the risk of renal failure, heart failure, myocardial infarction, cardiovascular mortality and, potentially, all-cause mortality. However, they are associated with clinically important adverse events, including diabetic ketoacidosis, volume depletion and genital infection. Because SGLT2 inhibitors result in marked glycosuria, it was anticipated that SGLT2 inhibitors might also cause urinary tract infection (UTI). In 2015, based on 19 cases of sepsis due to UTI among adults who received an SGLT2 inhibitor the FDA released a safety communication and updated the drug label about an increased risk of serious UTI. However, the available evidence to date suggests that SGLT2 inhibitors do not cause UTI. This was surprising, given that women with diabetes mellitus have a threefold higher odds of UTI compared with adults without diabetes mellitus. We hypothesize that the explanation may lie in the differing pathogenesis of genital infection compared with UTI, coupled with the diuresis induced by SGLT2 inhibitors. Approximately 80%–90% of glucose is reabsorbed at the proximal convoluted tubule via SGLT2. SGLT2 inhibitors act by inhibiting the reabsorption of glucose and by lowering the renal threshold for glucose excretion. The osmotic diuresis created by SGLT2 inhibitors results in up to 100 g of glucose being excreted into the urine each day, which is equivalent to about 400 cal, or 25 teaspoons of sugar. One of the most common causes of a genital infection is Candida albicans and glucose may act as a growth-limiting substrate for many Candida species. Although typically a harmless commensal organism, most women experience at least one symptomatic yeast infection in their lifetime. Diabetes is a known risk factor for genital infection, particularly in adults with poorly controlled diabetes who have glycosuria. In addition to the immunosuppressive effects of poorly controlled diabetes, it is thought that glycosuria results in an increased amount of glucose present on the genitalia, which could drive yeast growth and impair local neutrophil function. Candida are able to adhere to the genitalia through an expression of cell surface molecules called adhesins, which in bacteria may be modified by the presence of glucose. Attachment triggers the yeast-to-hypha transition, growth and expression of invasins, which mediates uptake of the fungus by the host cell. If untreated, this can result in a yeast infection of the genitalia, which typically causes pain, redness, swelling and pruritus. Based on clinical trial literature, approximately 6% of adults with diabetes randomized to an SGLT2 inhibitor experience a genital infection compared with approximately 2% with placebo. A recent metaanalysis, including 56 clinical trials confirmed this observation, and found that SGLT2 inhibitors were associated with a threefold higher risk ratio [RR = 3.30, 95% confidence interval (CI) 2.74, 3.99, I = 22%] for genital infection, regardless of sex, compared with placebo or other classes of diabetes medications. Nearly identical results have been found in observational studies (Table 1). For example, in the study by Dave et al., diagnostic codes specific to yeast infections caused by Candida were used and they observed a nearly threefold higher rate of genital infection among adults who received an SGLT2. In contrast, the current literature does not support an increased risk of UTI with SGLT2 inhibitors. The most recent meta-analysis included 68 clinical trials and found the rate of UTI with SGLT2 inhibitor to be no different than placebo/comparator medication (RR = 1.05, 95% CI 0.98–1.12, I = 0). Because clinical trials are often underpowered to detect adverse events, and often exclude patients at highest risk, observational studies using real-world data with much Received: 14 November 2019 Revised: 22 December 2019 Accepted: 4 January 2020