Vulvovaginitis and balanitis in patients with diabetes treated with dapagliflozin☆,☆☆
Introduction
Genital infections such as vulvovaginitis and balanitis (VV/B) are well known complications of type 2 diabetes mellitus (Bohannon, 1998, Donders, 2002, Goswami et al., 2000, Rahmoune et al., 2005, Rayfield et al., 1982), although the precise mechanism of this effect is not well understood. Inadequate glycemic control in patients with diabetes is known to result in both hyperglycemia and glucosuria, representing two of the potential mechanisms for increased incidence of VV/B in this population. Hyperglycemia, which may interfere with normal host defense mechanisms (eg, leukocyte function), is associated with vulvovaginal candidiasis (Bohannon, 1998, Goswami et al., 2000, Rayfield et al., 1982). C. albicans expresses a glucose-inducible protein that increases its adhesion to vaginal epithelial cells and reduces the activity of phagocytic cells. Glucosuria is also associated with increased incidence of candidal infection (Rayfield et al., 1982); it has been shown to increase adherence of bacteria and yeast to uroepithelial and vaginal epithelial cells (Bohannon, 1998, Donders, 2002, Rayfield et al., 1982) and may provide a favorable environment for the growth of commensal organisms such as C. albicans (Donders, 2002).
Glucosuria is a relevant issue within the context of an investigational class of antidiabetes therapy targeting sodium glucose cotransporter 2 (SGLT2). SGLT2 mediates the body’s reabsorption of the majority of glomerular-filtered glucose. Inhibitors of this protein reduce renal glucose reabsorption via an insulin-independent mechanism, thereby reducing blood glucose levels while increasing urinary glucose excretion (Ghosh et al., 2012, Rahmoune et al., 2005, Salvatore et al., 2011, Zhang et al., 2010). In light of the potential association between glucosuria and VV/B, medical treatments such as SGLT2 inhibitors that induce glucosuria should be evaluated to determine their level of risk for genital infection.
Dapagliflozin is a novel, orally administered, selective, potent SGLT2 inhibitor under review in the U.S. and approved in Europe and other markets for the treatment of type 2 diabetes (Han et al., 2008, Meng et al., 2008). Dapagliflozin has been studied in patients with type 2 diabetes in placebo-controlled clinical studies as monotherapy; as add-on therapy to metformin, insulin, sulfonylurea, or thiazolidinedione; and as first-line combination therapy with metformin (Bailey et al., 2010, Ferrannini et al., 2010, List et al., 2009, Rosenstock et al., 2012, Strojek et al., 2011, Wilding et al., 2009, Wilding et al., 2012). In each study, dapagliflozin was generally well tolerated, and patients who received dapagliflozin had significantly better glycemic control than those who received placebo. Dapagliflozin has been shown to induce dose-dependent increases in glucosuria (Rosenstock et al., 2012, Strojek et al., 2011, Wilding et al., 2009). Data from clinical pharmacology studies showed dose-related increases in glucose excretion for doses of 2.5, 5, and 10 mg (Parikh et al., 2011). In a Phase 2b trial, the 10 mg dose demonstrated near maximal antihyperglycemic benefit, while only small additional increments of urine glucose excretion were documented at higher doses (List et al., 2009). Because the mechanism of dapagliflozin induces glucosuria, controlled clinical trials of this agent provide an opportunity to better elucidate the relationship between glucosuria and the incidence of genital infections. A robust clinical development program to monitor these outcomes was undertaken as part of the drug development program.
Section snippets
Clinical trials and patients
Data from 12 randomized, placebo-controlled trials (Appendix 1) were pooled to evaluate the effect of pharmacologically-induced urinary glucose excretion on the rates of genital infections in patients with type 2 diabetes treated with dapagliflozin. These trials involved dapagliflozin as monotherapy (4), add-on to metformin (2), add-on to insulin (2), add-on to thiazolidinedione (TZD) (1), add-on to sulfonylurea (1), and initial combination with metformin (2) studies. Except where otherwise
Patients
The pooled patient population (N = 4545) for this analysis included 3152 patients who received once-daily dapagliflozin (2.5 mg [n = 814], 5 mg [n = 1145], or 10 mg [n = 1193]) and 1393 patients who received placebo. Across studies, 485 patients were randomized to 12 weeks of treatment, and 4060 were randomized to 24 weeks. The study groups were generally balanced with respect to baseline demographics and disease characteristics (Table 1). Patients had a baseline mean HbA1c of 8.1% to 8.4%. More than 85% of
Discussion
Throughout the course of the dapagliflozin development program, a meticulous, rigorous program was undertaken to capture all relevant events and accurately determine the level of risk of genital infection related to glucosuria. The proactive questioning at each study visit served to remind patients to be aware of relevant symptoms and report them, even if the symptoms were treated and resolved between study visits. Diagnosis was based on symptoms and clinical judgment. Cultures were not
Conclusions
This comprehensive pooled safety analysis of 12 clinical trials in 4545 patients with type 2 diabetes indicates that treatment with dapagliflozin 2.5 mg, 5 mg, or 10 mg once daily is accompanied by an increased risk of vulvovaginitis or balanitis related to the induction of glucosuria. These events were similar to those typically seen in patients with type 2 diabetes and were generally mild to moderate. Most resolved spontaneously or responded to standard antimicrobial therapy; the infections
Acknowledgment
Ann L. Davis, MPH, CMPP, an employee of Bristol-Myers Squibb, assisted in the development of the manuscript.
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Clinical trial registration numbers: NCT00263276, NCT00972244, NCT00528372, NCT00736879, NCT00528879, NCT00855166, NCT00357370, NCT00680745, NCT00683878, NCT00673231, NCT00643851, NCT00859898. Available at http://clinicaltrials.gov.
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Disclosure Statement: The studies included in this analysis were sponsored by Bristol-Myers Squibb and AstraZeneca. Authors Johnsson, Sugg, and Parikh are employees and stockholders of AstraZeneca. Authors Ptaszynska, Schmitz, and List are employees and stockholders of Bristol-Myers Squibb.