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Effects of SGLT-2 Inhibitors On UTIs and Genital Infections

Lowering HbA1c worth the risk of urinary tract and genital infections?

The new kids on the block for the management of type 2 diabetes, SGLT2 inhibitors, are becoming an increasingly popular option for patients. This newer class of medication exerts its glucose-lowering effect by down-regulating the glucose excretion threshold in the kidneys, thereby increasing glucose excretion through the urine. Studies have proven that SGLT2 inhibitors reduce HbA1c levels, fasting blood glucose, body weight and even blood pressure without increasing the risk or frequency of hypoglycemic events.1 Patients with type 2 diabetes are already at an increased risk of urinary tract infections and genital infections due to an increased amount of glucose in the urine. Because of how SGLT2 inhibitors exert their glucose-lowering effects, researchers became concerned about the increased risk of these infections in patients. Researchers evaluating the additive effects of SGLT2 inhibitors on the prevalence and severity of urinary tract and genital infections has resulted in inconclusive results. However, in December 2015, the FDA issued a warning regarding the risk of serious urinary tract infection with the use of SGLT2 inhibitors. Therefore, this study aimed to address the impact of SGLT2 inhibitors on urinary tract infections and non-sexually transmitted genital infections in patients with type 2 diabetes.1

Researchers evaluated articles from electronic databases such as: PubMed, EMBASE and the Cochrane Central Register for Controlled Trials using medical subject heading (MeSH) and free text terms. Randomized controlled trials (RCTs) of adults with type 2 diabetes taking either an SGLT2 inhibitor vs. placebo, SGLT2 inhibitor vs. other antidiabetic medications or SGLT2 inhibitors as monotherapy or combination therapy were included. Trials were required to be at least 12 weeks long and explicitly report data related to urinary tract infections, genital infections and events suggestive of either.1 For data analysis, researchers separately analyzed the aforementioned categories and evaluated patient characteristics, baseline treatment, details of the SGLT2 inhibitors used and the trial design. The Mantel-Haenszel method was used to calculate relative risk and a 95% confidence interval. The Cochran chi-square test and I-squared test was used to explore statistical heterogeneity. A total of 77 RCTs and one trial recruiting patients with established cardiovascular disease met inclusion criteria. Of the 77 trials, 96% blinded both patient and caregiver and 100% adequately generated their randomization sequence suggesting that the overall risk of bias for these studies was very low.

The 77 RCTs involved a total of 50,820 participants, mean follow-up time was 24 weeks, average HbA1c was 7.2%, ages ranged from 51.3 – 68.5 years old and mean BMI ranged from 24.8 – 35.5 kg/m2. A total of 68 trials documented 3,804 urinary tract infections from over 44,000 participants who were using at least one medication. Subgroup analysis of individual SGLT2 inhibitors vs. placebo showed a statistically significant difference in the incidence of urinary tract infections amongst the class.1 A total of 56 trials reported over 1,700 genital infections amongst 36,569 patients using SGLT2 inhibitors (vs control: 1,521/24,017 vs. 216/12,552, RR 3.30, 95% CI 2.74 to 3.99.)1

The current evidence confirms that SGLT2 inhibitors increase the risk of genital infections and that there is some variance amongst the different SGLT2 inhibitors. The effects of SGLT2 inhibitors and the risk of urinary tract infection was not statistically significant, however it is suggested that their use may increase the risk of urinary tract infections. This study along with other previously completed meta-analyses confirmed that the risk of urinary tract infection is greater with dapagliflozin in comparison to canagliflozin and empagliflozin. However, it should be noted that this risk was dose-dependent and the risk of urinary tract infection increased with higher doses of medication, 10 mg daily, while the most commonly used dose is 5 mg daily.2

These results confirmed what researchers had previously believed and this data should be taken into consideration when selecting a new diabetes regimen for a patient. Patients with a history of chronic urinary tract infections or genital infections may not be the best candidates for this class of drug. Further studies are warranted to determine the impact of SGLT2 inhibitors on the incidence of urinary tract infections and to establish if there is an increased risk with different SGLT2 inhibitors.

Practice Pearls:

  • Dapagliflozin has a dose-dependent relationship for the incidence of urinary tract infections and genital infections.
  • Severe UTI and genital infections have been seen with SGLT2 inhibitor use.
  • History of urinary tract or genital infections should be highly regarded when determining whether or not to initiate an SGLT2 inhibitor.

References:

Liu, Jiali, et al. “Effects of SGLT2 inhibitors on UTIs and genital infections in type 2 diabetes mellitus: a systematic review and meta-analysis.” Scientific Reports 7 (2017).

Li, Dandan, et al. “Urinary tract and genital infections in patients with type 2 diabetes treated with sodium‐glucose co‐transporter 2 inhibitors: A meta‐analysis of randomized controlled trials.” Diabetes, Obesity and Metabolism19.3 (2017): 348-355.

Jessica Lambert, University of South Florida College of Pharmacy, Doctor of Pharmacy Candidate 2018