Researchers have published reassuring findings that sodium-glucose cotransporter-2 (SGLT-2) inhibitors for the treatment of type 2 diabetes do not seem to increase the risk of urinary tract infections (UTIs) over other anti-diabetic medications.
“In a large cohort of patients seen in routine clinical practice, [the] risk for severe and non-severe UTI events among those initiating SGLT-2 inhibitor therapy was similar to that among patients initiating treatment with other second-line antidiabetic medications,” write Chintan Dave from Rutgers University and colleagues from Brigham and Women’s Hospital and Harvard Medical School.
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A new class of FDA-approved diabetes treatments
SGLT-2 inhibitors are a new class of FDA-approved oral medications that are prescribed in combination with diet and exercise for the treatment of type 2 diabetes.
The kidneys usually filter glucose out of the blood and then reabsorb it back into the blood via sodium-glucose transport proteins. SGLT-2 inhibitors lower the blood glucose level by blocking these proteins and preventing the kidneys from reabsorbing glucose back into the blood.
The excess glucose is instead excreted from the body via urine. Since SGLT-2 inhibitors remove glucose from the body, they are also be beneficial to individuals looking to lower their weight.
SGLT-2 inhibitors have been approved for use as a type 2 diabetes treatment (but not for type 1 diabetes) since 2013. They are suitable for people with type 2 diabetes with a high blood glucose level that has not responded to treatments such as metformin and insulin. They should not be prescribed to individuals with kidney disease because the condition prevents these inhibitors from working properly.
The drugs, which are available as a single-ingredient medication and in combination with other antidiabetic drugs are taken once a day with food.
SGLT-2 use linked to increased risk for genital infections
SGTL-2 inhibitors have previously been shown to increase the risk for genital infections, which arise as a result of more glucose being excreted in the urine.
Dave and colleagues previously published a 2018 study in the journal Diabetes, Obesity and Metabolism showing that the use of SLGT-2 inhibitors was associated with an approximately three-fold increase in genital infections, compared with dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 receptor (GLP-1) agonists.
This effect was evident within the first month of initiating treatment and remained throughout the duration of the therapy. The genital infections tested for were candida, vaginitis or vulvovaginitis in women, and candida, balanitis, balanoposthitis, phimosis or paraphimosis in men.
The association between SGLT-2 use and UTIs is less clear
However, the association between SGLT-2 inhibitors and the risk for UTIs is less clear.
“Prior studies evaluating risk for severe urinary tract infections with sodium–glucose cotransporter-2 inhibitors have reported conflicting findings,” say Dave and colleagues.
Nevertheless, in 2015, reports of UTIs among people who use the drugs prompted the FDA to add a warning about severe UTIs to the labels of all SGLT-2 inhibitors.
Checking for any association between SGLT-2 use and UTI risk
To assess whether patients who start taking SGLT-2 inhibitors are at an increased risk for severe UTIs, Dave and team conducted a population-based, propensity-matched cohort study including 235,730 people aged (18 years or older) with type 2 diabetes who had been newly prescribed SLG2-inhibitors, DPP-4 inhibitors or GLP-1 agonists.
The data came from two large, U.S.-based databases of commercial claims, from which two cohorts were created and matched 1:1 on a propensity score.
As reported in the Annals of Internal Medicine, the researchers identified 123,752 patients in cohort 1 and 111, 978 in cohort 2.
In cohort 1, which compared people taking SGLT-2 inhibitors with those taking DDP-4 inhibitors, there was no significant differences between the groups for the incidence rate (IR) of severe UTI events.
In cohort 2, there was also no significant differences in IR between people taking SGLT-2 inhibitors and those taking GLP-1 agonists, with the researchers in fact, observing a slightly lower incidence of severe UTI events in those taking SGLT-2 inhibitors (IRs 2.15 versus 2.96 per 1000 people, per year).
The findings remained the same after sensitivity analyses accounted for factors such as age, sex, and frailty.
Introduction to SGLT2 Inhibition
The implications of the study
The authors point out that currently patients who are good candidates for receiving SGLT-2 inhibitors to control their diabetes, but who have a history of recurrent UTIs, may be precluded from being prescribed these agents:
Because UTIs are highly prevalent in patients with diabetes, this could exclude a substantial number of patients from receiving an entire class of medications that has been shown to decrease risk for major cardiovascular events and death.”
Dave and colleagues suggest that other factors beyond UTI risk should be taken into account when deciding whether SGLT2- inhibitors should be prescribed to patients with diabetes.
In an accompanying editorial, Kristian Filion and Oriana Yu from McGill University said that the data provided reassuring, real-world evidence on the potential safety issue of UTI risk with SGLT-2 inhibitors.
However, they also pointed out that the study did not include people at high risk for or with a history of UTIs and that these subgroups would require investigation in the future.
The authors also note that their research was observational and therefore was subject to the usual associated limitations such as susceptibility to confounding. Another limitation was that the study only looked at people with health insurance.