Spotlight on initiation of SGLT-2 inhibitors

Early effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors were the focus of two recent studies.

The first study, published by Diabetes Care on April 2, assessed rates of urogenital infections in patients who started SGLT-2 inhibitors, comparing them to those in patients who took glucagon-like peptide-1 (GLP-1) receptor agonists. The cohort study sought to emulate a target trial by including all Danish patients with type 2 diabetes who were on metformin and began taking an SGLT-2 inhibitor (n=52,414) or GLP-1 receptor agonist (n=27,023) in 2016 to 2021. The median follow-up was 2.9 to 3.9 years.

The two groups had similar risks of urinary tract infection within a year of initiation: 10.0% with SGLT-2 inhibitors versus 10.2% with GLP-1 receptor agonists (risk ratio, 0.98; 95% CI, 0.94 to 1.03). SGLT-2 inhibitors were associated with a significantly higher risk of genital tract infections at 2.0% versus 0.7% (risk ratio, 2.95; 95% CI, 2.52 to 3.44). Over five-year follow-up, the relative risk for urinary tract infections (UTIs) held steady at 0.96 (95% CI, 0.94 to 0.99) but the relative increase in genital tract infections with an SGLT-2 inhibitor decreased to 1.64 (95% CI, 1.49 to 1.80).

“Our findings indicate that SGLT2i initiation in high-risk groups, particularly those with uropathology and a history of UTI, might even be associated with a slight protective effect against UTI, and not a harmful effect as previously assumed,” the study authors wrote, adding that the FDA warning on the drug class about this risk might merit reconsideration. “However, our findings support that SGLT2i treatment is associated with a considerably increased risk of [genital tract infection] compared with GLP-1RA, which must be weighed against benefits when initiating SGLT2i treatment,” they said.

The other study, published by the Journal of Clinical Endocrinology & Metabolism on April 2, looked at changes in estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) in patients initiating SGLT-2 inhibitors. The retrospective study included 8,222 Taiwanese patients with type 2 diabetes who began taking SGLT-2 inhibitors in 2016 to 2021. Patients were categorized based on changes in their eGFR (no decline, 0% to 10% decline, >10% decline) and UACR (no reduction, 0% to 30% reduction, >30% reduction) after three months of SGLT-2 inhibitor treatment.

The largest patient group (40.9%) had no initial eGFR decline, and of that population, 19.8% had no initial UACR reduction, 8.4% had a 0% to 30% reduction, and 12.7% had a greater than 30% reduction. Among the 21.5% of patients with greater than 10% initial eGFR decline, 6.5% had no UACR reduction, 4.3% had a 0% to 30% reduction, and 10.7% had a greater than 30% reduction. Patients with a decline of more than 10% in eGFR and no UACR reduction had significantly higher risks of adverse renal events (adjusted hazard ratio [aHR], 2.34; 95% CI, 1.32 to 4.15), cardiovascular events (aHR, 1.83; 95% CI, 1.01 to 3.29), and a combined outcome of heart failure hospitalization and cardiovascular (CV) death (aHR, 1.93; 95% CI, 1.05 to 3.55) compared to those with modest declines in both markers.

The results differ from recent meta-analyses finding “that a moderate eGFR dipping following SGLT2i treatment does not correlate with relevant CV or kidney adverse outcomes,” the study authors noted. They speculated that the differing results could be due to differences in adjustment for confounding, patient populations, or definitions of eGFR decline.

“While an initial eGFR dip following the initiation of an SGLT2i is often seen not as a negative signal for clinical outcomes, its prognostic significance appears to be modulated by concurrent changes in UACR. Our findings suggested that the absence of an early UACR reduction, even in the presence of an eGFR dip, may identify a subgroup of patients at higher risk who might benefit from closer monitoring and tailored therapeutic strategies,” the authors said.