Adverse events associated with SGLT-2 inhibitors do not appear dose-dependent

In a systematic review and meta-analysis, no difference was seen between high- and low-dose sodium-glucose cotransporter-2 (SGLT-2) inhibitors in overall safety or specific safety outcomes, other than a mild increased risk for adverse events with higher doses of canagliflozin.


Clinical adverse events associated with sodium-glucose cotransporter-2 (SGLT-2) inhibitors do not seem to vary by high versus low doses, according to a recent systematic review and meta-analysis.

Researchers searched for randomized clinical trials published between Jan. 1, 2006, and March 10, 2020, that reported adverse events of high- and low-dose SGLT-2 inhibitors in patients with type 2 diabetes. Included studies looked at SGLT-2 inhibitors as monotherapy or multidrug therapy, reported adverse events according to SGLT-2 dose, and had more than 12 weeks of follow-up. Primary outcomes of the meta-analysis were overall safety (defined as any adverse events, serious adverse events, adverse events leading to drug discontinuation or related to study drugs, and death associated with adverse events), specified safety outcomes (infections, musculoskeletal or gastrointestinal disorders, adverse events related to osmotic diuresis, volume- or renal-related adverse events, metabolism and nutrition, and other), and adverse events of clinical interest (including urinary tract infections, genital mycotic infections, and hypoglycemia). Results were published Aug. 25 by the Journal of Clinical Endocrinology and Metabolism.

Fifty-one trials involving 24,371 patients were included in the study. Overall, 12,208 patients received high-dose SGLT-2 inhibitors and 12,163 received low-dose. Of the 51 trials, 17 were of empagliflozin, 13 were of canagliflozin, 12 were of dapagliflozin, six were of ertugliflozin, two were of luseogliflozin, and one was of ipragliflozin. (Luseogliflozin has been approved for use only in Japan, while ipragliflozin has been approved only in Japan and Russia.) Across all trials, mean patient age was 57.8 years, and mean follow-up time was 43.9 weeks. The researchers found no significant differences between high doses and low doses of SGLT-2 inhibitors for overall safety in most cases or for specified safety outcomes. A small increase was seen in risk for adverse events related to high versus low doses of study drugs (relative risk, 1.08; 95% CI, 1.01 to 1.16), mainly due to results involving canagliflozin (relative risk, 1.17; 95% CI, 1.05 to 1.30).

The researchers noted that only studies with clinically approved SGLT-2 doses were included and that adverse events with very low incidence, such as amputation and necrotizing fasciitis, were not evaluated, among other limitations. They concluded that based on their analysis, rates of overall and certain specific adverse events do not differ with high and low doses of SGLT-2 inhibitors. “Among poorly controlled diabetic patients, the doses may be maximized to ideal the glycemic control,” the authors wrote. “Our study extrapolated that it is probably safe to adjust to high dose, if patients do not experience serious clinical adverse events with low dose of SGLT2 inhibitors.”