Research adds to SGLT2 inhibitor amputation risk debate
medwireNews: Researchers have found evidence to support an increased risk for amputation among patients with type 2 diabetes taking sodium-glucose cotransporter (SGLT)2 inhibitors relative to some oral treatments.
The retrospective study, for which the team used a large US insurance claims database, showed a nonsignificant 1.5-fold increased risk for lower extremity amputation among new users of SGLT2 inhibitors compared with dipeptidyl peptidase (DPP)-4 inhibitors and glucagon-like peptide (GLP)-1 agonists. And there was a significant 2.1-fold increased risk compared with sulfonylureas, metformin, or thiazolidinediones.
This increased risk was calculated after propensity score weighting and adjustment for potentially confounding covariates, including age and sex, diabetes severity, comorbidities, and medications.
G Caleb Alexander (Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA) and co-researchers write in JAMA Internal Medicine: “These findings are relevant because of how commonly SGLT-2 inhibitors are prescribed, the increased risk of foot and leg amputations with the use of canagliflozin in the CANVAS and CANVAS-R clinical trials, and the importance of this outcome for patients.”
In a related commentary Michael Fischer (Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA) and co-authors note that the rate of amputation reported in this trial is “strikingly lower” than that found in the CANVAS program. But they suggest that this may be explained, at least in part, by differences in baseline characteristics, including younger age, fewer patients with a history of heart disease, and unknown diabetes duration, as well as a shorter duration of follow-up and a low event rate in the current study.
The study participants comprised 39,869 new users of SGLT-2 inhibitors (4.2%), 105,023 new users of DPP-4 inhibitors (11.0%), and 39,120 new users of GLP-1 agonists (4.1%). The vast majority of patients in the SGLT-2 group were taking canagliflozin, at 28,036, while 8647 were taking dapagliflozin and 3186 empagliflozin. The final group of 769,984 patients were taking other oral antidiabetic drugs.
In spite of the large patient samples, the overall rates of amputation were low, the researchers note, with 18 events among patients taking SGLT-2 inhibitors, 41 among those in the DPP-4 inhibitor group, 11 among those taking GLP-1 agonists, and 231 in the other oral drugs group. But the crude incidence was still higher among patients in the SGLT-2 group, at 10.53 per 10,000 person–years (10.00 per 10,000 person–years for canagliflozin) versus 8.52, 7.10, and 4.90 per 10,000 person–years for those in the DPP-4 inhibitor, GLP-1 agonist, and other drug groups, respectively.
Fischer and fellow commentators believe that while the current study “helps to contextualize the risk [for amputation] in a relatively low-risk population,” some study limitations need to be considered, including new SGLT-2 users being compared with new and long-term users of other oral drugs, possible bias with the exclusion of patients initiating insulin at any point, and some important confounders going unmeasured.
The commentators therefore maintain that “[u]ntil more data are available, the results of the CANVAS trial provide the greatest evidence that canagliflozin is associated with an increased risk of amputation,” and this should influence prescribing habits accordingly.
By Lucy Piper
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