Dapagliflozin not linked to adverse limb events in DECLARE-TIMI 58
medwireNews: Dapagliflozin reduces the risk for cardiovascular (CV) events in people with type 2 diabetes, including those with peripheral artery disease (PAD), without increasing the risk for adverse limb events, show DECLARE-TIMI 58 data.
Writing in Circulation, Marc Bonaca (University of Colorado School of Medicine, Aurora, USA) and co-authors say “clinicians should feel comfortable using dapagliflozin in patients with type 2 diabetes mellitus and concomitant stable PAD.”
The preplanned exploratory analysis included data for 17,160 DECLARE-TIMI 58 participants who were randomly assigned to treatment with dapagliflozin or placebo. Of these, 1025 (6%) had lower extremity PAD.
The researchers report that, in the placebo arm, patients with PAD (n=503) had higher rates of major adverse CV events (MACE), defined as CV death, myocardial infarction, or stroke, than those without PAD (n=8075), at 15.9% versus 9.0%.
They also had higher rates of CV death or hospitalization for heart failure (HHF; 12.1 vs 5.4%) and progression of kidney disease (10.9 vs 5.3%). A similar pattern was observed among individuals with and without PAD who received dapagliflozin.
After adjustment for baseline demographic and disease-related characteristics, the team found that among individuals in the placebo group, those with PAD had a significant 60% higher risk for CV death or HHF and a significant 51% higher risk for progression of kidney disease than those without PAD, whereas the risk for MACE did not differ between the two groups.
Furthermore, the effect of dapagliflozin was consistent regardless of PAD status. Specifically, the risk for CV death or HHF was reduced by a significant 14% with dapagliflozin versus placebo among individuals with PAD and by a significant 18% in those without PAD. For progression of kidney disease, the corresponding risk reductions were a significant 22% and 24%.
During the trial, 1694 limb ischemic adverse events occurred in 560 patients, including 454 patients with at least one peripheral revascularization and 236 patients with at least one amputation. A total of 407 amputations were reported overall.
However, unlike the CV outcomes, Bonaca et al found no significant difference in the risk for adverse limb outcomes between individuals who received dapagliflozin or placebo. They did, however, note that the rates of these outcomes were significantly higher among the individuals with PAD relative to those without.
For example, the risk for any limb adverse event in the placebo group was a significant 8.4-fold higher in people with versus without PAD (20.3 vs 2.1%). The risk for amputation was 4.5-fold higher (5.6 vs 1.1%), and the risk for limb infection was 2.1-fold higher (8.2 vs 3.3%), with infection reported as the main reason for amputation.
The investigators note that these findings are in contrast to those of the CANVAS trial, which found a twofold increased risk for amputation with the sodium-glucose cotransporter (SGLT)2 inhibitor compared with placebo.
They conclude: “Patients with type 2 diabetes mellitus and PAD derive substantial clinical benefits with the SGLT2 inhibitor dapagliflozin [which are] not offset by an increased risk of limb ischemic events, limb infections or amputations overall or in patients with PAD.”
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