Sodium Glucose Cotransporter 2 Inhibitors and Amputation Risk
Achilles’ Heel or Opportunity for Discovery?
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Article, see p 1450
Numerous studies have established that patients with type 2 diabetes mellitus are at heightened risk of ischemic cardiovascular events, including myocardial infarction and stroke, and microvascular events, including nephropathy and retinopathy.1 Treatments to lower glucose concentrations have demonstrated consistent benefits for reducing microvascular complications regardless of mechanism. Establishing the link between glucose lowering and reducing cardiovascular risk has been more challenging, particularly over the durations of most clinical trials. Recently, findings from clinical trials of 2 classes of glucose-lowering agents (eg, sodium glucose cotransporter 2 inhibitors [SGLT2i] and glucagon-like peptide–1 receptor agonists) have demonstrated cardiovascular benefits with patterns and timing of efficacy that suggest mediation through mechanisms apart from glucose lowering alone.2–4 The SGLT2i appear to have particularly profound benefits in patients with established cardiovascular disease for reducing cardiovascular death and heart failure as well as adverse renal outcomes. Benefits have been reported in 2 completed randomized trials with consistent associations in observational studies,2–5 including those reported by Udell et al6 in this issue of Circulation.
In contrast to the more consistent cardiovascular benefits described across these studies, however, is a finding isolated to the CANVAS trial (Canagliflozin Cardiovascular Assessment Study) showing an excess risk of amputation with canagliflozin.4 These divergent signals of harm in the limb coupled with general cardiovascular benefit have raised questions, including whether the observation is a result of chance alone as well as the potential mechanisms of harm. They also stand in contrast to other recent studies that demonstrate consistency in cardiovascular and limb benefits for antithrombotic and lipid-lowering therapies.7–10
In this context, the results from Udell et al6 provide the …