Department of Family Medicine, University of Toledo College of Medicine, Ohio robert.gotfried@utoledo.edu
The authors reported no potential conflict of interest relevant to this article.
The author has lectured on behalf of Pfizer and Kos/Abbott. He has participated in clinical trials for Bristol-Myers Squibb, Novo Nordisk, AstraZeneca, KOS/Abbott, Novartis, and Janssen. He has wholly declined compensation from pharmaceutical and medical device manufacturers.
Patients on canagliflozin unexpectedly had an increased incidence of amputations (6.3 participants, compared with 3.4 participants, for every 1000 patient–years). This finding led to a black box warning for canagliflozin about the risk of lower-limb amputation.
DECLARE-TIMI 58. The Dapagliflozin Effect of Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 trial (DECLARETIMI 58) was the largest SGLT-2 inhibitor outcomes trial to date, enrolling 17,160 patients with T2D who also had established CV disease or multiple risk factors for atherosclerotic CV disease. The trial compared dapagliflozin, 10 mg/d, and placebo, following patients for a median 4.2 years.24 Unlike CANVAS and EMPA-REG OUTCOME, DECLARE-TIMI 58 included CV death and HHF as primary outcomes, in addition to MACE-3.
Dapagliflozin was noninferior to placebo with regard to MACE-3. However, its use did result in a lower rate of CV death and HHF by an RRR of 17% (ARR, 1.9%). Risk reduction was greatest in patients with HF who had a reduced ejection fraction (ARR = 9.2%).25
In October, the FDA approved dapagliflozin to reduce the risk of HHF in adults with T2D and established CV disease or multiple CV risk factors. Before initiating the drug, physicians should evaluate the patient's renal function and monitor periodically.
Meta-analyses of SGLT-2 inhibitors
Systematic review. Usman et al released a meta-analysis in 2018 that included 35 randomized, placebo-controlled trials (including EMPA-REG OUTCOME, CANVAS, and DECLARE-TIMI 58) that had assessed the use of SGLT-2 inhibitors in nearly 35,000 patients with T2D.26 This review concluded that, as a class, SGLT-2 inhibitors reduce all-cause mortality, major adverse cardiac events, nonfatal MI, and HF and HHF, compared with placebo.
