Ever since the United States Food and Drug Administration (FDA) issued the mandate for conducting cardiovascular outcomes trials (CVOTs) with type 2 diabetes drugs, eight CVOTs have already been completed, with three of them identifying cardiovascular (CV) benefit from the drugs.1 At the American Heart Association (AHA) Scientific Sessions 2018, Dr. Stephen Wiviott of the Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, United States, presented the study results from the DECLARE-TIMI 58 (Dapagliflozin Effect on CardiovascuLAR Events) trial.1 The study was simultaneously published in the New England Journal of Medicine.2
Given patients with diabetes are at high risk for adverse outcomes from atherosclerosis CV disease (ASCVD),3,4 the FDA issued a mandate in 2008, requiring all the new drugs used for type 2 diabetes to demonstrate CV safety by conducting CVOTs that evaluate combined CV endpoints as part of the approval requirement.5 Thus far, all of the completed CVOTs did not identify any excess CV risk, and instead, three CVOTs actually identified CV benefit.1 Recently, Dr. Wiviott presented the latest results from the DECLARE-TIMI 58 trial, which is a CVOT with dapagliflozin, making it the ninth completed CVOT.1
DECLARE-TIMI 58 trial was a randomized, double-blind, multinational, placebo-controlled, phase 3 trial of dapagliflozin in patients who were 40 years of age or older, had type 2 diabetes, a glycated hemoglobin level between 6.5% and 12.0%, a creatinine clearance of 60ml/min/1.73m2 or more, and with multiple risk factors for ASCVD or had established ASCVD (defined as clinically evident ischemic heart disease, ischemic cerebrovascular disease, or peripheral artery disease).2
Eligible patients were enrolled in a 4-to-8 week, single-blind run-in period with placebo first.2 Those with blood and urine test results that remained eligible after the run-in period were then randomly assigned in a 1:1 ratio (in a double-blind fashion) to receive either 10mg of dapagliflozin daily or a matching placebo.2 Patients were asked to return in-person every 6 months for follow-up on laboratory parameters, clinical and safety events, and adherence to the trial regimen.2 The primary safety outcome of this trial was MACE (defined as CV death, myocardial infarction, or ischemic stroke), and two primary efficacy outcomes were MACE and composite of CV death or hospitalization for heart failure (HF).2 All statistical analyses were performed according to the intention-to-treat principle.2
In total, 17,160 patients completed the run-in phase and remained eligible to undergo randomization.2 Median follow-up time was 4.2 years.2 The analyses showed that dapagliflozin met the prespecified criterion for noninferiority with respect to MACE (upper boundary of the 95% CI <1.3; p<0.001 for noninferiority).2 In terms of efficacy outcomes, the rate of MACE in the dapagliflozin arm was 8.8% (vs. 9.4% with placebo; HR=0.93; 95% CI: 0.84-1.03; p=0.17), and rate of CV death or hospitalization in the dapagliflozin arm was 4.9% (vs. 5.8% with placebo; HR=0.83; 95% CI: 0.73-0.95; p=0.005).2 “I think after the DECLARE-TIMI 58 trial we can definitely now say the biggest benefit of the SGLT2 inhibitors is on the prevention of heart failure, and the reduction in major cardiovascular events is limited to patients with existing underlying cardiovascular disease,” commented by Dr. Wiviott to theheart.org, Medscape Cardiology in response to the results.1
With the safety concerns for amputations, stroke, and fracture that were seen with the use of sodium-glucose co-transporter 2 (SGLT-2) inhibitors in sparse data from the other clinical trials, the DECLARE-TIMI 58 trial investigated whether dapagliflozin was associated with increased risk for these adverse events.2 Nevertheless, the results did not show any evidence that suggested a higher risk for amputation (HR=1.09; 95% CI: 0.84-1.40), stroke (HR=1.01; 95% CI: 0.84-1.21), or fracture (HR=1.04; 95% CI: 0.91-1.18).2
Of note, in response to the FDA warning about the occurrence of Fournier’s gangrene (a rare but serious infection of the genitals and area around the genitals) with the use of SGLT-2 inhibitors,6 DECLARE-TIMI 58 showed a higher rate of genital infections with dapagliflozin than placebo (HR=8.36; 95% CI: 4.19-16.68), but not with a higher rate of Fournier’s gangrene (six cases of Fournier’s gangrene were reported during the study, one in the dapagliflozin group and five in the placebo group).2
“These trials have now conclusively demonstrated that diabetes patients with underlying cardiovascular disease, or with multiple cardiovascular risk factors, should be taking these drugs to lower their risk of heart failure,” as concluded by Dr. Javed Butler, University of Mississippi Medical Center, Jackson, United States, who suggested the field of diabetes management are entering a paradigm shift with these positive evidence from CVOTs.
1. DECLARE-TIMI 58: Dapagliflozin Cuts Heart Failure in Diabetes. Medscape. 2018 (Accessed December 14, 2018, at https://www.medscape.com/viewarticle/904739#vp_1)
2. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2018.
3. Dailey G. Overall mortality in diabetes mellitus: where do we stand today? Diabetes Technol Ther. 2011;13(S1):S-65-S-74.
4. John M, Unnikrishnan AG, Kalra S, et al. Cardiovascular outcome trials for anti-diabetes medication: A holy grail of drug development? Indian Heart J. 2016;68(4):564-571.
5. Guidance for industry: Diabetes mellitus — Evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. US Food and Drug Administration. Accessed at http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf.
6. FDA warns about rare occurrences of a serious infection of the genital area with SGLT2 inhibitors for diabetes. (Accessed December 27, 2018, at https://www.fda.gov/Drugs/DrugSafety/ucm617360.htm.)