Itamar Raz, MD
Hadassah University Hospital, Jerusalem, Israel Stephen D. Wiviott, MD
Brigham and Women's Hospital, Boston, MA John P. Wilding, MD
University of Liverpool, Liverpool, UK Ofri Mosenzon, MD
Hadassah University Hospital, Jerusalem, Israel Lawrence A. Leiter, MD
University of Toronto, Toronto, ON, Canada
Many potential mechanisms have been proposed for the cardiovascular (CV) benefits of SGLT-2 inhibition. Dapagliflozin lowers systolic blood pressure by 3 to 5 mmHg compared with placebo. Dapagliflozin also results in loss of body weight compared with placebo, which is possibly related to both changes in fluid volume and alterations in caloric balance resulting in fat loss. In a meta-analysis of phase 2 and phase 3 studies of dapagliflozin, there was a suggestion of CV benefit, particularly a tendency toward reductions of a composite of CV events, including CV death, and hospitalizations for heart failure and MI, with no clear effects on stroke.
The DECLARE-TIMI 58 (Dapagliflozin Effect on CardiovascuLAR Events) study was designed to test the hypotheses that dapagliflozin (1) does not increase major adverse cardiac events (MACE) and that it (2) will reduce the incidence of CV events in patients with type 2 diabetes with established atherosclerotic cardiovascular disease (ASCVD), or with multiple risk factors for ASCVD but without established ASCVD.
17,160 patients with type 2 diabetes and established CV disease (n=6,974) or multiple risk factors (n=10,186) were enrolled.
Eligible patients were ≥40 years and had type 2 diabetes, HbA1c 6.5-12.0%, CrCl of ≥60 ml/min, and multiple risk factors for ASCVD or established ASCVD.
Participants with multiple risk factors were men 55 years of age or older or women 60 years of age or older who had one or more traditional risk factors, including hypertension, dyslipidemia or use of lipid-lowering therapies, or use of tobacco.
This event-driven trial continued until at least 1,390 subjects have a MACE outcome, thereby providing >99% power to test for the primary outcome of safety of dapagliflozin.
Primary outcome measures
The primary safety outcome was MACE (defined as CV death, myocardial infarction, or ischemic stroke).
The two primary efficacy outcomes were MACE and a composite of CV death or hospitalization for heart failure.
In the primary safety outcome analysis, dapagliflozin met the prespecified criterion for noninferiority to placebo with respect to MACE (P <0.001).
In the two primary efficacy analyses, dapagliflozin did not result in a lower rate of MACE (8.8% in the dapagliflozin group and 9.4% in the placebo group; HR, 0.93; 95% CI 0.84 to 1.03; P=0.17)
Dapagliflozin was associated with a lower rate of CV death or hospitalization for heart failure (4.9% vs. 5.8%; HR 0.83; 95% CI, 0.73 to 0.95; P=0.005), which reflected a lower rate of hospitalization for heart failure (HR 0.73; 95% CI 0.61 to 0.88) (Figure).
Dapagliflozin appeared to robustly reduce the risk of MACE, and particularly MI, in patients with prior MI.
This 22% relative risk reduction is comparable to other established therapies used in secondary prevention such as intensive lipid lowering.
Patients were less likely to develop adverse renal outcomes, and had a significant reduction in a composite cardiorenal outcome (HR 0.76; 95% CI 0.67-0.87; P <0.0001).
There were higher rates of improvement in the urine albumin/creatinine ratio vs. placebo.
Dapagliflozin had a good overall safety profile; acute kidney injury and major hypoglycemia were less frequent vs. placebo.
Jose C. Florez, MD, PhD
Chair, ADA Scientific Sessions Meeting Planning Committee
The 79th American Diabetes Association’s Scientific Sessions were held in San Francisco, California from June 7-11, 2019. The meeting was attended by over 15,000 professional attendees from 115 countries, … [ Read all ]
Presented by: Alison B. Evert, MD; Janice MacLeod, MA, RDN, CDE; William S. Yancy, Jr., MD, MHS; W. Timothy Garvey, MD; Ka Hei Karen Lau, MS, RD, LDN, CDE; Christopher D. Gardner, PhD; Kelly M. Rawlings, MS