Results from the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI 58) trial will be presented at 2:15 p.m. Sunday in W-3001 (West, Level 3). ADAMeetingNews.org asked the study’s co-principal investigator, Itamar Raz, MD, to discuss the background, objective, and significance of the study. Dr. Raz is Professor of Internal Medicine and Director Emeritus of the Diabetes Unit at Hadassah University Medical Center in Jerusalem, Israel.
Dr. Raz: In spite of intensive therapy for controlling cardiovascular risk factors in patients with type 2 diabetes, increased cardiovascular (CV) and renal events still exist in this population, as does excess mortality. The new class of SGLT2 inhibitors is known to reduce cardiovascular risk factors and has also been shown to reduce hospitalization for heart failure, CV death, and renal deterioration. However, these effects were mainly demonstrated in type 2 diabetes patients with established CV disease and progressive renal disease who were at high risk for CV events and who represent a small proportion of the diabetic population. Moreover, concerns regarding potential side effects of the class prevented expansion of its use to a large proportion of patients with diabetes.
Dr. Raz: We studied the effects of dapagliflozin in a broad population of patients with type 2 diabetes, most of them without established CV disease and with preserved renal function, who better represent the diabetic population. The safety outcomes of the drug, as well as possible beneficial effects on cardiovascular and renal outcomes were assessed.
We recruited 17,160 patients with type 2 diabetes who were age 40 or older with established cardiovascular disease (CVD), as well as men 55 or older and women 60 or older without established CVD but with one or more CV risk factors, A1C of 6.5 to 12, and creatinine clearance of at least 60 ml/min/1.73m2. These patients represent a wide range of a relatively healthy group of type 2 diabetes patients.
Patients were treated according to local guidelines and could be taking any glucose-lowering agents excluding thiazolidinediones and SGLT2 inhibitors. Patients were randomized to either dapagliflozin 10 mg daily or placebo and followed every six months in the clinic and every three months by telephone calls for a median of 4.2 years.
The dual-efficacy endpoints were the composite of cardiovascular death, myocardial infarction, or ischemic stroke (MACE), and the composite of CV death or hospitalization for heart failure (HF). MACE was analyzed for safety and then a potential beneficial effect was ascertained for the dual primary endpoints. The study was event driven and designed to accrue at least 1,390 MACE events.
Dr. Raz: The DECLARE-TIMI 58 trial should be an important milestone in defining the way we treat patients with type 2 diabetes. Recently, the American Heart Association and the American College of Cardiology, as well as the European Renal Association–European Dialysis and Transplant Association, recommended SGLT2 inhibitors as second-line therapy for patients with diabetes not achieving A1C target following treatment with metformin alone. The question we hope to answer is whether to consider recommending SGLT2 inhibitors in combination with metformin as first-line therapy in patients not at A1C target if there is no contraindication, such as underweight recurrent genital or urinary tract infection.