Results from the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI 58) trial presented Sunday at the Scientific Sessions suggest that the SGLT2 inhibitor dapagliflozin not only reduces insulin resistance and reduces cardiovascular risk factors, but also prevents heart failure and progression of kidney disease in most diabetes patients, including those with normal heart and kidney function, with high safety.

“In this trial, we studied the effects of dapagliflozin in a broad population of patients with type 2 diabetes who are more representative of the overall diabetic population than previous trials, including a majority without established cardiovascular disease and with preserved renal function,” said co-principal investigator Itamar Raz, MD, Professor of Internal Medicine and Director Emeritus of the Diabetes Unit at Hadassah University Medical Center in Jerusalem, Israel. “The dual efficacy endpoints were the composite of cardiovascular death, myocardial infarction, or ischemic stroke and the composite of cardiovascular death or hospitalization for heart failure.”

Stephen D. Wiviott, MD, FACC, a cardiovascular medicine specialist at Brigham and Women’s Hospital and Associate Professor of Medicine at Harvard Medical School, reported the primary and secondary outcomes related to the effect of dapagliflozin on the cardiovascular system.

“Dapagliflozin appeared to robustly reduce the risk of MACE (major adverse cardiac events), and particularly MI (myocardial infarction), in patients with prior MI,” Dr. Wiviott said. “The 22 percent relative risk reduction we saw in MI with dapagliflozin is comparable to other established therapies used in secondary prevention, like dual antiplatelet therapy and intensive lipid lowering.”

He reported that dapagliflozin reduced cardiovascular disease and hospitalization for heart failure and was safe with regard to MACE in the overall cohort, noting that dapagliflozin appeared to be particularly effective in reducing cardiovascular events in patients at high risk, including those with prior heart failure, reduced ejection fraction, and prior MI.

John P. Wilding, DM, FRCP, Professor of Medicine at the University of Liverpool and Aintree University Hospital in the United Kingdom, described the study outcomes in key prespecified subgroups, i.e. patients with established cardiovascular disease (CVD) versus those with cardiovascular risk factors. He also discussed outcomes related to other potential modifiers, including background glucose-lowering medication and insulin use.

“In the DECLARE trial, 59 percent of patients had multiple risk factors without CVD,” Dr. Wilding said. “After a median of 4.2 years, patients with multiple risk factors treated with dapagliflozin showed similar reductions in heart failure hospitalization to those with established CVD, had no significant reduction in three-point MACE, and were less likely to develop adverse renal outcomes.”

The results from DECLARE, he said, are supported by meta-analysis confirming that SGLT2 inhibitors reduce heart failure hospitalization in a broad range of patients with type 2 diabetes, but only reduce MACE in those with established CVD.

Ofri Mosenzon, MD, MSc, Professor of Internal Medicine at Hadassah Hebrew University Hospital in Jerusalem, Israel, presented data on renal outcomes and the effects of dapagliflozin on diabetic kidney disease.

“We found that patients treated with dapagliflozin had significantly reduced frequency of composite cardiorenal and renal-specific outcomes compared with those in the placebo group,” Dr. Mosenzon said. “Components of the composite outcomes were also significantly reduced with dapagliflozin.”

Dr. Mosenzon reported that patients treated with dapagliflozin had higher rates of improvement in categorical urine albumin-to-creatinine ratio (UACR) and lower rates of deterioration in categorical UACR compare to placebo.

“These benefits occurred in a large and broad population of patients with type 2 diabetes, with and without established atherosclerotic cardiovascular disease, most of whom had preserved renal function,” she said. “These results emphasize the value of SGLT2 inhibitors as an important component of both prevention and treatment of chronic kidney disease among patients with type 2 diabetes.”

Lawrence A. Leiter, MD, FRCPC, FACP, FACE, FAHA, FACC, Professor of Medicine at the University of Toronto, reported on the safety data of dapagliflozin.

“Dapagliflozin demonstrated remarkable overall safety across a broad array of subgroups,” he said. “Acute kidney injury and major hypoglycemia were less frequent with dapagliflozin. DKA (diabetic ketoacidosis) events and serious genital infections were rare, but more common in the dapagliflozin treatment group, consistent with the known safety profile of SGLT2 inhibitors. And there were no differences in other key safety outcomes.”

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