Results from DECLARE trials show drug may reduce CV death or hospitalizations for HF patients with Type 2 diabetes

The SGLT-2 inhibitor dapagliflozin met one primary composite endpoint with a statistically significant reduction in heart failure hospitalization or cardiovascular death versus placebo, according to results presented in a Late-Breaking Clinical Trial session at Scientific Sessions 2018 in Chicago.

The Dapagliflozin Effect on Cardiovascular Events-TIMI 58 (DECLARE) trial showed that dapagliflozin also met the primary safety endpoint of non-inferiority for major adverse cardiovascular events. However, the other primary composite endpoint of major adverse cardiovascular events wasn’t met.

DECLARE is a phase 3, double-blind, randomized, cardiovascular outcomes trial in 17,160 patients with Type 2 diabetes and multiple cardiovascular risk factors (n = 10,186) or established cardiovascular disease (n = 6,974).

The trial evaluated the effects of 10 mg dapagliflozin (n = 8582) daily versus placebo (n = 8,578) in 33 countries with a median follow-up of 4.2 years.

Stephen D. Wiviott, MD, senior investigator with the Thrombolysis in Myocardial Infarction Study Group and cardiovascular medicine specialist at Brigham and Women’s Hospital in Boston, presented the DECLARE results.

Enrollment criteria included diagnosis of Type 2 diabetes and established atherosclerotic cardiovascular disease including ischemic heart disease, cerebrovascular disease or peripheral artery disease (secondary prevention subgroup) or multiple risk factors for ASCVD (primary prevention subgroup). The latter group included men age >55 and women age >60 who had at least one additional risk factor such as dyslipidemia, hypertension or current tobacco use.

There were no significant differences in baseline characteristics or medication use between treatment arms, said Wiviott, who is also associate professor of medicine at Harvard Medical School in Boston. Medications were as expected in the trial patient population and included glucose-lowering therapies and cardiovascular therapies.

In the primary safety outcome analysis, dapagliflozin:

  • Met the prespecified endpoint for non-inferiority to placebo for MACE (P<0.001).
  • Didn’t result in a lower rate of MACE (8.8%) versus placebo (9.4%) (HR 0.93; CI 0.84-1.03; P=0.17 for superiority).
  • Reduced cardiovascular death or hospitalization for heart failure (4.9%) versus placebo (5.8%) (HR 0.83; CI 0.73-0.95; P=0.005 for superiority.

Because both primary endpoints weren’t met, Wiviott said the secondary endpoints have to be considered exploratory.

All-cause mortality wasn’t statistically significantly different between treatment groups. However, for the first renal composite endpoint of a 40-percent decrease in estimated glomerular filtration rate, end-stage renal disease, or renal or cardiovascular death, there were fewer events in the dapagliflozin group (4.3%) than in the placebo group (5.6%) (HR 0.76; CI 0.67-0.87; P<0.001).

Dapagliflozin was safe and generally well tolerated, with an increase in genital infections and diabetic ketoacidosis, no difference in amputation, stroke or fracture, and decreased hypoglycemia and bladder cancer, Wiviott said.

There were significantly more treatment-emergent serious adverse events in the dapagliflozin group (34.1%) versus placebo (36.2%; P<0.001), although treatment-emergent adverse events leading to drug discontinuation were higher in the dapagliflozin group (8.1%) than with placebo (6.9% P=0.01).

Specific adverse events that were higher in the dapagliflozin group than with placebo included diabetic ketoacidosis (0.3% versus 0.1% ; P=0.02) and genital infection (0.9% versus 0.1%; P<0.001). These are known adverse events to be associated with dapagliflozin. Hypoglycemia was lower with dapagliflozin than with placebo (0.7% versus 1.0%; P=0.02) as was cancer of the bladder (0.3% versus 0.5%; P=0.02).

There were no statistically significant differences between treatments for amputation, fracture, symptoms of volume depletion, urinary tract infection, Fournier’s gangrene, malignancy event or hepatic event.

Wiviott concluded that these data extend the benefit of SGLT-2 inhibition to a broader population of patients for primary and secondary prevention.

DECLARE was well conducted and stands out for the large proportion of patients with risk factors but without established atherosclerotic cardiovascular disease, said discussant Javed Butler, MD, MPH, MBA, Patrick H. Lehan Chair in Cardiovascular Research and chair of the Department of Medicine and professor of Medicine and Physiology at the University of Mississippi in Oxford.

Controlling the risk factors of HbA1c, smoking, LDLc, blood pressure and albuminuria reduced the risks of acute myocardial infarction and stroke in patients with Type 2 diabetes, but didn’t reduce the incidence of heart failure, Butler said.

“Anything that reduces the risk of heart failure is a welcome addition,” he said.

“Type 2 diabetes patients similar to those in trials of SGLT-2 inhibitors should be prescribed drugs to reduce the risk of heart failure regardless of their effect on MACE outcomes,” Butler said. For those patients with no risk factors or with heart failure, more data are needed.