DECLARE-TIMI 58: HF Benefit for Dapagliflozin in Diabetes?

September 25, 2018

Preliminary results of the largest, longest, and broadest cardiovascular outcomes trial (CVOT) to date with a type 2 diabetes drug reveal that the sodium-glucose cotransporter type 2 (SGLT2) inhibitor dapagliflozin (Farxiga/Forxiga, AstraZeneca) has a beneficial effect on CV outcomes, but only seemingly by improvement in heart failure.

AstraZeneca yesterday announced the top-line data from DECLARE-TIMI 58. The study evaluated the CV outcomes of dapagliflozin versus placebo over a period of up to 5 years across 33 countries and in more than 17,000 adults with type 2 diabetes who had multiple CV risk factors or established CVD. They expect to report the full findings in November at the American Heart Association (AHA) Scientific Sessions 2018 in Chicago, Illinois.

DECLARE is unique in that it is the first CVOT to have two coprimary efficacy outcomes. And a large percentage of the patients with type 2 diabetes enrolled, around 60%, were considered "primary prevention" in that they did not have overt CVD, rather just risk factors for it.

Dapagliflozin met its primary safety endpoint of noninferiority for major adverse cardiovascular events (MACE) and achieved a significant reduction in the composite endpoint of hospitalization for heart failure or CV death, one of the two primary efficacy endpoints.

But although fewer MACE events were observed with dapagliflozin for the other primary efficacy endpoint, this did not reach statistical significance, the company says in its press release.

Do DECLARE Findings Differ Because of Different Patient Population?

The DECLARE-TIMI 58 findings contrast somewhat with those from CVOTs of two other SGLT2 inhibitors, EMPA-REG OUTCOME with empagliflozin (Jardiance, Boehringer Ingelheim) conducted in around 7000 patients and Canagliflozin Cardiovascular Assessment Study (CANVAS) with canagliflozin (Invokana, Vokanamet, Janssen) in 10,000 patients.

Both empagliflozin and canagliflozin reduced MACE in their respective trials, and empagliflozin also reduced CV death. And the labels have been updated accordingly in the United States and European Union for empagliflozin and in the European Union for canagliflozin (with a US label change for the latter expected imminently).

But EMPA-REG enrolled almost primarily secondary prevention patients, that is, patients with type 2 diabetes and established CVD (less than 1% had only risk factors) whereas in CANVAS over 60% of patients were secondary prevention.

Asked for his thoughts, CANVAS steering committee member Vlado Perkovic, MBBS, PhD, executive director, The George Institute for Global Health, Sydney Australia, told Medscape Medical News by e-mail, "It is wonderful for people with diabetes that the DECLARE-TIMI 58 trial results sound like they will confirm the heart failure benefits already reported from EMPA-REG and CANVAS."

"But the apparent lack of clear benefit for the more standard MACE outcome contrasts with both of the previous trials and it will be important to see whether this is the result of the larger proportion of participants without pre-existing CVD, a chance result, or due to some other factor," he added.

"The renal outcome data will also be important and is eagerly awaited, given the strong evidence of benefit for this in the previous trials," Perkovic stressed.

In the company press release, coprincipal investigator of DECLARE-TIMI 58, Stephen Wiviott, MD, of Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, said the results "offer compelling evidence that dapagliflozin helps to address an important medical need among a diverse group of patients with type 2 diabetes by reducing the composite of hospitalization for heart failure or CV death, with a safety profile supportive of broad use."

Full Results of DECLARE to Be Presented at AHA

AstraZeneca says it plans a full presentation of the results on November 10 at the AHA meeting.

DECLARE-TIMI 58 is a randomized, double-blinded, placebo-controlled, multicenter trial designed to evaluate the effect of dapagliflozin 10 mg once-daily compared with placebo, in addition to standard therapy, on CV outcomes in more than 17,000 adults aged 40 years or older with type 2 diabetes and multiple CV risk factors or established cardiovascular disease (CVD) across 882 sites in 33 countries.

The trial is sponsored by AstraZeneca but was run in collaboration with academic investigators from the TIMI study group (Boston, Massachusetts) and Hadassah Hebrew University Medical Center (Jerusalem, Israel).

The two coprimary efficacy outcomes were (1) time to first event included in the composite endpoint of CV death, myocardial infarction, or ischemic stroke and (2) time to first event included in the composite endpoint of CV death or hospitalization because of heart failure.

Secondary outcome measures included (1) time to first event of the renal composite endpoint of confirmed sustained ≥ 40% decrease in estimated glomerular filtration rate to less than 60 mL/min/1.73m2 and/or end-stage renal disease and/or renal or CV death and (2) time to all-cause mortality.

Although dapagliflozin was one of the first SGLT2 inhibitors on the market, launched in the United States in 2014 a year after canagliflozin was approved, the CVOT for dapagliflozin was the longest and largest, and so took longer to complete.

The SGLT2 inhibitors have so far been hailed as game-changers in the treatment of type 2 diabetes because of the landmark results of EMPA-REG and CANVAS.

However, they are not without their drawbacks.

In CANVAS, canagliflozin was also associated with a two-fold increased risk for lower limb amputations, and a warning about the amputation risk is already included in the European labeling of all drugs in the SGLT2 inhibitor class. In the United States, the same warning is listed only on the canagliflozin label.

SGLT2 inhibitors have also been associated with an increased risk of diabetic ketoacidosis, genital yeast infections, and fractures, and have most recently been associated with an extremely rare but life-threatening side effect, necrotizing fasciitis of the perineum, also called Fournier's gangrene, a bacterial infection of the tissues underlying the skin surrounding the perineal muscles, nerves, fat, and blood vessels. 

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