DECLARE-TIMI 58 Supports HF Benefit of SGLT2 Inhibitors

Dapagliflozin did not reduce MACE, one of the co-primary endpoints, but it cut the risk of hospitalization for heart failure by a relative 27%.

DECLARE-TIMI 58 Supports HF Benefit of SGLT2 Inhibitors

CHICAGO, IL—DECLARE-TIMI 58, a trial of the selective sodium glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga; AstraZeneca) in patients with type 2 diabetes and high cardiovascular risk, met only one of its two co-primary endpoints, but it was still seen as supportive of the benefits of the SGLT2 inhibitor class for reducing heart failure risk.

MACE (CV death, MI, or ischemic stroke), one of the efficacy endpoints, occurred in 8.8% of patients treated with dapagliflozin and 9.4% of those who received placebo (HR 0.93; 95% CI 0.84-1.03), a difference that met criteria for noninferiority but not superiority. The other co-primary endpoint, a composite of CV death or hospitalization for heart failure, was significantly reduced with dapagliflozin (4.9% vs 5.8%; HR 0.83; 95% CI 0.73-0.95), driven entirely by a relative 27% reduction in the risk of heart failure hospitalization (HR 0.73; 95% CI 0.61-0.88).

Stephen Wiviott, MD (Brigham and Women’s Hospital, Boston, MA), reported the findings, which were published simultaneously online in the New England Journal of Medicine, here at the American Heart Association (AHA) 2018 Scientific Sessions. Topline results were released last month.

Taking into consideration results from the CANVAS trial program involving canagliflozin (Invokana; Janssen), the EMPA-REG OUTCOME trial of empagliflozin (Jardiance; Boehringer Ingelheim/Eli Lilly), and now DECLARE-TIMI 58, Wiviott said at a press conference that there are some conclusions that can be drawn about SGLT2 inhibitors as a class.

“They have moderate benefits on atherosclerotic MACE that appear confined to those with established disease, but they have robust effects on reducing the risk of heart failure and renal outcomes which do not appear dependent on baseline factors,” he said. “And we think these data from DECLARE-TIMI 58 extend the benefit to a broader population of patients for primary and secondary prevention.”

Commenting for TCTMD, Jacob Udell, MD (University of Toronto, Canada), said the reason dapagliflozin did not reduce MACE in this trial like the other SGLT2 inhibitors did in their respective trials boils down to study design. DECLARE-TIMI 58 had the largest primary prevention cohort out of the three trials; CANVAS mostly involved secondary prevention; and EMPA-REG OUTCOME was all secondary prevention. The risk of moving to a lower-risk group in a trial, Udell said, is that it can be more difficult to demonstrate a drug effect over the same length of follow-up, there could be a different mechanism of risk in that group, or the level of risk could be too low to see an effect. A little bit of each of those factors could have played into the dapagliflozin results.

What is reassuring, he said, is that the impact on heart failure hospitalization has been consistent with all three SGLT2 inhibitors.

“I think this demonstrates and kind of seals the deal that there is a class effect for at least heart failure, at a minimum, and likely for composite endpoints that have a mechanism of hemodynamic improvement,” Udell said.

It would be premature to use the DECLARE-TIMI 58 findings to state that the SGLT2 inhibitors are effective for primary prevention, but the potential for these drugs in expanded secondary prevention scenarios—both in diabetics and nondiabetics—is provocative, Udell said, adding that these drugs could be attractive options early after a cardiovascular event.

“There should be really no major safety concerns to go upstream and really try using these therapies early on after an event,” he said. “Though the labels of these therapies don’t necessarily preclude it and the guidelines don’t necessarily preclude it, technically in these trials we haven’t studied those types of patients.”

Renal Benefits Observed, Too

DECLARE-TIMI 58, conducted at 882 sites in 33 countries, randomized 17,160 patients with type 2 diabetes and either established atherosclerotic CVD (secondary prevention cohort: 41%) or a high risk for CVD (primary prevention cohort: 59%). Patients in the latter group were at least 55 years old for men and 60 years old for women and had at least one additional risk factor. Patients were required to have a creatinine clearance of 60 mL/min or higher. Overall, the mean age of the trial population was 64, and 37% were women; 10% had a history of heart failure at baseline.

Through a median follow-up of 4.2 years, dapagliflozin 10 mg/day reduced glycated hemoglobin, body weight, and blood pressure compared with placebo.

Looking at the components of the co-primary endpoints, there was a significant reduction in hospitalization for heart failure and a nonsignificant trend toward less MI (HR 0.89; 95% CI 0.77-1.01). Ischemic stroke and CV death occurred at similar rates in both groups.

Because only one of the co-primary endpoints was met, findings on secondary endpoints should be considered hypothesis-generating. A composite renal endpoint (at least a 40% drop in estimated glomerular filtration rate to less than 60 mL/min/m2, new end-stage renal disease, or renal or CV death) was reduced with dapagliflozin (4.3% vs 5.6%; HR 0.76; 95% CI 0.67-0.87). All-cause mortality was numerically—but not significantly—lower in the dapagliflozin group (6.2% vs 6.6%; HR 0.93; 95% CI 0.82-1.04).

In terms of safety, dapagliflozin led to higher rates of treatment-emergent adverse events leading to drug discontinuation (8.1% vs 6.9%), diabetic ketoacidosis (0.3% vs 0.1%), and genital infection (0.9% vs 0.1%). Those last two events are known side effects of the SGLT2 inhibitors, Wiviott said. Bladder cancer, amputation, and fracture were not increased with dapagliflozin.

Class Effects

To get a sense of the impact of SGLT2 inhibition overall, Wiviott and colleagues performed a meta-analysis of CANVAS, EMPA-REG OUTCOME, and DECLARE-TIMI 58, which was published online in the Lancet. For MACE, SGLT2 inhibition reduced risk in patients with established disease (HR 0.86; 95% CI 0.80-0.93) but not in those with risk factors (HR 1.00; 95% CI 0.87-1.16). In contrast, the risk of CV death or hospitalization for heart failure was lower with treatment in both types of patients.

Commenting for TCTMD, Steven Nissen, MD (Cleveland Clinic, OH), said the lack of a MACE benefit in DECLARE-TIMI 58 is likely due to differences in how the trials were conducted and not a difference between the SGLT2 inhibitors.

“I think these drugs are more similar than dissimilar,” he said.

At the press conference, Javed Butler, MD (University of Mississippi, Jackson), who served as a discussant for the trial, said DECLARE-TIMI 58 confirms and replicates findings from the other SGLT2 inhibitor trials. Together, they show robust renal protection and reductions in heart failure hospitalizations in both patients with established disease and those with risk factors, with a MACE benefit seen in those with established disease.

“Based on the data from these three trials and the plethora of other published data from real-world evidence, it stands to reason that for patients similar to those that were studied in the SGLT2 inhibitor trials, these drugs should be used for prevention of heart failure risk irrespective of their effect on MACE outcomes,” Butler said, adding that for other types of patients—such as diabetics without additional risk factors or with manifest heart failure—further research is needed.

Sources
Disclosures
  • DECLARE-TIMI 58 was sponsored by AstraZeneca.
  • Wiviott reports receiving grants from AstraZeneca, Amgen, and Sanofi Aventis; grants and personal fees from Arena, Daiichi Sankyo, Eisai, Eli Lilly, Janssen, and Bristol-Myers Squibb; grants, personal fees, and other from Merck; and personal fees from Aegerion, Allergan, AngelMed, Boehringer Ingelheim, the Boston Clinical Research Institute, Icon Clinical, Lexicon, St. Jude Medical, Xoma, Servier, and AstraZeneca.
  • Butler reports having relationships with AstraZeneca, Boehringer Ingelheim, Janssen, Sanofi, Novo Nordisk, and Merck.
  • Udell reports performing advisory board consulting for all of the SGLT2 inhibitor manufacturers.

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