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DECLARE-TIMI 58: Dapagliflozin reduces HF hospitalization in type 2 diabetes
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CHICAGO — The DECLARE-TIMI 58 trial of dapagliflozin in patients with type 2 diabetes who had or were at high risk for atherosclerotic CVD adds to the growing body of evidence demonstrating the favorable effects of SGLT2 inhibitors on CV risk.
Results from the international, multicenter, double-blind, randomized, placebo-controlled trial, which were simultaneously published in The New England Journal of Medicine, linked dapagliflozin 10 mg (Farxiga, AstraZeneca), as compared with placebo, to a significant 17% relative risk reduction in the co-primary efficacy endpoint of a composite of CV death or hospitalization for HF (4.9% vs. 5.8%; HR = 0.83; 95% CI, 0.73-0.95; P = .005 for superiority) after a median of 4.2 years of follow-up.
This finding was primarily driven by a 27% reduction in the rate of hospitalization for HF in the dapagliflozin group (HR = 0.73; 95% CI, 0.61-0.88), as there was not a significant difference in CV death between the two study arms (HR = 0.98; 95% CI, 0.82-1.17), Stephen D. Wiviott, MD, senior investigator and chairman of the Clinical Events Committee with the TIMI Study Group, cardiovascular medicine specialist at Brigham and Women’s Hospital and associate professor of medicine at Harvard Medical School, said during a presentation.
There was also no difference with dapagliflozin vs. placebo in the co-primary efficacy endpoint of major adverse CV events — CV death, MI or ischemic stroke — when compared with placebo (8.8% vs. 9.4%; HR = 0.93; 95% CI, 0.84-1.03; P < .001 for noninferiority; P = .27 for superiority).
Benefits in a broader population
Of 17,160 patients included in the trial, 10,186 had multiple risk factors for atherosclerotic CVD (ASCVD) but did not have established disease — a number that is three times higher than those in other studies of SGLT2 inhibitor, according to Wiviott.
“In previous CV outcomes studies with this class of agents, there have been reductions in CV and renal events, but predominantly in secondary prevention,” he said during a press conference.
In this trial, though, the researchers observed favorable effects of dapagliflozin in patients at high risk for ASCVD but without established disease as well as in patients with established disease.
In subgroup analyses, the effect of dapagliflozin, compared with placebo, on the composite rate of CV death or HF hospitalization in patients with multiple risk factors for ASCVD but without established disease (2.8% vs. 3.4%; HR = 0.84; 95% CI, 0.67-1.04) was comparable to that observed in patients with established disease (7.8% vs. 9.3%; HR = 0.83; 95% CI, 0.71-0.98).
Notably, the benefit was similar among patients with a history of HF (HR = 0.79; 95% CI, 0.63-0.99) as well as in patients without a history of HF (HR = 0.84; 95% CI, 95% CI, 0.72-0.99), Wiviott noted.
The MACE rate with dapagliflozin vs. placebo in patients without established disease (5.3% vs. 5.2%; HR = 1.01; 95% CI, 0.86-1.02) was also similar in patients with established disease (13.9% vs. 15.3%; HR = 0.9; 95% CI, 0.79-1.02).
“In DECLARE-TIMI 58, the largest SGLT2 inhibitor trial, which included a broad representation of primary and secondary prevention patients reduced CV death or hospitalization for HF and neither increased nor decreased MACE,” Wiviott said.
Safety, secondary outcomes
In terms of secondary outcomes, the renal composite outcome — a sustained decrease of at least 40% in estimated glomerular filtration rate to less than 60 mL/min/1.73 m2 or death from renal or CV causes — occurred less frequently in the dapagliflozin group than in the placebo group (4.3% vs. 5.6%; HR = 0.76; 95% CI, 0.67-0.87), but there was no difference between groups in all-cause mortality (6.2% vs. 6.6%; HR = 0.93; 95% CI, 0.82-1.04).
However, the analysis of secondary outcomes should be considered exploratory since only one of the two co-primary endpoints was positive, Wiviott said.
The researchers also evaluated key safety concerns that have been associated with SGLT2 inhibitors. Diabetic ketoacidosis, severe adverse events leading to discontinuation of the treatment regimen and severe genital infections were more common in patients taking dapagliflozin. Importantly, however, the rates of major hypoglycemia and bladder cancer were lower with dapagliflozin than with placebo and there was no difference in the rate of fracture or amputation between groups.
Patients treated with dapagliflozin, compared with placebo, also showed improvement in risk factors for ASCVD, including lower HbA1c levels and greater reductions in weight and systolic and diastolic BP throughout the trial.
Baseline characteristics were comparable between study groups. Wiviott noted, however, that the mean eGFR of 85 mL/min/1.73 m2 was higher than would normally be seen in these patients.
Findings in context
SGLT2 inhibitors have garnered attention for CV risk reduction, with empagliflozin (Jardiance; Boehringer Ingelheim, Eli Lilly) gaining an expanded indication in 2017. More recently, canagliflozin (Invokana, Janssen) also earned an expanded indication from the FDA for CV risk reduction in type 2 diabetes.
To gain a more complete picture of the effect of SGLT2 inhibitors, Thomas Zelnicker, MD, from the TIMI Study Group, department of cardiology, Brigham and Women’s Hospital, and colleagues included DECLARE-TIMI 58 in a meta-analysis of other major CV outcomes trials — EMPA-REG OUTCOME and the CANVAS Program — published today in The Lancet.
Results from the meta-analysis of more than 34,000 patients, about 60% of whom had established ASCVD, were fairly consistent with data from DECLARE-TIMI 58. SGLT2 inhibitors were associated with an 11% reduction in MACE (P = .0114), 23% reduction in CV death or hospitalization for HF (P < .0001) and 45% reduction in risk for progression of renal disease (P < .0001).
Notably, the reduction in MACE was restricted to patients with established disease, but the beneficial effect of SGLT2 inhibitors on CV death or hospitalization was seen among patients with and without established disease and patients with and without a history of HF. The risk reduction in progression of renal disease was also observed in both patients with and without established disease.
“In this context, something we can say now about SGLT2 inhibitors that is relatively consistent is that they have moderate benefits on atherosclerotic MACE that appear confined to those with established atherosclerotic CVD. SGLT2 inhibitors have robust effects on reducing the risk of HF and renal outcomes, which do not appear dependent on baseline atherosclerotic risk, prior HF or renal function,” Wiviott said.
“We think that these data with DECLARE-TIMI 58 extend the benefit of SGLT2 inhibitors to a broader population of patients for primary and secondary prevention,” he said.
Importance of CVD prevention
During a discussion of the data, Cardiology Today Editorial Board Member Javed Butler, MD, MPH, MBA, from the University of Mississippi, underscored the importance of prevention and treatment of CV complications in type 2 diabetes.
He also noted that prevention of macrovascular and microvascular complications are often a focus in type 2 diabetes, but these classifications are arbitrary, as there is biological overlap between the two. Additionally, they do not encompass all complications. For instance, macrovascular complications do not include HF while chronic kidney disease in type 2 diabetes should not be grouped with microvascular diseases such as neuropathy and retinopathy, according to Butler.
“All complications in diabetes are important to the patient, regardless of whether they are the primary endpoint or not,” Butler said.
In light of these data, there is a place for SGLT2 inhibitors in CVD prevention in patients with type 2 diabetes, according to Butler.
“It stands to reason that for patients similar to those studied in the SGLT2 inhibitor trials, these drugs should be used for prevention of HF, irrespective of their effect on MACE outcomes,” he said.
However, low-risk patients were not included in the SGLT2 inhibitor trials and the number of patients with a history of HF were insufficient to yield conclusive evidence. Therefore, more data are needed in these groups of patients, according to Butler. – by Melissa Foster
References:
Wiviott SD, et al. LBS.02 – Late Breaking Clinical Trials: Novel Approaches to CV Prevention. Presented at: American Heart Association Scientific Sessions; Nov. 10-12, 2018; Chicago.
Wiviott SD, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1812389.
Zelniker TA, et al Lancet. 2018;doi:10.1016/S0140-6736(18)32590-Xs.
Disclosure: The DECLARE-TIMI 58 trial was initially sponsored by AstraZeneca and Bristol-Myers Squibb and by AstraZeneca alone by the time of publication/presentation. Wiviott reports his spouse is an employee of Merck; he has received research grants from Amgen, Arena, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Eisai, Janssen, Merck and Sanofi Aventis; he is a consultant or on the advisory board for Aegerion, Allergan, Amgen, Angelmed, AstraZeneca, Boehringer Ingelheim, Boston Clinical Research Institute, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, ICON Clinical, Janssen, Lexicon, Merck and St. Jude Medical; and has other financial ties with Merck Research Laboratory. Butler reports he has financial ties with AstraZeneca, Boehringer Ingelheim, Janssen, Merck, Novo Nordisk and Sanofi.
Perspective
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Osama Hamdy, MD, PhD, FACE
This study is particularly important among all CV outcome studies, not only because it has the largest cohort that was followed for the longest duration, but, more importantly, because 59% of its participants did not have CVD at the start of the study. The study also, and in contrary to other previous studies, excluded patients with chronic kidney disease. This makes it more of a primary CV and renal prevention trial. So, any interpretation of the results should put these factors in full consideration.
From the half-cup-empty standpoint, it was not a surprise to me that the study missed one of its primary end points by showing no difference in MACE vs. placebo, which reflects the impact of the healthier selected cohort. From the other half-cup-full standpoint, the study showed dapagliflozin has benefit on the other primary endpoint of combined CV death and hospitalization for congestive HF, driven predominantly by the reduction in hospitalization for HF. It also showed significant slowed progression of renal impairment.
The important message for me as clinician is that dapagliflozin reduces hospitalization for HF in patients without previous history of congestive HF or CVD. It also reduced progression of renal disease among patients without previous history of chronic kidney disease. These are strong primary prevention messages.
The study showed clear difference in the safety profile of SGLT2 inhibitor class, especially in relation to amputations, stroke and fractures. However, commonality of increasing incidence of diabetic ketoacidosis and genital infection is not different.
Director of Inpatient Diabetes Program
Joslin Diabetes Center
Associate Professor of Medicine
Harvard Medical School
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