Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 - DECLARE–TIMI 58
Contribution To Literature:
Highlighted text has been updated as of August 23, 2022.
The DECLARE–TIMI 58 trial showed that dapagliflozin is superior to placebo in improving glycemic control and noninferior but not superior for reducing MACE in patients with DM2 and high CV risk.
The goal of the trial was to assess the cardiovascular (CV) safety of dapagliflozin in patients with type 2 diabetes mellitus (DM2) and either established CV disease (CVD) or multiple risk factors.
Patients were randomized in a 1:1 fashion to either dapagliflozin 10 mg (n = 8,582) or matching placebo (n = 8,578).
- Total number of enrollees: 17,160
- Duration of follow-up: 4.2 years
- Mean patient age: 64.0 years
- Percentage female: 37%
- Age ≥40 years
- Glycosylated hemoglobin (HbA1c) of ≥6.5% and ≤12%
- Glomerular filtration rate (GFR) of >60
- Established CVD or multiple risk factors including men ≥55 years or women ≥60 years with hypertension, dyslipidemia, or tobacco use
- Diagnosis of type 1 DM
- History of bladder cancer or history of radiation therapy to the lower abdomen or pelvis at any time
- Chronic cystitis and/or recurrent urinary tract infections
- Pregnant or breast-feeding patients
Other salient features/characteristics:
- White: 79%, Asian 13.5%
- Body mass index (BMI): 32 kg/m2
- Median duration of DM: 10.5 years
- HbA1c: 8.3%
- Established atherosclerotic CVD: 40.7%
- Insulin: 41%, metformin: 82%
- Statins: 75%
The primary outcome of major adverse cardiac events (MACE) for dapagliflozin vs. placebo: 8.8% vs. 9.4%, hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.84-1.03, p < 0.001 for noninferiority; p = 0.17 for superiority
Secondary outcomes for dapagliflozin vs. placebo:
- Reduction in HbA1c with dapagliflozin: 0.42%
- CV death or heart failure (HF) hospitalization: 4.9% vs. 5.8%, p = 0.005
- HF hospitalization: 2.5% vs. 3.3%, p < 0.005
- All-cause mortality: 6.2% vs. 6.6%, p > 0.05
- >40% decrease in GFR, end-stage renal disease, or death due to renal or CV causes: 4.3% vs. 5.6%, p < 0.05
- Diabetic ketoacidosis: 0.3% vs. 0.1%, p = 0.02
- Genital infections: 0.9% vs. 0.1%, p < 0.001
- Amputation: 1.4% vs. 1.3%, p = 0.53
Based on presence of peripheral artery disease (PAD): PAD was present in 1,025 (6%) of randomized patients, with nearly 75% being asymptomatic or with mild claudication symptoms. MACE and renal events were higher among PAD patients compared with those without PAD. Limb events were also higher (20.3% vs. 2.1% in the placebo arm). No effect modification was noted by PAD status for the effect of dapagliflozin vs. placebo. Limb events were also similar, including major adverse limb events (1.4% vs. 1.2%), urgent revascularization (0.5% vs. 0.6%), and elective revascularization (1.6% vs. 1.5%). Amputation rates were overall similar (1.4% vs. 1.3%). Among patients with PAD, event rates were higher, but rates were similar with dapagliflozin vs. placebo. There was a numerically higher rate of amputations among PAD patients with dapagliflozin (8.4% vs. 5.6%; HR 1.51, 95% CI 0.94-2.42).
Patients with prior myocardial infarction (MI): (n = 3,584). Dapagliflozin reduced the relative risk of MACE by 16% and the absolute risk by 2.6% among patients with prior MI (15.2% vs. 17.8%; HR 0.84, 95% CI 0.72-0.99, p = 0.039), whereas there was no effect in patients without prior MI (7.1% vs. 7.1%; HR 1.00, 95% CI 0.88-1.13, p = 0.97; p-interaction for relative difference 0.11).
Effect of ejection fraction (EF): 3.9% had HF with reduced EF (HFrEF). Dapagliflozin reduced CV death/hospitalization for HF more in patients with HFrEF (HR 0.62, 95% CI 0.45-0.86) than in those without HFrEF (HR 0.88, 95% CI 0.76-1.02; p-interaction 0.046). Dapagliflozin reduced hospitalization for HF both in those with (HR 0.64, 95% CI 0.43-0.95) and without HFrEF (HR 0.76, 95% CI 0.62-0.92); it reduced CV death only in patients with HFrEF (HR 0.55, 95% CI 0.34-0.90) but not in those without HFrEF (HR 1.08, 95% CI 0.89-1.31; p-interaction 0.012). Similar results were noted for all-cause mortality.
Effect on atrial fibrillation (AF): AF/atrial flutter (AFL) events were identified by search of the safety database using the MedDRA Preferred Terms (“atrial fibrillation”, “atrial flutter”). AF/AFL events for dapagliflozin vs. placebo: 7.8 vs. 9.6 events/1,000 patient-years, HR 0.81, 95% CI 0.68-0.95, p = 0.009). Reduction in AF/AFL events was consistent regardless of presence or absence of a history of AF/AFL at baseline (prior AF/AFL: HR 0.79, 95% CI 0.58-1.09, no AF/AFL: HR 0.81, 95% CI 0.67-0.98; p for interaction = 0.89). Dapagliflozin also reduced the total number (first and recurrent) of AF/AFL events (337 vs. 432; incidence rate ratio 0.77, 95% CI 0.64-0.92, p = 0.005).
Safety and efficacy based on eGFR and urinary albumin-to-creatinine ratio (UACR): 7.4% had eGFR <60, 30.9% had albuminuria (UACR >30 mg/g). Patients were categorized as having no more than chronic kidney disease (CKD) stage 2 (65.1%), at least one marker of CKD (31.7%), or both (3.3%). Patients with more markers of CKD were more likely to be older, male, and have atherosclerotic CVD and HF at baseline. Relative risk for CV death and HF hospitalization for dapagliflozin vs. placebo was similar across the three subgroups (p for interaction = 0.24). Absolute risk difference with dapagliflozin was highest among the subgroup with two markers of CKD (-8.3% vs. -1.0% vs. -0.5%, p for interaction = 0.02). Relative and absolute risk reduction was similar for the MACE endpoint. At 6 months, HbA1c reduction was lowest among patients with lower baseline eGFR (least squares mean difference -0.39 vs. -0.47 vs. -0.7 for eGFR <60, 60-<90 and ≥90, p for interaction < 0.001).
Effects on blood pressure (BP) and baseline hypertension: Effects of dapagliflozin on systolic BP (SBP) were apparent as early as at the first 6 months of trial assessment (least means square difference -3.1 mm Hg, 95% CI -3.5 to -2.7, p < 0.0001). Reductions in SBP with dapagliflozin remained sustained at 48 months of follow-up (least means square difference -2.4 mm Hg, 95% CI -2.9 to -1.9, p < 0.0001). The beneficial effects of dapagliflozin on HF hospitalization and renal outcomes were consistent across all baseline SBP categories, with no evidence of modification of treatment effect (p-interactions = 0.28 and 0.52, respectively), including among patients with baseline normotension.
Effect of obesity: Of 17,134 patients, 31.5% were overweight, 32.4% were moderately (BMI 30-<35 kg/m2), 17.2% severely (BMI 35-<40), and 9.8% were very severely (BMI ≥40) obese. Patients with higher BMI had a higher risk of HF hospitalization and AF/AFL. The effect of dapagliflozin compared with placebo was consistent across BMI categories for CV death/HF hospitalization (p for interaction = 0.33), HF hospitalization (p for interaction = 0.20), renal-specific composite outcome (p for interaction = 0.90), and AF/AFL (p for interaction = 0.97). No differences in safety were observed based on BMI either. When dichotomized as obese (BMI ≥30) vs. not, dapagliflozin showed a greater reduction in CV death/HF hospitalization compared with placebo (p for interaction = 0.02) and HF hospitalization (p for interaction = 0.02) among obese patients.
The results of this trial indicate that dapagliflozin is superior to placebo in improving glycemic control and noninferior but not superior for reducing MACE in patients with DM2 and high CV risk. There was a reduction in BP, HF hospitalizations, and also a salutary effect on renal outcomes. These findings were noted irrespective of baseline BP. Among patients with HFrEF, dapagliflozin reduced HF hospitalizations, and CV and all-cause mortality; however, this cohort comprised only about 4% of the total population.
The effect of dapagliflozin was consistent across BMI categories. However, in a hypothesis-generating analysis, obese patients (BMI ≥30) had a greater reduction in HF events compared with their nonobese counterparts. Effect and safety of CV events was similar irrespective of baseline eGFR and albuminuria. Unlike canagliflozin, there was no clear safety signal regarding increased amputations. These are important findings, and more or less consistent with findings noted with other selective inhibitor of sodium–glucose cotransporter 2 (SGLT-2) inhibitors. These drugs reduce hyperglycemia in patients with DM2 by reducing renal glucose reabsorption and thus increasing urinary glucose excretion.
The effect on atrial arrhythmias is hypothesis generating and should be tested in prospective trials. AF/AFL was not a prespecified endpoint, had no central adjudication, and was determined from the MedDRA database, and thus, dependent on the fidelity of reporting.
Following the much-publicized CV safety concerns with rosiglitazone, the FDA mandated that all new diabetes drugs conduct studies demonstrating CV safety. The upper limit of the 95% CI for the HR had to be <1.8 for premarketing studies and <1.3 for postmarketing studies. This trial thus establishes the CV safety profile of dapagliflozin for use in patients with DM2. The reduction in HF hospitalization was noted even among patients with prior HF, and has been noted for the other SGLT-2 inhibitors. Dipeptidyl peptidase-4 (DPP-4) inhibitors on the other hand, particularly saxagliptin, may increase the risk of HF.
Oyama K, Raz I, Cahn A, et al. Obesity and effects of dapagliflozin on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus in the DECLARE–TIMI 58 trial. Eur Heart J 2022;43:2958-67.
Furtado RH, Raz I, Goodrich EL, et al. Efficacy and Safety of Dapagliflozin in Type 2 Diabetes According to Baseline Blood Pressure: Observations From DECLARE-TIMI 58 Trial. Circulation 2022;145:1581-91.
Zelniker TA, Raz I, Mosenzon O, et al. Effect of Dapagliflozin on Cardiovascular Outcomes According to Baseline Kidney Function and Albuminuria Status in Patients With Type 2 Diabetes: A Prespecified Secondary Analysis of a Randomized Clinical Trial. JAMA Cardiol 2021;6:801-10.
Bonaca MP, Wiviott SD, Zelniker TA, et al. Dapagliflozin and Cardiac, Kidney and Limb Outcomes in Patients With and Without Peripheral Artery Disease in DECLARE-TIMI 58. Circulation 2020;142:734-47.
Zelniker TA, Bonaca MP, Furtado R, et al. Effect of Dapagliflozin on Atrial Fibrillation in Patients With Type 2 Diabetes Mellitus: Insights From the DECLARE-TIMI 58 Trial. Circulation 2020;141:1227–34.
DECLARE–TIMI 58 PAD: Presented by Dr. Marc P. Bonaca at the American College of Cardiology Annual Scientific Session (ACC 2019), New Orleans, LA, March 18, 2019.
DECLARE–TIMI 58 HFrEF: Presented by Dr. Eri T. Kato at the American College of Cardiology Annual Scientific Session (ACC 2019), New Orleans, LA, March 18, 2019.
Furtado RH, Bonaca MP, Raz I, et al. Dapagliflozin and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Prior Myocardial Infarction: A Sub-analysis From DECLARE TIMI-58 Trial. Circulation 2019;139:2516–27.
Kato ET, Silverman MG, Mosenzon O, et al. Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes Mellitus. Circulation 2019;139:2528–36.
Editorial: Verma S, McMurray JJ. The Serendipitous Story of SGLT2 Inhibitors in Heart Failure: New Insights From DECLARE-TIMI 58. Circulation 2019;139:2537–41.
Wiviott SD, Raz I, Bonaca MP, et al., on behalf of the DECLARE–TIMI 58 Investigators. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2019;380:347-57.
Presented by Dr. Stephen D. Wiviott at the American Heart Association Annual Scientific Sessions (AHA 2018), Chicago, IL, November 10, 2018.
Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Atherosclerotic Disease (CAD/PAD), Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Hypertension, Smoking
Keywords: ACC Annual Scientific Session, ACC19, AHA Annual Scientific Sessions, AHA18, Amputation, Atherosclerosis, Atrial Fibrillation, Atrial Flutter, Blood Pressure, Brain Ischemia, Diabetic Ketoacidosis, Diabetes Mellitus, Type 2, Dyslipidemias, Glomerular Filtration Rate, Heart Failure, Glycated Hemoglobin A, Hyperglycemia, Hypertension, Metabolic Syndrome, Myocardial Infarction, Myocardial Ischemia, Obesity, Peripheral Arterial Disease, Primary Prevention, Renal Insufficiency, Chronic, Smoking, Stroke, Vascular Diseases
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