Itamar Raz, MD
Diabetes Unit, Hadassah Hebrew University Hospital, Jerusalem, Israel Ofri Mosenzon, MD, MSc
Diabetes Unit, Hadassah Hebrew University Hospital, Jerusalem, Israel Avivit Cahn, MD
Diabetes Unit, Hadassah Hebrew University Hospital, Jerusalem, Israel
Many potential mechanisms have been proposed for the CV benefits of SGLT2 inhibition. Compared to placebo, dapagliflozin lowers systolic blood pressure by 3 to 5 mmHg and results in loss of body weight. In a meta-analysis of phase 2 and phase 3 studies of dapagliflozin, there was a suggestion of CV benefit, particularly a tendency toward reductions of a composite of CV events, including CV death, hospitalisations for heart failure and myocardial infarction (MI), with no clear effects on stroke.
The DECLARE-TIMI 58 (Dapagliflozin Effect on CardiovascuLAR Events) study was designed to test the hypotheses that dapagliflozin: (1) does not increase major adverse cardiac events (MACE); and (2) will reduce the incidence of CV events in patients with type 2 diabetes with established atherosclerotic cardiovascular disease (ASCVD), or with multiple risk factors for ASCVD but without established ASCVD.
A secondary cardiorenal composite outcome was also assessed.
17,160 patients with type 2 diabetes and established ASCVD (n = 6974) or multiple risk factors (n = 10,186) were enrolled.
Eligible patients were ≥40 years and had type 2 diabetes, HbA1c 6.5-12.0%, CrCl of ≥60 mL/min, and multiple risk factors for ASCVD or established ASCVD.
Participants with multiple risk factors were men 55 years of age or older or women 60 years of age or older who had one or more traditional risk factors, including hypertension, dyslipidemia or use of lipid-lowering therapies, or use of tobacco.
This event-driven trial continued until at least 1,390 subjects have a MACE outcome, thereby providing >99% power to test for the primary outcome of safety of dapagliflozin.
Primary outcome measure
The primary safety outcome was MACE (defined as CV death, MI, or ischaemic stroke).
The two primary efficacy outcomes were MACE and a composite of CV death or hospitalisation for heart failure.
A prespecified secondary cardiorenal composite outcome was further defined as a sustained decline of at least 40% in estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73m2, end-stage renal disease (defined as dialysis for at least 90 days, kidney transplantation, or confirmed sustained eGFR <15mL/min/1.73 m2), or death from renal or cardiovascular causes; a prespecified renal-specific composite outcome was the same but excluding death from cardiovascular causes.
In the primary safety outcome analysis, dapagliflozin met the prespecified criterion for noninferiority to placebo with respect to MACE (P <0.001).
In the two primary efficacy analyses, dapagliflozin did not result in a lower rate of MACE (8.8% in the dapagliflozin group and 9.4% in the placebo group; HR, 0.93; 95% CI 0.84-1.03; P = 0.17).
Dapagliflozin was associated with a lower rate of CV death or hospitalisation for heart failure (4.9% vs. 5.8%; HR 0.83; 95% CI, 0.73-0.95; P = 0.005)
The cardiorenal secondary composite outcome was significantly reduced with dapagliflozin versus placebo (HR 0.76, 95% CI 0.67-0.87; P <0.0001); excluding death from cardiovascular causes, the HR for the renal-specific outcome was 0.53 (0.43-0.66; P <0.0001).
A 46% reduction in sustained decline in eGFR by at least 40% to less than 60 mL/min per 1.73 m2 (HR 0.54 (95% CI 0.43-0.67); P <0.0001) was identified.
The risk of end-stage renal disease or renal death was lower with dapagliflozin than placebo (HR 0.41 (95% CI 0.20-0.82); P = 0.012).
Dapagliflozin also provided clinically relevant benefits to patients regardless of age.
In DECLARE TIMI-58 dapagliflozin did not lower the risk of MACE, but did reduce CV death and hospitalisation for heart failure.
Dapagliflozin seemed to prevent and reduce progression of kidney disease compared with placebo in patients with type 2 diabetes with and without established ASCVD, most of whom had preserved renal function.
Key Messages/Clinical Perspectives
SGLT2 inhibition represents a new approach to glycaemic management, allowing tailored therapy according to cardiorenal status.
Physicians should strive to treat all patients with drugs that improve the patient’s outlook with an SGLT2 inhibitor and/or GLP-1 receptor agonist.
Based on the results of DECLARE TIMI-58, it has been suggested that early combination therapy with metformin and a SGLT2 inhibitor and/or GLP-1 receptor agonist might be considered for any patient not at target or with comorbidities.
Mosenzon O, Wiviott SD, Cahn A, et al. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial. Lancet Diabetes Endocrinol 2019 Aug;7(8):606-17
Presenter disclosure: The presenters has reported the follow relationships: I. Raz: AstraZeneca, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, Sanofi, Insulin Medical, Medial EarlySing Ltd., Excopia, Orgenesis Ltd., Glucome Ltd., DariopHealth, Diabot, Janssen, Servier. O. Mosenzon: no relationships exist relevant to the contents of this presentation. A. Cahn: AstraZeneca, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, Sanofi, Boehringer Ingelheim, Glucome Ltd., MedialEarlySing.
Medical writer: Patrick Moore, PhD
Reviewer: Marco Gallo, MD
Local reviewers: Marco Gallo, MD (Italia); Anna Novials Sardá, MD, PhD (España); Eric Renard, MD, PhD (France); Peter Schwarz, MD, PhD (Deutschland)