Efficacy and Safety of Dapagliflozin According to Background Use of Cardiovascular Medications in Patients With Type 2 Diabetes: A Prespecified Secondary Analysis of a Randomized Clinical Trial

Kazuma Oyama; Itamar Raz; Avivit Cahn; Erica L Goodrich; Deepak L Bhatt; Lawrence A Leiter; Darren K McGuire; John P H Wilding; Ingrid A M Gause-Nilsson; Ofri Mosenzon; Marc S Sabatine; Stephen D Wiviott

doi:10.1001/jamacardio.2022.2006

. 2022 Jul 20;7(9):914–923. doi: 10.1001/jamacardio.2022.2006

Efficacy and Safety of Dapagliflozin According to Background Use of Cardiovascular Medications in Patients With Type 2 Diabetes

A Prespecified Secondary Analysis of a Randomized Clinical Trial

Kazuma Oyama ^1,², Itamar Raz ^3,⁴, Avivit Cahn ^3,⁴, Erica L Goodrich ¹, Deepak L Bhatt ⁵, Lawrence A Leiter ⁶, Darren K McGuire ⁷, John P H Wilding ⁸, Ingrid A M Gause-Nilsson ⁹, Ofri Mosenzon ^3,⁴, Marc S Sabatine ¹, Stephen D Wiviott ^1,^✉

¹TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts

²Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan

³Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Jerusalem, Israel

⁴Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel

⁵Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts

⁶Li Ka Shing Knowledge Institute, St Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada

⁷Division of Cardiology, University of Texas Southwestern Medical Center, Parkland Health and Hospital System, Dallas

⁸Department of Cardiovascular and Metabolic Medicine, University of Liverpool, Liverpool, United Kingdom

⁹BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden

Accepted for Publication: May 19, 2022.

Published Online: July 20, 2022. doi:10.1001/jamacardio.2022.2006

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Corresponding Author: Stephen D. Wiviott, MD, TIMI Study Group, 60 Fenwood Rd, Ste 7022, Boston, MA 02115 (swiviott@bwh.harvard.edu).

Author Contributions: Dr Wiviott had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Oyama, Raz, Bhatt, McGuire, Gause-Nilsson, Sabatine.

Acquisition, analysis, or interpretation of data: Oyama, Cahn, Goodrich, Bhatt, Leiter, McGuire, Wilding, Gause-Nilsson, Mosenzon, Sabatine, Wiviott.

Drafting of the manuscript: Oyama, Raz.

Critical revision of the manuscript for important intellectual content: Oyama, Cahn, Goodrich, Bhatt, Leiter, McGuire, Wilding, Gause-Nilsson, Mosenzon, Sabatine, Wiviott.

Statistical analysis: Oyama, Goodrich.

Obtained funding: Oyama, Sabatine.

Supervision: Raz, Cahn, Bhatt, Gause-Nilsson, Sabatine.

Conflict of Interest Disclosures: Dr Oyama reported grants from the Uehara Memorial Foundation and JSPS Overseas Research Fellowships during the conduct of the study. Dr Raz reported advisory board fees from AstraZeneca, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, and Sanofi; consultant fees from AstraZeneca, Insuline Medical, Medial EarlySign, CamerEyes, Exscopia, Orgenesis, BOL Pharma, Glucome, DarioHealth, Diabot, Concenter BioPharma, and CuraLife; speaker’s bureau fees from AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme, Novo Nordisk, and Sanofi; and stocks for Glucome, Orgenesis, DarioHealth, CamerEyes, Diabot, and BOL Pharma. Dr Cahn reported grants and personal fees from AstraZeneca and Novo Nordisk and personal fees from Abbott, Eli Lilly, Sanofi, Boehringer Ingelheim, Merck Sharp & Dohme, Medial Early-Sign, and GlucoMe. Ms Goodrich reported research grant support through Brigham and Women’s Hospital from Abbott Laboratories, Amgen, Anthos Therapeutics, AstraZeneca, Bayer HealthCare Pharmaceuticals, Critical Diagnostics, Daiichi-Sankyo, Eisai, Genzyme, Gilead, GlaxoSmithKline, Intarcia, Janssen Research and Development, The Medicines Company, MedImmune, Merck, Novartis, Poxel, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Roche Diagnostics, Siemens Healthcare Diagnostics, Takeda, and Zora Biosciences. Dr Bhatt reported serving on an advisory board for AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Janssen, Level Ex, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; serving on a board of directors for AngioWave (stock options), Boston VA Research Institute, DRS.LINQ (stock options), Society of Cardiovascular Patient Care, and TobeSoft; being the inaugural chair of the American Heart Association Quality Oversight Committee; serving on data monitoring committees for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St Jude Medical, now Abbott), Boston Scientific (chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute; and Rutgers University (for the NIH-funded MINT Trial); receiving honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor, Associate Editor), K2P (co-chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (course director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and US national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees), Wiley (steering committee); other from Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (chair), VA CART Research and Publications Committee (chair); research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, and 89Bio; royalties from Elsevier (Editor, Braunwald’s Heart Disease); serving as a site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St Jude Medical (now Abbott), Philips, Svelte, and Vascular Solutions; serving as a trustee for the American College of Cardiology; and unfunded research for FlowCo and Takeda. Dr Leiter reported grants and personal fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi; and personal fees from Lexicon, Merck, Pfizer, and Servier. Dr McGuire reported personal fees from Lilly US, AstraZeneca, Sanofi, Janssen, Boehringer Ingelheim, Merck & Co, Novo Nordisk, Lexicon, Eisai, GlaxoSmithKline, CSL Behring, and Esperion and consultancy for Afimmune, AstraZeneca, Bayer, Sanofi, Lilly US, Boehringer Ingelheim, Merck & Co, Pfizer, Novo Nordisk, Applied Therapeutics, and Metavant. Dr Wilding reported grants, personal fees, and/or consultancy fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Janssen, Napp, Mundipharma, Sanofi, Takeda, Alnylam, Pfizer, Rhythm Pharmaceuticals, Saniona, Wilmington Healthcare, and Ysopia. Dr Gause-Nilsson reported being an employee and shareholder of AstraZeneca, Gothenburg, Sweden, and reported other from BioPharmaceuticals R&D. Dr Mosenzon reported grants and personal fees from BOL Pharma, AstraZeneca, Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, Janssen, and Bayer. Dr Sabatine reported research grant support through Brigham and Women’s Hospital from Amgen, Abbott, ARCA Biopharma, AstraZeneca, Bayer, Daiichi-Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, Janssen Research and Development, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron, Roche, Siemens Healthcare Diagnostics, Softcell Medical, Takeda, The Medicines Company, and Zora Biosciences and consulting for Althera, Amgen, Anthos Therapeutics, AstraZeneca, Beren Therapeutics, Bristol-Myers Squibb, CVS Caremark, DalCor, Dr Reddy’s Laboratories, Dyrnamix, Esperion, Fibrogen, IFM Therapeutics, Intarcia, Janssen Research and Development, Medicines Company, MedImmune, Merck, Novo Nordisk, Novartis, and Silence Therapeutics. Dr Wiviott reported grants from AstraZeneca, Bristol-Myers Squibb, Sanofi Aventis, and Amgen; grants and personal fees from Arena, Daiichi Sankyo, Eisai, Eli Lilly, and Janssen; grants and consulting fees from Merck; personal fees from Aegerion, Allergan, AngelMed, Boehringer Ingelheim, Boston Clinical Research Institute, Icon Clinical, Lexicon, Novo Nordisk, Pfizer, St Jude Medical, Xoma, Servier, AstraZeneca, and Bristol-Myers Squibb; his spouse being employed by Merck; and, as a member of the TIMI Study Group, institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, ARCA Biopharma, AstraZeneca, Bayer HealthCare Pharmaceuticals, Daiichi-Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, Janssen Research and Development, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Roche, Siemens Healthcare Diagnostics, Softcell Medical, The Medicines Company, and Zora Biosciences. No other disclosures were reported.

Funding/Support: The DECLARE–TIMI 58 trial was supported by AstraZeneca.

Role of the Funder/Sponsor: The trial was designed as a collaboration among the TIMI Study Group, the Hadassah Medical Center, the executive and steering committees, and AstraZeneca. The TIMI Study Group, Hadassah Medical Center, and AstraZeneca were responsible for the design and conduct of the trial and the collection and management of the data. The TIMI Study Group was responsible for the present analysis; interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 3.

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Corresponding author.

PMCID: PMC9301591 PMID: 35857296

This randomized clinical trial analyzes data according to use of common cardiovascular medications to determine the cardiorenal efficacy and safety of dapagliflozin in patients with type 2 diabetes.

Key Points

Question

Are the cardiorenal efficacy and safety of dapagliflozin consistent with and without background use of cardiovascular (CV) medications commonly used for heart failure and kidney disease in patients with type 2 diabetes?

Findings

Dapagliflozin consistently reduced the risk of a composite of CV death or hospitalization for heart failure (HHF), HHF alone, and progression of kidney disease regardless of background use of CV medications, including angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, β-blockers, diuretics, and mineralocorticoid receptor antagonists, without any treatment interaction for key safety events.

Meaning

These data show the clinical benefit and safety of dapagliflozin in a broad range of patients with type 2 diabetes regardless of background therapy.

Abstract

Importance

Dapagliflozin was shown to reduce the cardiovascular (CV) and kidney outcomes in patients with type 2 diabetes. However, data are limited on the relationship of the effect and safety with the concurrent use of CV medications in patients with type 2 diabetes.

Objective

To assess whether the cardiorenal efficacy and safety of dapagliflozin were consistent with and without background use of CV medications commonly used for heart failure (HF) and kidney disease in patients with type 2 diabetes.

Design, Setting, and Participants

This study is a prespecified secondary analysis of DECLARE-TIMI 58, which was a randomized trial of dapagliflozin vs placebo in 17 160 patients with type 2 diabetes and either atherosclerotic disease or multiple risk factors for CV disease. Patients were stratified by baseline use of the following CV medications: angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers (ACEI/ARBs), β-blockers, diuretics, and mineralocorticoid receptor antagonists (MRAs). The study was conducted from May 2013 to September 2018, and data were evaluated for this analysis from February 2021 to May 2022.

Interventions

Dapagliflozin or placebo.

Main Outcomes and Measures

The outcomes of interest were the composite of CV death or hospitalization for HF (HHF), HHF alone, and a kidney-specific composite outcome (persistent ≥40% decrease in estimated glomerular filtration rate [eGFR], end-stage kidney disease, or kidney-related death).

Results

Among 17 160 patients, 13 950 (81%) used ACEI/ARBs, 9030 (53%) used β-blockers, 6205 (36%) used diuretics, and 762 (4%) used MRAs at baseline. Changes in blood pressure and eGFR at 48 months with dapagliflozin compared with placebo did not differ regardless of concurrent therapy (placebo-corrected change, −1.6 mm Hg [95% CI, −4.2 to 1.0] to −2.6 mm Hg [95% CI, −3.3 to −2.9]; P > .05 for each interaction). Dapagliflozin consistently reduced the risk of CV death/HHF, HHF alone, and the kidney-specific composite outcome regardless of background use of selected medications (hazard ratio [HR] range: HR, 0.50; 95% CI, 0.39-0.63; to HR, 0.82; 95% CI, 0.72-0.95; P > .05 for each interaction). In patients receiving ACEI/ARBs + β-blockers + diuretics (n = 4243), dapagliflozin reduced the risk of CV death/HHF and of the kidney-specific outcome by 24% (HR, 0.76; 95% CI, 0.62-0.93) and 38% (HR, 0.62; 95% CI, 0.44-0.87), respectively. There were no significant treatment interactions with the concomitant CV medications for adverse events of volume depletion, acute kidney injury, or hyperkalemia (range: HR, 0.12; 95% CI, 0.02-0.99; to HR, 1.04; 95% CI, 0.83-1.32; P > .05 for each interaction).

Conclusions and Relevance

Dapagliflozin consistently reduced the risk of CV and kidney outcomes irrespective of background use of various CV medications without any treatment interaction for key safety events. These data show the clinical benefit and safety of dapagliflozin in a broad range of patients with type 2 diabetes regardless of background therapy.

Trial Registration

ClinicalTrials.gov Identifier: NCT01730534

Introduction

Sodium-glucose cotransporter 2 (SGLT2) inhibitors block glucose reabsorption in the proximal tubule of the kidney and promote glucosuria with proven effects for reducing selected cardiovascular (CV) events and kidney disease progression in patients with type 2 diabetes.^1,2,3 Across several large CV outcomes trials in patients with type 2 diabetes, SGLT2 inhibitors have, in general, reduced CV death or hospitalization for heart failure (HHF), with the magnitude of effect typically greater for HHF than for CV death, in addition to preventing progression of kidney disease.^1,2,3,4,5

Because of various CV and kidney comorbidities, patients with type 2 diabetes frequently use angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers (ACEI/ARBs), β-blockers, diuretics, and mineralocorticoid receptor antagonists (MRAs) that also affect the risk of HF or progression of kidney disease.^6,7,8,9 In addition, since SGLT2 inhibitors are known to have diuretic and antihypertensive effects, there is a theoretical concern that their use could be deleterious with concomitant use of medications with similar effects. However, data are limited on any potential treatment interaction between these CV medications and the risk of efficacy and safety outcomes with SGLT2 inhibitors in large CV outcome trials in patients with type 2 diabetes.^1,3,4

In these prespecified subanalyses from the DECLARE-TIMI 58 trial (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58), we sought to examine whether dapagliflozin consistently reduced the risk of CV and kidney outcomes and whether the safety of dapagliflozin differed with or without background use of various CV medications commonly used by patients with type 2 diabetes.

Methods

Study Design and Population

The trial design, baseline characteristics, and main results of the DECLARE-TIMI 58 trial have previously been published (trial protocol in Supplement 1).^2,10,11 In brief, DECLARE-TIMI 58 was a randomized, double-blind, multinational trial involving 17 160 patients with type 2 diabetes and either established atherosclerotic CV disease (ASCVD) or multiple risk factors for ASCVD and with a creatinine clearance of 60 mL/min or greater. Established ASCVD was defined as age 40 years or older and either ischemic heart disease, cerebrovascular disease, or peripheral arterial disease. Patients with multiple risk factors for ASCVD were required to be 55 years or older for men and 60 years or older for women and have at least 1 of dyslipidemia, hypertension, or current tobacco use.

Patients were randomly assigned to receive dapagliflozin, 10 mg, once daily or matching placebo. Concurrent antihyperglycemic and CV medications were at the discretion of the treating physician. The trial protocol was approved by the institutional review board for each participating site, and all participants provided written informed consent. The study was conducted from May 2013 to September 2018, and data were evaluated for this analysis from February 2021 to May 2022.

Efficacy and Safety Outcomes

Baseline CV medication use was a prespecified subgroup of interest and collected at enrollment, including data on ACEI/ARBs, β-blockers, diuretics, and MRAs. The trial had prespecified dual-primary efficacy outcomes: a composite of CV death or HHF and a composite of CV death, myocardial infarction, or stroke (MACE).^2,11 The present analyses focus on CV death/HHF, as there was no effect of dapagliflozin on MACE demonstrated in the overall trial. Also evaluated were individual components of CV death/HHF and the kidney-specific composite outcome (persistent ≥40% decrease in estimated glomerular filtration rate [eGFR], end-stage kidney disease, or kidney-related death).^2,11,12 End-stage kidney disease was defined as receiving dialysis for 90 days or longer, kidney transplantation, or confirmed sustained eGFR less than 15 mL/min/1.73 m². Measurement of serum creatinine was done at screening, baseline, 6 months, 12 months, and yearly thereafter. Serum creatinine was also measured at the end of the trial, or at the last on-treatment visit, in patients who prematurely discontinued study product.

All key events were prespecified and adjudicated in a blinded manner by an independent clinical events committee using previously published definitions.¹¹ All efficacy analyses included the intention-to-treat population. Safety assessments were performed in a safety analysis population, which consisted of patients who were randomized and received at least 1 dose of study medication (dapagliflozin or placebo). Safety outcomes were assessed on treatment, which included all events that occurred after the first dose of the study product to the earlier of 30 days (for serious adverse events [SAEs]) or 7 days (for nonserious AEs) after the last dose of the study product or the closing visit.

Statistical Analyses

In these prespecified analyses, patients were stratified by the use of CV medications commonly used for HF and kidney disease at baseline: ACEI/ARBs, β-blockers, diuretics, and MRAs. Diuretics included loop, thiazide, and other diuretics but excluded MRAs. Heart failure with reduced ejection fraction (HFrEF) was defined as having a prespecified EF cut point of less than 45% with a reported history of HF. Of 1987 patients with a history of HF, 1479 had known EF data (671 with EF <45% and 808 with EF ≥45%) and 508 without documented EF.¹³ Baseline characteristics are presented as medians (IQRs) for continuous variables and frequencies for categorical variables and are compared with and without the concomitant use of each medication at baseline and further between treatment allocations with a Mann-Whitney U test for continuous variables and χ² test for categorical variables. Frequencies of patients receiving CV medications at baseline and 12 months are also compared between treatment groups with a χ² test. Mixed models for repeated measures in systolic and diastolic blood pressure, eGFR, body weight, and hemoglobin A_1c (HbA_1c) were analyzed to produce least-squares mean differences from baseline to 48 months between treatment groups within each of patients with and without the concomitant use of each medication at baseline. P values for interactions of CV medication and treatment group of placebo or dapagliflozin at 48 months were also analyzed.

Cox proportional hazards models were used to compare the randomized treatment effect within the subgroups of participants with and without the background use of each CV medication. Effect heterogeneity between groups based on the concomitant use of CV medications was analyzed with a test for treatment × subgroup interaction for each concomitant CV medication. Cumulative incidence rates at 4 years after randomization were calculated from Kaplan-Meier failure rates. All analyses were performed with SAS software version 9.4 (SAS Institute Inc). Unless otherwise stated, all tests are 2-sided, and a value of P < .05 was considered statistically significant. No adjustment for multiplicity was performed.

Results

Baseline Patient Characteristics

The number of participants randomized and constituting follow-up have been published previously² and are shown in eFigure 1 in Supplement 2. Of 17 160 patients, 13 950 (81%) used ACEI/ARBs, 9030 (53%) used β-blockers, 6205 (36%) used diuretics, and 762 (4%) used MRAs at baseline. Because enrollment completed coincident with regulatory approvals of sacubitril/valsartan, no patients took this drug at baseline. Baseline characteristics by concurrent use of CV medications are shown in the Table. Patients using CV medications at baseline had a greater prevalence of ASCVD risk factors, history of HF, and established CV disease than those without. Baseline characteristics were substantially similar between treatment groups within each category based on baseline use of CV medications (eTables 1 and 2 in Supplement 2). Proportion of patients receiving CV medications at 12 months by treatment group, shown in eTable 3 in Supplement 2, showed slight increases in each group but consistent use between treatment groups.

Table. Baseline Characteristics of Patients by Use of Cardiovascular Medications.

	ACEI or ARB, No. (%)			β-Blocker, No. (%)			Diuretic, No. (%)			MRA, No. (%)
	Yes (n = 13 950)	No (n = 3210)	P value	Yes (n = 9030)	No (n = 8130)	P value	Yes (n = 6205)	No (n = 10 955)	P value	Yes (n = 762)	No (n = 16 398)	P value
Age, median (IQR), y	64 (60-68)	63 (59-68)	<.001	64 (59-68)	64 (60-68)	.02	65 (61-69)	63 (59-68)	<.001	63 (59-67)	64 (60-68)	.008
Female	5187 (37)	1235 (38)	.17	3154 (35)	3268 (40)	<.001	2579 (42)	3843 (35)	<.001	229 (30)	6193 (38)	<.001
Male	8763 (63)	1975 (62)		5876 (65)	4862 (60)		3626 (58)	7112 (65)		533 (70)	10 205 (62)
White race	11 435 (82)	2218 (69)	<.001	7674 (85)	5979 (74)	<.001	5292 (85)	8361 (76)	<.001	666 (87)	12 987 (79)	<.001
BMI, median (IQR)	32 (28-36)	29 (26-34)	<.001	32 (29-36)	30 (27-35)	<.001	33 (30-37)	30 (27-34)	<.001	34 (30-38)	31 (28-35)	<.001
Duration of type 2 diabetes, median (IQR), y	11 (6-16)	10 (5-15)	<.001	11 (6-16)	10 (6-16)	<.001	11 (7-17)	10 (6-16)	<.001	10 (5-16)	11 (6-16)	.15
HbA_1c, median (IQR), %	8.0 (7.3-9.0)	8.1 (7.4-9.2)	<.001	8.0 (7.3-9.0)	8.0 (7.4-9.0)	.19	8.0 (7.3-8.9)	8.1 (7.4-9.0)	<.001	8.1 (7.4-9.3)	8.0 (7.3-9.0)	.03
Hypertension	13 479 (97)	1948 (61)	<.001	8576 (95)	6851 (84)	<.001	6083 (98)	9344 (85)	<.001	715 (94)	14 712 (90)	<.001
Dyslipidemia	11 386 (82)	2410 (75)	<.001	7697 (85)	6099 (75)	<.001	5124 (83)	8672 (79)	<.001	664 (87)	13 132 (80)	<.001
Current smoker	1868 (13)	630 (20)	<.001	1241 (14)	1257 (16)	.001	726 (12)	1772 (16)	<.001	99 (13)	2399 (15)	.21
Established ASCVD	5735 (41)	1239 (39)	.009	5069 (56)	1905 (23)	<.001	2346 (38)	4628 (42)	<.001	494 (65)	6480 (40)	<.001
History of coronary artery disease	4725 (34)	933 (29)	<.001	4500 (50)	1158 (14)	<.001	1896 (31)	3762 (34)	<.001	447 (59)	5211 (32)	<.001
History of peripheral artery disease	817 (6)	208 (7)	.18	580 (6)	445 (6)	.009	351 (6)	674 (6)	.19	58 (8)	967 (6)	.05
History of cerebrovascular disease	1059 (8)	242 (8)	.92	776 (9)	525 (7)	<.001	488 (8)	813 (7)	.29	85 (11)	1216 (7)	<.001
History of heart failure	1483 (11)	241 (8)	<.001	1392 (15)	332 (4)	<.001	808 (13)	916 (8)	<.001	347 (46)	1377 (8)	<.001
eGFR, median (IQR), mL/min/1.73 m²	88 (74-96)	91 (79-98)	<.001	87 (73-96)	90 (78-97)	<.001	85 (70-95)	90 (78-97)	<.001	81 (66-93)	89 (75-97)	<.001
CV therapies
Antiplatelet agent	8864 (64)	1623 (51)	<.001	6405 (71)	4082 (50)	<.001	3870 (62)	6617 (60)	.01	531 (70)	9956 (60.7)	<.001
Statin	10 628 (76)	2131 (66)	<.001	7260 (80)	5499 (68)	<.001	4764 (77)	7995 (73)	<.001	641 (84)	12 118 (74)	<.001

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Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ASCVD, atherosclerotic cardiovascular disease; eGFR, estimated glomerular filtration rate; HbA_1c, hemoglobin A_1c; MRA, mineralocorticoid receptor antagonist.

Effect of Dapagliflozin on Blood Pressure, Kidney Function, Body Weight, and HbA_1c

Differences in change of systolic blood pressure from baseline to 48 months between treatment groups as estimated by the least-squares mean percent differences did not differ regardless of the background use of each CV medication (placebo-corrected change, −1.6 to −2.6 mm Hg; P > .05 for each interaction) (Figure 1). The mean decrease in eGFR from baseline to 48 months was consistently less in the dapagliflozin group than in the placebo group irrespective of use of each CV medication at baseline (placebo-corrected change, 0.9 to 1.9 mL/min/1.73 m²; P > .05 for each interaction) (Figure 1). Differences in changes of body weight, HbA_1c, and diastolic blood pressure between treatment groups by baseline use of CV medication were consistent and shown in eTable 4 in Supplement 2.

Figure 1. — ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; Dapa, dapagliflozin; MRA, mineralocorticoid receptor antagonist; PBO, placebo; Rx, medication.

Effect of Dapagliflozin on Clinical Outcomes

Dapagliflozin consistently reduced the risk of CV death/HHF regardless of the background use of CV medications, including ACEI/ARBs, β-blockers, diuretics, and MRAs (P > .05 for each interaction) (Figure 2A). The reduction in CV death/HHF with dapagliflozin also did not differ between patients with the concurrent use of all 3 of ACEI/ARBs, β-blockers, and diuretics (n = 4243, 25%) and those with 2 or fewer of these medications (P > .05 for interaction) (Figure 2A). Similar observations were found for individual components of CV death/HHF (Figure 2B and eFigure 2 in Supplement 2). Dapagliflozin also consistently reduced the risk of the kidney-specific composite outcome regardless of the concomitant use of CV medications except for diuretics (P > .05 for each interaction) (Figure 2C). There was a quantitative interaction between treatment groups and diuretics use for the kidney-specific outcome (P = .003 for interaction) with a greater benefit among patients not taking diuretics. Of 17 160 patients, 671 (3.9%) had HFrEF, 1316 (7.7%) had HF without known reduced EF, and 15 173 (88.4%) had no history of HF at baseline. Sensitivity analyses in patients with HFrEF, patients with HF without known reduced EF, and those with no history of HF showed that the reduction in CV death/HHF with dapagliflozin was also consistent irrespective of the background use of CV medications (P > .05 for each interaction) (eFigures 3-5 in Supplement 2).

Figure 2. — ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; HR, hazard ratio; KM, Kaplan-Meier; MRA, mineralocorticoid receptor antagonist.

Safety Outcomes of Dapagliflozin

The safety profile for serious adverse events, symptoms of volume depletion, acute kidney injury, and incident hyperkalemia (potassium >6.0 mEq/L) with dapagliflozin vs placebo did not differ, without effect modification between patients with and without the use of CV medications at baseline (P > .05 for each interaction) (Figure 3 and eTable 5 in Supplement 2). Notably, there was a tendency toward an interaction between treatment groups and MRA use for incident hyperkalemia (P = .10 for interaction). Specifically, dapagliflozin appeared to be potentially effective at reducing the risk of hyperkalemia in patients with MRA use at baseline compared with those without. Other safety outcomes of dapagliflozin vs placebo are shown in eTable 5 in Supplement 2.

Figure 3. — ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; Dapa, dapagliflozin; HR, hazard ratio; MRA, mineralocorticoid receptor antagonist; PBO, placebo.

Discussion

In these analyses from the DECLARE-TIMI 58 trial, dapagliflozin reduced systolic blood pressure and slowed the decline in eGFR to a similar degree regardless of concurrent CV therapy. Dapagliflozin consistently reduced the risk of CV death/HHF, HHF alone, and a kidney-specific composite outcome regardless of background use of CV medications, including ACEI/ARBs, β-blockers, diuretics, and MRAs. Even in patients receiving ACEI/ARBs + β-blockers + diuretics, dapagliflozin reduced the risk of CV death/HHF and of the kidney-specific outcome by 24% and 38%, respectively. There were no significant treatment interactions by the concomitant CV medications for adverse events, including symptoms of volume depletion, acute kidney injury, and hyperkalemia.

While results from randomized clinical trials in patients with HFrEF, with or without diabetes, revealed the benefits of SGLT2 inhibitors without prohibitive safety concerns with prevalent baseline use of medications used to treat HF,^14,15,16,17 efficacy and safety data from trials of a broader population of patients with type 2 diabetes with regard to interactions with common CV mediations are sparse. In the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) and the CANVAS Program (Canagliflozin Cardiovascular Assessment Study), subgroup analyses according to background CV medications reported the effect on their primary outcome, MACE (CV death, nonfatal myocardial infarction, or nonfatal stroke), that generally did not differ in patients with and without the use of these medications but did not report results on CV death/HHF, HHF alone, or kidney outcomes.^1,3 In the CANVAS Program, the efficacy of canagliflozin on MACE was only different between patients with and without diuretic use at baseline.¹ In the VERTIS CV trial (Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes), subgroup analyses of CV death/HHF outcomes by background use of CV medications were reported, although ertugliflozin did not reduce the risk for CV death/HHF in the overall trial population, and therefore, the evaluation of treatment interactions is not reliable.⁴ The present analyses dedicated to examining the effect of dapagliflozin on HF and kidney outcomes and its safety with the concurrent use of CV medications may help inform clinical practice.

Renin-angiotensin-aldosterone system (RAAS) inhibitors, including ACEIs, ARBs, and MRAs, are among the most widely used classes of antihypertensive medications with a robust effect on major CV events, kidney disease progression, and mortality outcomes.¹⁸ Previous studies have shown that ACEI/ARBs combined with diuretics may increase the risk of acute kidney injury.¹⁹ The present findings reveal that dapagliflozin reduced the risk of acute kidney injury overall in patients with type 2 diabetes, and the reduction was also consistent irrespective of background use of CV medications, including RAAS inhibitors and diuretics.

Because SGLT2 reabsorbs sodium in addition to glucose in the proximal renal tubule, SGLT2 inhibition leads to natriuresis, as well as an increase in urinary glucose and accompanying water excretion.²⁰ Consequently, SGLT2 inhibitors have a diuretic action and antihypertensive effects, raising concern that this could be deleterious with concomitant use of diuretics. However, in a subanalysis from the DAPA-HF trial (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), the benefits, tolerability, and safety of dapagliflozin did not differ regardless of background diuretic therapy and across the range of background doses of diuretics used in patients with HFrEF, although diuretic dose did not differ between the dapagliflozin and placebo groups after randomization.¹⁶ The present findings also suggest that dapagliflozin was similarly effective on CV outcomes in patients with type 2 diabetes who were and who were not treated with diuretic therapy. However, the beneficial effect of dapagliflozin on the kidney-specific composite outcome seems to be relatively greater in the subgroup of patients not taking any diuretics (P = .003 for interaction). Although this could be a chance finding and should be interpreted with caution, it could be related to the patient population prescribed diuretics or might be associated with the potential kidney protective mechanisms of SGLT2 inhibitors.

Limitations

There are limitations to these analyses. First, the trial was not powered to detect event reductions in individual subgroups based on the background use of CV medications and treatment × subgroup interactions between the subgroups. Second, because we did not record the dose of each medication, we could not examine the treatment interaction across a range of doses and change in dosage during the trial. Third, because this was not a heart failure trial, only a small number of patients were taking MRAs at baseline, and none were taking sacubitril/valsartan, precluding meaningful analyses of these subgroups. Fourth, although differences in baseline characteristics influence the use of CV medications, we used baseline medications at study entry and compared randomized treatments so we would not anticipate any bias. While it is possible that use of these medications could alias for other clinical characteristics, this would also be true in clinical practice. Furthermore, we were not able to explore a causal relationship between dapagliflozin-mediated changes in CV medications and clinical outcomes. However, use of CV medications remained quite consistent in both randomized groups over the first year.

Conclusions

Dapagliflozin consistently reduced the risk of CV death/HHF and progression of kidney disease irrespective of the baseline concurrent use of various CV medications commonly used for HF and kidney disease in patients with type 2 diabetes, with significant reductions in the risk of both even in patients receiving ACEI/ARBs, β-blockers, and diuretics. The safety profile of dapagliflozin was consistent in patients regardless of their use of these medications. These data support efforts to develop and implement strategies to optimize the use of SGLT2 inhibitors in a broad range of patients with type 2 diabetes regardless of background therapy.

Supplement 1.

Trial protocol

Click here for additional data file.^{(2MB, pdf)}

Supplement 2.

eTable 1. Baseline Characteristics of Patients by Treatment Groups and Use of Cardiovascular Medications

eTable 2. Baseline Characteristics of Patients by Treatment Groups and Use of Cardiovascular Medications

eTable 3. Numbers and Proportions of Patients on Cardiovascular Medications at 12 Months by Treatment Arms

eTable 4. Change in Body Weight, HbA1c, and Diastolic Blood Pressure During 48 Months Between Treatment Arms by Baseline Use of Cardiovascular Medications

eTable 5. Safety Endpoints by Baseline Use of Cardiovascular Medications

eFigure 1. Consort Diagram

eFigure 2. Effect of Dapagliflozin on Cardiovascular Death by Baseline Use of Cardiovascular Medications

eFigure 3. Effect of Dapagliflozin by Baseline Use of Cardiovascular Medications in Patients with Heart Failure With Reduced Ejection Fraction

eFigure 4. Effect of Dapagliflozin by Baseline Use of Cardiovascular Medications in Patients with Heart Failure without Known Reduced Ejection Fraction

eFigure 5. Effect of Dapagliflozin by Baseline Use of Cardiovascular Medications in Patients with No History of Heart Failure

Click here for additional data file.^{(1.1MB, pdf)}

Supplement 3.

Data sharing statement

Click here for additional data file.^{(11.6KB, pdf)}

References

1.Neal B, Perkovic V, Mahaffey KW, et al. ; CANVAS Program Collaborative Group . Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657. doi: 10.1056/NEJMoa1611925 [DOI] [PubMed] [Google Scholar]
2.Wiviott SD, Raz I, Bonaca MP, et al. ; DECLARE–TIMI 58 Investigators . Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347-357. doi: 10.1056/NEJMoa1812389 [DOI] [PubMed] [Google Scholar]
3.Zinman B, Wanner C, Lachin JM, et al. ; EMPA-REG OUTCOME Investigators . Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi: 10.1056/NEJMoa1504720 [DOI] [PubMed] [Google Scholar]
4.Cannon CP, Pratley R, Dagogo-Jack S, et al. ; VERTIS CV Investigators . Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. 2020;383(15):1425-1435. doi: 10.1056/NEJMoa2004967 [DOI] [PubMed] [Google Scholar]
5.McGuire DK, Shih WJ, Cosentino F, et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. JAMA Cardiol. 2021;6(2):148-158. doi: 10.1001/jamacardio.2020.4511 [DOI] [PMC free article] [PubMed] [Google Scholar]
6.Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. Circulation. 2019;140(11):e596-e646. doi: 10.1161/CIR.0000000000000678 [DOI] [PMC free article] [PubMed] [Google Scholar]
7.Maddox TM, Januzzi JL Jr, Allen LA, et al. ; Writing Committee . 2021 update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction, a report of the American College of Cardiology solution set oversight committee. J Am Coll Cardiol. 2021;77(6):772-810. doi: 10.1016/j.jacc.2020.11.022 [DOI] [PubMed] [Google Scholar]
8.Nathan DM, Bayless M, Cleary P, et al. ; DCCT/EDIC Research Group . Diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: advances and contributions. Diabetes. 2013;62(12):3976-3986. doi: 10.2337/db13-1093 [DOI] [PMC free article] [PubMed] [Google Scholar]
9.Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Hypertension. 2018;71(6):e13-e115. [DOI] [PubMed] [Google Scholar]
10.Raz I, Mosenzon O, Bonaca MP, et al. DECLARE-TIMI 58: participants’ baseline characteristics. Diabetes Obes Metab. 2018;20(5):1102-1110. doi: 10.1111/dom.13217 [DOI] [PubMed] [Google Scholar]
11.Wiviott SD, Raz I, Bonaca MP, et al. The design and rationale for the dapagliflozin effect on cardiovascular events (DECLARE)-TIMI 58 trial. Am Heart J. 2018;200:83-89. doi: 10.1016/j.ahj.2018.01.012 [DOI] [PubMed] [Google Scholar]
12.Zelniker TA, Bonaca MP, Furtado RHM, 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(15):1227-1234. doi: 10.1161/CIRCULATIONAHA.119.044183 [DOI] [PubMed] [Google Scholar]
13.Kato ET, Silverman MG, Mosenzon O, et al. Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus. Circulation. 2019;139(22):2528-2536. doi: 10.1161/CIRCULATIONAHA.119.040130 [DOI] [PubMed] [Google Scholar]
14.Docherty KF, Jhund PS, Inzucchi SE, et al. Effects of dapagliflozin in DAPA-HF according to background heart failure therapy. Eur Heart J. 2020;41(25):2379-2392. doi: 10.1093/eurheartj/ehaa183 [DOI] [PMC free article] [PubMed] [Google Scholar]
15.Ferreira JP, Zannad F, Pocock SJ, et al. Interplay of mineralocorticoid receptor antagonists and empagliflozin in heart failure: EMPEROR-Reduced. J Am Coll Cardiol. 2021;77(11):1397-1407. doi: 10.1016/j.jacc.2021.01.044 [DOI] [PubMed] [Google Scholar]
16.Jackson AM, Dewan P, Anand IS, et al. Dapagliflozin and diuretic use in patients with heart failure and reduced ejection fraction in DAPA-HF. Circulation. 2020;142(11):1040-1054. doi: 10.1161/CIRCULATIONAHA.120.047077 [DOI] [PMC free article] [PubMed] [Google Scholar]
17.Packer M, Anker SD, Butler J, et al. ; EMPEROR-Reduced Trial Committees and Investigators . Influence of neprilysin inhibition on the efficacy and safety of empagliflozin in patients with chronic heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial. Eur Heart J. 2021;42(6):671-680. doi: 10.1093/eurheartj/ehaa968 [DOI] [PMC free article] [PubMed] [Google Scholar]
18.Ettehad D, Emdin CA, Kiran A, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet. 2016;387(10022):957-967. doi: 10.1016/S0140-6736(15)01225-8 [DOI] [PubMed] [Google Scholar]
19.Chen Q, Zhu S, Liao J, He W. Study of acute kidney injury on 309 hypertensive inpatients with ACEI/ARB - diuretic treatment. J Natl Med Assoc. 2018;110(3):287-296. doi: 10.1016/j.jnma.2017.06.008 [DOI] [PubMed] [Google Scholar]
20.Sattar N, McLaren J, Kristensen SL, Preiss D, McMurray JJ. SGLT2 inhibition and cardiovascular events: why did EMPA-REG outcomes surprise and what were the likely mechanisms? Diabetologia. 2016;59(7):1333-1339. doi: 10.1007/s00125-016-3956-x [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

Trial protocol

Click here for additional data file.^{(2MB, pdf)}

Supplement 2.

eTable 1. Baseline Characteristics of Patients by Treatment Groups and Use of Cardiovascular Medications

eTable 2. Baseline Characteristics of Patients by Treatment Groups and Use of Cardiovascular Medications

eTable 3. Numbers and Proportions of Patients on Cardiovascular Medications at 12 Months by Treatment Arms

eTable 4. Change in Body Weight, HbA1c, and Diastolic Blood Pressure During 48 Months Between Treatment Arms by Baseline Use of Cardiovascular Medications

eTable 5. Safety Endpoints by Baseline Use of Cardiovascular Medications

eFigure 1. Consort Diagram

eFigure 2. Effect of Dapagliflozin on Cardiovascular Death by Baseline Use of Cardiovascular Medications

eFigure 3. Effect of Dapagliflozin by Baseline Use of Cardiovascular Medications in Patients with Heart Failure With Reduced Ejection Fraction

eFigure 4. Effect of Dapagliflozin by Baseline Use of Cardiovascular Medications in Patients with Heart Failure without Known Reduced Ejection Fraction

eFigure 5. Effect of Dapagliflozin by Baseline Use of Cardiovascular Medications in Patients with No History of Heart Failure

Click here for additional data file.^{(1.1MB, pdf)}

Supplement 3.

Data sharing statement

Click here for additional data file.^{(11.6KB, pdf)}

[hoi220035r1] 1.Neal B, Perkovic V, Mahaffey KW, et al. ; CANVAS Program Collaborative Group . Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657. doi: 10.1056/NEJMoa1611925 [DOI] [PubMed] [Google Scholar]

[hoi220035r2] 2.Wiviott SD, Raz I, Bonaca MP, et al. ; DECLARE–TIMI 58 Investigators . Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347-357. doi: 10.1056/NEJMoa1812389 [DOI] [PubMed] [Google Scholar]

[hoi220035r3] 3.Zinman B, Wanner C, Lachin JM, et al. ; EMPA-REG OUTCOME Investigators . Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi: 10.1056/NEJMoa1504720 [DOI] [PubMed] [Google Scholar]

[hoi220035r4] 4.Cannon CP, Pratley R, Dagogo-Jack S, et al. ; VERTIS CV Investigators . Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. 2020;383(15):1425-1435. doi: 10.1056/NEJMoa2004967 [DOI] [PubMed] [Google Scholar]

[hoi220035r5] 5.McGuire DK, Shih WJ, Cosentino F, et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. JAMA Cardiol. 2021;6(2):148-158. doi: 10.1001/jamacardio.2020.4511 [DOI] [PMC free article] [PubMed] [Google Scholar]

[hoi220035r6] 6.Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. Circulation. 2019;140(11):e596-e646. doi: 10.1161/CIR.0000000000000678 [DOI] [PMC free article] [PubMed] [Google Scholar]

[hoi220035r7] 7.Maddox TM, Januzzi JL Jr, Allen LA, et al. ; Writing Committee . 2021 update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction, a report of the American College of Cardiology solution set oversight committee. J Am Coll Cardiol. 2021;77(6):772-810. doi: 10.1016/j.jacc.2020.11.022 [DOI] [PubMed] [Google Scholar]

[hoi220035r8] 8.Nathan DM, Bayless M, Cleary P, et al. ; DCCT/EDIC Research Group . Diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: advances and contributions. Diabetes. 2013;62(12):3976-3986. doi: 10.2337/db13-1093 [DOI] [PMC free article] [PubMed] [Google Scholar]

[hoi220035r9] 9.Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Hypertension. 2018;71(6):e13-e115. [DOI] [PubMed] [Google Scholar]

[hoi220035r10] 10.Raz I, Mosenzon O, Bonaca MP, et al. DECLARE-TIMI 58: participants’ baseline characteristics. Diabetes Obes Metab. 2018;20(5):1102-1110. doi: 10.1111/dom.13217 [DOI] [PubMed] [Google Scholar]

[hoi220035r11] 11.Wiviott SD, Raz I, Bonaca MP, et al. The design and rationale for the dapagliflozin effect on cardiovascular events (DECLARE)-TIMI 58 trial. Am Heart J. 2018;200:83-89. doi: 10.1016/j.ahj.2018.01.012 [DOI] [PubMed] [Google Scholar]

[hoi220035r12] 12.Zelniker TA, Bonaca MP, Furtado RHM, 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(15):1227-1234. doi: 10.1161/CIRCULATIONAHA.119.044183 [DOI] [PubMed] [Google Scholar]

[hoi220035r13] 13.Kato ET, Silverman MG, Mosenzon O, et al. Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus. Circulation. 2019;139(22):2528-2536. doi: 10.1161/CIRCULATIONAHA.119.040130 [DOI] [PubMed] [Google Scholar]

[hoi220035r14] 14.Docherty KF, Jhund PS, Inzucchi SE, et al. Effects of dapagliflozin in DAPA-HF according to background heart failure therapy. Eur Heart J. 2020;41(25):2379-2392. doi: 10.1093/eurheartj/ehaa183 [DOI] [PMC free article] [PubMed] [Google Scholar]

[hoi220035r15] 15.Ferreira JP, Zannad F, Pocock SJ, et al. Interplay of mineralocorticoid receptor antagonists and empagliflozin in heart failure: EMPEROR-Reduced. J Am Coll Cardiol. 2021;77(11):1397-1407. doi: 10.1016/j.jacc.2021.01.044 [DOI] [PubMed] [Google Scholar]

[hoi220035r16] 16.Jackson AM, Dewan P, Anand IS, et al. Dapagliflozin and diuretic use in patients with heart failure and reduced ejection fraction in DAPA-HF. Circulation. 2020;142(11):1040-1054. doi: 10.1161/CIRCULATIONAHA.120.047077 [DOI] [PMC free article] [PubMed] [Google Scholar]

[hoi220035r17] 17.Packer M, Anker SD, Butler J, et al. ; EMPEROR-Reduced Trial Committees and Investigators . Influence of neprilysin inhibition on the efficacy and safety of empagliflozin in patients with chronic heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial. Eur Heart J. 2021;42(6):671-680. doi: 10.1093/eurheartj/ehaa968 [DOI] [PMC free article] [PubMed] [Google Scholar]

[hoi220035r18] 18.Ettehad D, Emdin CA, Kiran A, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet. 2016;387(10022):957-967. doi: 10.1016/S0140-6736(15)01225-8 [DOI] [PubMed] [Google Scholar]

[hoi220035r19] 19.Chen Q, Zhu S, Liao J, He W. Study of acute kidney injury on 309 hypertensive inpatients with ACEI/ARB - diuretic treatment. J Natl Med Assoc. 2018;110(3):287-296. doi: 10.1016/j.jnma.2017.06.008 [DOI] [PubMed] [Google Scholar]

[hoi220035r20] 20.Sattar N, McLaren J, Kristensen SL, Preiss D, McMurray JJ. SGLT2 inhibition and cardiovascular events: why did EMPA-REG outcomes surprise and what were the likely mechanisms? Diabetologia. 2016;59(7):1333-1339. doi: 10.1007/s00125-016-3956-x [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Efficacy and Safety of Dapagliflozin According to Background Use of Cardiovascular Medications in Patients With Type 2 Diabetes

Kazuma Oyama, MD, MPH, PhD

Itamar Raz, MD

Avivit Cahn, MD

Erica L Goodrich, MS

Deepak L Bhatt, MD, MPH

Lawrence A Leiter, MD

Darren K McGuire, MD, MHSc

John P H Wilding, MD

Ingrid A M Gause-Nilsson, MD, PhD

Ofri Mosenzon, MD, MSc

Marc S Sabatine, MD, MPH

Stephen D Wiviott, MD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Interventions

Main Outcomes and Measures

Results

Conclusions and Relevance

Trial Registration

Introduction

Methods

Study Design and Population

Efficacy and Safety Outcomes

Statistical Analyses

Results

Baseline Patient Characteristics

Table. Baseline Characteristics of Patients by Use of Cardiovascular Medications.

Effect of Dapagliflozin on Blood Pressure, Kidney Function, Body Weight, and HbA1c

Figure 1. Change in Systolic Blood Pressure and Estimated Glomerular Filtration Rate (eGFR) Over Time by Baseline Use of Cardiovascular Medications.

Effect of Dapagliflozin on Clinical Outcomes

Figure 2. Effects of Dapagliflozin by Baseline Use of Cardiovascular Medications on Cardiovascular (CV) Death or Hospitalization for Heart Failure (HHF), HHF Alone, and a Kidney-Specific Composite Outcome.

Safety Outcomes of Dapagliflozin

Figure 3. Safety End Points by Baseline Use of Cardiovascular Medications.

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases

Effect of Dapagliflozin on Blood Pressure, Kidney Function, Body Weight, and HbA_1c