Efficacy and Safety of Dapagliflozin by Baseline Insulin Regimen and Dose: Post Hoc Analyses From DECLARE-TIMI 58

Type 2 diabetes mellitus (T2DM) is a progressive disease, often requiring treatment intensification over time to achieve optimal glycemic control. The last two decades have witnessed the introduction of new classes of glucose-lowering agents (GLA) with established cardiovascular (CV) and renal benefits; yet, one-quarter of patients with T2DM are still treated with insulin in striving to optimize glycemic control (1). While treatment intensification with insulin may reflect differences in regional practices, it suggests clinical disease progression with decreased β-cell reserve. Although insulin use does not directly impact CV risk or overall mortality, it is associated with a less favorable cardiometabolic risk profile (2,3). Patients treated with insulin are often older, with multiple comorbidities, and are at greater risk for diabetes-related complications (4).

Sodium–glucose cotransporter 2 (SGLT2) inhibitors as a class have demonstrated multiple clinical benefits beyond their glucose-lowering effects including improved metabolic, CV, and renal effects (5–11). Furthermore, they lower blood glucose levels independent of β-cell function, are effective in any duration of disease, and carry minimal risk of hypoglycemia (12,13). Given these favorable effects, SGLT2 inhibitors are an attractive therapeutic option for patients with long-standing T2DM receiving intensive insulin therapy including short-acting (SA) insulin. In a phase 3 study, dapagliflozin improved glycemic control, stabilized insulin dosing, and reduced weight without increasing severe hypoglycemic episodes in patients with diabetes inadequately controlled on high doses of insulin (14,15). However, limited data exist regarding the CV and renal efficacy and safety of SGLT2 inhibitors in patients treated with intensive insulin regimens including SA insulin or exceptionally higher insulin doses.

In Dapagliflozin Effect on Cardiovascular Events trial (DECLARE-TIMI 58), the CV and renal outcomes of dapagliflozin were assessed versus placebo in a broad population of patients with T2DM (5). A reduction in the composite of CV death/hospitalization for heart failure (CVD/HHF) was observed, driven by a reduction in HHF, as well as a marked reduction in adverse renal outcomes (5). In post hoc analyses, these benefits were demonstrated independent of baseline HbA_1c or baseline GLA (16,17). In the overall study population, major adverse CV events (MACE) were balanced with dapagliflozin versus placebo, although a tendency toward lower rates of MACE with dapagliflozin versus placebo was observed in patients using insulin at baseline (HR 0.84 [95% CI 0.74–0.97], P = 0.02, in insulin users vs. 1.02 [0.89–1.18], P = 0.76, in noninsulin users; P_interaction = 0.06) (17). In the present analysis, we studied whether these observed benefits were maintained in patients treated with intensive insulin regimens including SA insulin and across varying weight-based doses.

In DECLARE-TIMI 58, a total of 17,160 patients, including 7,013 insulin users, with T2DM and established atherosclerotic CV disease or risk factors were randomly assigned to receive dapagliflozin or placebo in addition to standard of care and followed for a median of 4.2 years. All patients were treated according to guidelines and regional standards of care for CV risk factors, including blood pressure, LDL cholesterol, antithrombotic treatment, and HbA_1c. The trial protocol was approved by the institutional review board at each participating site, and all participants provided written informed consent. The design, baseline characteristics, and principal results of this study have previously been published (5,18,19). Insulin dose was reliably captured in 6,577 of the insulin users, and the total daily dose per kilogram was calculated at baseline for each patient. Patients were divided by insulin regimen into categories of those using any type of SA insulin (human, aspart, lispro, glulisine) alone, as part of a basal-bolus regimen, or in a fixed ratio combination versus those not using any form of SA insulin. Insulin use and specific regimens were at the discretion of the investigator in accordance with local standards.

All study outcomes reported are by intention to treat. The dual primary composite efficacy points were CVD/HHF and MACE, which included the composite of CVD, myocardial infarction (MI), or ischemic stroke. A secondary prespecified cardiorenal composite outcome was a sustained decrease of ≥40% in estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m², new end-stage renal disease, or death from renal or CV causes. A renal-specific composite outcome was similarly defined, yet excluded CVD.

Safety end points were assessed for all patients who received at least one dose of study drug. The reported safety outcomes were assessed on treatment, which included all events that occurred after the first dose of the study drug to the earlier of 30 (for serious adverse events) or 7 (for nonserious AEs) days after the last dose of the study drug or the closing visit. Acute kidney injury was identified based on the listing of this term according to the prespecified lists of Medical Dictionary for Regulatory Activities (MedDRA), version 21.0. Severe (major) hypoglycemia was defined as symptomatic events requiring external assistance due to severe impairment of consciousness with prompt recovery after glucose or glucagon administration. Diabetic ketoacidosis (DKA) events were adjudicated as definite or probable clinical events for which no alternative diagnosis was considered a more likely primary cause of presentation (20).

Baseline characteristics are reported as frequencies and percentages for categorical variables and as mean (SD) or median (interquartile range) for continuous variables by insulin dose and regimen groups. P values for categorical variables are calculated from the χ² test, and continuous variables are calculated from the Kruskal-Wallis test. Baseline and efficacy analyses were performed on an intention-to-treat basis. Safety assessments were performed in the safety analysis population (18).

The effect of dapagliflozin on the incidence of the outcomes within each insulin dose or regimen subgroup was calculated with Cox regression models that included the randomization stratification factor of baseline hematuria and the risk category (atherosclerotic CV disease or multiple risk factors), and we report the hazard ratios (HRs) and 95% CIs, as described in the design paper (18).

Mixed models for repeated measures in HbA_1c, weight, and systolic blood pressure were analyzed to produce least-squares mean estimates of the change in each treatment and baseline insulin dose and regimen group. Models included baseline values, hematuria status, risk category, treatment, visit, and the interaction of treatment and visit. We calculated the interaction of insulin category, metabolic outcome, and treatment allocation at 6 months as this is the earliest study time point after randomization.

The proportion of patients attaining the glycemic target of HbA_1c ≤7% or ≤8% with dapagliflozin versus placebo was calculated at each time point for each baseline insulin category, and the χ² test was used to compare between the treatment arms. A logistic regression model was used to calculate the interaction of insulin dose or type, treatment allocation, and attainment of glycemic target for each time point postbaseline.

There was no statistical adjustment for multiple comparisons. A P value <0.05 was considered statistically significant.

All analyses were performed with SAS software, version 9.4 (SAS Institute, Cary, NC).

The study included 7,013 insulin users at baseline, including 4,650 (66.3%) patients on insulin regimens including SA insulin and 2,363 (33.7%) on regimens without SA insulin. Baseline characteristics by insulin regimen and dose are shown in Table 1. As expected, multiple differences were noted in comparing patients using SA insulin with non-SA insulin users. SA insulin users had higher BMI and lower eGFR and longer diabetes duration compared with non-SA insulin users. A higher prevalence of established atherosclerotic CV disease, congestive heart failure, hypertension, and hyperlipidemia were noted in SA insulin users, as was increased use of antiplatelet therapy, β-blockers, statins, diuretics, and mineralocorticoid receptor agonists. SA insulin users were treated with fewer GLA compared with those not on SA insulin. With categorization according to total daily insulin dose, 2,443 (34.8%) patients were receiving <0.5 IU/kg, 2,795 (39.9%) 0.5 to ≤1 IU/kg, and 1,339 (19.1%) >1 IU/kg. Patients receiving higher weight-based insulin doses had increased BMIs, higher baseline HbA_1c, longer diabetes duration, and increased prevalence of established atherosclerotic CV disease, hypertension, and dyslipidemia. They were more often treated with antiplatelet therapy, β-blockers, ACE inhibitors/angiotensin receptor blockers, statins, diuretics, and mineralocorticoid receptor agonists and less commonly treated with oral GLA at baseline.

Dapagliflozin reduced the composite of CVD/HHF among overall insulin users (HR 0.82 [95% CI 0.69–0.97]). This reduction was consistent among patients using insulin regimens containing SA (0.83 [0.67–1.03]) and non-SA (0.78 [0.57–1.07]; P_interaction = 0.75) insulin (Fig. 1A). No heterogeneity was noted by insulin dose either (P_interaction = 0.43) (Fig. 1B). This efficacy was mainly driven by a lower rate of HHF with dapagliflozin versus placebo in SA and non-SA insulin users, with no heterogeneity between the groups (0.79 [0.60–1.04) and 0.66 [0.43–1.02] respectively; P_interaction = 0.49) (Fig. 1A). A consistent effect by insulin dose was noted as well (P_interaction = 0.16) (Fig. 1B).

The HR for MACE with dapagliflozin among insulin users was 0.84 [95% CI 0.74–0.97]. There was no heterogeneity by insulin regimen or dose on MACE (P_interaction > 0.05) (Fig. 1A and B). Data for the individual components of MACE (CVD, MI, ischemic stroke) were similar (P_interaction > 0.05) (Fig. 1A and B).

The cardiorenal outcome was reduced with dapagliflozin versus placebo in overall insulin users (HR 0.79 [95% CI 0.66–0.95]), with no heterogeneity between patients on regimens including SA insulin or not (0.86 [0.68–1.08] and 0.67 [0.48–0.93] respectively; P_interaction = 0.23) (Fig. 1A). This reduction was similar across the range of insulin doses (P_interaction = 0.97) (Fig. 1B). Dapagliflozin reduced the prespecified renal-specific outcome in insulin users overall compared with placebo (0.57 [0.42–0.77]), with a particularly large effect in patients not using SA insulin (P_interaction = 0.03) (Fig. 1A). The effects were consistent across the weight-based insulin doses (P_interaction = 0.09) (Fig. 1B).

A greater decline in HbA_1c, weight, and systolic blood pressure with dapagliflozin versus placebo was noted throughout the entire trial, regardless of insulin dose or regimen (Supplementary Tables 1–6). A greater proportion of patients randomized to dapagliflozin versus placebo attained the HbA_1c targets of ≤7.0% or ≤8.0%, irrespective of insulin regimen or dose (Fig. 2A–D). This effect was maintained at years 1, 2, and 3 in all subgroups, yet was somewhat attenuated at year 4, particularly in the SA insulin group. There was no interaction of attainment of target HbA_1c ≤7%, treatment allocation, or insulin regimen or dose at any time point during the study (P_interaction > 0.05). Target HbA_1c ≤8% was more likely attained with dapagliflozin versus placebo in patients on insulin regimens excluding SA insulin at months 6, 12, and 48 (P_interaction = 0.01, 0.02, and 0.04, respectively), yet there was no heterogeneity by regimen at other time points or by insulin dose throughout the trial (P_interaction > 0.05).

Among insulin users, severe hypoglycemia was reduced with dapagliflozin in non-SA insulin users (HR 0.20 [95% CI 0.06–0.70]), yet not in SA insulin users (0.86 [0.57–1.30]; P_interaction = 0.03. No heterogeneity was noted in the effect of dapagliflozin versus placebo on severe hypoglycemia by baseline insulin dose (Fig. 3).

In overall insulin users, DKA was observed in 0.6% of patients with dapagliflozin vs. 0.3% on placebo (HR 1.52 [95% CI 0.74–3.11]) (Fig. 3). The vast majority of DKA events occurred in patients with baseline use of SA insulin, 19 vs. 9 with dapagliflozin vs. placebo, compared with 1 vs. 3 with dapagliflozin vs. placebo in those using insulin regimens that did not include SA insulin.

Acute kidney injury was reduced with dapagliflozin among insulin users (HR [95% CI 0.66 [0.49–0.89]), with a consistent effect across insulin regimens and some heterogeneity across doses (Supplementary Fig. 1). Events consistent with volume depletion were balanced with dapagliflozin versus placebo overall and across categories of insulin users. Urinary tract infections were not increased with dapagliflozin versus placebo in any insulin subgroup. Genital infections were increased with no heterogeneity by insulin dose or regimen (Supplementary Fig. 1).

In the present analyses of DECLARE-TIMI 58, treatment with dapagliflozin versus placebo demonstrated overall consistent CV, renal, and metabolic benefits, as well as safety, in patients with T2DM irrespective of baseline insulin regimen or dose. The outcomes of patients on intensive insulin regimens including SA insulin or high insulin doses randomized to dapagliflozin versus placebo were in line with those of the overall study population.

Limited data exist regarding cardiorenal outcomes in patients treated with SGLT2 inhibitors in combination with insulin therapy. In a post hoc analysis of the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial investigators reported a consistent reduction of cardiorenal outcomes with empagliflozin in 2,252 patients treated with insulin at baseline (P_interaction > 0.05) (21). Analyses based on insulin regimen or dose were not reported. Metabolic efficacy of SGLT2 inhibitors in combination with insulin was demonstrated in a meta-analysis of nine randomized controlled trials including 3,069 patients, with a significant reduction in HbA_1c and weight independent of insulin dose, without an increased risk of hypoglycemia (22).

In our study, 7,013 patients were using insulin at baseline, with approximately two-thirds on intensive insulin regimens including SA insulin and one-third on basal long- or intermediate-acting insulin only. Patients using SA insulin had higher prevalence of long-standing diabetes (median duration 15 years), CV disease, congestive heart failure, and chronic kidney disease compared with non-SA insulin users. Nevertheless, the reductions in CVD/HHF, MACE, and adverse renal outcomes with dapagliflozin in this cohort were similar to those in overall insulin users. Despite increased prevalence of CV risk factors at baseline, patients treated with higher weight-based insulin doses experienced consistent cardiorenal benefits with dapagliflozin.

Dapagliflozin led to significant improvements in metabolic parameters compared with placebo. A greater decline in HbA_1c and weight was observed, and a significantly higher proportion of patients achieved target HbA_1c levels with dapagliflozin. These benefits were observed irrespective of insulin regimen or dose. Although patients treated with higher insulin doses had increased HbA_1c at baseline, the addition of dapagliflozin resulted in greater achievement of glycemic targets compared with placebo, similar to in those treated with lower insulin doses. Notably, the eGFR was >81 mL/min per 1.73 m² in all subgroups, enabling good glycemic efficacy of dapagliflozin.

Dapagliflozin was well tolerated when used in combination with insulin therapy, with no increase in adverse events compared with noninsulin users. These findings are in line with previous randomized controlled trials examining the safety of SGLT2 inhibitors in combination with insulin (21,23,24). Severe hypoglycemia was decreased with dapagliflozin versus placebo regardless of insulin dose. A particularly marked reduction was observed in patients using insulin regimens that did not include SA insulin at baseline. These findings may help provide reassurance to clinicians initiating SGLT2 inhibitors in patients treated with insulin, as fear of hypoglycemia is a major barrier to achieving glycemic targets. While DKA in the overall study population was relatively uncommon, it was more frequent with dapagliflozin versus placebo. In overall insulin users, although rare, the absolute number of events was increased with dapagliflozin, particularly in patients using SA insulin. As intensive insulin therapy including SA insulin is associated with long-standing diabetes and decreased β-cell reserve, the addition of dapagliflozin to regimens including SA insulin mandates more experience in insulin dose titration to prevent hypoglycemia and DKA.

Some limitations of our study should be noted. The association of baseline insulin use with CV and renal outcomes is post hoc and, thus, should be viewed as hypothesis generating. Second, only baseline insulin regimen and dose were considered in these analyses, and we did not account for the impact of changes in treatment regimen or dose over time on outcomes. Finally, the number of events was small in some of the subgroups, and no correction for multiplicity was performed.

In conclusion, our results in DECLARE-TIMI 58 suggest that the use of dapagliflozin in patients with T2DM managed with insulin, including intensive insulin regimens, provided significant CV and renal benefits. Adverse events associated with dapagliflozin, including hypoglycemia and DKA, were rare in this high-risk population.

Funding and Duality of Interest. The sponsor of DECLARE-TIMI 58 was initially AstraZeneca and Bristol-Myers Squibb, and AstraZeneca later became the sole sponsor of the study. DECLARE-TIMI 58 was a collaboration between the funder and two academic research organizations (TIMI Study Group and Hadassah Medical Organization). The funder was involved in the study design, data collection, data analysis and interpretation, and writing of this manuscript. I.A.M.G.-N. and A.M.L. are employed by the study funder. R.P. reports personal fees from Eli Lilly, Novo Nordisk, Sanofi, Boehringer Ingelheim, AstraZeneca, and Merck Sharp & Dohme. I.R. reports personal fees from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Concenter BioPharma and Silkim, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, Orgenesis, Pfizer, Sanofi, SmartZyme Innovation, Panaxia, FuturRx, InsuLine Medical, Medial EarlySign, CameraEyes, Exscopia, Dermal Biomics, Johnson & Johnson, Novartis, Teva, GlucoMe, and DarioHealth. S.D.W. discloses grants from Amgen, AstraZeneca, Daiichi Sankyo, Eisai, Janssen, Merck, and Pfizer and consulting fees from AstraZeneca, Boston Clinical Research Institute, Icon Clinical, and Novo Nordisk. The spouse of S.D.W., Dr. Caroline Fox, is an employee of Merck. S.D.W. is a member of the TIMI Study Group, which has received 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 Therapeutics, Ionis Pharmaceuticals, Janssen Research and Development, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Roche, and Siemens Healthcare Diagnostics. S.A.M. and E.L.G. report grants from AstraZeneca, during the conduct of the study, and are members of the TIMI Study Group. O.M. reports grants and personal fees from AstraZeneca, Bristol-Myers Squibb, and Novo Nordisk and personal fees from Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, Johnson & Johnson, and Novartis. D.L.B. discloses the following relationships: advisory board, AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; board of directors, AngioWave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, and TobeSoft; Inaugural Chair, American Heart Association Quality Oversight Committee; data monitoring committees, Acesion Pharma, Assistance Publique–Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute) (for the Portopulmonary Hypertension Treatment wIth Macitentan - a Randomized Clinical Trial [PORTICO trial], funded by St. Jude Medical, now Abbott), Boston Scientific (chair, Pulmonary Embolism Thrombolysis [PEITHO] trial), Cleveland Clinic (including for CENTERA THV System in Intermediate Risk Patients Who Have Symptomatic, Severe, Calcific, Aortic Stenosis Requiring Aortic Valve Replacement [ExCEED trial], funded by Edwards), Contego Medical (chair, Protection Against Emboli During Carotid Artery Stenting Using the Neuroguard IEP System [PERFORMANCE II]), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for Edoxaban Compared to Standard Care After Heart Valve Replacement [ENVISAGE trial], funded by Daiichi Sankyo, and for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute, and Rutgers University (for the National Institutes of Health–funded Myocardial Ischemia and Transfusion [MINT] trial); honoraria, American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org, Chair, ACC Accreditation Oversight Committee), Arnold & Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute) (Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention [RE-DUAL PCI trial] steering committee funded by Boehringer Ingelheim, ApoA-I Event reducinG in Ischemic Syndromes II [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 A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease [PRONOUNCE], 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 Cardiovascular Outcomes for People Using Anticoagulation Strategies [COMPASS] operations committee, publications committee, steering committee, and U.S. 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, Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), and VA CART Research and Publications Committee (Chair); patent, Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women’s Hospital who assigned to Lexicon; neither D.L.B. nor Brigham and Women’s Hospital receive any income from this patent); research funding, Abbott, Acesion Pharma, Afimmune, Aker BioMarine, Amarin, Amgen, AstraZeneca, Bayer, Beren Therapeutics, 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, Elsevier (Editor, Braunwald’s Heart Disease); site co-investigator, Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, Svelte, and Vascular Solutions; trustee, American College of Cardiology; and unfunded research, FLOWCO and Takeda. L.A.L. reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Lexicon, Merck, Novo Nordisk, Pfizer, Sanofi, and Servier. D.K.M. discloses the following relationships: personal fees for clinical trial leadership from GlaxoSmithKline, Janssen, Lexicon, AstraZeneca, Sanofi, Boehringer Ingelheim, Merck & Co, Pfizer, Novo Nordisk, Eisai, Esperion, and Lilly USA and personal fees for consultancy from AstraZeneca, Lilly USA, Boehringer Ingelheim, Merck & Co, Novo Nordisk, Metavant, Applied Therapeutics, Sanofi, and Afimmune. J.P.H.W., outside the submitted work, has grants, personal fees for lectures, and consultancy fees (paid to his institution) from AstraZeneca and Novo Nordisk; personal fees for lectures and consultancy fees (paid to his institution) from Boehringer Ingelheim, Janssen, Lilly, Mundipharma, Napp, Sanofi, and Takeda; and consultancy fees (paid to his institution) from Pfizer, Rhythm Pharmaceuticals, Saniona, Wilmington Healthcare, and Ysopia. M.S.S. reports research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Daiichi-Sankyo, Eisai, Intarcia, Ionis, Merck, Novartis, and Pfizer and consulting for Althera, Amgen, Anthos Therapeutics, AstraZeneca, Beren Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Fibrogen, Intarcia, Merck, Moderna, Novo Nordisk, and Silence Therapeutics. Additionally, M.S.S. is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women’s Hospital from ARCA Biopharma, Inc.; Janssen Research and Development, LLC; Pfizer; Regeneron Pharmaceuticals, Inc.; Roche; Siemens Healthcare Diagnostics, Inc.; Softcell Medical Limited; and Zora Biosciences. A.C. reports grants and personal fees from AstraZeneca and Novo Nordisk and personal fees from Eli Lilly, Sanofi, Boehringer Ingelheim, Pfizer, and Medial EarlySign. No other potential conflicts of interest relevant to this article were reported.

Data analyses were done by the academic TIMI Study Group, which has access to the complete study database, allowing independent analyses of the results; any discrepancies were resolved by discussion. The DECLARE-TIMI 58 publication committee made the decision to submit for publication.

Author Contributions. R.P., I.R., S.D.W., A.M.L., I.A.M.G.-N., M.S.S., and A.C. contributed to the study design. R.P., I.R., S.D.W., A.M.L., I.A.M.G.-N., M.S.S., and A.C. performed the literature search. R.P., I.R., S.D.W., E.L.G., S.A.M., I.Y., A.R., A.M.L., I.A.M.G.-N., M.S.S., and A.C. designed the figures. R.P., I.R., S.D.W., A.M.L., I.A.M.G.-N., M.S.S., and A.C. contributed to data collection, and R.P., I.R., S.D.W., E.L.G., S.A.M., I.Y., A.R., O.M., A.M.L., I.A.M.G.-N., D.L.B., L.A.L., D.K.M., J.P.H.W., M.S.S., and A.C. contributed to data analysis. R.P., I.R., S.D.W., E.L.G., S.A.M., I.Y., A.R., O.M., A.M.L., I.A.M.G.-N., D.L.B., L.A.L., D.K.M., J.P.H.W., M.S.S., and A.C. contributed to data interpretation. R.P., I.R., S.D.W., E.L.G., S.A.M., I.Y., A.R., O.M., A.M.L., I.A.M.G.-N., D.L.B., L.A.L., D.K.M., J.P.H.W., M.S.S., and A.C. contributed to the writing of the manuscript and approved the final submitted version. R.P. and A.C. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.