Diabetes Care 1

fi Avivit Cahn,1 Ofri Mosenzon,1 Ef cacy and Safety of Stephen D. Wiviott,2 Aliza Rozenberg,1 fl Ilan Yanuv,1 Erica L. Goodrich,2 Dapagli ozin in the Elderly: Sabina A. Murphy,2 Deepak L. Bhatt,2 – Lawrence A. Leiter,3 Darren K. McGuire,4 Analysis From the DECLARE John P.H. Wilding,5 Ingrid A.M. Gause-Nilsson,6 TIMI 58 Study Martin Fredriksson,6 Peter A. Johansson,6 6 2 https://doi.org/10.2337/dc19-1476 Anna Maria Langkilde, Marc S. Sabatine, and Itamar Raz1

OBJECTIVE Data regarding the effects of sodium–glucose cotransporter 2 inhibitors in the elderly (age ‡65 years) and very elderly (age ‡75 years) are limited.

RESEARCH DESIGN AND METHODS The Dapagliflozin Effect on Cardiovascular Events (DECLARE)–TIMI 58 assessed cardiac and renal outcomes of dapagliflozin versus placebo in patients with type 2 diabetes. Efficacy and safety outcomes were studied within age subgroups for treatment effect and age-based treatment interaction. 1Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, He- RESULTS brew University of Jerusalem, The Faculty of

< ‡ < Medicine, Jerusalem, Israel RISK METABOLIC AND CARDIOVASCULAR Of the 17,160 patients, 9,253 were 65 years of age, 6,811 65 to 75 years, and 2 ‡ fl TIMI Study Group, Division of Cardiovascular 1,096 75 years. Dapagli ozin reduced the composite of cardiovascular death or Medicine, Brigham and Women’s Hospital and hospitalization for heart failure consistently, with a hazard ratio (HR) of 0.88 (95% CI Harvard Medical School, Boston, MA 0.72, 1.07), 0.77 (0.63, 0.94), and 0.94 (0.65, 1.36) in age-groups <65, ‡65 to <75, 3Li Ka Shing Knowledge Institute, St. Michael’s ‡ P fl Hospital, University of Toronto, Toronto, Canada and 75 years, respectively (interaction value 0.5277). Overall, dapagli ozin did 4 fi University of Texas Southwestern Medical Cen- not signi cantly decrease the rates of major adverse cardiovascular events, with HR ter, Dallas, TX 0.93(95% CI 0.81,1.08), 0.97 (0.83,1.13), and 0.84 (0.61, 1.15) inage-groups <65,‡65 5Institute of Ageing and Chronic Disease, Uni- to <75, and ‡75 years, respectively (interaction P value 0.7352). The relative risk versity of Liverpool, Liverpool, U.K. 6 reduction for the secondary prespecified cardiorenal composite outcome ranged AstraZeneca, Molndal,¨ Sweden from 18% to 28% in the different age-groups with no heterogeneity. Major Corresponding author: Avivit Cahn, avivit@ hadassah.org.il hypoglycemia was less frequent with dapagliflozin versus placebo, with HR 0.97 (95% < ‡ < Received 26 July 2019 and accepted 17 November CI 0.58, 1.64), 0.50 (0.29, 0.84), and 0.68 (0.29, 1.57) in age-groups 65, 65 to 75, 2019 and ‡75 years, respectively (interaction P value 0.2107). Safety outcomes, including Clinical trial reg. no. NCT01730534, clinicaltrials fractures, volume depletion, cancer, urinary tract infections, and amputations were .gov. balanced with dapagliflozin versus placebo, and acute kidney injury was reduced, all This article contains Supplementary Data online regardless of age. Genital infections that were serious or led to discontinuation of the at http://care.diabetesjournals.org/lookup/suppl/ study drug and diabetic ketoacidosis were uncommon, yet more frequent with doi:10.2337/dc19-1476/-/DC1. dapagliflozin versus placebo, without heterogeneity (interaction P values 0.1058 and © 2019 by the American Diabetes Association. 0.8433, respectively). Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More infor- CONCLUSIONS mation is available at http://www.diabetesjournals The overall efficacy and safety of dapagliflozin are consistent regardless of age. .org/content/license. Diabetes Care Publish Ahead of Print, published online December 16, 2019 2Efficacy and Safety of Dapagliflozin in Elderly Diabetes Care

Type 2 diabetes mellitus (T2DM) is a that ascertained the CV and renal effects serious adverse events [SAEs]) or 7 (for prevalent disorder in the elderly, with of dapagliflozin on a large patient pop- nonserious AEs) days after the last dose of approximately one-quarter of people ulationbothwithandwithoutestablished the study drug or the closing visit. Major age .65 years with diabetes and an cardiovascular disease, including a large hypoglycemia was defined as symptomatic expected increase in rates of diabetes cohort of elderly and very elderly pa- events requiring external assistance due to in the upcoming years (1). Diabetes care tients (4). In the present analysis, we the severe impairment of consciousness in the elderly is challenging due to high studied the efficacy and safety of dapa- with prompt recovery after glucose or rates of concomitant comorbidities, func- gliflozin stratified by age. glucagon administration. The urinary tional disability, frailty, cognitive impair- tract and genital infections collected were ment,and polypharmacy. The complexity RESEARCH DESIGN AND METHODS only those that were either serious or led of treatment, side effects, and drug inter- Study Overview to the discontinuation of the study drug. actions are important considerations when In the DECLARE–TIMI 58 trial, a total of choosing the appropriate glucose-lowering 17,160 patients, including 7,907 age $65 Statistical Analysis pharmacotherapy for older patients with years and 1,096 age $75 years, with T2DM Prespecified age-groups were ,65, $65 diabetes (1,2). However, data regarding andestablishedatheroscleroticcardiovas- and ,75, and $75 years. The data pre- the efficacy and safety of glucose-lowering cular disease or risk factors, 41% and 59%, sented in the main article are for three agents are often lacking, particularly in respectively, were randomly assigned to age-groups (,65, $65 to ,75, and $75 the very elderly, age $75 years. The receive dapagliflozin or placebo in addi- years) to enable the description of data U.S. Food and Drug Administration as tiontostandardofcareandfollowedfora fromallagesubgroups,including65to,75 well as the European Medicines Agency median period of 4.2 years. The study years, which comprised 39.7% of the recommended collecting comprehen- enrolled patients at least 40 years old, study population. Efficacy and safety data limited to the prespecified age- sive data especially in very elderly with HbA1c 6.5%212.0% and creatinine patients with diabetes to enable ap- clearance $60 mL/min. Patients who re- groups are included in the Supplementary propriate assessment of their drug mained eligible after a 4–8-week placebo Material. responses (2,3). run-in period were randomized in a 1:1 Baseline characteristics are reported Sodium–glucose cotransporter 2 (SGLT2) double-blind fashion to dapagliflozin 10 mg as frequencies and percentages for cat- inhibitors have been available for the daily or matched placebo. All patients were egorical variables and as median and in- treatment of diabetes since 2012. Mul- to be treated according to regional stand- terquartile range (IQR) for continuous tiple clinical benefits beyond glucose ards of care for CV risk factors: blood variables. Incidence rates and log-rank test lowering have been established with pressure, lipids, antithrombotic treat- for trend P values in efficacy and safety end points are reported for the three age- this drug class. These include reduced ment, and HbA1c. The design, baseline hospitalizations for heart failure, renal characteristics, and principal results of groups. protection, and improvements in weight this study have been published (4,11,12). Analyses were performed on an intention- and blood pressure (4–8). Furthermore, to-treat basis. Hazard ratios (HRs) and 95% the drugs are taken orally and at any time Assessment of Outcomes CIs were determined from Cox regression of the day and have no known significant The dual primary composite efficacy end models with stratification factor (athero- drug interactions (8). Considering their points were CV death or hospitalization sclerotic cardiovascular disease or multiple multiple favorable effects, minimal in- for heart failure (CVD/HHF) and major CV risk factors and hematuria status) as cremental risk for hypoglycemia, and adverse cardiovascular events (MACE; strata in models comparing treatment in simplicity of administration, they appear the composite of CV death, MI, or ische- age-groups. to be an attractive therapeutic option for mic stroke). A secondary prespecified Mixedmodelsforrepeatedmeasuresin older adults addressing the many comor- cardiorenal composite outcome was a HbA1c, weight, systolic blood pressure, and bidities more prevalent in this popula- sustained decrease of 40% or more in diastolic blood pressure were analyzed to tion. Nevertheless, there has been some estimated glomerular filtration rate (eGFR) produce least squares mean estimates and hesitance in clinical practice prescribing to ,60 mL/min/1.73 m2, new end-stage 95% CIs in each treatment and age-group. these agents to the elderly, mostly due to renal disease (ESRD), or death from renal Attainment of glycemic and weight targets insufficient long-term safety data (1). or CV causes. A renal-specific composite was compared between groups using Older patients are more prone to the outcome included a 40% decrease in eGFR logistic regression models. P values for development of fractures and acute kid- to ,60 mL/min/1.73 m2, ESRD, or death the covariate of interest were adjusted ney injury (AKI), and safety alerts re- from renal cause. for baseline HbA1c or weight accordingly. garding these potential risks with some Safety end points were assessed in all There was no statistical adjustment for SGLT2 inhibitors have been issued (9). patients who received at least one dose of multiple comparisons. All analyses were Moreover, due to the limited therapeutic study drug (the safety population). For performed using SAS software, version experience in patients age 75 years and amputations, fractures, and malignancies, 9.4 (SAS Institute Inc., Cary, NC) and Stata older, initiation of SGLT2 inhibitor ther- events ocurring from first dose until the version 14.2 (College Station, TX). apy at this age has so far not been rec- endoftrialwereincludedintheanalyses. ommended by some authorities (10). The remaining safety outcomes were as- RESULTS The Dapagliflozin Effect on Cardiovas- sessed on treatment, which included all Baseline Characteristics cular Events (DECLARE)–TIMI 58 study events that occurred after the first dose of The study included 9,253 patients age ,65 is a cardiovascular (CV) outcome study the study drug to the earlier of 30 (for years, 6,811 patients age $65 to ,75 care.diabetesjournals.org Cahn and Associates 3

years, and 1,096 patients age $75 years. dapagliflozin for MACE was 0.93 (95% CI dichotomous age-groups showed similar Their baseline characteristics are shown 0.81, 1.08), 0.97 (0.83, 1.13), and 0.84 resultswithnoage-basedtreatment in Supplementary Table 1. Chronic kidney (0.61, 1.15) in age-groups ,65, $65 interactions (Supplementary Fig. 1). disease and history of heart failure were to ,75, and $75 years, respectively more prevalent with increasing age as (interaction P value 0.7352). Rates of Metabolic Outcomes fl was use of ACE inhibitors or angiotensin HHF were reduced with dapagli ozin, Changes in HbA1c,weight,andblood receptor blockers (ARBs), diuretics, loop with HR 0.88 (95% CI 0.68, 1.15), 0.60 pressure by age subgroups and treat- diuretics, and antiplatelet therapy. (0.46, 0.79), and 0.81 (0.50, 1.30), re- ment allocation are shown in Fig. 2. , $ , spectively, in age-groups 65, 65 to 75, Baseline HbA1c in the elderly and very Efficacy and $75 years (interaction Pvalue 0.1402). elderly was lower compared with the Overall incidence rates of the dual pri- The other components of the primary end younger population (median levels 8.2 mary composite efficacy end points and pointsaswellasall-causemortalitywere [IQR 7.5, 9.3], 7.9 [7.3, 8.7], and 7.8 [7.2, of their individual components were unchanged, with effects consistent across 8.5] in age-groups ,65, $65 to ,75, higher with increasing age. Incidence all age-groups (Fig. 1). and $75 years, respectively; P-trend rates of CVD/HHF were 10.9, 14.8, and The cardiorenal secondary composite ,0.0001). Nevertheless, significant and 26.7 (P , 0.0001) and those of MACE outcome (sustained decrease of 40% or similar declines in HbA1c with dapagli- were 20.9, 24.7, and 37.4 cases per 1,000 more in eGFR to ,60 mL/min/1.73 m2, flozin versus placebo were observed for person-years in age-groups ,65, $65 new ESRD, or death from renal or CV all age-groups (Fig. 2). At 1 year, least to ,75, and $75 years, respectively (P , causes) was reduced with dapagliflozin squares mean difference between the 0.0001). versus placebo, with HR 0.72 (95% CI treatment groups was 20.58 (95% CI 20.63, Dapagliflozin reduced the composite 0.59, 0.88), 0.80 (0.65, 0.98), and 0.82 20.53), 20.46 (20.51, 20.41), and 20.51 CVD/HHF consistently, with HR 0.88 (95% (0.52,1.29)inage-groups,65,$65to,75, (20.63, 20.40) in age-groups ,65, $65 CI 0.72, 1.07), 0.77 (0.63, 0.94), and 0.94 and $75 years, respectively (interaction P to ,75, and $75 years, respectively (all (0.65, 1.36) in age-groups ,65, $65 value 0.7299). Similar results were ob- P , 0.0001). At 1, 2, and 3 years, patients to ,75, and $75 years, respectively served for the renal-specific composite allocated to dapagliflozin versus placebo, (interaction P value 0.5277). The HR for outcome (Fig. 1). Efficacy end points by at all age subgroups, were statistically

Figure 1—Efficacy outcomes by age-groups. CVD, cardiovascular death. 4Efficacy and Safety of Dapagliflozin in Elderly Diabetes Care

Figure 2—Changes in metabolic parameters over time. Change in HbA1c (A), weight (B), systolic blood pressure (C), and diastolic blood pressure (D) with dapagliflozin vs. placebo according to age-group. Dapa, dapagliflozin.

more likely to attain an HbA1c of ,7.0% regardless of age, with HR 0.93 (95% CI age subgroups studied, with no hetero- (excluding age $75 years at year 3) 0.86, 1.00), 0.88 (0.81, 0.95), and 1.02 geneity. Events of volume depletion in or,8.0%ortoreducetheirHbA1c by $0.5% (0.85, 1.21) in age-groups ,65, $65 the overall safety study population in- (Fig. 3). The effect was somewhat atten- to ,75, and $75 years, respectively, creased with increasing age, with inci- uated at year 4, particularly in the very with no age-based treatment interac- dence rates of 5.6, 7.8, and 14.9 cases per elderly. tion (interaction P value 0.2667) (Fig. 1,000 person-years in age-groups ,65, Dapagliflozin yielded a greater reduc- 4). Moreover, no heterogeneity across $65 to ,75, and $75 years, respectively tion in weight versus placebo, and this age-groups was observed for any of the (P , 0.0001). Similarly, AKI was reported was maintained in all age-groups during outcomes assessed, although the num- overall at higher rates with increasing age, the entire study period (all P , 0.0001) ber of events in the very elderly was with incidence rates of 4.2, 5.4, and 9.3 (Fig. 2). Patients allocated to dapagliflo- often quite small, yielding wide CIs in cases per 1,000 person-years in age- zin versus placebo were more likely to this age category. groups ,65, $65 to ,75, and $75 attain a 5% weight loss at all age-groups, Major hypoglycemia events increased years, respectively (P 5 0.0001). Vol- which was sustained throughout the with increasing age in the overall safety ume depletion events were balanced study (Fig. 3). In the 4th year, a 5% population, with incidence rates of 1.7, between the dapagliflozin and placebo weight reduction was observed in 37.0% 2.6, and 6.5 cases per 1,000 person-years groups, and AKI events were overall vs. 23.2%, 40.5% vs. 24.6%, and 52.9% vs. in age-groups ,65, $65 to ,75, and $75 fewer with dapagliflozin versus placebo, 31.2% with dapagliflozin versus placebo years, respectively (P , 0.0001). Major withnoage-based treatmentinteraction. in age-groups ,65, $65 to ,75, and $75 hypoglycemia was less frequent with da- The amputation rate did not differ by age years, respectively (all P , 0.0001). pagliflozin versus placebo, with the effect (P 5 0.3201) and was balanced between more predominantly observed in the age- dapagliflozin and placebo, with no age- Safety group $65 vs. ,65 years (HR 0.53 [95% based treatment interaction. Diabetic ke- SAEs in the overall safety population CI 0.34, 0.83] vs. 0.97 [0.58, 1.64], re- toacidosis was rare, but more events were were more common in the elderly and spectively; interaction P value 0.0896) observed with dapagliflozin versus pla- very elderly compared with the younger (Supplementary Fig. 2). Overall fractures cebo, consistently across age-groups. patients, with incidence rates of 107.3, were more common in the elderly and Genital infections that led to the discon- 131.2, and 191.1 cases per 1,000 person- very elderly, with incidence rates of 11.2, tinuation of the study drug were more years in age-groups ,65, $65 to ,75, 15.8, and 17.4 cases per 1,000 person- common with dapagliflozin versus placebo, and $75 years, respectively (P , 0.0001). years in age-groups ,65, $65 to ,75, and there were two SAE genital infections The incidence of SAEs was lower with and $75 years, respectively (P , 0.0001), in each treatment arm, with no heteroge- dapagliflozin versus placebo overall in yet events were balanced between the neity. There was no statistically significant the trial, and this pattern was consistent dapagliflozin and placebo groups at all increase in urinary tract infections (serious care.diabetesjournals.org Cahn and Associates 5

Figure 3—Attainment of HbA1c and weight targets. Percentage of patients attaining HbA1c ,8(A), HbA1c ,7(B), reducing HbA1c by .0.5% (C), or reducing weight by .5% (D) with dapagliflozin vs. placebo by age-group. Black bars, dapagliflozin; white bars, placebo. *P , 0.0001; 1P , 0.05. or leading to drug discontinuation) with ARBs, b-blockers, anddiuretics. Although monitoring and adjustment of insulin dos- dapagliflozin versus placebo in the over- fewer events of MACE were observed in ing (1). Hypoglycemia should be particu- all population or in any of the age-groups. patients treated with dapagliflozin, it did larly avoided in older patients due to their Overall malignancies were balanced be- not result in a significant reduction in the greater risk of other major adverse out- tween treatment arms across all age- incidence of MACE. The study met its comes secondary to hypoglycemia, such groups (Fig. 4). primary safety noninferiority end point as falls or fractures (1). Patients ran- Safety end points by dichotomous age- for MACE across all studied age-groups. domized to dapagliflozin versus placebo groups revealed consistent results with SAEs, though generally more frequent in addition to standard of care attained no age-based treatment interaction for in older versus younger individuals, were superior glycemic control with lower rates any of the outcomes (Supplementary Fig. 2). not increased in the elderly or the very of hypoglycemia, irrespective of age, high- elderly with dapagliflozin versus placebo, lighting the benefit of the drug. CONCLUSIONS and there was no age-based treatment The greater morbidity of the elderly In this manuscript, we present analyses interaction for any of the safety outcomes and very elderly population in our study, of data from the DECLARE–TIMI 58 study assessed. Several adverse outcomes are as reflected by higher rates of baseline HF that establish the beneficial CV and renal of particular concern in older patients and chronic kidney disease, strengthens effects of dapagliflozin in a robust num- with diabetes. Events of volume deple- the clinical impact of our results, which ber of elderly and very elderly partici- tion increase with increasing age, and demonstrate consistent efficacy and safety pants. The overall pattern of efficacy and there is greater concern related to pos- of dapagliflozin extending across all age- safety of dapagliflozin was consistent sible adverse consequences of volume groups. regardless of age. depletion in older patients, including falls The paradigm of diabetes treatment Care of older patients with diabetes and kidney injury. In that respect, the has shifted from a glucose-focused ap- represents an ongoing challenge. Rates observed reduction in HHF and renal ben- proach to the pursuit of a therapeutic of HHF, CV disease, and MI are increased efit with dapagliflozin with no excess risk of regimen that will yield a reduction in in those age $65 years and are markedly volume depletion and fewer events of morbidity and mortality. This is particu- increased in patients with age $75 years. AKIisreassuring.Olderadultsareat larly true in the elderly, whose life ex- The robust reduction in HHF observed higher risk of hypoglycemia from both pectancy is shorter and for whom event with dapagliflozin is thus of great clinical insulin and sulfonylurea treatment as a rates are higher (13). Treatment goals for significance, particularly when viewed result of insulin deficiency, progressive T2DM in the elderly should be individ- in light of the fact that many of these renal insufficiency, and higher rates of ualized; thus, in healthy patients with patients were already treated with stan- cognitive deficits, which may cause diffi- good functional status, few comorbid- dard of care, including ACE inhibitors, culty in disease management, i.e., glucose ities, and intact cognitive function, goals 6Efficacy and Safety of Dapagliflozin in Elderly Diabetes Care

Figure 4—Safety outcomes by age-groups. DKA, diabetic ketoacidosis.

may be similar to those of younger adults. changes which are probably beneficial at age-group studied, and safety outcomes However, in patients with an intermediate all ages. of DPP-4 inhibitors were shown to be remaining life expectancy, targets should Few studies have been published to similar in older versus younger patients be less stringent as part of individualized date on the use of SGLT2 inhibitors in the (19,20). GLP-1 receptor agonists have care and a target HbA1c ,8.0% may be elderly. Arandomized, double-blind, age- also shown efficacy and safety in the acceptable (13). Dapagliflozin enabled stratified trial of dapagliflozin versus pla- elderly that are comparable to that of more patients to attain a clinically sig- cebo demonstrated a beneficial effect of younger patients, and post hoc analysis nificant HbA1c reduction, whether striving dapagliflozinonglucose,weight,andblood of the Liraglutide Effect and Action in for the standard or less stringent target. pressure across all age-groups studied, Diabetes: Evaluation of Cardiovascular Weight loss is generally not a treat- with no outstanding safety issues in the Outcome Results (LEADER) trial pro- ment goal in the very elderly population; elderly or very elderly, although not posed greater benefit in the elderly (21). nevertheless, in our analysis, we observed many very elderly patients were included Our study is the first to substantiate the sustained weight loss across all age- (15). Postmarketing reports from Japan efficacy and safety of an SGLT2 inhibitor groups. This did not appear to lead to any reported no age-related safety issues in the elderly and very elderly and may untoward effects in the elderly during with tofogliflozin, ipragliflozin, and can- pave the way for relaxing the warning the time frame of the study, although agliflozin, yet these studies are limited by placed on this drug in the geriatric pop- notably, median BMI was 31.1 and the lack of comparator and dependence ulation, although individualization of 30.2 kg/m2 at baseline in the elderly and upon physician reporting of AEs (16–18). therapy is pivotal, particularly in this very elderly patients in the study, re- The efficacy and safety of other glucose- vulnerable population. spectively. SGLT2 inhibitors have been lowering agents in the elderly have Some limitations of our study should shown to reduce adipose tissue mass been studied. Dipeptidyl peptidase 4 (DPP- be noted. Creatinine clearance ,60 mL/ while maintaining lean body mass (14), 4) inhibitors showed no CV benefit in any min was an exclusion criterion in the care.diabetesjournals.org Cahn and Associates 7

study, and this may have led to exclusion Novartis, Pfizer, Poxel, Quark Pharmaceut- personal fees for lectures, and consultancy fees of the frailer elderly patients, which are icals, Roche, Takeda, and Zora Biosciences. (paid to his institution) from AstraZeneca and fi more prone to volume depletion, AKI, D.L.B. is af liated with the following: (advisory Novo Nordisk; personal fees for lectures and board) Cardax, Cereno Scientific, Elsevier Prac- consultancy fees (paid to his institution) from fractures, and other adverse outcomes. tice Update Cardiology, Medscape Cardiology, Boehringer Ingelheim, Janssen, Lilly, Mundipharma, Moreover, there were no assessments of PhaseBio, and Regado Biosciences; (board of Napp, Sanofi, and Takeda; and consultancy cognitive function, functional capacity, directors) Boston VA Research Institute, Society fees (paid to his institution) from Wilmington or frailty at baseline or at any time during of Cardiovascular Patient Care, and TobeSoft; Healthcare. I.A.M.G.-N., M.F., P.A.J. and A.M.L. (chair) American Heart Association Quality Over- are employees of AstraZeneca. M.S.S. reports the study; however, as a randomized sight Committee; (data monitoring committee) research grant support through Brigham and trial, one would expect that these un- Baim Institute for Clinical Research (formerly Women ’s Hospital from Amgen, AstraZeneca, measured features would be balanced Harvard Clinical Research Institute, for the Bayer, Daiichi Sankyo, Eisai, GlaxoSmithKline, between groups. Additionally, the very PORTICO trial, funded by St. Jude Medical, Intarcia, Janssen Research and Development, elderly subgroup consisted of a small now Abbott), Cleveland Clinic (including for The Medicines Company, MedImmune, Merck the ExCEED trial, funded by Edwards), Duke Sharp & Dohme, Novartis, Poxel, Pfizer, Quark, subset (6.4%) of the total population of Clinical Research Institute, Mayo Clinic, Mount and Takeda and consulting fees from Alnylam, 17,160, and the number of events was Sinai School of Medicine (for the ENVISAGE trial, Anthos Therapeutics, Amgen, AstraZeneca, small, yet it still accounted for 1,096 fundedby Daiichi Sankyo), andPopulation Health Bristol-Myers Squibb, CVS Caremark, Dyrnamix, participants. Finally, the analyses of met- Research Institute; (honoraria) American College Esperion, IFM Therapeutics, Intarcia, Ionis, Jans- abolic outcomes were post hoc and should of Cardiology (Senior Associate Editor, Clinical sen Research and Development, The Medicines Trials and News, ACC.org, Vice-Chair, ACC Ac- Company, MedImmune, Merck Sharp & Dohme, be considered exploratory. creditation Committee), Baim Institute for Clin- and Novartis, and is a member of the TIMI Study In conclusion, our study establishes ical Research (formerly Harvard Clinical Research Group, which has also received institutional the CV and renal benefits of dapagliflozin Institute, RE-DUAL PCI clinical trial steering com- research grant support through Brigham and in the elderlyand very elderly. Theoverall mittee funded by Boehringer Ingelheim, AEGIS-II Women’s Hospital from: Abbott, Aralez, Roche, efficacy and safety of dapagliflozin were executive committee funded by CSL Behring), and Zora Biosciences. I.R. reports personal Belvoir Publications (Editor in Chief, Harvard fees from AstraZeneca, Bristol-Myers Squibb, consistent regardless of age; thus, this Heart Letter), Duke Clinical Research Institute Boehringer Ingelheim, Concenter BioPharma drug may be considered a valuable glucose- (clinical trial steering committees), HMP Global and Silkim, Eli Lilly, Merck Sharp & Dohme, Novo lowering agent regardless of age. (Editor in Chief, Journal of Invasive Cardiology), Nordisk, Orgenesis, Pfizer, Sanofi, SmartZyme Journal of the American College of Cardiology Innovation, Panaxia, FuturRx, Insuline Medical, (Guest Editor, Associate Editor), Medtelligence/ Medial EarlySign, CameraEyes, Exscopia, Dermal Funding. The DECLARE–TIMI 58 trial was a ReachMD (CME steering committees), Popula- Biomics, Johnson & Johnson, Novartis, Teva, collaboration between AstraZeneca and two tion Health Research Institute (for the COMPASS GlucoMe, and DarioHealth. No other potential academic research organizations (TIMI Study operations committee, publications commit- conflicts of interest relevant to this article were Group and Hadassah Medical Organization). tee, steering committee, and U.S. national co- reported. Data analyses were performed by the academic leader, funded by Bayer), Slack Publications AstraZeneca was involved in the study design, TIMI Study Group, which has access to the (Chief Medical Editor, Cardiology Today’s Inter- data collection, data analysis, interpretation, and complete study database, allowing independent vention), Society of Cardiovascular Patient Care writing of the manuscript. analyses of the results; any discrepancies were (Secretary/Treasurer), and WebMD (CME steer- Author Contributions. A.C., O.M., S.D.W., A.R., resolved by discussion. The DECLARE–TIMI 58 pub- ing committees); (other) Clinical Cardiology I.Y., E.L.G., S.A.M., D.L.B., L.A.L., D.K.M., J.P.H.W., lication committee made the decision to submit (Deputy Editor), NCDR-ACTION Registry Steer- I.A.M.G.-N., M.F., P.A.J., A.M.L., M.S.S., and I.R. for publication. ing Committee (Chair), and VA CART Research contributed to data analysis. A.C., O.M., S.D.W., DualityofInterest. The sponsorsof theDECLARE– and Publications Committee (Chair); (research A.R., I.Y., E.L.G., S.A.M., D.L.B., L.A.L., D.K.M., TIMI 58 study were initially AstraZeneca and funding) Abbott, Amarin, Amgen, AstraZeneca, J.P.H.W., I.A.M.G.-N., M.F., P.A.J., A.M.L., M.S.S., Bristol-Myers Squibb, and AstraZeneca later Bayer, Boehringer Ingelheim, Bristol-Myers and I.R. contributed to the writing of the man- became the sole sponsor of the study. A.C. Squibb,Chiesi,CSLBehring,Eisai,Ethicon,Ferring uscriptand approved the final submittedversion. reports grants and personal fees from Astra- Pharmaceuticals, Forest Laboratories, Idorsia, A.C., O.M., S.D.W., A.R., I.Y., D.L.B., L.A.L., Zeneca and Novo Nordiskand personal fees from Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, D.K.M., J.P.H.W., I.A.M.G.-N., M.F., A.M.L., Abbott, Eli Lilly, Sanofi, Boehringer Ingelheim, Pfizer, Regeneron, Roche, Sanofi, Synaptic, and M.S.S., and I.R. contributed to data interpreta- Merck Sharp & Dohme, Medial Early-Sign, and The Medicines Company; (royalties) Elsevier tion. A.C., S.D.W., A.R., I.Y., E.L.G., S.A.M., GlucoMe. O.M. reports grants and personal fees (Editor,Cardiovascular Intervention: A Compan- I.A.M.G.-N., A.M.L., M.S.S., and I.R. designed the from AstraZeneca, Bristol-Myers Squibb, and ion to Braunwald’s Heart Disease); (site coinves- figures. A.C., S.D.W., I.A.M.G.-N., M.F., A.M.L., Novo Nordisk and personal fees from Eli Lilly, tigator) Biotronik, Boston Scientific, St. Jude M.S.S., and I.R. contributed to the study design. Sanofi, Merck Sharp & Dohme, Boehringer In- Medical (now Abbott), and Svelte; (trustee) A.C., S.D.W., I.A.M.G.-N., M.F., A.M.L., M.S.S., gelheim, Johnson & Johnson, and Novartis. American College of Cardiology; and (un- and I.R. contributed to data collection. A.C., S.D.W. reports grants from AstraZeneca, Bristol- funded research) FlowCo, Fractyl, Merck Sharp S.D.W., I.A.M.G.-N., A.M.L., M.S.S., and I.R. per- Myers Squibb, Sanofi, and Amgen, grants and & Dohme, Novo Nordisk, PLx Pharma, and formed the literature search. A.C., S.D.W., E.L.G., personal fees from Arena, Daiichi Sankyo, Eisai, Takeda. L.A.L. reports grants and personal fees and S.A.M., and I.R. are the guarantors of this Eli Lilly, and Janssen, grants and consulting fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, work and, as such, had full access to all the data in from Merck Sharp & Dohme (additionally his Janssen, Novo Nordisk, and Sanofi; personal fees the study and take responsibility for the integrity spouse is employed by Merck Sharp & Dohme), from Merck Sharp & Dohme and Servier; and of the data and the accuracy of the data analysis. and personal fees from Aegerion, Allergan, An- grants from GlaxoSmithKline. D.K.M. reports Prior Presentation. These data were presented gelMed, Boehringer Ingelheim, Boston Clinical personal fees for clinical trial leadership from as a poster and at a symposium at the European Research Institute, Icon Clinical, Lexicon, St. Jude GlaxoSmithKline, Janssen, Lexicon AstraZeneca, Associationforthe StudyofDiabetes55thAnnual Medical, Xoma, Servier, AstraZeneca, and Bristol- Sanofi, Boehringer Ingelheim, Merck Sharp & Meeting, Barcelona, Spain, 16–20 September Myers Squibb. E.L.G. and S.A.M. report research Dohme, Pfizer, Novo Nordisk, Eisai, Esperion, and 2019. grant support through Brigham and Women’sHos- Lilly and personal fees for consultancy from pital from Abbott, Amgen, Aralez, AstraZeneca, AstraZeneca, Lilly, Boehringer Ingelheim, Merck References Bayer HealthCare Pharmaceuticals, Inc., Daiichi- Sharp & Dohme, Novo Nordisk, Metavant, Ap- 1. AmericanDiabetesAssociation.12.Olderadults: Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, plied Therapeutics, Sanofi,andAfimmune. 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