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 CARDIOVASCULAR AND METABOLIC RISK 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).