Molecular and cellular changes in the diabetic heart lead to aberrant myocardial remodeling, characterized by left ventricular hypertrophy (LVH) and eventual diastolic and/or systolic dysfunction (1,2). Although the differential effects of antihypertensive therapy on cardiovascular outcomes in patients with type 2 diabetes and LVH have been studied, those of antihyperglycemic therapy have not (3). In this post hoc analysis of the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial, we report the effects of empagliflozin on cardiovascular outcomes in subjects with type 2 diabetes, established cardiovascular disease, and electrocardiogram (ECG) evidence of LVH.
EMPA-REG OUTCOME (NCT01131676, ClinicalTrials.gov) enrolled patients with type 2 diabetes, inadequate glycemic control, and established cardiovascular disease who had an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 at baseline. In total, 7,020 subjects were treated with empagliflozin 10 mg/day, empagliflozin 25 mg/day, or placebo in addition to standard of care (4). In subgroups with/without LVH at baseline (defined on ECG as RV5/V6 + SV1/V2 >3.5 mV or RaVL ≥1.3 mV plus ≥1 of the following: left atrial abnormality, left axis deviation, and ST- and/or T-wave changes consistent with LVH), we assessed the risks of cardiovascular death, all-cause mortality, and 3-point major adverse cardiovascular events (MACE) with pooled empagliflozin doses versus placebo. We excluded 134 participants without a baseline ECG, 7 who had a baseline ECG that was uninterpretable or did not have QT interval data, and 906 who took the study drug prior to ECG. Therefore, 5,973 participants had a usable baseline ECG (manually analyzed; 2,008 in the placebo group and 3,965 in the empagliflozin groups), of whom 140 had LVH (45 in the placebo group and 95 in the empagliflozin groups). We used a Cox proportional hazards model with factors for age, sex, region, treatment, BMI, HbA1c, eGFR, LVH at baseline, and treatment-by-baseline-LVH interaction. Interaction P values, without adjustment for multiple testing, are presented.
Baseline characteristics were similar in patients with versus without LVH for age (mean ± SD 62.5 ± 8.4 vs. 63.2 ± 8.6 years), proportion of patients with a duration of diabetes of >10 years (57.9% vs. 56.9%), baseline HbA1c (8.03% vs. 8.07%), BMI (29.0 kg/m2 vs. 30.6 kg/m2), male sex (74.3% vs. 71.7%), history of hypertension (93.6% vs. 91.4%), eGFR <60 (21.4% vs. 26.4%), myocardial infarction (54.3% vs. 45.7%), and history of heart failure (5.7% vs. 4.1%). Baseline cardiovascular medication use was also relatively equal between groups (92.9% vs. 95.0% for antihypertensive therapy [ACE inhibitors/angiotensin receptor blockers 80.7% vs. 80.6% and β-blockers 59.3% vs. 64.8%] and 75.0% vs. 81.0% for lipid-lowering therapy).
In the placebo group, the rate of cardiovascular death was 4 times greater in patients with LVH (78.9 vs. 19.1 per 1,000 patient-years), and rates of all-cause mortality and 3-point MACE were 3.5 times greater (Fig. 1). Empagliflozin reduced the risk of cardiovascular death versus placebo irrespective of LVH at baseline; hazard ratio (HR) 0.40 (95% CI 0.16, 1.01) vs. 0.60 (95% CI 0.47, 0.78) in patients with versus without LVH (P = 0.40 for interaction). Since the baseline risk was higher in patients with LVH, the absolute risk reductions with empagliflozin versus placebo were numerically higher in this cohort. Empagliflozin also reduced the risk of all-cause mortality irrespective of LVH at baseline (P = 0.11 for interaction). Statistical heterogeneity was observed in the reduction in 3-point MACE with empagliflozin (P = 0.03 for interaction); HR 0.39 (95% CI 0.19, 0.81) in patients with LVH vs. 0.89 (95% CI 0.76, 1.05) in patients without LVH. For the 3-point MACE components myocardial infarction and stroke, similar trends were observed; P values for interaction could not be calculated due to very low event numbers.
The presence of LVH was a strong determinant of cardiovascular events and mortality in patients with type 2 diabetes enrolled in the EMPA-REG OUTCOME trial. The sodium–glucose cotransporter 2 inhibitor empagliflozin consistently reduced the risks of cardiovascular and all-cause mortality in this population. The risk reduction for 3-point MACE appears to be larger in patients with type 2 diabetes and LVH than in those without LVH, although given the small numbers analyzed and the post hoc nature of the analysis, this remains hypothesis generating. It would be interesting to investigate, in future analyses, the relationship between empagliflozin effects and less stringent ECG criteria of LVH, such as RaVL ≥1.1 mV vs. the RaVL 1.3 mV criterion used in this analysis. Although various postulated mechanisms may explain the benefits of empagliflozin on the myocardium (5), whether empagliflozin causes a regression in left ventricular mass remains to be determined.
Acknowledgments. The authors thank Paul Nistor, Envision Medical Affairs, for medical writing assistance, limited to collation of co-author comments, supported financially by Boehringer Ingelheim.
Funding and Duality of Interest. The EMPA-REG OUTCOME trial was funded by the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance. S.V. has received research grants and/or speaking honoraria from Boehringer Ingelheim/Eli Lilly and Company, AstraZeneca, Janssen, Merck, Amgen, Sanofi, Valeant, Bayer, and Pfizer. C.D.M. has received consulting fees from Amgen, Boehringer Ingelheim, and Octapharma. D.L.B. discloses the following relationships: advisory board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; board of directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, and ToBeSoft; chair: American Heart Association Quality Oversight Committee; data monitoring committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), and Population Health Research Institute; honoraria: American College of Cardiology (senior associate editor, Clinical Trials and News, ACC.org, and vice chair, American College of Cardiology Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim), Belvoir Publications (editor in chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), HMP Global (editor in chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor, associate editor), Population Health Research Institute (for the 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), and WebMD (CME steering committees); other: Clinical Cardiology (deputy editor), National Cardiovascular Data Registry-ACTION Registry Steering Committee (chair), Veterans Affairs Clinical Assessment Reporting and Tracking Research and Publications Committee (chair); research funding: Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood, Ischemix, Eli Lilly and Company, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi, Synaptic, and The Medicines Company; royalties: Elsevier (editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); site co-investigator: Biotronik, Boston Scientific, St. Jude Medical (now Abbott), and Svelte; trustee: American College of Cardiology; unfunded research: Flowco, Merck, Novo Nordisk, PLx Pharma, and Takeda. S.R.R. has received consulting fees from GE Healthcare, Lundbeck LLC, Allergan, Abbott Laboratories, and Boston Scientific Corporation. E.F. has been a speaker and consultant for Merck Sharp & Dohme, Sanofi, Eli Lilly and Company, Boehringer Ingelheim, Johnson & Johnson, and AstraZeneca and has received research funds from Boehringer Ingelheim and Eli Lilly and Company. B.Z. has received research grants awarded to his institution from Boehringer Ingelheim, AstraZeneca, and Novo Nordisk and honoraria from Janssen, Sanofi, Eli Lilly and Company, Boehringer Ingelheim, Novo Nordisk, and Merck. G.S., J.L., and J.T.G. are employees of Boehringer Ingelheim. D.F. reports honoraria from Sanofi, Merck, Amgen, AstraZeneca, Eli Lilly and Company, and Boehringer Ingelheim. No other potential conflicts of interest relevant to this article were reported.
Boehringer Ingelheim had a role in study design, data collection, data analysis, data interpretation, and writing of the report. Eli Lilly and Company had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
Author Contributions. S.V. drafted the manuscript. S.V., B.Z., and D.F. conceived and designed the analysis. S.V., C.D.M., D.L.B., S.R.R., A.T.Y., A.V., E.F., G.S., J.L., B.Z., J.T.G., and D.F. contributed to the analysis and interpretation of data and critically revised the manuscript. G.S. provided statistical expertise. All authors were fully responsible for all content and editorial decisions and were involved at all stages of manuscript development and have approved the final version. S.V. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Prior Presentation. Parts of this study were presented in poster form at the European Society of Cardiology Congress, Munich, Germany, 25–29 August 2018; at the Diabetes Canada/CSEM Professional Conference, Halifax, Canada, 10–13 October 2018; at the Canadian Cardiovascular Congress, Toronto, Canada, 20–23 October 2018; and at the World Congress of Cardiology and Cardiovascular Health, Dubai, United Arab Emirates, 5–8 December 2018.
Clinical trial reg. no. NCT01131676, clinicaltrials.gov