Effects of Empagliflozin on Left Ventricular Remodeling in Patients with Type 2 Diabetes and Coronary Artery Disease: Echocardiographic Substudy of the EMPA-HEART CardioLink-6 Randomized Clinical Trial

Recent clinical trials have demonstrated significant reductions in heart failure hospitalization and cardiovascular death with sodium-glucose cotransport protein 2 inhibitors in patients with or without type 2 diabetes mellitus.1Zinman B. Wanner C. Lachin J.M. Fitchett D. Bluhmki E. Hantel S. et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373: 2117-2128Crossref PubMed Scopus (7198) Google Scholar, 2Neal B. Perkovic V. Mahaffey K.W. de Zeeuw D. Fulcher G. Erondu N. et al.Canagliflozin and cardiovascular and renal events in type 2 diabetes.N Engl J Med. 2017; 377: 644-657Crossref PubMed Scopus (2190) Google Scholar, 3McMurray J. Solomon S.D. Inzucchi S.E. Kober L. Kosiborod M.N. Martinez F.A. et al.Dapagliflozin in patients with heart failure and reduced ejection fraction.N Engl J Med. 2019; 381: 1995-2008Crossref PubMed Scopus (2828) Google Scholar The mechanism of cardiovascular benefit with sodium-glucose transport coprotein 2 inhibitors was investigated in the EMPA-HEART CardioLink-6 trial, a double-blind, placebo-controlled clinical trial that randomized patients with type 2 diabetes and stable coronary artery disease to empagliflozin 10 mg once daily (n = 49) or placebo (n = 48). The EMPA-HEART CardioLink-6 trial showed via cardiac magnetic resonance imaging that empagliflozin use was associated with a reduction in left ventricular mass index (LVMI) at 6 months, with an average decrease of −2.6 g/m2 compared with −0.01 g/m2 in the placebo group (adjusted difference, −3.35 g/m2; 95% CI, −5.9 to −0.81 g/m2; P = .0103).4Verma S. Mazer C.D. Yan A.T. Mason T. Garg V. Teoh H. et al.Effect of empagliflozin on left ventricular mass in patients with type 2 diabetes and coronary artery disease: the EMPA-HEART CardioLink-6 randomized clinical trial.Circulation. 2019; 140: 1693-1702Crossref PubMed Scopus (273) Google Scholar The goal of this prespecified substudy was to determine if structural changes identified on transthoracic echocardiography might provide further insight into the mechanism of empagliflozin-associated left ventricular (LV) reverse remodeling and the effect of empagliflozin on diastolic function. The study design and primary results have been published separately.4Verma S. Mazer C.D. Yan A.T. Mason T. Garg V. Teoh H. et al.Effect of empagliflozin on left ventricular mass in patients with type 2 diabetes and coronary artery disease: the EMPA-HEART CardioLink-6 randomized clinical trial.Circulation. 2019; 140: 1693-1702Crossref PubMed Scopus (273) Google Scholar Every participant underwent transthoracic echocardiography at baseline and at 6 months (±14 days) after randomization. Measurements were performed according to standard guidelines,5Mitchell C. Rahko P.S. Blauwet L.A. Canaday B. Finstuen J.A. Foster M.C. et al.Guidelines for performing a comprehensive transthoracic echocardiographic examination in adults: recommendations from the American Society of Echocardiography.J Am Soc Echocardiogr. 2019; 32: 1-64Abstract Full Text Full Text PDF PubMed Scopus (713) Google Scholar and sonographers and readers were blinded to the treatment assignment. The primary outcome of this substudy was the change in E/e′ ratio from baseline to the 6-month visit. Secondary outcomes of interest included changes in other LV diastolic parameters. The mean baseline E/e′ ratio, LVMI, and LV ejection fraction were normal in both the empagliflozin and placebo groups (Table 1). At 6 months, there was no significant difference in the change in average E/e′ ratio in the empagliflozin versus placebo group (0.15 vs −0.35, respectively; adjusted difference, −0.23; 95% CI, −1.29 to 0.82; P = .66). Similarly, there was no difference between the groups in change in medial E/e′ ratio, lateral E/e′ ratio, or left atrial volume index (Table 1).Table 1Changes in echocardiographic parameters in patients treated with empagliflozin versus placeboEchocardiographic parameterPlacebo (n = 48)Empagliflozin (n = 49)Adjusted difference between groups95% CIPBaseline6 moChangeBaseline6 moChangeLVEF (%)∗Measured using cardiac magnetic resonance imaging.55.5 ± 8.754.3 ± 8.9−1.0 ± 6.558.0 ± 7.559.1 ± 8.570.72 ± 5.12.2(−0.2 to 4.7).10LV chamber quantification LVISd (cm)3.2 ± 0.83.2 ± 0.7−0.02 ± 0.63.0 ± 0.63.0 ± 0.70.05 ± 0.6−0.03(−0.3 to 0.2).80 LVIDd (cm)4.6 ± 0.84.5 ± 0.7−0.08 ± 0.64.4 ± 0.54.3 ± 0.6−0.16 ± 0.5−0.14(−0.4 to 0.1).20 IVS (cm)1.0 ± 0.21.0 ± 0.20 ± 0.21.0 ± 0.21.0 ± 0.20.03 ± 0.20.01(−0.1 to 0.1).80 PWT (cm)0.9 ± 0.20.9 ± 0.20.01 ± 0.20.9 ± 0.20.9 ± 0.20.05 ± 0.20.03(−0.004 to 0.1).40Diastolic parameters Mitral DTIAverage E/e′ ratio10.1 ± 3.110.3 ± 2.50.2 ± 3.010.6 ± 3.010.5 ± 3.6−0.4 ± 2.5−0.2(−1.3 to 0.8).70Medial E/e′ ratio12.3 ± 3.912.5 ± 3.60.1 ± 3.712.6 ± 4.212.6 ± 5.2−0.3 ± 3.3−0.3(−1.7 to 1.1).70Lateral E/e′ ratio8.0 ± 2.88.2 ± 2.20.2 ± 2.78.7 ± 2.68.4 ± 2.5−0.4 ± 2.7−0.1(−1.0 to 0.8).80 Mitral E velocity (cm/sec)68.6 ± 15.270.6 ± 14.71.8 ± 15.474.4 ± 18.271.2 ± 16.8−3.2 ± 15.1−2.3(−7.9 to 3.3).40 Mitral A velocity (cm/sec)74.7 ± 17.977.9 ± 18.82.9 ± 15.976.2 ± 16.575.8 ± 14.5−1.4 ± 11.7−3.5(−8.9 to 1.9).20 Pulmonary vein S wave (cm/s)52.1 ± 10.549.0 ± 10.0−4.3 ± 13.850.0 ± 10.147.8 ± 8.3−4.6 ± 11.3−0.9(−6.1 to 4.4).70 Pulmonary vein D wave (cm/s)43.5 ± 7.640.8 ± 8.1−2.6 ± 8.341.2 ± 11.539.9 ± 9.4−2.6 ± 13.0−0.8(−5.8 to 4.2).70 Pulmonary vein S:D ratio1.2 ± 0.31.2 ± 0.30 ± 0.41.3 ± 0.31.2 ± 0.2−0.1 ± 0.30.0(−0.2 to 0.2).90 LA volume index (mL/m2)32.7 ± 7.930.8 ± 8.1−2.0 ± 6.730.2 ± 6.728.7 ± 5.5−1.8 ± 6.5−0.9(−3.4 to 1.6).50Blood pressure†As reported in Verma et al.4DTI, Doppler tissue imaging; IVS, interventricular septum; LA, left atrial; LVEF, LV ejection fraction; LVIDd, LV internal diastolic dimension; LVISd, LV internal systolic diameter; PWT, posterior wall thickness.Data are expressed as mean ± SD.∗ Measured using cardiac magnetic resonance imaging.† As reported in Verma et al.4Verma S. Mazer C.D. Yan A.T. Mason T. Garg V. Teoh H. et al.Effect of empagliflozin on left ventricular mass in patients with type 2 diabetes and coronary artery disease: the EMPA-HEART CardioLink-6 randomized clinical trial.Circulation. 2019; 140: 1693-1702Crossref PubMed Scopus (273) Google Scholar Open table in a new tab DTI, Doppler tissue imaging; IVS, interventricular septum; LA, left atrial; LVEF, LV ejection fraction; LVIDd, LV internal diastolic dimension; LVISd, LV internal systolic diameter; PWT, posterior wall thickness. Data are expressed as mean ± SD. Subgroup analyses showed no significant change in E/e′ ratio among patients with average baseline E/e′ ≥ 13 (n = 16): −1.3 ± 3.5 with empagliflozin versus −2.5 ± 4.6 with placebo (adjusted difference, 1.99; 95% CI, −2.3 to 6.2) or among patients with baseline LVMI ≥ 60 g/m2 (n = 37): 0.2 ± 2.7 with empagliflozin versus −0.06 ± 3.6 with placebo (adjusted difference, 0.88; 95% CI, −0.9 to 2.6). There was also no difference in those with baseline LV ejection fraction > 50% versus ≤50%. This echocardiographic substudy of the EMPA-HEART CardioLink-6 trial had some limitations. The sample size calculation was based on detecting changes in LVMI using cardiac magnetic resonance imaging, and thus the study may have been underpowered to detect changes in diastolic function on echocardiography. Second, the majority of patients demonstrated only grade 1 diastolic dysfunction, with mostly normal left atrial size. Future studies are warranted to determine the impact empagliflozin may have on individuals who have more advanced diastolic dysfunction. In conclusion, this prespecified echocardiographic study revealed no significant change in key LV diastolic parameters with empagliflozin treatment for 6 months. These findings suggest that in the EMPA-HEART CardioLink-6 population, changes in loading conditions (i.e., preload) did not mediate the observed reduction in LV mass.