Empagliflozin treatment effects across categories of baseline HbA1c, body weight and blood pressure as an add-on to metformin in patients with type 2 diabetes

Abstract

Aim: To investigate the association of different categories of baseline cardio-metabolic risk factors on the treatment effects of empagliflozin 10 and 25 mg when added as second-line therapy to metformin in patients with type 2 diabetes (T2D).

Materials and methods: Patients aged 18 years or older with HbA1c 7.0%-10.0% were included. Analysis of covariance compared change from baseline to weeks 24 and 76 in HbA1c, body weight (BW) and systolic blood pressure (SBP) by respective baseline categories (HbA1c <8.5/≥8.5%; BW <80/80-90/>90 kg, SBP <130/130-140/>140 mmHg). Analyses were also conducted with a model using continuous covariates of cardio-metabolic factors.

Results: In total, 637 patients (56.7% males; mean [SD] age 55.7 [9.9] years, HbA1c 7.9% [0.9%], BW 81.2 [18.8] kg, SBP 129.4 [14.6] mmHg) received one or more dose of either empagliflozin 10 mg (n = 217) or 25 mg (n = 213), or placebo (n = 207). At both time points, empagliflozin 10/25 mg versus placebo significantly (P < .0001) reduced HbA1c and BW, with greater reductions in HbA1c at higher baseline HbA1c (P interaction week 24/76 categorical and continuous models: .0290/.1431 and .0004/.0042, respectively) and in BW (P interaction .1340/.0012 and .0202/<.0001, respectively). Both empagliflozin doses also significantly lowered SBP versus placebo at both time points, with similar efficacy by subgroups of baseline SBP. Adverse events were consistent with the established empagliflozin safety profile across treatment groups.

Conclusions: Empagliflozin, as add-on to metformin, decreases HbA1c and BW, particularly in patients with higher HbA1c and BW baseline values, and effectively lowers SBP.

Trial registration: ClinicalTrials.gov NCT01159600 NCT01289990.

Keywords: SGLT2 inhibitor; body weight; empagliflozin; glycaemic control; metformin; type 2 diabetes.

Conflict of interest statement

S.E.I. has consulted for Janssen, vTv Therapeutics and Alere, served on Clinical Trial Steering/Executive Committees for AstraZeneca, Boehringer Ingelheim, Daiichi‐Sankyo, Eisai, Novo Nordisk and Sanofi/Lexicon Pharmaceuticals, and has served on Data Monitoring Committees for Intarcia Therapeutics, Inc. M.J.D. has acted as consultant, speaker and advisory board member for AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Merck Sharp & Dohme, Novo Nordisk and Sanofi‐Aventis, has acted as a speaker for Mitsubishi Tanabe Pharma Corporation, and has received grants in support of investigator and investigator‐initiated trials from Eli Lilly and Company, Novo Nordisk and Sanofi‐Aventis. K.K. has received research grants and acted as a consultant, advisory board member and speaker for AstraZeneca, Berlin‐Chemie AG/Menarini Group, Boehringer Ingelheim, Bristol‐Myers Squibb, Eli Lilly and Company, Merck Sharp & Dohme, Novo Nordisk, Roche and Sanofi. P.T. and I.Z. are employees of Boehringer Ingelheim. J.T.G. and O.E.J. were employed by Boehringer Ingelheim at the time of writing the manuscript, but are now employed elsewhere. N.S. has consulted for Amgen, Boehringer Ingelheim, Eli Lilly and Company, Napp, Novo Nordisk, Pfizer and Sanofi and has received grant support from Boehringer Ingelheim.

© 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

FIGURE 1

The change from baseline at week 24 in subgroups of A, HbA1c, B, body weight, and C, SBP by baseline categories (FAS [LOCF]) from the ANCOVA model. CI, confidence interval; diff., difference; FAS, full analysis set; LOCF, last observation carried forward; SBP, systolic blood pressure; SE, standard error

FIGURE 2

The change from baseline at week 76 in subgroups of A, HbA1c, B, body weight, and C, SBP by baseline categories (FAS [LOCF]) from ANCOVA model. CI, confidence interval; diff., difference; FAS, full analysis set; LOCF, last observation carried forward; SBP, systolic blood pressure; SE, standard error

FIGURE 3

Placebo‐adjusted ANCOVA regression lines for the change from baseline to week 24 by A, HbA1c, and B, body weight at baseline considering treatment by baseline factor interactions (FAS [LOCF]). The ANCOVA model included baseline eGFR, geographical region and treatment as fixed effects, and the baseline efficacy variable of interest by treatment interaction and A, baseline HbA1c as a linear covariate or B, baseline weight and baseline HbA1c as linear covariates. ANCOVA, analysis of covariance; eGFR, estimated glomerular filtration rate; FAS, full analysis set; LOCF, last observation carried forward; LS, least squares

FIGURE 4

Placebo‐adjusted ANCOVA regression lines for the change from baseline to week 76 by A, HbA1c, and B, body weight at baseline considering treatment by baseline factor interactions (FAS [LOCF]). The ANCOVA model included baseline eGFR, geographical region and treatment as fixed effects, and the baseline efficacy variable of interest by treatment interaction and A, baseline HbA1c as a linear covariate or B, baseline weight and baseline HbA1c as linear covariates. ANCOVA, analysis of covariance; eGFR, estimated glomerular filtration rate; FAS, full analysis set; LOCF, last observation carried forward; LS, least squares