Effects of empagliflozin on insulin initiation or intensification in patients with type 2 diabetes and cardiovascular disease: Findings from the EMPA-REG OUTCOME trial

Abstract

Aim: To evaluate the effects of empagliflozin versus placebo on subsequent insulin initiation or dosing changes in a large cardiovascular outcomes trial.

Materials and methods: In EMPA-REG OUTCOME, 7020 patients with type 2 diabetes and cardiovascular disease received empagliflozin 10 mg, 25 mg, or placebo. Median follow-up was 3.1 years. After 12 weeks of treatment, changes in background antihyperglycaemic therapy were permitted. Among insulin-naïve patients, we assessed the effects of pooled empagliflozin arms versus placebo on time to initiation of insulin. Among insulin-treated patients, we assessed effects on time to an increase or decrease in insulin dose of more than 20%.

Results: In 3633 (52%) participants not treated with insulin at baseline, empagliflozin reduced new use of insulin versus placebo by 60% (7.1% vs. 16.4%; adjusted HR 0.40 [95% CI 0.32-0.49]; P < .0001). In 3387 (48%) patients using insulin at baseline, empagliflozin reduced the need for a greater than 20% insulin dose increase by 58% (14.4% vs. 29.3%; adjusted HR 0.42 [95% CI 0.36-0.49]; P < .0001) and increased the proportion achieving sustained greater than 20% insulin dose reductions without subsequent increases in HbA1c compared with placebo (9.2% vs. 4.9%; adjusted HR 1.87 [95% CI: 1.39-2.51]; P < .0001). Sensitivity analyses confirmed consistent findings when insulin dose changes of more than 10% or more than 30% were considered.

Conclusions: In patients with type 2 diabetes and cardiovascular disease, empagliflozin markedly and durably delays insulin initiation and substantial increases in insulin dose, while facilitating sustained reductions in insulin requirements over time.

Trial registration: ClinicalTrials.gov NCT01131676.

Keywords: diabetes; insulin; sodium-glucose co-transporter-2 inhibitors.

Conflict of interest statement

MV has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, and Relypsa; speaker engagements with Novartis and Roche Diagnostics; and participates on clinical endpoint committees for studies sponsored by Galmed and Novartis. SEI has served as a consultant, speaker, or as a member of clinical trial steering committees for BI, AZ, NN, Sanofi/Lexicon Pharmaceuticals, Merck, vTv Therapeutics, and Abbott/Alere. NS has consulted for Amgen, BI, Eli Lilly (EL), Napp, Novo Nordisk (NN), Pfizer, and Sanofi; and has received grant support from BI. DHF has received financial support from Amgen, AZ, BI, EL, Merck & Co., and Sanofi. SV is President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not‐for‐profit physician organization; holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; and has also received grants and personal fees for speaker honoraria and advisory board participation from AZ, Amgen, Bayer, BI, EL, Janssen, and Merck. He has received grants and personal fees for advisory board participation from Amgen, grants from Bristol‐Myers Squibb, personal fees for speaker honoraria and advisory board participation from EL, NN, and Sanofi; and personal fees for speaker honoraria from EOCI Pharmacomm Ltd, Novartis, Sun Pharmaceuticals, and Toronto Knowledge Translation Working Group. CW has received financial support from AZ, Bayer, BI, EL, MSD, and Mundipharma. BZ has received financial support from AZ, BI, EL, Janssen, Merck, NN, and Sanofi. JB has received research support from the National Institutes of Health, Patient Centered Outcomes Research, and the European Union; and has served as a consultant to Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, AZ, Bayer, BerlinCures, Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, Sequana Medical, V‐Wave Limited, and Vifor. APO, MB, JTG, and MM are employees of BI.

© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

FIGURE 1

Sustained new insulin initiation among insulin‐naїve participants at baseline (n = 3633). Outcome of sustained insulin initiation was defined to be maintained on ≥2 consecutive visits ≥13 weeks apart. Displayed event rates are based on Kaplan‐Meier estimates. Cox regression model adjusted for baseline HbA1c, time since type 2 diabetes diagnosis, body mass index, estimated glomerular filtration rate, geographic region, and treatment status. CI, confidence interval; HR, hazard ratio

FIGURE 2

Sustained total daily insulin dose increase by >20% among insulin‐treated participants at baseline (n = 3387). Displayed event rates are based on Kaplan‐Meier estimates. Cox regression model adjusted for baseline HbA1c, time since type 2 diabetes diagnosis, body mass index, estimated glomerular filtration rate, geographic region, and treatment status. CI, confidence interval; HR, hazard ratio

FIGURE 3

Sustained total daily insulin dose reduction by >20% among insulin‐treated participants at baseline (n = 3387). Dose reductions were considered appropriate if they were accompanied by no subsequent change (defined as

FIGURE 4

Long‐term benefit of empagliflozin on survival free from insulin initiation in the EMPA‐REG OUTCOME trial. Estimated mean insulin‐free survival times, A, in the empagliflozin and placebo arms are displayed. Treatment differences and 95% CIs are estimated for insulin‐free survival, B, after application of a locally weighted scatterplot‐smoothing procedure to age‐based Kaplan‐Meier estimates

FIGURE 5

Residual survival free from insulin initiation by age at randomization. Age‐based Kaplan‐Meier curves are displayed for patients aged, A, 45, B, 60, and C, 75 years for insulin‐free survival between the empagliflozin and placebo arms. Area under the survival curve (up to a maximum of 90 years) reflected average time alive and free from insulin initiation. The difference in these survival time estimates is the time that empagliflozin prolongs lifespan without the need for insulin initiation among insulin‐naïve patients