Lower rates of cardiovascular events and mortality associated with liraglutide use in patients treated with basal insulin: A DEVOTE subanalysis (DEVOTE 10)

Kirstine Brown-Frandsen, Scott S Emerson, Darren K McGuire, Thomas R Pieber, Neil R Poulter, Richard E Pratley, Bernard Zinman, Mattis F Ranthe, Randi Grøn, Martin Lange, Alan C Moses, Petra Örsy, John B Buse, DEVOTE Study Group, Kirstine Brown-Frandsen, Scott S Emerson, Darren K McGuire, Thomas R Pieber, Neil R Poulter, Richard E Pratley, Bernard Zinman, Mattis F Ranthe, Randi Grøn, Martin Lange, Alan C Moses, Petra Örsy, John B Buse, DEVOTE Study Group

Abstract

Aim: To compare the associations between concomitant liraglutide use versus no liraglutide use and the risk of major adverse cardiovascular events (MACE) and all-cause mortality among patients receiving basal insulin (either insulin degludec [degludec] or insulin glargine 100 units/mL [glargine U100]) in the Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE).

Materials and methods: Patients with type 2 diabetes and high cardiovascular risk were randomized 1:1 to degludec or glargine U100. Hazard ratios for MACE/mortality were calculated using a Cox regression model adjusted for treatment and time-varying liraglutide use at any time during the trial, without interaction. Sensitivity analyses were adjusted for baseline covariates including, but not limited to, age, sex, smoking and prior cardiovascular disease.

Results: At baseline, 436/7637 (5.7%) patients were treated with liraglutide; after baseline, 187/7637 (2.4%) started and 210/7637 (2.7%) stopped liraglutide. Mean liraglutide exposure from randomization was 530.2 days. Liraglutide use versus no liraglutide use was associated with significantly lower hazard rates for MACE [0.62 (0.41; 0.92)95%CI ] and all-cause mortality [0.50 (0.29; 0.88)95%CI ]. There was no significant difference in the rate of severe hypoglycaemia with versus without liraglutide use. Multiple sensitivity analyses yielded similar results.

Conclusions: Use of liraglutide was associated with significantly lower risk of MACE and death in patients with type 2 diabetes and high cardiovascular risk using basal insulin.

Keywords: cardiovascular disease; hypoglycaemia; insulin therapy; liraglutide; randomized trial; type 2 diabetes.

Conflict of interest statement

Data sharing statement

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Analyses of major clinical outcomes by time‐varying liraglutide use. Full analysis set (all randomized patients). HRs presented are for time to the first confirmed event (in days), comparing concomitant liraglutide use with no concomitant liraglutide use. HRs are based on a Cox regression model adjusted for treatment and time‐varying liraglutide use at any time during the trial, without interaction. Thus, the analyses are adjusted for patients initiating, interrupting or discontinuing liraglutide treatment during the trial. For one patient who experienced an event occurring on the same day as liraglutide initiation, half a day was added to the day of the event. CI, confidence interval; HR, hazard ratio; MACE, major adverse cardiovascular events; N, number of events; Rate, events per 100 patient‐years of observation
Figure 2
Figure 2
Adjusted analyses of major clinical outcomes by time‐varying liraglutide use. Full analysis set (all randomized patients). HRs presented are for time to the first confirmed event (in days), comparing concomitant liraglutide use with no concomitant liraglutide use. HRs are based on a Cox regression model adjusted for treatment and time‐varying liraglutide use at any time during the trial alongside additional baseline factors and covariates, including age, sex, smoking status, race, diabetes duration, cardiovascular risk group, insulin treatment, HbA1c, BMI, systolic blood pressure, LDL cholesterol, HDL cholesterol, hepatic impairment category and renal impairment category, all without interaction. Thus, the analyses are adjusted for patients initiating, interrupting or discontinuing liraglutide treatment during the trial. For one patient who experienced an event occurring on the same day as liraglutide initiation, half a day was added to the day of the event. CI, confidence interval; HR, hazard ratio; MACE, major adverse cardiovascular events; N, number of events; Rate, events per 100 patient‐years of observation, BMI, body mass index; LDL, low‐density lipoprotein; HDL, high‐density lipoprotein

References

    1. Diabetes mellitus: a major risk factor for cardiovascular disease. A joint editorial statement by the American Diabetes Association; The National Heart, Lung, and Blood Institute; The Juvenile Diabetes Foundation International; The National Institute of Diabetes and Digestive and Kidney Diseases; and The American Heart Association. Circulation. 1999;100:1132‐1133.
    1. FDA . Guidance for industry. Diabetes mellitus — evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. December 2008. . Accessed March 2019.
    1. Gerstein HC, Bosch J, Dagenais GR, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367:319‐328.
    1. Marso S, McGuire DK, Zinman B, et al. Efficacy and safety of degludec versus glargine in type 2 diabetes. N Engl J Med. 2017;377:723‐732.
    1. Marso SP, Daniels GH, Brown‐Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311‐322.
    1. American Diabetes Association . Standards of medical care in diabetes – 2017. Diabetes Care. 2017;40(suppl 1):S1‐S135.
    1. American Diabetes Association . Standards of medical care in diabetes – 2018. Diabetes Care. 2018;41(suppl 1):S1‐S159.
    1. Davies M, D'Alessio D, Fradkin J, et al. Management of Hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41:2669‐2701.
    1. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm – 2018 executive summary. Endocr Pract. 2018;24:91‐120.
    1. Holst JJ, Vilsbøll T. Combining GLP‐1 receptor agonists with insulin: therapeutic rationales and clinical findings. Diabetes Obes Metab. 2013;15:3‐14.
    1. Ahmann A, Rodbard HW, Rosenstock J, et al. Efficacy and safety of liraglutide versus placebo added to basal insulin analogues (with or without metformin) in patients with type 2 diabetes: a randomized, placebo‐controlled trial. Diabetes Obes Metab. 2015;17:1056‐1064.
    1. Lind M, Hirsch IB, Tuomilehto J, et al. Liraglutide in people treated for type 2 diabetes with multiple daily insulin injections: randomised clinical trial (MDI Liraglutide trial). BMJ. 2015;351:h5364.
    1. Valentine V, Goldman J, Shubrook JH. Rationale for, initiation and titration of the basal insulin/GLP‐1RA fixed‐ratio combination products, IDegLira and IGlarLixi, for the management of type 2 diabetes. Diabetes Ther. 2017;8:739‐752.
    1. Lingvay I, Pérez Manghi F, García‐Hernández P, et al. Effect of insulin glargine up‐titration vs insulin degludec/liraglutide on glycated haemoglobin levels in patients with uncontrolled type 2 diabetes: the DUAL V randomized clinical trial. JAMA. 2016;315:898‐907.
    1. Billings LK, Doshi A, Gouet D, et al. Efficacy and safety of IDegLira versus basal‐bolus insulin therapy in patients with type 2 diabetes uncontrolled on metformin and basal insulin; DUAL VII randomized clinical trial. Diabetes Care. 2018;41:1009‐1016.
    1. Marso SP, McGuire DK, Zinman B, et al. Design of DEVOTE (trial comparing cardiovascular safety of insulin Degludec vs insulin glargine in patients with type 2 diabetes at high risk of cardiovascular events) – DEVOTE 1. Am Heart J. 2016;179:175‐183.
    1. World Medical Association . World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310:2191‐2194.
    1. International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) . ICH Harmonised Tripartite Guideline: guideline for good clinical practice. J Postgrad Med. 2001;47:199‐203.
    1. Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care. 2013;36:1384‐1395.
    1. Tack C, Desouza C, Bain SC, et al. Liraglutide effects in insulin‐treated patients in LEADER. Diabetes. 2018;67(suppl 1):A117.
    1. Liraglutide highlights of prescribing information 2017. . Accessed March 2019.
    1. Vergès B, Charbonnel B. After the LEADER trial and SUSTAIN‐6, how do we explain the cardiovascular benefits of some GLP‐1 receptor agonists? Diabetes Metab. 2017;43(suppl 1):2S3‐2S12.
    1. Armstrong MJ, Hull D, Guo K, et al. Glucagon‐like peptide 1 decreases lipotoxicity in non‐alcoholic steatohepatitis. J Hepatol. 2016;64:399‐408.
    1. Vilsbøll T, Belvins T, Bode BW, et al. IDegLira improves cardiovascular risk markers in patients with type 2 diabetes uncontrolled on basal insulin: analyses of DUAL II and DUAL V. Diabetologia. 2017;60(suppl 1):S50.

Source: PubMed

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