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Research

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ORIGIN

Official Title

The ORIGIN Trial (Outcome Reduction with Initial Glargine Intervention)

Status

Completed

Overview

To evaluate the effects of Lantus (Insulin Glargine) versus standard care, and of Omega-3 Fatty Acids versus placebo, in reducing Cardiovascular morbidity and mortality in high risk people with Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT) or early Type 2 Diabetes Mellitus.

Study Design

Randomized, treatment, open label, active control, factorial assignment, efficacy study.

Primary Endpoint

The composite of CV death, non-fatal MI, non-fatal stroke, and significant heart failure. Secondary endpoints: Decline in the ability to perform everyday activities (key secondary outcome), Renal dysfunction (Primary outcome: end stage renal disease [ESRD] requiring dialysis or transplantation or doubling of serum creatinine), Total mortality. All primary and secondary endpoints are adjudicated.

Number of Patients

12612

Number of Sites

578

Number of Countries

40

Study Period

2003–2010

Principal Investigator

Hertzel Gerstein, Salim Yusuf

Program Manager

Jackie Bosch

Research Coordinator

Jessica Tyrwhitt

Key Publications

  • Investigators OT. Cardiovascular and Other Outcomes Postintervention With Insulin Glargine and Omega-3 Fatty Acids (ORIGINALE). Diabetes Care 2016;39:709-16.
  • Shah HS, Gao H, Morieri ML, et al. Genetic Predictors of Cardiovascular Mortality During Intensive Glycemic Control in Type 2 Diabetes: Findings From the ACCORD Clinical Trial. Diabetes Care 2016.
  • Gerstein HC, Pare G, Hess S, et al. Growth Differentiation Factor 15 as a Novel Biomarker for Metformin. Diabetes Care 2017;40:280-3.
  • Gerstein HC, Pare G, McQueen MJ, Lee SF, Hess S, Investigators OT. Validation of the ORIGIN Cardiovascular Biomarker Panel and the Value of Adding Troponin I in Dysglycemic People. J Clin Endocrinol Metab 2017;102:2251-7.
  • Origin Trial Investigators. Rationale, design, and baseline characteristics for a large international trial of cardiovascular disease prevention in people with dysglycemia: the ORIGIN Trial (Outcome Reduction with an Initial Glargine Intervention). Am Heart J 2008;155:26-32.
  • Hanefeld M, Koehler C, Hoffmann C, Wilhelm K, Kamke W, Gerstein H. Effect of targeting normal fasting glucose levels with basal insulin glargine on glycaemic variability and risk of hypoglycaemia: a randomized, controlled study in patients with early Type 2 diabetes. Diabet Med 2010;27:175-80.
  • Badings EA, Dyal L, Schoterman L, et al. Strategies to detect abnormal glucose metabolism in people at high risk for cardiovascular disease from the ORIGIN trial population (Outcome Reduction with Initial Glargine Intervention). J Diabetes 2011.
  • Gerstein HC, Bosch J, Dagenais GR, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 2012;367:319-28.
  • Bosch J, Gerstein HC, Dagenais GR, et al. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med 2012;367:309-18.
  • Ramachandran A, Riddle MC, Kabali C, Gerstein HC. Relationship between A1C and fasting plasma glucose in dysglycemia or type 2 diabetes: an analysis of baseline data from the ORIGIN trial. Diabetes Care 2012;35:749-53.
  • Lonn EM, Bosch J, Diaz R, et al. Effect of Insulin Glargine and n-3FA on Carotid Intima-Media Thickness in People With Dysglycemia at High Risk for Cardiovascular Events: The Glucose Reduction and Atherosclerosis Continuing Evaluation Study (ORIGIN-GRACE). Diabetes Care 2013;36:2466-74.
  • Origin Trial Investigators. Characteristics Associated With Maintenance of Mean A1C <6.5% in People With Dysglycemia in the ORIGIN Trial. Diabetes Care 2013.
  • Origin Trial Investigators. Does hypoglycaemia increase the risk of cardiovascular events? A report from the ORIGIN trial. Eur Heart J 2013;34:3137-44.
  • Gilbert RE, Mann JF, Hanefeld M, et al. Basal insulin glargine and microvascular outcomes in dysglycaemic individuals: results of the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial. Diabetologia 2014.
  • Bordeleau L, Yakubovich N, Dagenais GR, et al. The Association of Basal Insulin Glargine and/or n-3 Fatty Acids With Incident Cancers in Patients With Dysglycemia. Diabetes Care 2014;37:1360-6.
  • Lamy A, Tong W, Jung H, et al. Cost implications of the use of basal insulin glargine in people with early dysglycemia: The ORIGIN trial. J Diabetes Complications 2014;28:553-8.
  • Lopez-Jaramillo P, Cohen DD, Gomez-Arbelaez D, et al. Association of handgrip strength to cardiovascular mortality in pre-diabetic and diabetic patients: A subanalysis of the ORIGIN trial. Int J Cardiol 2014;174:458-61.
  • Cukierman-Yaffe T, Bosch J, Diaz R, et al. Effects of basal insulin glargine and omega-3 fatty acid on cognitive decline and probable cognitive impairment in people with dysglycaemia: a substudy of the ORIGIN trial. Lancet Diabetes Endocrinol 2014;2:562-72.
  • Origin Trial Investigators. Predictors of nonsevere and severe hypoglycemia during glucose-lowering treatment with insulin glargine or standard drugs in the ORIGIN trial. Diabetes Care 2015;38:22-8.
  • Ford RJ, Fullerton MD, Pinkosky SL, et al. Metformin and salicylate synergistically activate liver AMPK, inhibit lipogenesis and improve insulin sensitivity. Biochem J 2015;468:125-32.
  • Dunkler D, Gao P, Lee SF, et al. Risk Prediction for Early CKD in Type 2 Diabetes. Clin J Am Soc Nephrol 2015;10:1371-9.
  • Riddle MC, Gerstein H. Response to Comment on: The ORIGIN Trial Investigators. Characteristics Associated With Maintenance of Mean A1C <6.5% in People With Dysglycemia in the ORIGIN Trial. Diabetes Care 2013;36:2915-2922. Diabetes Care 2013;36:e181.
  • Gerstein HC, Pare G, McQueen MJ, et al. Identifying Novel Biomarkers for Cardiovascular Events or Death in People With Dysglycemia. Circulation 2015;132:2297-304. 24. Rautio A, Boman K, Gerstein HC, et al. The effect of basal insulin glargine on the fibrinolytic system and von Willebrand factor in people with dysglycaemia and high risk for cardiovascular events: Swedish substudy of the Outcome Reduction with an Initial Glargine Intervention trial. Diab Vasc Dis Res 2017;14:345-52.
  • Bordeleau L, Gerstein HC. Response to Zanders et al. The association of basal insulin glargine and/or n-3 fatty acids with incident cancers in patients with dysglycemia. Diabetes Care 2014;37:1360-1366. Diabetes Care 2014;37:e223.
  • Bordeleau L, Gerstein HC. Response to Suissa and Azoulay. The association of basal insulin glargine and/or n-3 fatty acids with incident cancers in patients with dysglycemia. Diabetes Care 2014;37:1360-1366. Diabetes Care 2014;37:e217.
  • Gerstein HC, Ferrannini E, Riddle MC, Yusuf S, Investigators OT. Insulin Resistance and Cardiovascular Outcomes in the ORIGIN Trial. Diabetes Obes Metab 2018;20:564-70.
  • Gerstein HC, Jung H, Ryden L, et al. Effect of Basal Insulin Glargine on First and Recurrent Episodes of Heart Failure Hospitalization: The ORIGIN Trial (Outcome Reduction With Initial Glargine Intervention). Circulation 2018;137:88-90.
  • Sjaarda J, Gerstein HC, Yusuf S, et al. Blood HER2 and Uromodulin as Causal Mediators of CKD. J Am Soc Nephrol 2018.
  • Papademetriou V, Nylen ES, Doumas M, et al. Chronic Kidney Disease, Basal Insulin Glargine, and Health Outcomes in People with Dysglycemia: The ORIGIN Study. Am J Med 2017;130:1465 e27- e39.
  • Yates T, Davies MJ, Jung H, et al. Effect of insulin glargine on recreational physical activity and TV viewing: Analysis of the randomised ORIGIN trial. Diabetes research and clinical practice 2017;132:137-43.
  • Aung T, Halsey J, Kromhout D, et al. Associations of Omega-3 Fatty Acid Supplement Use With Cardiovascular Disease Risks: Meta-analysis of 10 Trials Involving 77917 Individuals. JAMA Cardiol 2018.
  • Sjaarda J, Gerstein H, Chong M, et al. Blood CSF1 and CXCL12 as Causal Mediators of Coronary Artery Disease. J Am Coll Cardiol 2018;72:300-10. 34. Birkeland KI, Grill V, Wium C, et al. The association of basal insulin treatment versus standard care with outcomes in anti-GAD positive and -negative subjects. A post-hoc analysis of the ORIGIN-trial. Diabetes Obes Metab 2018.
  • Wang A, Arver S, Boman K, et al. Testosterone, sex hormone-binding globulin and risk of cardiovascular events: A report from the Outcome Reduction with an Initial Glargine Intervention trial. Eur J Prev Cardiol 2018:2047487318819142.
  • Cukierman-Yaffe T, Bosch J, Jung H, Punthakee Z, Gerstein HC. Hypoglycemia and Incident Cognitive Dysfunction: A Post Hoc Analysis From the ORIGIN Trial. Diabetes Care 2018.
  • Mohammadi-Shemirani P, Sjaarda J, Gerstein HC, et al. A Mendelian Randomization-Based Approach to Identify Early and Sensitive Diagnostic Biomarkers of Disease. Clin Chem 2018.
  • Origin Trial Investigators, Gerstein H, Yusuf S, Riddle MC, Ryden L, Bosch J. Rationale, design, and baseline characteristics for a large international trial of cardiovascular disease prevention in people with dysglycemia: the ORIGIN Trial (Outcome Reduction with an Initial Glargine Intervention).Am Heart J. 2008;155:26-32, 32.e1-6. Epub 2007 Nov 26.
  • The ORIGIN Trial Investigators (2012). Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 26;367(4):319-28.
  • The ORIGIN Trial Investigators (2012). n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med 26;367(4):309-18.

For more information, please visit http://www.origintrial.org/