, Volume 57, Issue 7, pp 1325–1331 | Cite as

Basal insulin glargine and microvascular outcomes in dysglycaemic individuals: results of the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial

  • The ORIGIN trial investigators
  • Richard E. GilbertEmail author
  • Johannes F. E. Mann
  • Markolf Hanefeld
  • Giatgen Spinas
  • Jackie Bosch
  • Salim Yusuf
  • Hertzel C. Gerstein



As glycaemia and the incidence of microvascular diabetes complications follow a log-linear relationship, it becomes increasingly difficult to demonstrate a microvascular benefit of glucose-lowering when the HbA1c level is close to normal.


The Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial randomised 12,537 people with diabetes, impaired glucose tolerance or impaired fasting glucose to receive standard glycaemic care or standard care with the addition of basal insulin glargine (A21Gly,B31Arg,B32Arg human insulin), targeting a fasting plasma glucose level ≤5.3 mmol/l. Microvascular outcomes during a median follow-up of 6.2 years were examined in participants whose baseline HbA1c was above or below the median of 6.4% (46.4 mmol/mol).


Allocation to the insulin glargine group reduced the incidence of the primary microvascular composite outcome of kidney and eye disease in participants whose baseline HbA1c level was ≥6.4% (46.4 mmol/mol; HR 0.90 [95% CI 0.81, 0.99]) but not in participants with a lower baseline HbA1c (HR 1.07 [95% CI 0.95, 1.20]; p value for interaction 0.031). In people whose baseline HbA1c level was ≥6.4% (46.4 mmol/mol), the median post-randomisation change in HbA1c was −0.65% (interquartile range −0.16, −0.91%) after allocation to insulin glargine and −0.33% (−0.83, 0.13%) after allocation to standard care (median HbA1c difference 0.33%; p < 0.0001). A smaller median difference of 0.22% was noted in people whose baseline HbA1c was <6.4% (p < 0.0001).


In patients with dysglycaemia, intervention targeting normal fasting glucose levels reduced HbA1c and attenuated the risk of microvascular outcomes in participants with a baseline HbA1c level ≥6.4% (46.4 mmol/mol). A neutral effect was seen in those with a lower baseline HbA1c level.

Trial registration: NCT00069784


Albuminuria Diabetic nephropathy Insulin glargine Microvascular Retinopathy 



Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation


Angiotensin-converting enzyme


Angiotensin receptor blocker


Interquartile range


Outcome Reduction with an Initial Glargine Intervention


UK Prospective Diabetes Study



The ORIGIN trial was funded by Sanofi, who also provided regulatory support, site monitoring and insulin glargine. Pronova Bio Pharma Norge supplied the n-3 fatty acids supplements and placebo.

Duality of interest

REG received consulting and lecture fees from Sanofi, Merck, AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Boehringer Ingelheim and other funds through his institution from Merck, AstraZeneca and Bristol-Myers Squibb. JFEM received consulting and lecture fees from Abbott, NovoNordisk, Novartis, Amgen, Roche, and Boehringer Ingelheim and other funds through his institution from Roche, Celgene and the European Union through framework-7 grant SysKid 241544. GS received consulting and lecture fees from Eli Lilly, Merck, AstraZeneca, Novo Nordisk, Novartis, Sanofi-Aventis and Servier, and research support from Novo Nordisk. MH received speaker honoraria from Takeda, Glaxo SmithKline, Roche, Bayer, Eli Lilly and Sanofi and advisory board honoraria from Sanofi, Takeda, Bristol-Myers Squibb and Glaxo SmithKline. SY received consulting and lecture fees and grant support from Sanofi. HCG reports consulting and lecture fees from Sanofi, Bayer, Merck, Glaxo SmithKline, Roche, Novartis, Janssen, Abbott and AstraZeneca and other funds through his institution from Sanofi, Merck, Novo Nordisk, Eli Lilly and Boehringer Ingelheim. JB reports no duality of interest associated with her contribution to this manuscript.

Contribution statement

The work presented here was undertaken in collaboration between all authors. REG and HCG defined the research idea, designed the study’s methodology and wrote the report. REG, HCG, JFEM, MH, GS, JB and SY contributed to the data collection, study design and discussion, review and editing of the report. All authors have seen and approved the current version of the report. HCG is responsible for the integrity of the work as a whole.

Supplementary material

125_2014_3238_MOESM1_ESM.pdf (192 kb)
ESM Fig. 1 (PDF 192 kb)
125_2014_3238_MOESM2_ESM.pdf (48 kb)
ESM Fig. 2 (PDF 47 kb)
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ESM Table 1 (PDF 58 kb)
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ESM Table 2 (PDF 59 kb)
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ESM Table 3 (PDF 58 kb)
125_2014_3238_MOESM6_ESM.pdf (48 kb)
ESM Table 4 (PDF 47 kb)


  1. 1.
    (1997) Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 20:1183–1197Google Scholar
  2. 2.
    Krolewski AS, Laffel LM, Krolewski M, Quinn M, Warram JH (1995) Glycosylated hemoglobin and the risk of microalbuminuria in patients with insulin-dependent diabetes mellitus. N Engl J Med 332:1251–1255PubMedCrossRefGoogle Scholar
  3. 3.
    Raskin P, Rosenstock J (1986) Blood glucose control and diabetic complications. Ann Intern Med 105:254–263PubMedCrossRefGoogle Scholar
  4. 4.
    Stratton IM, Adler AI, Neil HA et al (2000) Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321:405–412PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Diabetes Control and Complications Trial Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986CrossRefGoogle Scholar
  6. 6.
    Patel A, MacMahon S, Chalmers J et al (2008) Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 358:2560–2572PubMedCrossRefGoogle Scholar
  7. 7.
    Ismail-Beigi F, Craven T, Banerji MA et al (2010) Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet 376:419–430PubMedCrossRefGoogle Scholar
  8. 8.
    UK Prospective Diabetes Study (UKPDS) Group (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853CrossRefGoogle Scholar
  9. 9.
    ORIGIN Trial Investigators, Gerstein HC, Bosch J et al (2012) Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 367:319–328PubMedCrossRefGoogle Scholar
  10. 10.
    ORIGIN Trial Investigators, Bosch J, Gerstein HC et al (2012) n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med 367:309–318PubMedCrossRefGoogle Scholar
  11. 11.
    Origin Trial Investigators, Gerstein H, Yusuf S et al (2008) 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 155:26–32PubMedGoogle Scholar
  12. 12.
    Zoungas S, Chalmers J, Ninomiya T et al (2012) Association of HbA1c levels with vascular complications and death in patients with type 2 diabetes: evidence of glycaemic thresholds. Diabetologia 55:636–643PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • The ORIGIN trial investigators
  • Richard E. Gilbert
    • 1
    • 2
    Email author
  • Johannes F. E. Mann
    • 3
  • Markolf Hanefeld
    • 4
  • Giatgen Spinas
    • 5
  • Jackie Bosch
    • 6
  • Salim Yusuf
    • 6
    • 7
  • Hertzel C. Gerstein
    • 6
    • 7
  1. 1.Division of Endocrinology, St Michael’s HospitalUniversity of TorontoTorontoCanada
  2. 2.Keenan Research Centre for Biomedical Sciences and Li Ka Shing Knowledge Institute, St Michael’s HospitalUniversity of TorontoTorontoCanada
  3. 3.Department of NephrologyFriedrich Alexander University, Erlangen and Munich General HospitalsMunichGermany
  4. 4.Centre for Clinical Studies, Gesellschaft für Wissens-und TechnologietransferTechnical University DresdenDresdenGermany
  5. 5.Division of Endocrinology, Diabetes and Clinical NutritionUniversity Hospital ZurichZurichSwitzerland
  6. 6.Population Health Research InstituteMcMaster University and Hamilton Health SciencesHamiltonCanada
  7. 7.Department of MedicineMcMaster UniversityHamiltonCanada

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