ORIGIN
Outcome Reduction with an Initial Glargine Intervention
(ORIGIN) Trial
Overview
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Large international randomized controlled trial in patients with new or
recently diagnosed diabetes, impaired fasting glucose (IFG) or impaired
glucose tolerance (IGT) and additional CV risk factors
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With follow-up of ~6 years, ORIGIN was the longest investigation of the
effect of insulin treatment on CV outcomes and cancer incidence in this
population
ORIGIN
Objectives
•Assess the relationship between long-term n-3 fatty acid
supplementation and the rate of CV events
•Assess effects of insulin glargine on CV outcomes
ORIGIN
Trial Design
Patients and Methods
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12,537 patients from 573 sites treated with insulin glargine (open) vs standard
care and n-3 fatty acids (1g per day) versus placebo (double-blind)
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Median follow-up, 6.2 years
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Baseline characteristics
- Mean age, 63.5 years
- Females, 35%
- Median FPG, 125 mg/dL
- Median HbA1c, 6.4%
ORIGIN
Primary outcomes
• CV death or MI or stroke
• CV death or MI or stroke or revascularization or CHF hospitalization
Secondary outcomes
• Microvascular composite
• New T2DM
• All cause death
ORIGIN
Results: n-3 Fatty Acids
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CV death: No effect (HR, 0.98; 95% CI, 0.87 to 1.10; p=0.72)
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MACE: No effect (HR, 1.01; 95% CI, 0.93 to 1.10; p=0.81)
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Lowered triglycerides: Change from baseline, fatty acid vs placebo
(–0.27 vs –0.10; p<0.001)
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Well tolerated
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High adherence (88%), follow-up (99%) at study end
ORIGIN
n-3 Fatty Acid Implications
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Conflicting results in previous randomized trials on efficacy of n-3 fatty acid
supplementation for preventing CV events
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In ORIGIN, 1 g/day n-3 fatty acids in patients with dysglycemia and
additional CV risk factors did not reduce CV events
•
Differences in background clinical conditions, risks, and therapies may
explain the difference in results between the ORIGIN population and higher
risk populations
•
Further studies will provide important information related to n-3 fatty acids
at various stages of CVD
- Rischio 3 Prevenzione (n=12,513)
- ASCEND (n=15,480)
ORIGIN
ORIGIN: Main Results
Interventions
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Insulin glargine: Add evening glargine to 0 or 1 oral agent (DM and non-DM)
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Standard care: No insulin until ≥ 2 OADs, no glargine (DM)
Results
•Median FPG of 95 mg/dL in glargine group vs 123 mg/dL in standard
therapy group
•Median HbA1c:
•
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Glargine group: 6.2%
Standard therapy group: 6.5%
•Differences in cancer incidence were not significant (HR, 1.00; 95%
CI, 0.88 to 1.13; p=0.97).
ORIGIN
Median FPG (Conventional Units)
ORIGIN
ORIGIN: Main Results
ORIGIN
Diabetes Prevention
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New diabetes developed in 24.7% of glargine vs 31.2% of standard therapy
subjects without baseline diabetes
• OR, 0.72; 95% CI, 0.58 to 0.91; p=0.006
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Consistent but attenuated effect noted after 2nd OGTT
• OR, 0.80; 95% CI, 0.64 to 1.00; p=0.050
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In people at risk for future diabetes, 6 years of basal insulin glargine titrated
to normal FPG reduces incidence of diabetes
ORIGIN
ORIGIN
Hypoglycemia
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Significantly higher rates of hypoglycemia with glargine vs standard
therapy (p<0.001)
Weight and BMI
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Median weight change:
• Glargine: 1.6 kg (95% CI, –2.0 to 5.5)
• Standard therapy: –0.5 kg (95% CI, –4.3 to 3.2; p<0.001)
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BMI change:
• Glargine: 0.81 kg/m2 (95% CI, –0.6 to 2.3)
• Standard therapy: no change (95% CI –1.4 to 1.6;p<0.001)
ORIGIN
Hypoglycemia
ORIGIN
Implications for Insulin Therapy
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Compared with standard therapy in patients with T2DM, IGT, or IFG, using
once-daily basal insulin glargine to target FPG ≤95 mg/dL for a median 6.2
years:
- Maintains near normal glycemic control
- Has neutral effect on CV outcomes and cancers
- Slows progression of dysglycemia
- Modestly increases hypoglycemia
- Modestly increases weight
ORIGIN
Implications for Insulin Therapy
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Supplementing endogenous insulin with basal insulin slows dysglycemia
progression
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Although later benefits or harms cannot be ruled out, over 6 to 7 years
exogenous basal insulin flexibly lowers glucose
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Despite lower glucose levels, routine early use of basal insulin glargine is
not better than guideline-based standard care in limiting important health
outcomes
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Basal insulin glargine currently is the best studied glucose-lowering drug
available
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No new safe safety outcomes limit early use when needed