ORIGIN

Outcome Reduction with an Initial Glargine Intervention (ORIGIN) Trial

Overview

• 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

• 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

• 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)

• Median follow-up, 6.2 years

• Baseline characteristics- Mean age, 63.5 years- Females, 35%- Median FPG, 125 mg/dL

- Median HbA1c, 6.4%

Patients and Methods

Trial Design

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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

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Results: n-3 Fatty Acids

• CV death: No effect (HR, 0.98; 95% CI, 0.87 to 1.10; p=0.72)

• MACE: No effect (HR, 1.01; 95% CI, 0.93 to 1.10; p=0.81)

• Lowered triglycerides: Change from baseline, fatty acid vs placebo(–0.27 vs –0.10; p<0.001)

• Well tolerated

• High adherence (88%), follow-up (99%) at study end

ORIGIN

n-3 Fatty Acid Implications

• Conflicting results in previous randomized trials on efficacy of n-3 fatty acid supplementation for preventing CV events

• 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

• Insulin glargine: Add evening glargine to 0 or 1 oral agent (DM and non-DM)

• 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:

• 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).

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Median FPG (Conventional Units)

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ORIGIN: Main Results

ORIGIN

Diabetes Prevention

• 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

• Consistent but attenuated effect noted after 2nd OGTT

• OR, 0.80; 95% CI, 0.64 to 1.00; p=0.050

• In people at risk for future diabetes, 6 years of basal insulin glargine titrated to normal FPG reduces incidence of diabetes

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Hypoglycemia

• Significantly higher rates of hypoglycemia with glargine vs standard therapy (p<0.001)

Weight and BMI

• 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)

• 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)

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Hypoglycemia

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Implications for Insulin Therapy

• 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

• Supplementing endogenous insulin with basal insulin slows dysglycemia progression

• Although later benefits or harms cannot be ruled out, over 6 to 7 years exogenous basal insulin flexibly lowers glucose

• Despite lower glucose levels, routine early use of basal insulin glargine is not better than guideline-based standard care in limiting important health outcomes

• Basal insulin glargine currently is the best studied glucose-lowering drug available

• No new safe safety outcomes limit early use when needed