1. 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

2. 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

3. 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 HbA 1c, 6.4% Patients and Methods Trial Design

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

5. ORIGIN 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

6. 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)

7. 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)

8. Results Median FPG of 95 mg/dL in glargine group vs 123 mg/dL in standard therapy group Median HbA 1c : 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).

9. ORIGIN Median FPG (Conventional Units)

10. ORIGIN ORIGIN: Main Results

11. 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 2 nd 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

12. ORIGIN

13. 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/m 2 (95% CI, –0.6 to 2.3) Standard therapy: no change (95% CI –1.4 to 1.6;p<0.001)

14. ORIGIN Hypoglycemia

15. ORIGIN 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

16. 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