Transcript origin
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 Trial Design Patients and Methods • 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% 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 • 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). ORIGIN Median FPG (Conventional Units) ORIGIN 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 ORIGIN ORIGIN 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) ORIGIN Hypoglycemia 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 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