Charles Wang 4 th Year PharmD Candidate University of Georgia College of Pharmacy 8/27/2012

1. Basal Insulin and Cardiovascular and Other Outcomes in DysglycemiaThe ORIGIN Trial InvestigatorsNEJM July 26, 2012: 367;4 Charles Wang 4th Year PharmD Candidate University of Georgia College of Pharmacy 8/27/2012

2. Overview • ORIGIN Trial • Outcome Reduction with Initial Glargine Intervention Tested if sufficient basal insulin to normalize fasting plasma glucose levels may reduce cardiovascular events. • Funding • Sanofi • BioPharma Norge • Study Dates • September 2003 – December 2011

3. Background • Diabetes is a chronic metabolic disease in which a person has high blood glucose levels. • It involves either the body not producing enough insulin or because the cells do not respond to the insulin that is produced. • Globally, as of 2012, an estimated 346 million people have type 2 diabetes. • Diabetes has many complications: • Cardiovascular disease • Ischemic heart disease • Stroke • Peripheral vascular disease • Diabetic retinopathy, nephropathy, and neuropathy

4. Background • Elevated blood glucose indicates that there is not enough endogenous insulin to regulate the glucose levels or to overcome underlying insulin resistance • Correction of this deficiency may reduce cardiovascular outcomes. • United Kingdom Prospective Diabetes Study (UKPDS) • 15% reduction in myocardial infarction • 13% reduction in death among people with a new-onset type 2 diabetes • Normalizing fasting plasma glucose levels may safely reduce incident CV outcomes • Exogenous insulin may slow the decline in pancreatic function with time

5. Background • Insulin glargine • Brand name: Lantus • Long acting basal insulin • Consists of microcrystals that slowly release insulin • Usually given once daily • “peakless” profile according to package insert • Formulated at an acidic pH of 4 • Water soluble at that pH • Physiologic pH (~7.4) causes the insulin to come out of solution that forms hexamers • Hexamers slows dissociation into insulin monomers which is the physiologically active unit of insulin. • Do not mix Lantus with any other insulin • Precipitates out of solution and reduces effectiveness

6. Design • Trial tested the effects of titrated basal insulin glargine versus standard of care and of n-3 fatty acid supplements versus placebo on cardiovascular outcomes • Study Design • Used 2-by-2 factorial design • Double-blinded • Randomized • 537 cardiology, diabetes, or other clinical sites • 40 countries

7. Design

8. Inclusion Criteria • Impaired Glucose Tolerance • PPG ≥ 140 < 200 mg/dL • FPG < 126 mg/dL • OR Impaired Fasting Glucose without DM • FPG ≥ 110 and < 126 • PPG must be <200 mg/dL • OR early type 2 diabetes • FPG ≥ 126 mg/dL or a PPG ≥ 200 or a previous diagnosis of DM and either: • No pharmacologic treatment for at least 10 weeks prior to screening or • An A1c of < 150% of the upper limit for the laboratory (<9% if 6%)

9. Inclusion Criteria • OR taking one oral antidiabetic drugs for at least 10 weeks at the time of screening and <8.5% A1c • Men or women ≥ 50 years old • Must be at risk for cardiovascular disease • Prior MI • Prior Stroke • Prior coronary, carotid, or peripheral arterial revascularization • Angina with documented ischemic changes • Microalbuminuria or clinical albuminuria • A:C ratio > 30 mg/mg • LV hypertrophy • At least 50% stenosis on angiography of a coronary, carotid, or lower extremity artery • Ankle/brachial index <0.9

10. Exclusion Criteria • Type 1 diabetes • Requiring insulin treatment • Known anti-GAD Ab positivity in the past • Autoimmune antibodies differentiates between types of diabetes • HgA1c >150% of upper limit (≥9%) • CABG within 4 years of screening • SrCr > 2.0 mg/dL • ALT or AST > 2.5 times upper limit of normal • Chronic or recurrent treatment of systemic corticosteroids or niacin treatment • Heart Failure of NYHA Class III or IV • Prior heart transplant or awaiting heart transplant

11. Methods • 12,537 participants • 2-by-2 factorial design • Follow up for 7 years • 6,264 in the Insulin Glargine Group • 6,273 in the Standard Care Group • In the insulin group, participants added an evening injection to their control regimen and increased the dose at least once weekly • Targeting a FPG level of 95 mg/dL • Those without a diabetes diagnosis • Reduced dose of insulin by 10 units per day and stopped any metformin by the last visit

12. Methods • Those in the Standard Care arms were treated on the basis of the investigator’s best judgment and local guidelines • Also, those that did not have a diabetes diagnosis and were not using glucose lowering drugs were scheduled for a Glucose Tolerance Test and retested if it did not establish a diagnosis of diabetes.

13. Baseline Characteristics

14. Baseline Characteristics

15. Baseline Characteristics

16. Baseline Characteristics

17. Outcomes • Co-primary Outcomes • Death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke • A revascularization procedure (cardiac, carotid, or peripheral) or hospitalization for heart failure • Other outcomes • Microvascular events • Incident cases of diabetes in participants without baseline diabetes • All-cause mortality • New or recurrent cancers • Hypoglycemic episodes • Weight

18. Results

19. Results

20. Results

21. Hazard Ratio • Used when presenting results with survival analysis data • Should not be considered the same as relative risk ratio • A hazard is the rate at which events happen • Probability=length of time x hazard • The hazard ratio is an expression of the hazard or chance of events occurring in the treatment arm as a ratio of the hazard of the events occurring in the control arm • Assume proportional hazard • Risk does not depend on time • A hazard ration of 2 means that the treatment will cause the patient to progress more quickly, that a person that has not progressed has twice the chance of having progressed to a certain point when compared to someone in the control group.

22. Results • Coprimary Outcomes • No significant difference in either outcome • MI, Stroke, or death from CV causes • HR: 1.02; 95%CI 0.94-1.11; P=0.63 • Revascularization or Hospitalization for CHF • HR: 1.04; 95%CI 0.97-1.11; P=0.27 • Other Outcomes • All-outcome death • HR: 0.98; 95%CI 0.9 to 1.08; P=0.7 • Microvascular Events • HR: 0.97; 95%CI 0.90 to 1.05; P 0.43

23. Results • 1,456 participants without diabetes at randomization, (737 assigned to Lantus and 719 assigned to standard care) • Lantus Group were 28% less likely to develop diabetes • OR:0.72; 95%CI, 0.58 to 0.91; P=0.006 • No significant difference of incidence of cancer • HR: 1.00; 95%CI, 0.88 to 1.13; P=0.97 • Incidence of first episode of severe hypoglycemia • 1 per 100 person-years in Lantus • 0.31 per 100 person years in standard care • P=<0.001

24. Results • Weight Changes • +1.6 kg in Lantus Group • -0.5 kg in standard of care group

25. Author’s Conclusion • When used to target normal fasting plasma glucose levels for more than 6 years, insulin glargine had a neutral effect on cardiovascular outcomes and cancers • Reduced new-onset diabetes • Increased hypoglycemia events • Modest increase in weight

26. Strengths • Very large sample size • Long follow up duration and high rate of follow-up and treatment adherence • 6.2 year average follow up time • Well distributed baseline • Large and diverse data collection

27. Limitations • Only included relatively controlled diabetics • Did not include patients currently on insulin • No standard, standard care, thus allowing each physician to determine course of care. • Guideline-suggested degrees of glycemic control • Did not test more intense versus less intense glucose control

28. Discussion • Metformin was used in 47% of the insulin-glargine group • Cardioprotective effect of metformin might have mitigated cardiovascular harm of insulin. • 60% of standard care was also on [ • Patients that were not diagnosed with diabetes had a reduced incidence of developing diabetes in the Lantus group. • Most likely due to the masking of the hyperglycemia by residual Lantus.