Risk for Myocardial Infarction in Patients Treated with Thiazolidinediones

1. Risk for Myocardial Infarction in Patients Treated with Thiazolidinediones Endocrinologic and Metabolic/Drug Safety and Risk Management Advisory Committees Meeting July 30, 2007 Samuel R. Nussbaum, M.D.Executive Vice President and Chief Medical OfficerWellPoint, Inc.

2. 34 million members; 1 in 9 Americans have WellPoint coverage; Blue Cross/Blue Shield Plans in 14 states Specialty medical companies: WellPoint NextRx PBM PrecisionRx Specialty Solutions WellPoint Behavioral Health Lumenos Consumer-driven health solutions Health Management Corporation Disease and integrated care management HealthCore Health outcomes and health services research WellPoint

3. HealthCore, the health outcomes research subsidiary of WellPoint, conducted an analysis to provide additional insight into the safety of the thiazolidinediones compared to other anti-diabetic agents This research was conducted over the past five weeks by HealthCore’s Safety & Epidemiology and Health Plan Analytics teams and was entirely funded by WellPoint Medical and pharmacy claims data for the period of January 1, 2001 through December 31, 2006 were extracted from five WellPoint health plans for members meeting study eligibility criteria We found no evidence for an increase in risk for either acute myocardial infarction or unstable angina in patients taking either rosiglitazone (Avandia) or pioglitazone (Actos) This study is fully compliant with HIPAA privacy and confidentiality requirements We have the ability to combine these data with data elements from charts and/or survey and expand this research to additional WellPoint health plans Risk for Myocardial Infarction in Patients Treated with Thiazolidinediones Study Overview

4. Primary objective: Determination of the comparative risk for acute myocardial infarction in patients taking rosiglitazone (Avandia) or pioglitazone (Actos) compared to members utilizing other anti-diabetic agents Analytic Technique: Retrospective, longitudinal cohort design utilizing health plan administrative data Primary outcome: Acute myocardial infarction requiring hospitalization or an emergency room visit using the ICD 9-CM code 410.XX Sensitivity analysis: Enhanced by adding unstable angina, ICD-9 code 411.1X, to acute myocardial infarction Patient Criteria: All patients taking insulin or patients taking both thiazolidinediones during the evaluation period were excluded. Patients taking rosiglitazone (Avandia) or pioglitazone (Actos) as single therapy or in combination with other oral anti-diabetic agents were classified in the rosiglitazone (Avandia) or pioglitazone (Actos) cohorts Assessment of cohort severity of illness was determined by evaluation of covariates, including identified markers for cardiovascular risk and disease for the 365-day period prior to initiating therapy (index date) Risk for Myocardial Infarction in Patients Treated with Thiazolidinediones Study Design

5. Multivariate Cox-proportional hazards modeling was performed to evaluate the independent effects of exposure to rosiglitazone (Avandia), pioglitazone (Actos) and other oral anti-diabetic agents, being adjusted for the previously described covariates To evaluate the impact of the definitions of outcome and exposure, the following sensitivity analysis was performed: Regression model 1: Outcome defined as Acute myocardial infarction (ICD: 410.XX) or unstable angina (411.1X) Regression model 2: Patient’s exposure censored at the end of therapy Regression model 3: Patient’s exposure censored 60 days past therapy discontinuation Regression model 4: Comparison of patients exposed to rosiglitazone (Avandia) or pioglitazone (Actos), as monotherapy, to other oral anti-diabetic drugs Risk for Myocardial Infarction in Patients Treated with Thiazolidinediones Analyses

6. Risk for Myocardial Infarction in Patients Treated with Thiazolidinediones Patient Demographics • Patients taking rosiglitazone (Avandia) and pioglitazone (Actos) were significantly older and had a higher comorbidity burden than patients taking all other oral anti-diabetic agents + Significant at p<0.05 between rosiglitazone (Avandia) and oral anti-diabetic patients ** Significant at p<0.05 between rosiglitazone (Avandia) and pioglitazone (Actos)

7. Risk for Myocardial Infarction in Patients Treated with Thiazolidinediones Pre-Index Cardiovascular Events and Medications • Patients taking rosiglitazone (Avandia) and pioglitazone (Actos) had a significantly higher pre-index cardiovascular disease and cardiovascular medication utilization + Significant at p<0.05 between rosiglitazone (Avandia) and oral anti-diabetic patients ** Significant at p<0.05 between rosiglitazone (Avandia) and pioglitazone (Actos)

8. Risk for Myocardial Infarction in Patients Treated with Thiazolidinediones Pre-index Severity of Complications of Diabetes • Patients taking rosiglitazone (Avandia) and pioglitazone (Actos) had higher frequencies of pre-index complications of diabetes than patients taking all other anti-diabetic agents + Significant at p<0.05 between rosiglitazone (Avandia) and oral anti-diabetic patients ** Significant at p<0.05 between rosiglitazone (Avandia) and pioglitazone (Actos)

9. Risk for Myocardial Infarction in Patients Treated with Thiazolidinediones Incidence Rates of Cardiac Events *Incidence rate per 100 patient-years of therapy

10. Risk for Myocardial Infarction in Patients Treated with Thiazolidinediones Adjusted Risk of Cardiac Events

11. Risk for Myocardial Infarction in Patients Treated with Thiazolidinediones Risk of Cardiac Events When Limited to Treatment Period

12. Risk for Myocardial Infarction in Patients Treated with Thiazolidinediones Adjusted Risk of Cardiac Events Limited to Monotherapy Cohorts

13. We studied all patients taking any oral-anti-diabetic agents during the period of observation The use of a limited data set (with dates of service) which allows for sequencing of events that can not be achieved using a de-identified data set Because of our integrated research environment, we have the ability to follow up with surveys and chart abstractions to further validate events and/or supplement these findings with other clinical measures Risk for Myocardial Infarction in Patients Treated with Thiazolidinediones Unique Characteristics of This Study

14. Patients with diabetes receiving rosiglitazone (Avandia) and pioglitazone (Actos) were older by three years and had a greater cardiovascular and overall burden of illness than patients receiving oral agents for the treatment of diabetes We did not identify a statistically significant increase in the risk for acute cardiac events, including myocardial infarction and unstable angina, in patients who received rosiglitazone or pioglitazone when compared to patients taking other oral anti-diabetic agents A sub-cohort of patients treated with rosiglitazone (Avandia) or pioglitazone (Actos) as monotherapy were also found to not have elevated risk of acute cardiac events These analyses were performed utilizing administrative databases. We have the ability to expand this analysis utilizing chart abstraction and survey methodologies after appropriate patient confidentiality measures has been taken Risk for Myocardial Infarction in Patients Treated with Thiazolidinediones Summary