1. As of 8/18/2015 1 A Comparison of Select Cardiovascular Outcomes by Anti- Diabetic Prescription Drug Classes Used to Treat Type 2 Diabetes among Military Health System (MHS) Beneficiaries, Fiscal Year 2003-200 6 Office of the Assistant Secretary of Defense for Health Affairs/TRICARE Management Activity Michael R. Peterson, DVM, MPH, DrPH Director, Health Program Analysis and Evaluation Thomas Bacon, PharmD, MS LtCol, USAF, BSC Director, Pharmacy Utilization Management

2. As of 8/18/2015 2 Background May 2007 article in NEJM by Nissen and Wolski reporting on association of Avandia use and risk of MI and death from cardiovascular causes DoD interested in determining very quickly if our beneficiaries were at similar risk Is there an increased incidence of select cardiovascular events (acute MI and CHF) among MHS beneficiaries who filled a script for Avandia compared to those who filled scripts for other anti-diabetic medications?

3. As of 8/18/2015 3 Methods MHS has 9.1M beneficiaries TRICARE Prime is an HMO-like benefit (65+ not eligible) – study limited to these beneficiaries Cross-sectional analyses of data from fiscal years 2003-2006

4. As of 8/18/2015 4 Methods (cont.) Data sources: –Defense Eligibility Enrollment System (DEERS) – gender/age/bencat/location –Inpatient/outpatient encounter claims – not clinical data – date of service/source of service/diagnoses (ICD-9)/procedure codes (DRG) –Pharmacy Data Transaction Service (PDTS) – real-time pharmacy fill record regardless of source of fill (military, mail order, civilian)

5. As of 8/18/2015 5 Methods (cont.) Data sources linked by identifiers Case definition for type 2 diabetics based on ICD-9 codes Individual drugs grouped into therapeutic classes of anti-diabetic drugs Drug categories not mutually exclusive (therefore unable to perform statistical comparisons) Date of earliest diagnosis used to identify incident cases

6. As of 8/18/2015 6 Table 1. Demographics of Military Health System (MHS) TRICARE Prime Beneficiaries with a Diagnosis of Type 2 Diabetes, Fiscal Year 2003-2006 * N% Total N231,962 Gender Male 105,66045.55 Female 126,30254.45 Age Category 0-2416,1116.95 25 to 3417,7777.66 35 to 4435,51715.31 45 to 64161,32969.55 65 and over1,2280.53 Beneficiary Category † Active Duty17,7637.66 Dependent of Active Duty35,62915.36 Retired & Dependent of Retired124,94953.87 Other5,7532.48 Missing Beneficiary Category Info47,868 20.64 * Data sources: SIDR, SADR, TED-I, TED-N, DEERS. ICD9 = 250.X0 or 250.X2 was used to identify individuals with type 2 diabetes; TRICARE Prime is the HMO-like option for MHS beneficiaries. † Active Duty includes Guard/Reserve personnel enrolled in TRICARE Prime; Dependent of Active Duty includes dependents of Guard/Reserve personnel enrolled in TRICARE Prime; Beneficiaries with "other" as the beneficary category include Presidential Appointees, DoD civil service, DoD Contractors, Disabled Veterans, former service members who were eligible to retire but chose to discharge, Medal of Honor persons, Transitional Assistance Management Program, Foreign Military, and Foreign national employees.

7. As of 8/18/2015 7 Table 2: Cardiovascular Outcomes (AMI and CHF) by Anti-Diabetic Prescription Drug Class among MHS TRICARE Prime Enrollees with a Diagnosis of Type 2 Diabetes, Fiscal Year 2003-2006 * AMICHF Prescription Drug N Dispensed DrugN Average Annual Incidence per 10,000N TZD2000229937.3772190.12 Avandia 1340020237.6946386.38 Actos783111135.4429192.90 Biguanides5809176933.09157667.82 Sulfonylureas2352045748.58984104.59 Insulin1185424551.67541114.10 Meglitinides (Prandin & Starlix)1009 †† Amylin Analogs (Byetta & Symlin) 1310 Alpha-Glucosidase Inhibitors (Glyset & Precose) 299 * Data source: PDTS. Therapeutic Class Code= 6820XX for antidiabetic drugs; SIDR, SADR, TED-I, TED-N. ICD9 = 250.X0 or 250.X2 for Diabetes Type II. ICD9 = 410.XX for AMI. ICD9 = 428.XX for CHF; Data are presented at patient level; TRICARE Prime is the HMO-like option for MHS beneficiaries; Drug Categories are not Mutually Exclusive; Combination drugs are assigned to each drug group within the combination. † Data suppressed due to small N

8. As of 8/18/2015 8 Results Table 1 –232,000 Prime enrollees with dx of type 2 diabetes between fiscal year 2003 – 2006 54% female; 70% 45 – 64 years old; 8% active duty; 15% dependents of active duty; 54% retirees and their dependents; 21% missing beneficiary information

9. As of 8/18/2015 9 Results (cont.) Table 2 Annual incidence rates averaged over 4 years AMI: range from 33/10,000 (biguanides) to 52/10,000 (insulin); 38/10,000 for Avandia, 35/10,000 for Actos, 37/10,000 for any TZD class of drugs, 49/10,000 for sulfonylureas

10. As of 8/18/2015 10 Results (cont.) CHF: range from 68/10,000 (biguanides) to 114/10,000 (insulin); 86/10,000 for Avandia, 93/10,000 for Actos, 90/10,000 for any TZD class of drugs, 105/10,000 for sulfonylureas Bottom line: No increased incidence of select cardiovascular events (acute MI and CHF) among MHS Prime beneficiaries who filled a script for Avandia compared to those who filled scripts for other anti-diabetic medications

11. As of 8/18/2015 11 Limitations Cannot determine from these data if differences in average annual incidence rates of outcomes are due to anti-diabetic drug; disease progression; number, types and severity of comorbidities; or, other risk factors such as age Study did not include those 65 and older Claims data do not include socioeconomic status, comorbid conditions, current health status, medical history, drug dose, time on drug, concurrent medications, individual characteristics (e.g. BMI)

12. As of 8/18/2015 12 Limitations (cont.) AMI/CHF attributed to anti-diabetic class if script filled any time prior to event (assumes cause-effect relationship) Because drug categories were not mutually exclusive, unable to make statistical comparisons for significance

13. As of 8/18/2015 13 Future Efforts Possible studies –Retrospective cohort study to include medical record review/time to event analysis –Prospective study of cohort of type 2 diabetics with reference cohort and appropriate uniform medical evaluation DoD/FDA working on an MOU to permit surveillance of DoD pharmacy data to track sentinel events