1. Analysis of the ADVANCE Trial Sapna N. Patel UCSF Pharm. D. Candidate 2008 Preceptor Dr. Craig S. Stern March 28, 2008

2. Background Total Prevalence: 20.8 million people (7% of U.S. population)  Diagnosed: 14.6 million  Undiagnosed: 6.2 million ~176,500 < 20 years old 1/600 children have type 1 diabetes 6 th leading cause of death contributing to 224,000 deaths/year

3. Relevance Diabetes is a very common, serious disease Medications to improve outcomes of diabetes are much needed Pro Pharma consultants should be aware of new drug strategies being studied to improve outcomes of diabetes Diabetes associated with increased health costs Identifying patterns of use and improved biologic markers can help clients control expenditures by finding more effective strategies to deal with this chronic disease

4. Perindopril (Aceon) Mechanism: Reduces blood pressure by inhibiting the activity of ACE which results in decreased plasma angiotensin II which then decreases vasoconstriction and aldosterone secretion Therapeutic Use: Lower blood pressure, reduce coronary events Adverse Effects: Hypotension, Hyperkalemia, Nausea, Dizziness, Cough Clinical Effect: Lower blood pressure in 2-3 weeks

5. Indapamide (Lozol) Mechanism of Action: antihypertensive: not well understood Therapeutic Use: lower blood pressure, decrease edema Adverse Effects: Hypotension, Hyperkalemia, Nausea, Dizziness, Cough Clinical Effect: 4 weeks

6. ADVANCE Trial The Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus, a randomised controlled trial

7. Study Aim Objective: Determine the effect of ACE inhibitor-diuretic combination on serious vascular events in patients in diabetes, irrespective of initial blood pressure levels or the use of other blood pressure lowering drugs Study Design: Multicenter, randomized, double-blind, placebo-controlled

8. Methods 6-week pre-randomisation: all patients receive perindopril (2mg) and indapamide (0.625mg) Randomization: perindopril (2mg) and indapamide (0.625mg) OR placebo Monitoring: Post-randomization: 3, 4, 6 months and 6 months thereafter for trial duration Trial duration: 4.3 years

9. Outcomes Primary Endpoint:  Composites of major macrovascular & microvascular events Macrovascular events: cardiovascular events, non-fatal myocardial infarction, or non-fatal stroke Microvascular events: new or worsening nephropathy, retinopathy Secondary Endpoints:  All cause mortality, cardiovascular death, major coronary events

10. Results Primary Endpoint:  Decreased microvascular & macrovascular events (15.5% vs. 16.8% placebo, 95% CI* 0.83-1.00, p=0.04)  Decreased microvascular OR macrovascular events: not significant *=Confidence interval **= Cardiovascular disease

11. Results (cont) Secondary Endpoint:  Decreased death from CV disease** (3.8% vs. 4.6% placebo, 95% CI* 0.68- 0.98, p=0.03)  Decreased death from any-cause (7.3% vs. 8.5% placebo, 95% CI 0.75-0.98, p=0.03) *=Confidence interval **= Cardiovascular disease

12. Results (cont) Safety:  Cough (3.3% vs. 1.3% placebo)  Hypotension/dizziness (1.2% vs.0.4%)  Serious adverse events (1.2% vs. 1.2%)

13. Pros Randomized, Double-blind, Placebo-controlled Large study group  N=11140 Extended Duration  4.3 years Clinically significant area for study  Mortality outcomes Mimic real-world setting  Patients on background therapy Intention to treat applied  All patients accounted

14. Cons Inclusion Criteria  Selection of low-risk patients: diabetes diagnosis ≥ 30 years Bias between groups  Background concomittant therapy Wide Confidence Intervals  Unclear if results due to chance Composite of secondary endpoints arbitrary  Worsening nephropathy as doubling of serum creatinine Response to outcome effects not clearly defined  Adherence measurements not defined

15. Relevance Diabetes is a chronic disease that affects many individuals in the U.S. Diabetes associated with increased health costs Identifying the place for different therapies for chronic diseases is essential for cost- effectiveness analysis and to improve outcomes New indications for therapy can change formularies and placement of drugs in categories when coding

16. References http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5708a 5.htm http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5708a 5.htm http://www.cdc.gov/diabetes/statistics/incidence/fig1.htm CDC Diabetes Fact Sheet 2005 Patel A, ADVANCE Collaborative Group, MacMahon S, et.al Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomized controlled trial. Lancet. 2007 Sep 8;370(9590):829-40.

17. References Chobanian AV, Bakris GL, Black HR et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report Micromedex Drugdex Evaluations-Perindopril, copyright 2006 by Thomson MICROMEDEX. Micromedex Drugdex Evaluations-Indapamide, copyright 2006 by Thomson MICROMEDEX. http://www.delfini.org/page_Glossary.htm