1	PROactive Study
2	PRESIDENT OF THE EASD Professor Ele Ferrannini
3	PROactive Study
4	Duality of Interest Declaration
5	Programme Rationale and study design: Professor Erland Erdmann Baseline characteristics: Professor Massimo Massi-Benedetti Cardiovascular results: Professor John Dormandy Metabolic results: Professor Bernard Charbonnel Safety: Professor Pierre LefËbvre Summary / Conclusion: Professor John Dormandy Commentary: Professor Hannele Yki-J”rvinen Questions and answers
6	RATIONALE Professor Erland Erdmann
7	Global Projections for the Diabetes Epidemic: 2003-2025 (millions)
8	Reduction in Life Expectancy of Patients with Type 2 Diabetes by Age at Diagnosis
9	Fatal and Non-fatal Myocardial Infarction and Stroke in Patients with Type 2 Diabetes (adjusted to age 60)
10	Cardiovascular Events in Patients with Type 2 Diabetes Compared to General Population
11	Annual Macrovascular Event Rates Macrovascular event rates in diabetes No evidence of cardiovascular disease 2% Established cardiovascular risk markers 5% Evidence of cardiovascular disease (MI etc.) 5ñ8% UKPDS (newly diagnosed people with diabetes)¹ macrovascular endpoint 2% 4S Study CHD death or non-fatal MI in diabetes² on simvastatin 5% on placeboÝÝÝÝ 11% VA HIT Study (Documented CV diseases, low HDL, 25% with diabetes)³ 5.8%
12	Summary 195 million people with type 2 diabetes mellitus in the world 50 million patients with type 2 diabetes mellitus in Europe Fatal and non-fatal cardiovascular events in 4-6% of patients with type 2 diabetes every year Total mortality and major non-fatal cardiovascular events 3 times more likely than in age-matched non-diabetic population Life expectancy reduced by up to 10 years
13	Current glucose-lowering agents
14	Pioglitazone Glucose-lowering agent Improves insulin sensitivity Improves diabetic dyslipidaemia Elevates HDL cholesterol levels Lowers triglyceride levels Increases size of LDL particles
15	Pioglitazone Glucose-lowering agent Improves insulin sensitivity Improves diabetic dyslipidaemia Elevates HDL cholesterol levels Lowers triglyceride levels Increases size of LDL particles May be able to positively modulate vessel wall disease by: Reducing CRP Inhibiting smooth muscle cell proliferation Inhibiting cell migration Decreasing vascular inflammation
16	PROactive Study Objectives In high-risk patients with type 2 diabetes: To demonstrate that pioglitazone reduces total mortality and macrovascular morbidity To further characterise the safety of pioglitazone
17	Participating Countries
18	Committees
19	National Principal Investigators
20	Committees
21	Role of NCRL and ICON Nottingham Clinical Research Study Coordinating Centre Project management Data management Central randomisation services Statistical analysis ICON Clinical Research Site management and monitoring Regulatory affairs Central laboratory measurements
22	STUDY DESIGN
23	PROactive Study Design Prospective, multi-centre, randomised, double-blind, placebo-controlled, parallel-group study Planned recruitment of 5000 patients Minimum of 2.5 years exposure to treatment Event driven: >760 endpoint events 91% power to detect a 20% reduction in the hazard rate
24	PROactive Study Design Prospective, multi-centre, randomised, double-blind, placebo-controlled, parallel-group study Planned recruitment of 5000 patients Minimum of 2.5 years exposure to treatment Event driven: >760 endpoint events 91% power to detect a 20% reduction in the hazard rate Existing therapy continued with diet and glucose-lowering agents, as well as antihypertensives, lipid-altering agents, antithrombotic agents Patient management throughout study to be according to the 1999 International Diabetes Federation (Europe) Guidelines
25	Allocation to Treatment
26	Inclusion Criteria (1) Male or female patients with type 2 diabetes mellitus, aged 35ñ75 years inclusive HbA_1c above the upper limit of normal (i.e. the local equivalent of 6.5% for a DCCT traceable assay) as determined by local laboratory At increased cardiovascular risk as defined by the inclusion criteria
27	Inclusion Criteria (2) Established history of macrovascular disease, defined as one or more of: Myocardial infarction (MI) ≥6 months Stroke ≥6 months Percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) ≥6 months Acute coronary syndrome (ACS) ≥3 months Objective evidence of coronary artery disease (positive exercise test or scintigraphy, angiography showing at least one lesion >50% stenosis) Symptomatic peripheral artery disease or amputation due to ischaemia
28	Principal Exclusion Criteria Evidence of type 1 diabetes Patients requiring insulin as sole therapy for glycaemic control of diabetes Heart failure (NYHA Class IIñIV) Pre-planned coronary angiogram or endovascular or surgical intervention Leg ulcers, gangrene or pain at rest Significantly impaired hepatic function Pre-planned appointment for an angiogram, endovascular or surgical intervention for leg ischaemia Patient requires dialysis Current use of pioglitazone or other thiazolidinediones
29	Titration of Study Medication Forced titration Objective: to reach maximum dose of 45 mg The dose was to be increased after the first month from 15 to 30 mg and after the second month up to 45 mg to achieve the maximum tolerated dose The dose could be modified at any time in the study
30	Primary Endpoint Time from randomisation to first occurrence of any of the events in the following composite: All-cause mortality Non-fatal MI (including silent MI) Stroke Major leg amputation (above the ankle) Acute coronary syndrome (ACS) Cardiac intervention including coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI) Leg revascularisation
31	Principal Secondary Endpoint Time from randomisation to first occurrence of any of the events in the following composite: All-cause mortality Non-fatal MI (including silent MI) Stroke Major leg amputation (above the ankle) Acute coronary syndrome (ACS) Cardiac intervention including coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI) Leg revascularisation
32	Secondary Endpoints Pre-Defined in Statistical Analysis Plan In order of pre-defined priority: All-cause mortality Non-fatal MI (excluding silent MI) Stroke
33	Secondary Endpoints Pre-Defined in Statistical Analysis Plan In order of pre-defined priority: All-cause mortality Non-fatal MI (excluding silent MI) Stroke Cardiovascular mortality
34	Secondary Endpoints Pre-Defined in Statistical Analysis Plan In order of pre-defined priority: All-cause mortality Non-fatal MI (excluding silent MI) Stroke Cardiovascular mortality Individual components of the primary composite endpoint
35	BASELINE CHARACTERISTICS Professor Massimo Massi-Benedetti
36	PROactive Study Charbonnel B, Dormandy J, Erdmann E, Massi-Benedetti M, Skene A. The Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive): Can pioglitazone reduce cardiovascular events in diabetes? Study design and baseline characteristics of 5,238 patients Diabetes Care 2004; 27: 1647ñ1653
37	Recruitment
38	Recruitment
39	Baseline (1)
40	Baseline (2)
41	Entry Criteria: Evidence of Macrovascular Disease
42	Overlap of Previous Macrovascular Events
43	Overlap of Previous Macrovascular Events
44	Overlap of Previous Macrovascular Events
45	Other History
46	Glucose-Lowering Medication at Baseline
47	Cardiovascular Medication at Baseline (1)
48	Cardiovascular Medication at Baseline (2)
49	Baseline Laboratory Values
50	Summary: Baseline Characteristics Well matched Severe macrovascular disease 95% receiving cardiovascular medication
51	CARDIOVASCULAR RESULTS Professor John Dormandy
52	5602 Patients Screened (a)
53	5602 Patients Screened (b)
54	5602 Patients Screened (c)
55	5602 Patients Screened (d)
56	5602 Patients Screened (f)
57	Study Quality
58	Pattern of Dose Titration
59	Primary Endpoint Time from randomisation to first occurrence of any of the events in the following composite: All-cause mortality Non-fatal MI (including silent MI) Stroke Major leg amputation (above the ankle) Acute coronary syndrome (ACS) Cardiac intervention including coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI) Leg revascularisation
60	Time to Primary Composite Endpoint
61	Principal Secondary Endpoint Time from randomisation to first occurrence of any of the events in the following composite: All-cause mortality Non-fatal MI Stroke
62	Time to Death, MI (Excluding Silent) or Stroke
63	Summary of Results
64	Numbers of First Events Contributing to the Primary Composite Endpoint
65	Numbers of First Events Contributing to the Principal Secondary Endpoint
66	Numbers of First Events Contributing to the Primary Composite and Principal Secondary Endpoints
67	Numbers of First Events Contributing to the Primary Composite and Principal Secondary Endpoints
68	Numbers of First Events Contributing to the Primary Composite and Principal Secondary Endpoints
69	Total Numbers of Events for each Component of the Primary Endpoint
70	Demographic Subgroups
71	Entry Criteria Subgroups
72	Metabolic Subgroups
73	Baseline Medication Subgroups
74	Other Variables with p >0.05 Gender BMI Duration of diabetesÝÝÝÝÝÝÝÝ (<5 / 5ñ<10 / „10 years) Metformin/Sulphonylurea use Combined blood pressureÝÝ (low risk/high risk) TriglyceridesÝÝÝÝÝÝÝÝÝÝÝÝÝÝÝÝÝÝÝÝÝ (low risk/at risk/high risk) HDL cholesterolÝÝÝÝÝÝÝÝÝÝÝÝÝÝÝÝÝÝÝÝÝÝÝÝÝÝÝÝÝÝÝÝÝ (low risk/at risk/high risk)
75	Multivariate Analysis (Significance p < 0.05)
76	Summary: PROactive Cardiovascular Results We now know that pioglitazone can reduce macrovascular events: 10% relative risk reduction in the primary endpoint 16% relative risk reduction in the principal secondary endpoint (non-fatal MI, stroke and death), which was statistically significant The effect appeared to be consistent across the subgroups
77	METABOLIC RESULTS
78	Change in Concomitant Medication Use to Final Visit
79	Time to Permanent Insulin Use
80	Time Course of HbA_1c
81	Time Course of Triglycerides
82	Time Course of HDL Cholesterol
83	Time Course of LDL/HDL
84	Change in Laboratory Data from Baseline to Final Visit
85	Blood Pressure
86	Factors Possibly Contributing to the Beneficial Effect of Pioglitazone
87	Summary of PROactive Metabolic Results Decrease in HbA_1c 50% reduction in progression to permanent insulin use Improved diabetic dyslipidaemia Reduction in blood pressure Mechanism is being investigated
88	SAFETY
89	Safety Data Collected SAEs, including SAEs that were also endpoints Detailed information on specified non-serious AEs (AEs causing withdrawal, heart failure, oedema, hypoglycaemia) Other AEs Liver and renal tests regularly throughout the study Vital signs at every visit
90	Definition of a Serious Adverse Event An adverse event that falls in any of the following categories: Fatal Life-threatening Requires in-patient hospitalisation or occurs while in hospital and prolongs hospital stay Results in persistent or significant disability or incapacity Congenital anomaly / birth defect Important medical event that requires intervention to prevent one of the above
91	Summary of Serious Adverse Events
92	Serious Adverse Events Occurring in >1% of Patients (Excluding Endpoints)
93	Heart Failure
94	Malignant Neoplasms
95	Bladder Cancer
96	Other Pre-defined Adverse Events of Interest
97	Time Course of ALT
98	Summary: PROactive Safety Conclusions PROactive has demonstrated: No liver toxicity No increase in malignant neoplasms No increase in heart failure resulting in death 1.6% increase in congestive heart failure requiring hospitalisation Increase in non-serious hypoglycaemia Increase in peripheral oedema Average weight gain of 3.6 kg
99	STUDY CONCLUSIONS
100	Summary of Results
101	Summary of Results
102	PROactive Study Conclusions We have now shown for the first time in a prospective study that a glucose-lowering medication can prevent macrovascular events In high-risk patients with type 2 diabetes: Pioglitazone reduces the composite of all-cause mortality, non-fatal myocardial infarction and stroke Pioglitazone decreases the need for conversion to insulin therapy
103	PROactive Study