1. Overcoming the challenge of blood pressure control in prediabetic and diabetic patients: PICASSO T2D Study Efficacy and tolerability of fixed dose combination perindopril/indapamide in type 2 diabetes

2. Background and objective of the study 2 The “bad companions” make blood pressure control challenging Objective of the study  The objective of PICASSO T2D study is to assess the efficacy and the tolerability of a fixed-dose combination of perindopril and indapamide in lowering blood pressure  Hypertension and type 2 diabetes deteriorate the vascular environment and lead to micro- and macrovascular disease  Epidemiologic data from key studies (NHANES and I-SEARCH) highlight the need for improving treatment strategies Diabetic patients are more likely to be treated with antihypertensive drugs However, they were 53% less likely to reach control than non diabetic patients Recent guidelines recommend to use combinations  For diabetic hypertensive patients, European guidelines (ESH/ESC 2013) recommend the use of combination therapy, especially including RAAS inhibitors  Perindopril/indapamide is thus well suited for the treatment of diabetic patients Ferrannini E, Cushman WC. Diabetes and hypertension: the bad companions. Lancet. 2012;380:601-10 / United States 2010 National Health and Nutrition Examination Survey / International Survey Evaluating Microalbuminuria Routinely by Cardiologists in Patients with Hypertension / ESH-ESC 2013 Guidelines

3. Methodology involved a retrospective analysis of a subgroup of patients of PICASSO study 3 Patient profile Treatment and follow-up Endpoints  Patients with hypertension as defined by 2007 ESC/ESH guidelines, with systolic blood pressure (SBP)/diastolic blood pressure (DBP) <130/80 mm Hg  Blood pressure targets for patients with prediabetes are defined as <140/90 mm Hg  Patients with T2D were reported on case files, prediabetic patients were defined as patients with a fasting blood glucose 5.6-6.9 mmol/L or with a positive oral glucose tolerance test  PICASSO study was a 3-month observational study conducted on 9 257 uncontrolled hypertensive patients  Data of a subgroup of 2 762 patients with type 2 diabetes (T2D, N=1 887) or prediabetes (N=875) were retrospectively analyzed  Patients received a fixed-dose combination of perindopril/indapamide 10mg/2.5mg for 3 months  Additional antihypertensive agents were allowed to be maintained or added according to the doctor’s appreciation  Patients were measured at baseline, after one month and after 3 months of treatment  Office and ambulatory blood pressure (SBP/DBP)  Laboratory parameters to assess tolerance (fasting plasma glucose, serum total cholesterol, HDL- C, LDL-C, triglycerides, potassium, creatinine and uric acid), at baseline and at 3 months Farsang C, on behalf of the PICASSO investigators. Blood Press. 2013;22 Suppl 1:3-10 / ESH-ESC 2007 guidelines

4.  Changes from baseline to 3 months were statistically significant (-26.9±14.8/-12.7±9.8 mm Hg; p <0.001)  After 3 months of treatment, blood pressure control was reached in 69% of patients  Significant reductions were achieved regardless of the severity of hypertension at inclusion Results for office blood pressure 4 Mean office SBP/DBP change over three months  Mean office SBP/DBP decreased significantly regardless of previous other treatments  In particular, office blood pressure decreased significantly in patients previously treated by a RAAS inhibitor±HCTZ (n = 1991), from 159.5±14.7/92.5±9.7 to 132.3±9.8/80.0±6.3 mm Hg (p <0.001)  The decrease in office blood pressure was similar for patients previously on ACE inhibitors±HCTZ or on ARB±HCTZ (both p <0.001) Mean office SBP/DBP change according to previous other treatments Farsang C, on behalf of the PICASSO investigators. Blood Press. 2013;22 Suppl 1:3-10

5. Results for ambulatory blood pressure 5  Mean day-time, night-time, and 24-hour BP as well as mean 24-hour pulse pressure, mean arterial pressure, and mean 24-hour heart rate decreased significantly over 3 months of treatment (p <0.001) Ambulatory SBP/DBP change after three months  In patients previously treated with ACE inhibitor±HCTZ (n = 67) or ARB±HCTZ (n = 10), mean 24-hour blood pressure decreased by 23.4±13.9/11.5±9.7 mm Hg and 22.3±8.7/10.4±13.2 mm Hg, respectively (p <0.001) Ambulatory SBP/DBP change after three months and compared with other previous treatments  93 patients were followed up through ambulatory blood pressure monitoring system Farsang C, on behalf of the PICASSO investigators. Blood Press. 2013;22 Suppl 1:3-10

6. Results for tolerability 6  Metabolic markers were measured according to doctors’ willingness  Significant reductions of total cholesterol, LDL-C, glucose and triglycerides were measured after three months  Treatment was overall well tolerated, with 36 cases of drug-related adverse events reported, including Ankle edema (N=11 patients, 0.4% of patients) Dizziness (N=7 patients, 0.3% of patients) Cough (N=6 patients, 0.2% of patients) Seven serious adverse events were reported, none of which related to the study Metabolic parameters change after three months of treatment with fixed dose combination of Perindopril/Indapamide Farsang C, on behalf of the PICASSO investigators. Blood Press. 2013;22 Suppl 1:3-10

7. Conclusion 7  PICASSO T2D study sticks to the challenges of daily medical practice (uncontrolled hypertension in diabetic or prediabetic patients, despite treatment)  BP was significantly reduced after three months of treatment  The treatment was well tolerated and improved laboratory parameters  Ambulatory SBP, BP variability and pulse pressure are predictors of cardiovascular risk  In addition, BP variability through the day is impacting organ damage  Thus, a long-term study would be interesting to assess the impact of perindopril/indapamide on organ damage and cardiovascular risk  For diabetic patients, treatment with ACE inhibitors is recommended for their cardioprotective and nephroprotective effects  This recommendation has been confirmed in a recent analysis (CMAJ 2013)  In addition, the British Society of Hypertension has recently recommended the use of indapamide or chlortalidone rather than HCTZ Key elements Significant results relevant to real life practice Significant results with long-term impact to be further assessed Results in line with guidelines Farsang C, on behalf of the PICASSO investigators. Blood Press. 2013;22 Suppl 1:3-10 / Lv J, Ehteshami P, Sarnak MJ, et al. CMAJ 2013.