1. BLOOD PRESSURE LOWERING

2. UKPDS design Aim To determine whether intensified blood glucose control, with either sulphonylurea or insulin, reduces the risk of macrovascular or microvascular complications in type 2 diabetes. To determine the effect of aggressive blood pressure control. Study Population 3867 newly diagnosed type 2 diabetic patients who were asymptomatic after 3 months of diet ; fasting glucose 6.1–15 mmol/l (110–270 mg/dl) ; treat for 10 years. Aim To determine whether intensified blood glucose control, with either sulphonylurea or insulin, reduces the risk of macrovascular or microvascular complications in type 2 diabetes. To determine the effect of aggressive blood pressure control. Study Population 3867 newly diagnosed type 2 diabetic patients who were asymptomatic after 3 months of diet ; fasting glucose 6.1–15 mmol/l (110–270 mg/dl) ; treat for 10 years. Adapted from UK Prospective Diabetes Study (UKPDS) Group Lancet 1998;352:837-853; Turner R et al Ann Intern Med 1996;124(1 pt 2):136-145.

3. UKPDS : diabetes related endpoints Diabetes related death Diabetes related death Non fatal myocardial infarction, heart failure or angina Non fatal myocardial infarction, heart failure or angina Non fatal stroke Non fatal stroke Amputation Amputation Renal failure Renal failure Retinal photocoagulation or vitreous haemorrhage Retinal photocoagulation or vitreous haemorrhage Cataract extraction or blind in one eye Cataract extraction or blind in one eye Diabetes related death Diabetes related death Non fatal myocardial infarction, heart failure or angina Non fatal myocardial infarction, heart failure or angina Non fatal stroke Non fatal stroke Amputation Amputation Renal failure Renal failure Retinal photocoagulation or vitreous haemorrhage Retinal photocoagulation or vitreous haemorrhage Cataract extraction or blind in one eye Cataract extraction or blind in one eye

4. UKPDS 38 : 154/87 versus 144/82 UK Prospective Diabetes Study (UKPDS) Group (38). BMJ 1998;317:703–713 MI Microvascular endpoint –34% Heart failure –35% Stroke –37% All macrovascular endpoints –44% Retinal photocoagulation –56% Any diabetes-related endpoint –24% 0-10-20-30-40-50 % Reduction in risk -24 Significant -34 Significant -21 Non significant -44 Significant -56 Significant -37 Significant -35 Significant

5. UKPDS : diabetes-related deaths 0% 5% 10% 15% 20% 0369 % of patients with events Years from randomisation Tight blood pressure control (758) Less tight blood pressure control (390) Risk reduction 32% ( p=0.019 )

6. UKPDS : microvascular endpoints 0% 5% 10% 15% 20% 25% 0369 % patients with event Years from randomisation Tight Blood Pressure Control (758) Less Tight Blood Pressure Control (390) Risk reduction 37% ( p=0.0092 )

7. In 1148 type 2 diabetic patients a tight blood pressure control policy which achieved blood pressure of 144 / 82 mm Hg gave reduced risk for : Any diabetes-related endpoint 24% p=0.0046 Diabetes-related deaths 32% p=0.019 Stroke 44% p=0.013 Microvascular disease 37% p=0.0092 Heart failure56% p=0.0043 Retinopathy progression 34% p=0.0038 Deterioration of vision 47% p=0.0036 In 1148 type 2 diabetic patients a tight blood pressure control policy which achieved blood pressure of 144 / 82 mm Hg gave reduced risk for : Any diabetes-related endpoint 24% p=0.0046 Diabetes-related deaths 32% p=0.019 Stroke 44% p=0.013 Microvascular disease 37% p=0.0092 Heart failure56% p=0.0043 Retinopathy progression 34% p=0.0038 Deterioration of vision 47% p=0.0036 UKPDS blood pressure control study

8. Risk of Diabetes Complications by BP and HbA1c%

9. BP Treatment Targets: Moving the Goalposts BP Treatment Targets: Moving the Goalposts 145 / 85 140 / 80 130 / 80 QOF Alphabet Strategy JBS2

10. Blood pressure lowering agents What will you use?

11. Blood pressure lowering agents

13. ALLHAT 33,357 subjects : > 55 years with BP+ and at least one other CHD risk factor. 33,357 subjects : > 55 years with BP+ and at least one other CHD risk factor. Randomised to chlorthalidone, amlodipine or lisinopril. Randomised to chlorthalidone, amlodipine or lisinopril. Target BP < 140 / 90 : achieved 135 / 75. Target BP < 140 / 90 : achieved 135 / 75. Primary endpoint : combined fatal CHD or nonfatal MI. Primary endpoint : combined fatal CHD or nonfatal MI. Mean follow-up 4.9 years. Mean follow-up 4.9 years. No major differences between agents. No major differences between agents. 33,357 subjects : > 55 years with BP+ and at least one other CHD risk factor. 33,357 subjects : > 55 years with BP+ and at least one other CHD risk factor. Randomised to chlorthalidone, amlodipine or lisinopril. Randomised to chlorthalidone, amlodipine or lisinopril. Target BP < 140 / 90 : achieved 135 / 75. Target BP < 140 / 90 : achieved 135 / 75. Primary endpoint : combined fatal CHD or nonfatal MI. Primary endpoint : combined fatal CHD or nonfatal MI. Mean follow-up 4.9 years. Mean follow-up 4.9 years. No major differences between agents. No major differences between agents.

15. ASCOT-BPLA Study 19,257 subjects : 40-79 years with BP+ and at least three other CHD risk factors. 19,257 subjects : 40-79 years with BP+ and at least three other CHD risk factors. Randomised to amlodipine + perindopril or atenolol + bendroflumethiazide. Randomised to amlodipine + perindopril or atenolol + bendroflumethiazide. Target BP < 140 / 90 : 130 / 80 in diabetes. Target BP < 140 / 90 : 130 / 80 in diabetes. Mean follow-up 5.5 years. Mean follow-up 5.5 years. Fewer strokes, CV events & procedures and deaths in amlodipine group... Fewer strokes, CV events & procedures and deaths in amlodipine group... … and 30% less new diabetes. … and 30% less new diabetes. 19,257 subjects : 40-79 years with BP+ and at least three other CHD risk factors. 19,257 subjects : 40-79 years with BP+ and at least three other CHD risk factors. Randomised to amlodipine + perindopril or atenolol + bendroflumethiazide. Randomised to amlodipine + perindopril or atenolol + bendroflumethiazide. Target BP < 140 / 90 : 130 / 80 in diabetes. Target BP < 140 / 90 : 130 / 80 in diabetes. Mean follow-up 5.5 years. Mean follow-up 5.5 years. Fewer strokes, CV events & procedures and deaths in amlodipine group... Fewer strokes, CV events & procedures and deaths in amlodipine group... … and 30% less new diabetes. … and 30% less new diabetes.

16. GFR Proteinuria Aldosterone release Glomerular sclerosis Angiotensin II may play a central role in organ damage Adapted from Willenheimer R et al Eur Heart J 1999; 20(14): 997  1008, Dahlöf B J Hum Hypertens 1995; 9(suppl 5): S37  S44, Daugherty A et al J Clin Invest 2000; 105(11): 1605  1612, Fyhrquist F et al J Hum Hypertens 1995; 9(suppl 5): S19  S24, Booz GW, Baker KM Heart Fail Rev 1998; 3: 125  130, Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy. 17th ed. Whitehouse Station, NJ: Merck Research Laboratories 1999: 1682  1704, Anderson S Exp Nephrol 1996; 4(suppl 1): 34  40, Fogo AB Am J Kidney Dis 2000; 35(2):179  188 A II AT 1 receptor Atherosclerosis Vasoconstriction Vascular hypertrophy Endothelial dysfunction LV hypertrophy Fibrosis Remodeling Apoptosis Stroke DEATH LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate Hypertension Heart failure MI Renal failure

17. HOPE Study 9300 high-risk subjects : 3500 with diabetes 9300 high-risk subjects : 3500 with diabetes Ramipril 10 mg versus placebo Ramipril 10 mg versus placebo CV death, MI, stroke  25% in diabetic subjects CV death, MI, stroke  25% in diabetic subjects Difference in BP between groups = 3/1 Difference in BP between groups = 3/1 Mechanism uncertain Mechanism uncertain ? Specific effect of ACE inhibition ? Specific effect of ACE inhibition ? BP lowering ? BP lowering Specific to ramipril or a class effect ? Specific to ramipril or a class effect ? 9300 high-risk subjects : 3500 with diabetes 9300 high-risk subjects : 3500 with diabetes Ramipril 10 mg versus placebo Ramipril 10 mg versus placebo CV death, MI, stroke  25% in diabetic subjects CV death, MI, stroke  25% in diabetic subjects Difference in BP between groups = 3/1 Difference in BP between groups = 3/1 Mechanism uncertain Mechanism uncertain ? Specific effect of ACE inhibition ? Specific effect of ACE inhibition ? BP lowering ? BP lowering Specific to ramipril or a class effect ? Specific to ramipril or a class effect ? HOPE Study Investigators, Lancet 2000; 355:253

18. 0.00 0.02 0.04 0.06 0.08 0.10 0.12 0.14 0.16 0500100015002000 Days of Follow-up Kaplan-Meier Rates ramiprilPlacebo HOPE : MI rate - ramipril vs placebo in diabetics RRR = 22% (6 - 36) p= 0.01

19. HOPE : stroke rate - ramipril vs placebo in diabetics 0.00 0.02 0.04 0.06 0.08 0500100015002000 Days of Follow-up Kaplan-Meier Rates ramiprilPlacebo RRR = 33% (10 - 50) p=0.0074

20. HOPE : CV death - ramipril vs placebo in diabetics 0.00 0.02 0.04 0.06 0.08 0.10 0.12 0500100015002000 Days of Follow-up Kaplan-Meier Rates ramiprilPlacebo RRR = 37% (21 - 51) p=0.0001

22. LIFE Study 9200 patients with hypertension and LVH : 1200 with diabetes 9200 patients with hypertension and LVH : 1200 with diabetes Losartan versus atenolol (with add-on medications) Losartan versus atenolol (with add-on medications) Target BP 140/90 : BP lowering similar in both groups Target BP 140/90 : BP lowering similar in both groups In diabetics 1 0 endpoint  25%, CV mortality  37% In diabetics 1 0 endpoint  25%, CV mortality  37% More LVH regression in losartan group More LVH regression in losartan group Fewer losartan patients developed albuminuria (7% versus 13%) Fewer losartan patients developed albuminuria (7% versus 13%) Cannot extrapolate to subjects without LVH ? Cannot extrapolate to subjects without LVH ? 9200 patients with hypertension and LVH : 1200 with diabetes 9200 patients with hypertension and LVH : 1200 with diabetes Losartan versus atenolol (with add-on medications) Losartan versus atenolol (with add-on medications) Target BP 140/90 : BP lowering similar in both groups Target BP 140/90 : BP lowering similar in both groups In diabetics 1 0 endpoint  25%, CV mortality  37% In diabetics 1 0 endpoint  25%, CV mortality  37% More LVH regression in losartan group More LVH regression in losartan group Fewer losartan patients developed albuminuria (7% versus 13%) Fewer losartan patients developed albuminuria (7% versus 13%) Cannot extrapolate to subjects without LVH ? Cannot extrapolate to subjects without LVH ? Lindholm LH et al (2002) Lancet 359, 1004 - 1010.

23. * Other antihypertensives excluding ACEIs, AII antagonists, beta-blockers. Dahlöf B et al (1997) Am J Hypertens 10:705  713. LIFE : study design Day  14 Day  7 Day 1 Mth 1 Mth 2 Mth 4 Mth 6 Yr 1 Yr 1.5 Yr 2 Yr 2.5 Yr 3 Yr 3.5 Yr 4 Yr 5 Titration to target blood pressure: <140 / <90 mmHg Placebo Losartan 50 mg Atenolol 50 mg Losartan 50 mg + HCTZ 12.5 mg Losartan 100 mg + HCTZ 12.5 mg Losartan 100 mg + HCTZ 12.5-25 mg + others* Atenolol 50 mg + HCTZ 12.5 mg Atenolol 100 mg + HCTZ 12.5 mg Atenolol 100 mg + HCTZ 12.5-25 mg + others*

27. Adverse events LosartanAtenololP Withdrawals 2 (0.3%) 9 (2%) 0.065 Bradycardia 6 (1%) 50 (8%) < 0.0001 Albuminuria 43 (7%) 79 (13%) 0.002 Lindholm LH et al (2002) Lancet 359, 1004 - 1010.

29. LIFE: New Onset Diabetes by Treatment Group Study Month 0612182430364248546066 0 2 4 6 8 10 Proportion of patients, % Atenolol Losartan

30. The Alphabet Strategy AdviceSmoking, diet, exercise AdviceSmoking, diet, exercise Blood pressure < 140/80 Blood pressure < 140/80 Cholesterol Cholesterol TC < 4.0 mmol/l, LDL ≤ 2.0 mmol/l HDL > 1.0 mmol/l, TGs 1.0 mmol/l, TGs < 1.7 mmol/l Diabetes control HbA1c ≤ 7% Diabetes control HbA1c ≤ 7% Eye examination Annual examination Eye examination Annual examination Feet examination Annual examination Feet examination Annual examination Guardian drugs Aspirin, ACEI, ARB, statins Guardian drugs Aspirin, ACEI, ARB, statins AdviceSmoking, diet, exercise AdviceSmoking, diet, exercise Blood pressure < 140/80 Blood pressure < 140/80 Cholesterol Cholesterol TC < 4.0 mmol/l, LDL ≤ 2.0 mmol/l HDL > 1.0 mmol/l, TGs 1.0 mmol/l, TGs < 1.7 mmol/l Diabetes control HbA1c ≤ 7% Diabetes control HbA1c ≤ 7% Eye examination Annual examination Eye examination Annual examination Feet examination Annual examination Feet examination Annual examination Guardian drugs Aspirin, ACEI, ARB, statins Guardian drugs Aspirin, ACEI, ARB, statins

31. Thank you for listening !