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BLOOD PRESSURE LOWERING

BLOOD PRESSURE LOWERING. 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 .

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BLOOD PRESSURE LOWERING

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  1. BLOOD PRESSURE LOWERING

  2. UKPDS design Aim To determine whether intensified blood glucosecontrol , 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 • Non fatal myocardial infarction , heart failure or angina • Non fatal stroke • Amputation • Renal failure • Retinal photocoagulation or vitreous haemorrhage • Cataract extraction or blind in one eye

  4. 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 UKPDS 38 : 154/87 versus 144/82 -21Non significant -34 Significant -35Significant -37Significant -44Significant -56 Significant -24 Significant UK Prospective Diabetes Study (UKPDS) Group (38). BMJ 1998;317:703–713

  5. UKPDS : diabetes-related deaths 20% Less tight blood pressure control (390) Tight blood pressure control (758) 15% % of patients with events 10% 5% Risk reduction32% ( p=0.019 ) 0% 0 3 6 9 Years from randomisation

  6. UKPDS : microvascular endpoints 25% Less Tight Blood Pressure Control (390) Tight Blood Pressure Control (758) 20% 15% % patients with event 10% 5% Risk reduction37% ( p=0.0092 ) 0% 0 3 6 9 Years from randomisation

  7. UKPDS blood pressure control study 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=0.0092Heart failure 56% p=0.0043 Retinopathy progression 34% p=0.0038 Deterioration of vision 47% p=0.0036

  8. Risk of Diabetes Complications by BP and HbA1c%

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

  10. Blood pressure lowering agents What will you use?

  11. Blood pressure lowering agents

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

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

  14. Angiotensin II may play a central role in organ damage Atherosclerosis Vasoconstriction Vascular hypertrophy Endothelial dysfunction Stroke Hypertension A II AT1 receptor LV hypertrophy Fibrosis Remodeling Apoptosis Heart failure MI DEATH GFR Proteinuria Aldosterone release Glomerular sclerosis Renal failure LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate 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

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

  16. HOPE : MI rate -ramipril vs placebo in diabetics 0.16 ramipril Placebo 0.14 RRR = 22% (6 - 36) p= 0.01 0.12 0.10 0.08 Kaplan-Meier Rates 0.06 0.04 0.02 0.00 0 500 1000 1500 2000 Days of Follow-up

  17. HOPE : stroke rate - ramipril vs placebo in diabetics 0.08 ramipril Placebo 0.06 RRR = 33% (10 - 50) p=0.0074 0.04 Kaplan-Meier Rates 0.02 0.00 0 500 1000 1500 2000 Days of Follow-up

  18. HOPE : CV death - ramipril vs placebo in diabetics 0.12 ramipril Placebo 0.10 RRR = 37% (21 - 51) p=0.0001 0.08 Kaplan-Meier Rates 0.06 0.04 0.02 0.00 0 500 1000 1500 2000 Days of Follow-up

  19. LIFE Study • 9200 patients with hypertension and LVH : 1200 with diabetes • Losartan versus atenolol (with add-on medications) • Target BP 140/90 : BP lowering similar in both groups • In diabetics 10 endpoint  25%, CV mortality  37% • More LVH regression in losartan group • Fewer losartan patients developed albuminuria (7% versus 13%) • Cannot extrapolate to subjects without LVH ? Lindholm LH et al (2002) Lancet359, 1004 - 1010.

  20. LIFE : study design Titration to target blood pressure: <140 / <90 mmHg Losartan 100 mg + HCTZ 12.5-25 mg + others* Losartan 100 mg + HCTZ 12.5 mg Losartan 50 mg + HCTZ 12.5 mg Losartan 50 mg Placebo Atenolol 50 mg Atenolol 50 mg + HCTZ 12.5 mg Atenolol 100 mg + HCTZ 12.5 mg Atenolol 100 mg + HCTZ 12.5-25 mg + others* 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 *Other antihypertensives excluding ACEIs, AII antagonists, beta-blockers. Dahlöf B et al (1997) Am J Hypertens 10:705713.

  21. Adverse events Lindholm LH et al (2002) Lancet359, 1004 - 1010.

  22. 10 Atenolol Losartan 8 6 Proportion of patients, % 4 2 0 0 6 12 18 24 30 36 42 48 54 60 66 Study Month LIFE: New Onset Diabetes by Treatment Group

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

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