Treating Hypertension in Individuals with Diabetes

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1 Treating Hypertension in Individuals with Diabetes

2 Copyright 2017 by Sea Courses Inc. All rights reserved. No part of this document may be reproduced, copied, stored, or transmitted in any form or by any means graphic, electronic, or mechanical, including photocopying, recording, or information storage and retrieval systems without prior written permission of Sea Courses Inc. except where permitted by law. Sea Courses is not responsible for any speaker or participant s statements, materials, acts or omissions.

3 Accessed Feb 18, 2017

4 accessed Feb 18, 2017

5 INTERHEART study, Yusuf et al; Lancet 2004; 364:937-52

6 Proportion of Diabetic Complications Attributable to Hypertension Complication Proportion attributable to hypertension Stroke 75% Coronary Artery Disease 35% End stage renal disease 50% Eye disease 35% Leg amputation 35% Can J Cardiol 2009;25:

7 accessed Feb 18, 2017

8 How well is HTN Managed in Canadians with Diabetes? CMAJ, 2008;178:

9 Average Number of Antihypertensive Agents Used to Achieve Target BP in people with DM UKPDS (< 85 mm Hg - diastolic) ABCD (< 75 mm Hg - diastolic) MDRD (< 92 mm Hg average BP) HOT (< 80 mm Hg - diastolic) AASK (< 92 mm Hg average BP) RENAAL (< 90 mm Hg - diastolic) IDNT (< 90 mm Hg - diastolic) Number of Antihypertensive Agents (per patient) 4.5

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11 Syst Eur: Benefits of BP Lowering Significantly Greater in Patients With than Without Diabetes Tuomilehto et al for SYST-Eur. NEJM 1999;340:

12 Mean Blood Pressure (mmhg) Blood Pressure Reduction Placebo Perindopril-Indapamide Average BP during follow-up Δ 5.6 mmhg (95% CI ); p<0.001 Systolic mmhg mmhg Diastolic Δ 2.2 mmhg (95% CI ); p<0.001 R Follow-Up (Months) 77.0 mmhg 74.8 mmhg

13 Deaths Cardiovascular Non-Cardiovascular 5% Placebo Perindopril-Indapamide 5% Placebo Perindopril-Indapamide HR 0.82 (95% CI ) p=0.027 HR 0.92 (95% CI ) p= Follow-Up (Months) Follow-Up (Months)

14 Events / 1000 Pt-Years HOT Trial:Cardiovascular Events in Diabetics and Nondiabetics Effect of Diastolic Target at 4 Years % Risk Reduction <90 <85 <80 <90 <85 <80 Diabetic Patients n=1,501; p=0.016 Nondiabetic Patients n=18,790; p=ns Hansson L et al. Lancet 1998;351:

15 Probability (%) FACET: Risk of Cardiovascular Disease Amlodipine Fosinopril 51 % risk reduction p = 0.03 NOTE: Cardiovascular disease defined as a fatal or nonfatal stroke, fatal or nonfatal acute MI, or hospitalization for angina Follow-up (years) Tatti P et al. Diabetes Care 1998;21(4):

16 Proportion of patients with first event, % LIFE: Diabetes Primary Composite Endpoint Primary composite endpoint (CV death, MI and stroke) Atenolol Losartan Adjusted Risk Reduction = 24.5%; p= Study Month Losartan (n) Atenolol (n)

17 % of patients with an event Any Diabetes Related Endpoint (cumulative) 50% 40% 30% 20% 10% Less tight BP control (n=390) Beta blocker (n=358) ACE inhibitor (n=400) Less tight vs Tight p= of 1148 patients (37%) 0% ACE vs Beta blocker p= Years from randomisation ukpds

18 ONTARGET Pre-specified Subgroup Analysis No. Patients %Primary Outcome in Ramipril Group Primary Composite Hx of CVD No Hx of CVD SBP < > Diabetes No Diabetes Low Risk Medium Risk High Risk Age < > Male Female Telmisartan Ramipril better better RR (95% CI) in Telmisartan Group

19 ALLHAT Nonfatal MI + CHD Death Subgroup Comparisons RR (95% CI) Total 0.98 (0.90, 1.07) Age < (0.85, 1.16) Age>= (0.88, 1.08) Men 0.98 (0.87, 1.09) Women 0.99 (0.85, 1.15) Black 1.01 (0.86, 1.18) Non-Black 0.97 (0.87, 1.08) Diabetic 0.99 (0.87, 1.13) Non-Diabetic 0.97 (0.86, 1.09) Amlodipine Better Chlorthalidone Better Total 0.99 (0.91, 1.08) Age < (0.81, 1.12) Age >= (0.91, 1.12) Men 0.94 (0.85, 1.05) Women 1.06 (0.92, 1.23) Black 1.10 (0.94, 1.28) Non-Black 0.94 (0.85, 1.05) Diabetic 1.00 (0.87, 1.14) Non-Diabetic 0.99 (0.88, 1.11) Lisinopril Better Chlorthalidone Better JAMA. 2002;288:

20 Summary: MIDAS: Thiazides are better than Ca blockers ABCD, FACET: ACEI better than Ca blockers ONTARGET: ARBs look the same as ACEI LIFE: ARBs look better than beta blockers UKPDS: Beta blockers trend to be better than ACEI ALLHAT: Diuretic = ACEI = Ca blockers Shouldn t we use ACEI first line??

21 Heart Outcomes Prevention Evaluation Study: Diabetic subgroup ACE-Inhibitors in Diabetic Patients at High-Risk for CV events

22 Mean Change in BP with Ramipril - Diabetic Patients Baseline Value (mmhg) 1 MonthD 2 Year D End D Arm Systolic BP Ramipril Placebo * 0.6* 0.55** Arm Diastolic BP Ramipril Placebo * -1.05* -2.3 *p=0.0001, ** p=0.0002, p=0.008, for change from baseline (ramipril vs placebo)

23 RRR (%) Ramipril vs Placebo Relative Risk Reduction on Primary Adjudicated Events and Mortality-Diabetic Patients Ml, Strokes, CV Death (p=0.0004) *not mutually exclusive MI* (p=0.010) Strokes* (p=0.0074) (Outcome) CV Death* (p=0.0001) Total Mortalit y (p= )

24 (Hypertension. 2001;38:e28-e32.)

25

26 A

27 Cumulative event rate Kaplan Meier for Primary Endpoint ACEI / HCTZ CCB / ACEI 20% Risk Reduction p = Time to 1 st CV morbidity/mortality (days) HR (95% CI): 0.80 (0.72, 0.90)

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30 Swedish NDR-BP

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33 Systolic Pressures (mean + 95% CI) Mean # Meds Intensive: Standard: Average after 1 st year: Standard vs Intensive, Delta = 14.2

34 Patients with Events (%) 20 Primary Outcome Nonfatal MI, Nonfatal Stroke or CVD Death HR = % CI ( ) Years Post-Randomization

35 Patients with Events (%) Patients with Events (%) Nonfatal Stroke Total Stroke HR = % CI ( ) 15 HR = % CI ( ) Years Post-Randomization Years Post-Randomization

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40 Unchanged for 2017

41 No changes since

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49 Pharmacotherapy of Hypertension in Diabetes without Nephropathy, CVD or CV Risk Factors THRESHOLD equal or over 130/80 mmhg and TARGET below 130/80 mmhg DIABETES without Nephropathy, CVD or CV risk factors 1. ACE Inhibitor or ARB or 2. Dihydropyridine CCB or Thiazide diuretic IF ACE Inhibitor, ARB, DHP-CCB and Thiazide are contraindicated or not tolerated, SUBSTITUTE Cardioselective BB* or Long-acting NON DHP-CCB Combination of first line agents Addition of one or more of: Cardioselective BB or Long-acting CCB Combinations of an ACE Inhibitor with an ARB are specifically not recommended in the absence of proteinuria *Cardioselective BB: Acebutolol, Atenolol, Bisoprolol, Metoprolol guidelines.diabetes.ca BANTING ( ) diabetes.ca Copyright 2013 Canadian Diabetes Association CHEP guidelines, Canadian Journal Cardiology 2016; 32(5):

50 Pharmacotherapy of Hypertension with Nephropathy, CVD or CV Risk Factors THRESHOLD equal or over 130/80 mmhg and TARGET below 130/80 mmhg DIABETES with Nephropathy or CVD or CV risk factors ACE Inhibitor or ARB IF ACEI and ARB are contraindicated or not tolerated, SUBSTITUTE Long-acting CCB or Thiazide diuretic Addition of a Dihydropyridine CCB is preferable to HCTZ 3-4 drugs in combination may be needed If Creatinine over 150 µmol/l or creatinine clearance below 30 ml/min (0.5 ml/sec), a loop diuretic should be substituted for a thiazide diuretic if control of volume is desired Monitor serum potassium and creatinine carefully in patients with CKD prescribed an ACEI or ARB CCB = Calcium Channel Blocker; HCTZ = Hydrochlorothiazide; CKD = Chronic Kidney Disease guidelines.diabetes.ca BANTING ( ) diabetes.ca Copyright 2013 Canadian Diabetes Association CHEP guidelines, Canadian Journal Cardiology 2016; 32(5):

51 Summary: Lowering BP lowers CV events In the diabetic without nephropathy, the initial drug to treat BP is probably not relevant lowering the BP is. In the diabetic with nephropathy, an ACEI or ARB would be the initial drugs of choice. Ca blocker is the drug of second choice after a RAAS blocker Night time dosing of at least one drug is indicated.

52 Summary: Canadian guidelines continue to support a target of 130/80. American guidelines support a target of 140/90 Worse glycemic control worsens endothelial function, morning BP surges and prognosis at any given BP

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