presented in endocrinology conference, Jeddah October 2009.

1. Management of Hypertension in Diabetes-2009 Dr Mohamed Al-Ameen Nephrologist & Transplant Physician KAAH&OC- Jeddah

2. بسم الله الرحمن الرحيم

3. 1.5 billions

5. Over 1.5 billion people worldwide are hypertensive Or 1 in 3 adult

6. > 7 Millions

8. Hypertension 7 million deaths/ year

9. 171,000,000 Prevalence of DM worldwide “2000” 366,000,000 Prevalence of DM worldwide “2030” Prevalence of DM KSA “2000” 890,000 Prevalence of DM KSA “2030” 2,523,000 e DM + HTN KSA “2000” 543,000 e DM + HTN KSA “2030” 1,513,800

10. Dark Numbers 171,000,000 Prevalence of DM worldwide “2000” 366,000,000 Prevalence of DM worldwide “2030” Prevalence of DM KSA “2000” 890,000 Prevalence of DM KSA “2030” 2,523,000 e DM + HTN KSA “2000” 543,000 e DM + HTN KSA “2030” 1,513,800

12. 29% unaware about that diagnosis.

13. 43% untreated.

14. 65% uncontrolled (≥140/90).

15. Only 12% had BP <130/85.Am J Prev Med 22:42–48, 2002 Hypertension 52:818-827, 2008

16. Management of Hypertension in Diabetics Hypertension in Diabetes Prevalence NEJM 2000; 342:905 DiabetesCare 2005; 28:310 AmJKidDis 2007; 49 (Suppl 2):S74

18. Management of Hypertension in Diabetics HTN in DM:PARTNERS IN CRIME Diabetes Hypertension HTN vs No HTN DM vs No DM 2.4x ↑ in DM 2.0x ↑ in HTN NEJM 2000; 342:905 Diabetes Care 2005; 28:310

19. Management of Hypertension in Diabetics HTN in DM:PARTNERS IN CRIME NEJM 2005; 352:341 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 66, NUMBER 7 / OCTOBER 1, 2002

20. Management of Hypertension in Diabetics HTN in DM:PARTNERS IN CRIME “Refractory HTN” The HIPERFRE study, 2008 The HIPERFRE study, 2008 1,724 hypertensive patients, 35 physicians, 14 Primary Care Units 1,724 hypertensive patients, 35 physicians, 14 Primary Care Units Association between refractory hypertension and cardiometabolic risk

21. Management of Hypertension in Diabetics HTN in DM:PARTNERS IN CRIME Diabetes Hypertension Cause: Mainly renoparenchymal and pointing to DN Onset: Typically with microalbuminuria American diabetic association, Diab Care 2004 DM-1 Cause: Mainly Insulin Resistance as a facet of MS. Onset: with onset of Diabetes or may precede that by Ys. Ritz et al. J Int Med.2001;249: 215-223. DM-2

22. Kidney Disease DM-1 Metabolic Syndrome HTN DM-2

23. Management of Hypertension in Diabetics HTN in DM:PARTNERS IN CRIME So, The pathogenesis of development is distinct in each type BUT The pathogenesis of marked enhancement of the already high risk of cardiovascular and renal disease in types 1 and 2 are similar in both Landsberg L, Molitch M. Clin Exp Hypertens 2004 Oct-Nov;26(7-8):621-8.

24. Management of Hypertension in Diabetics Diabetes Hypertension Studies 1- Pollare T et al. Metabolism 1990, 39(2):167-174 : There are resistance to insulin and hyperinsulinemia: in hypertensive pts non diabetic compared with normotensive controls. 2- Bosch J et al. N Engl J Med 2006, 355(15):1551-1562: About 20% of patients with hypertension will develop type 2 diabetes in a three year period 3- BarzilayJ I et al. Arch Intern Med. 2006;166:2191-2201: Fasting glucose levels increase in older adults with hypertension regardless of treatment type.

25. Management of Hypertension in Diabetics Diabetes Hypertension Studies 4- Jandeleit-Dahm KA et al. J Hypertens 2005, 23(3):463-473 : - The RAS itself plays imp. role in the development of diabetes. - Over activity of RAS appears to be linked to reduced insulin and glucose delivery to the peripheral skeletal muscle and impaired glucose transport and response to insulin signalling pathways, thus increasing insulin resistance. 5- Ferrannini E et al. Diabetologia 2003, 46(9):1211-1219: Activation of a local pancreatic RAS, in particular within the islets, may represent an independent mechanism for the progression of islet cell damage in diabetes.

26. Diabetes Hypertension Drugs Elliott WJ, Meyer PM: anetwork meta-analysis. Lancet 2007, 369(9557):201-207.

27. Diabetes Hypertension Drugs Gupta AK et al. Diabetes Care. 2008 May;31(5):982-8.

30. This adverse effect of BB must be weighed against the proven benefits of this drug in reducing the risk of cardiovascular events

31. Diabetes Hypertension Risk Verdecchia P et al. Hypertension. 2004;43:963-969.

32. Diabetes Hypertension Predictors

33. Diabetes Hypertension Prevention Screen for NOD in hypertensive Pts. As they share common etiological factors. Use of drugs that inhibit RAS. LIFE, ALLHAT and CAPP. Fixed dose combination ACE-I + CCB (Trandolapril + Verapamil): lower risk of NOD Cheung BM. Diabetes Care. 2008 Sep;31(9):1889-91. Bakris G et al. Diabetes Obes Metab. 2008 Jun 16

34. Any 3 of the following 5 features Central obesity 􀂄 apple vs pear shape Elevated TG Low HDL-cholesterol Elevated blood pressure Elevated fasting plasma glucose or previously undiagnosed type 2 diabetes Management of Hypertension in Diabetics HTN in DM:PARTNERS IN CRIME

35. Any 3 of the following 5 features Central obesity 􀂄 apple vs pear shape Elevated TG Low HDL-cholesterol Elevated blood pressure Elevated fasting plasma glucose or previously undiagnosed type 2 diabetes Management of Hypertension in Diabetics HTN in DM:PARTNERS IN CRIME

36. Management of Hypertension in Diabetics HTN in DM:PARTNERS IN CRIME Criteria of MS Central obesity: Waist circumference 􀂄 &gt; 40 inches (men) 􀂄 &gt; 35 inches (women) Elevated Triglycerides 􀂄 &gt; 150 mg/dl or on TG therapy Low HDL-cholesterol 􀂄 &lt; 40 (men) 􀂄 &lt; 50 (women) 􀂄 Or on therapy to increase HDL-cholesterol

37. Management of Hypertension in Diabetics HTN in DM:PARTNERS IN CRIME Criteria of MS Elevated blood pressure &gt; 130/85 mmHg or on bp therapy Elevated fasting plasma glucose Fasting glucose &gt; 100 mg/dl or Previously undiagnosed type 2 diabetes Fasting glucose &gt; 126 mg/dl on 2 separate occasions

38. Management of Hypertension in Diabetics HTN in DM:PARTNERS IN CRIME Risk of MS Heart Disease Type 2 Diabetes Polycystic Ovarian Syndrome Kidney Disease 2.5 fold increase of microalbuminuria 3.5 fold increase of chronic kidney disease Cancer Nonalcoholic steatohepatitis Alzheimer’s

39. Management of Hypertension in Diabetics HTN in DM:PARTNERS IN CRIME

40. Effect of Tight Control of Blood Pressure

41. Management of Hypertension in Diabetics HTN in DM:Effect of BP Control Tight BP Control vs. Tight Glucose Control Microvascular Any DM Stroke DM Death Complications End Point 0 - -10 - -20 - Reduction in Risk (%) -30 - Tight Glucose Control -40 - Tight BP Control *P &lt; 0.05 -50 - UKPDS. BMJ. 1998:317;703-712.

42. Management of Hypertension in Diabetics HTN in DM:Effect of BP Control Tight BP Control vs. Tight Glucose Control Whelton, P. K. et al. JAMA 2002;288:1882-1888

43. Management of Hypertension in Diabetics HTN in DM:Effect of BP Control Tight BP Control vs. Tight Glucose Control Tight BP Control Tight Glucose Control

44. Management of Hypertension In Diabetes

45. 636 pts. 24 months 4 groups: Usual care. Behavioral intervention (bimonthly tailored nurse-administered telephone intervention targeting hypertension-related behaviors. Home BP monitoring. Combined behavioral intervention plus home BP monitoring.

47. WEB TRAINING

49. Home BP Monitoring Behavioral intervention Web Training Pharmacist Care Appointment reminder systems

50. HTN in DM:Practical Strategy Measure: Measure BP properly. Define: Define Hypertensive Patients. Evaluate: Evaluate hypertensive pts. Treat: Therapy

51. HTN in DM:Practical Strategy Measure: Measure BP properly. Define: Define Hypertensive Patients. Evaluate: Evaluate hypertensive pts. Treat: Therapy

52. HTN in DM: 1- Measure BP Properly The measurement of BP is likely the clinical procedure of greatest importance that is performed in the sloppiest manner.” (Norman Kaplan, M.D.) Lancet 2007; 370:591 Health care professionals should take particular care to ensure that they are using accurate techniques to measure BP in all their patients.” (International Working Group, 2008) JHumHypertens 2008; 22:63 CanJCard 2007; 23:529

53. HTN in DM: 1- Measure BP Properly Joint National Commitee Caffeine, exercise, and smoking should be avoided for at least 30 minutes prior to measurement. JNC-7

54. HTN in DM: 1- Measure BP Properly Joint National Commitee

55. Mercury Sphygmomanometers What is about automated devices ????????

56. We recommend that this device not be used when accurate BP measurement is needed for therapeutic decision-making.

60. HTN in DM: 1- Measure BP Properly

61. Ambulatory BP monitoring: White Coat HTN with TOD. Episodic HTN Autonomic dysfunction Drug resistance Self Measurement (Out of Office BP): if consistently &lt;130/80 and No TOD despite high office BP  24h monitoring & drug therapy can be avoided. HTN in DM: 1- Measure BP Properly

62. HTN in DM:Practical Strategy Measure: Measure BP properly. Define: Define Hypertensive Patients. Evaluate: Evaluate hypertensive pts. Treat: Therapy

63. HTN in DM:Practical Strategy Measure: Measure BP properly. Define: Define Hypertensive Patients. Evaluate: Evaluate hypertensive pts. Treat: Therapy

64. Management of Hypertension in Diabetics HTN in DM: 2- Define Hypertensive Patients Joint National Committee 7 (JNC-7)

65. High Normal BP and CVD Risk

67. Management of Hypertension in Diabetics HTN in DM:2- Define Hypertensive Patients Systolic or Diastolic Hypertension??????? 250 Nondiabetic Diabetic 200 CVmortalityrate/10,000 person-yr 150 100 50 0 &lt;120 120-139 140-159 160-179 180-199 ≥200 Systolic BP (mm Hg) CV, cardiovascular; SBP, systolic blood pressure. Stamler J et al. Diabetes Care. 1993;16:434-444. CV Mortality Risk Doubles WithEach 20/10 mm Hg BP Increment*

69. Diabetic Nephropathy65% of DM hypertensives have isolated systolic hypertension. Lancet 2002; 360:1903 Hypertension 2003; 42:1206 National Kidney Foundation: Guideline 8. Am J Kidney Dis 43 (Suppl. 1):S142 –S159, 2004. Sowers JR et al. Hypertension 37:1053 –1059, 2001.

70. Systolic BP should be the primary target of antihypertensive therapy

71. Systolic BP represent an important risk factor for CV events which can be prevented or reduced by pharmacological treatment

72. Management of Hypertension in Diabetics HTN in DM:2- Define Hypertensive Patients Systolic or Diastolic Hypertension??????? DBP is a more potent cardiovascular risk factor than SBP until age 50; thereafter, SBP is more important. Diastolic hypertension predominates before age 50, either alone or in combination with SBP elevation. Systolic BP increases with age, and above 50 years of age, systolic hypertension represents the most common form of hypertension. SBP control rates are lower than that of DBP. J ClinHypertens 2002;4:393-404. Hypertension 2001;37:12-8.

74. Most physicians have been taught that the diastolic pressure is more important than SBP and thus treat accordingly.

75. Most primary care physicians did not pursue control to <140 mmHg.J ClinHypertens. 2000;2:324-30.

76. HTN in DM:Practical Strategy Measure: Measure BP properly. Define: Define Hypertensive Patients. Evaluate: Evaluate hypertensive pts. Treat: Therapy

77. HTN in DM:Practical Strategy Measure: Measure BP properly. Define: Define Hypertensive Patients. Evaluate: Evaluate hypertensive pts. Treat: Therapy

78. Evaluate for: CV Risk Factors. Target Organ Damage. Secondary Causes of HTN. Routine Laboratory work up: eg.. ECG, lipid profile and urinary albumin. Management of Hypertension in Diabetics HTN in DM:3- Evaluate Hypertensive Pts.

79. HTN DM* Age: Older than 55 years for men Older than 65 years for women Abnormal Lipid Profile*: Elevated LDL (or total) cholesterol Low HDL cholesterol* Estimated GFR &lt;60 mL/min Family history of premature CVD: men &lt;55 years of age women &lt;65 years of age Microalbuminuria Obesity* (BMI &gt;30 kg/m2) Physical inactivity Tobacco usage, particularly cigarettes Management of Hypertension in Diabetics HTN in DM:3- Evaluate Hypertensive Pts. Cardiovascular Risk Factors (140-age) x weight x 1.23 x (0.85 if female) S Creatinine (micromol/l) (140-age) x Weight (Kg) x (0.85 if female) 72 x S Creatinine (mg/dl) Normoalbuminuria &lt; 30 mg/day Microalbuminuria 30 - 300 mg /d Macroalbuminuria &gt; 300 mg / day BMI= Weight (Kg) / (Height in meter)2

80. Heart LVH Angina/prior MI Prior coronary revascularization Heart failure Brain Stroke or transient ischemic attack Dementia Kidney: CKD Eye: Retinopathy Vessels: Peripheral arterial disease Management of Hypertension in Diabetics HTN in DM:3- Evaluate Hypertensive Pts. Target Organ Damage

81. Management of Hypertension in Diabetics HTN in DM:3- Evaluate Hypertensive Pts. 2ry Causes of HTN ABCD diagnosis of 2ry HTN A: Accuracy, Apnea, Aldosteronism B: Bruit, Bad Kidney C:Catecholamines, Coarctation, Cushing&apos;s S. D: Drugs, Diet

85. HTN in DM:Practical Strategy Measure: Measure BP properly. Define: Define Hypertensive Patients. Evaluate: Evaluate hypertensive pts. Treat: Therapy

86. HTN in DM:Practical Strategy Measure: Measure BP properly. Define: Define Hypertensive Patients. Evaluate: Evaluate hypertensive pts. Treat: Therapy

87. Goal Blood Pressure Life Style Modification Drug Therapy

88. Goal Blood Pressure Life Style Modification Drug Therapy

89. Management of Hypertension in Diabetics HTN in DM:4- Therapy Goal Blood Pressure Less Than 130/80 HOT (Hypertension Optimal Treatment). ABCD-NT (Appropriate Blood Pressure Control in Diabetes) UKPDS (UK Prospective Diabetes Study) IDNT (Irbesartan in Diabetic Nephropathy Trial) INVEST (International Verapamil-Trandolapril) ADA (American Diabetic association) ISHIB (International Society of Hypertension in Blacks) CHEP (Canadian Hypertension Education Program) BHS (British Hypertension Society) JNC 7 (Joint National Committee 7)

90. Management of Hypertension in Diabetics HTN in DM:4- Therapy Goal Blood Pressure Less Than 130/80 Can We Go to More Lower Target ? National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis. 2000;36(3):646-661. American Association of Clinical Endocrinologist, 2006 Target BP 125/75 If Proteinuria &gt; 1gm IDNT JASN 2005;16(7):2170–2179

91. Management of Hypertension in Diabetics HTN in DM:4- Therapy Goal Blood Pressure Less Than 130/80 Can We Go to More Lower Target ? 20,358 individuals studied, 1549 (7.6%) had CKD HR of Stroke vs SBP Lowest Systolic Blood Pressure Is Associated with Stroke inStages 3 to 4 Chronic Kidney Disease J Am Soc Nephrol18: 960–966, 2007

92. Lowest Systolic Blood Pressure Is Associated with Stroke in Stages 3 to 4 Chronic Kidney Disease J Am Soc Nephrol18: 960–966, 2007

93. Goal Blood Pressure Life Style Modification Drug Therapy

94. Goal Blood Pressure Life Style Modification Drug Therapy

95. HTN in DM:4- Therapy Life Style Modifications Decrease Weight 5-20 mmHg/10 kg Decrease Sodium 2-8 mmHg 4-9 mmHg Do Ph. Activity 8-14 mmHg DASH diet 2-4 mmHg Decrease Alcohol Smoke free enviroment D/C Smooking

97. 2,300 mg sodium = 1 level teaspoon of table salt

99. At least 30 min 4 times / Week Only walking, jogging or non competetive swimming

101. HTN in DM:4- Therapy Life Style Modifications

102. HTN in DM:4- Therapy Life Style Modifications

103. Goal Blood Pressure Life Style Modification Drug Therapy

104. Goal Blood Pressure Life Style Modification Drug Therapy

105. The need of multiple drugs. Best drug for compelling indications. Critical contraindications of anti HTN drugs.

106. Management of Hypertension in Diabetics HTN in DM:4- Therapy Drug Therapy: Need for Multiple Drugs No. of antihypertensive agents Target BP (mm Hg) Trial 1 2 3 4 UKPDS DBP &lt;85 ABCD DBP &lt;75 MDRD MAP &lt;92 HOT DBP &lt;80 AASK MAP &lt;92 IDNT SBP &lt;135/DBP &lt;85 ALLHAT SBP &lt;140/DBP &lt;90 DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressure. Bakris GL et al. Am J Kidney Dis. 2000;36:646-661. Lewis EJ et al. N Engl J Med. 2001;345:851-860. Cushman WC et al. J Clin Hypertens. 2002;4:393-404.

107. Management of Hypertension in Diabetics HTN in DM:4- Therapy Drug Therapy: Compelling Indications 2003 WHO/ ISH Statement on Hypertension

109. 2003 WHO/ ISH Statement on Hypertension

110. Management of Hypertension in Diabetics HTN in DM:4- Therapy Practical View Pts. At goal BP &lt; 130 / 80 LSM / Recheck 2. Pts. with BP 130-139 / 80-89 LSM /3m  Drug Th 3. Pts. With BP ≥ 140 /90 LSM + Drug Th 4. Pts. With BP &gt; 150 /90 LSM +2 Drug Th If Compelling Indications  Treat accordingly

112. Recommended Drug Therapy

115. Second-line Therapy: Calcium channel blocker or a diuretic (usually bendroflumethiazide, 2.5 mg daily). Add the other drug (that is, the calcium channel blocker or diuretic) if the target is not reached with dual therapy. Third-line Therapy: Alpha-blocker, a beta-blocker or a potassium-sparing diuretic (the last with caution if the individual is already taking an ACE inhibitor or an angiotensin II-receptor antagonist). The National Institute for Health and Clinical Excellence (NICE) 2008

116. ACE-I & ARBs Can we add ARBs to ACE-I ?? Hyperkalemia ?? Cough ?? Renal impairment ?? Direct anti renin ??

121. RASILEZ

123. Management of Hypertension in Diabetics Drug Considerations: CCBs If d-CCB Chosen: Not to be used without ACEi or ARB agents. Short-acting d-CCB should not be used in IHD because of their potential to increase risk of mortality, particularly in the setting of acute myocardial infarction

124. Management of Hypertension in Diabetics Drug Considerations: BBs Beta Blockers Less appealing as first-line agents for treatment of HTN in DM 1 or 2 (grade A). Have proved effective in the management of the ischemic and congestive cardiomyopathies that are more common in patients with diabetes than in those without diabetes. Because the major adverse effects of BBs may be mediated by peripheral vasoconstriction and increasing insulin resistance, the use of the new third-generation BBs (such asNebivolol) or drugs that block both a and b receptors (such asCarvedilol) may prove to be particularly beneficial (grade A). These agents cause vasodilatation and an increase in insulin sensitivity. American Association of Clinical Endocrinologist, 2006

125. Management of Hypertension in Diabetics Nebivolol: 3rd generation BB

128. Management of Hypertension in Diabetics Drug Considerations: Diuretics If Diuretic Chosen: Creatinine &lt;1.8 mg/dL Thiazide Diuretic Creatinine ≥1.8 mg/dL Loop Diuretic If a diuretic is not used in 2 drug therapy, it should included in triple therapy.

129. Management of Hypertension in Diabetics Drug Considerations:Anti-Proteinuric Type 1: ACE-I Type 2: ACE-i or ARBs as a first line. Second-line (unable to tolerate ACEi or ARBs: Verapamil or diltiazem. BB is a potent antiproteinuric.

130. Management of Hypertension in Diabetics HTN in DM:4- Therapy Resistant Hypertension

131. Anti Hypertensive Drugs

132. Anti Hypertensive Drugs

133. Anti Hypertensive Drugs

134. Anti Hypertensive Drugs

135. Anti Hypertensive Drugs

136. Thanks

137. ALLHAT--the &quot;Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial“. LIFE: Losartan Intervention For Endpoint . CAPP: Captopril Prevention Project ABCD: Appropriate Blood Pressure Control in Diabetes MDRD: Modification of Diet in Renal Disease AASK: African American Study of Kidney Disease and Hypertension

138. antihypertensivetreatment with indapamide (sustained release), with or withoutperindopril, in persons 80 years of age or older is beneficia N Engl J Med. 2008 May 1;358(18):1887-98