1. AGENDA• Magnitude of the problem.• Diabetes-Hypertension inter-relationship.• Diabetes-Hypertension CVS Burden.• RAS SYSTEM IN HYPERTENSION.• ACE-Is in diabetic hypertension management.• ACE-Is VS ARBS.• Take-Home Message.
3. Prevalence of diabetes in Eastern Mediterraneanand Middle East Region in 2003Saudi Arabia Afghanistan9.4% 8.2%1 million 0.9 million Egypt Pakistan 9.8% 8.5% 3.9 million 6.2 million Sudan 3.1% 0.5 million United Arab Emirates 20.1% Yemen 0.4 million 7.7% 0.6 million Total cases > 19 million adults International Diabetes Federation. Diabetes Atlas. 2nd Edition. www.eatlas.idf.org. Accessed 27 October, 2006.
4. PREVELANCE OFHYPERTENSION 30 25 20 % 15 26.3 20.4 22 10 13.6 12.08 5 6.07 0 India China Egypt Bangladesh USA Candada
5. Global Rates (%) of HTN Control <140/90 mm Hg <160/95 mmHg Germany 23United States 34France24 Finland 21Canada22 Spain 20Italy 9Egypt 8 Australia 19England 6 Scotland 18Korea 5 India 9China 3 Zaire 3 Poland 2 3. Colhoun et al. J Hypertens 1998;16:747 4. Chamontin et al. Am J Hypertens 1998;11(6pt 1):759 5. Marques-Vidal et al. J Hum Hypertens 1997;11:213
6. Diabetes-Hypertension Relationship
7. Hypertension and Diabetes• Hypertension co-exists with type II in about 40% at age 45 rising to 60% at age 75.• 70% of type II patients die from cardio- vascular disease.• At least 60% of patients will require 2 or 3 antihypertensive agents to achieve tight control.Kieran McGlade Nov 2001 Department of General Practice QUB
8. Hypertension and Diabetes American Diabetes Association “There is a strong epidemiological connection between hypertension in diabetes and adverse outcomes of diabetes. Clinical trials demonstrate the efficacy of drug therapy versus placebo in reducing these outcomes and in setting an aggressive blood pressure–lowering target of <130/80 mmHg.”Arauz-Pacheco C et al. Diabetes Care. 2003;26(suppl):S80–S82.
9. Percent Chance of Cardiovascular Event in 5 Years Men No Diabetes Women Nonsmoker Smoker Nonsmoker Smoker Total Chol.:HDL-Chol. Chol.:HDL- Total Chol.:HDL-Chol. Chol.:HDL- 4 5 6 7 8 4 5 6 7 8 4 5 6 7 8 4 5 6 7 8 180/105 >20% 160/95 Age 15%-20% 15%- 140/85 70 10%-15% 10%- 120/75 5%-10% 5%- 180/105 2.5%-5% 2.5%- 160/95 Age <2.5% 140/85 60 120/75 180/105 160/95 Age 140/85 50 120/75Slide 26
10. Percent Chance of Cardiovascular Event in 5 Years Men Diabetes Women Nonsmoker Smoker Nonsmoker Smoker Total Chol.:HDL-Chol. Chol.:HDL- Total Chol.:HDL-Chol. Chol.:HDL- 4 5 6 7 8 4 5 6 7 8 4 5 6 7 8 4 5 6 7 8 180/105 >20% 160/95 Age 15%-20% 15%- 140/85 70 10%-15% 10%- 120/75 5%-10% 5%- 180/105 2.5%-5% 2.5%- 160/95 Age <2.5% 140/85 60 120/75 180/105 160/95 Age 140/85 50 120/75Slide 27
11. The Hypertensive Patient Exhibits...• More frequent insulin resistance• More hyperinsulinemia• Dyslipidemia• Microalbuminuria• Obesity...than non-hypertensive patients!Diabetes. 1988.37;1595-1607 and Hypertension.202;40:781-788.
12. HypertensionHyperinsulinemia can enhance renal sodiumreabsorption and vascular reactivityAngiotensinogen from fat cells can increaseangiotensin II and thus blood pressureBoth systolic and diastolic blood pressure increasewith increasing body mass index
13. Diabetes-Hypertension CVS Burden
14. Hypertension & Diabetes; A major risk for CVD Hypertension Type 2 Diabetes The relationship between BP and risk of CVD events is continuous, Associated with up to consistent, and independent of 80% chance of other risk factors. The higher the BP, the greater the premature death from chance of heart attack, HF, stroke, CVD and stroke. and kidney diseases. According to JNC 7# Guidelines; There is a strong linkage of the two conditions (Hypertension & Diabetes) with all CVD.The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood 1. Pressure.NIH Publication 2004.
15. Coexistence of Hypertension in Diabetes Even in newly diagnosed diabetes . . . hypertension is associated with a doubling of the presence of Left ECG signs of MIMicroalbuminuria ventricular and a prior history hypertrophy of overt CV events Kaplan, 1997.
16. CV Mortality Risk Doubles with Each 20/10 mm Hg BP Increment* 8 7 6 CV 5mortality 4 risk 3 2 1 0 115/75 135/85 155/95 175/105 SBP/DBP (mm Hg)*Individuals aged 40-69 years, starting at BP 115/75 mm Hg.CV, cardiovascular; SBP, systolic blood pressure; DBP, diastolic blood pressureLewington S, et al. Lancet. 2002; 60:1903-1913.JNC VII. JAMA. 2003.
17. Association of SBP and CV Mortality in Men With Type 2 Diabetes 250 Nondiabetic Diabetic 200 CV mortality 150 rate/ 10,000 person-yr 100 50 0 <120 120-139 140-159 160-179 180-199 ≥200 SBP (mm Hg)CV, cardiovascular; SBP, systolic blood pressure.Stamler J et al. Diabetes Care. 1993;16:434-444.
18. Significant benefits from intensive BP reduction in diabetic patients Major CV events / 100 patient-yr30 24.42520 18.615 11.91050 < 90 mm Hg < 85 mm Hg < 80 mm Hg (target DBP)
19. Increased risk of cardiac complicationsin diabetic hypertensives In diabetic hypertensives; Every 10 mm Hg decrease in mean SBP* above 120 mm Hg was associated with: 1. Adler AI, et al. Association of systolic blood pressure with macrovascular and microvascular complications 1. of type 2 diabetes (UKPDS 36): prospective observational study. BMJ 2000; 321: 412-9. 2. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment 2. of High Blood Pressure. NIH Publication 2004.
20. Increased risk of kidney problemsin diabetic hypertensives Incident rates of end-stage renal disease, by primary diagnosis* According to JNC 7# Guidelines; There is a strong linkage of the two conditions (Hypertension & Diabetes) with progression of High Blood 1. disease.1 The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of renal Pressure. NIH Publication 2004.
21. Renin Angiotensin SYSTEM (RAS)
22. pathophysiologic phenomena induced by activation of RAAS:– Increased oxidative stress– Increased vasoconstriction– Promotion of• Proinflammatory• Procoagulatory• Proliferative environment• Endothelial dysfunction– Disruption of insulin signaling pathways
23. ACE-Is in diabetic hypertension management
24. Benefit of ACE Inhibitors in Diabetes: Important Findings of 5 Major Clinical Trials• UKPDS (1998) • ABCD (1998)• HOPE & MICRO-HOPE Substudy (2000)• ABCD, CAPPP, FACET and UKPDS meta- analysis (2000) • ACEIs compared to other agents significantly reduced the frequency of acute myocardial infarction, cardiovascular events, and all-cause mortality
25. ABCD, CAPPP & FACET Meta-AnalysisTo assess whether ACE inhibitors are superior to other agents in theprevention of cardiovascular events in hypertensive type 2 diabeticsReview and meta-analysis of randomized controlled trials of patientstreated with ACEIs or other agents, followed for 2 years, withadjudicated cardiovascular events3 trials eligible • ABCD (n=470) compared enalapril with nisoldipine • CAPPP (n=572) compared captopril with diuretic or beta-blockers • FACET (n=380) compared fosinopril with amlodipine Pahor M, et al. Diabetes Care. 2000;23:888-892.
26. CV risk reduction with ACEIs in type 2 diabetes: ABCD, CAPPP, and FACET ACEI (n=733) vs other antihypertensive agents (n=689) 0 Acute MI CV events All-cause Stroke -10 mortalityRelative risk -20 -24 %reduction ((%) -30 P= -40 0.3 -51 -50 % -62 % -60 -63 % P < 0.001 -70 P = 0.001 P < 0.001 Pahor M et al. Diabetes Care. 2000;23:888-892.
28. Conditions favouring use of some antihypertensive drugs versus others (cont)ACE Inhibitors Angiotensin receptor antagonistsHeart Failure Heart FailureLV dysfunction Post MIPost MI Diabetic nephropathyDiabetic nephropathy Proteinuria/MicroalbuminuriNon- diabetic nephropathyaLV hypertrophy LV hypertrophyCarotid atheroscelerosis Atrial fibrillationProteinuria/Microalbuminuria Metabolic syndromeAtrial fibrillation ACEI- induced coughMetabolic syndrome European Guidelines on Treatment of Hypertension,Journal of Hypertension,Vol 25 No 6,2007
29. Angiotensin ConvertingEnzyme (ACE) Inhibitors•Increased NO at vessel for vasodilatation•Improved glucose disposal•Reduction in LV geometry changesRed ction in inflammation•Reduction •Stabilization of fibrous cap of lipid lesion•Decreased proteinuria•Improves endothelial health•Reduced mortality in patients with CHF•Decreases post-MI mortalityJAMA. 2003:289:2560-2577.
30. 2008 CHEP Recommendations for the Management of Hypertension
31. Treatment Of Hypertension In Association With DM Persons with DM should be treated to attain systolic blood pressures of less than 130 mm Hg (Grade C) and diastolic blood pressures of less than 80 mm Hg (Grade A). For persons with diabetes and normal urinary albumin excretion and without chronic kidney disease, any of: an ACE inhibitor (Grade A for persons aged greater than or equal to 55 years, Grade B for persons aged less than 55 years),
32. ARB (Grade A for persons with LVH and age greater than or equalto 55 years, Grade B for persons without LVH irrespective of age),If these drugs are contraindicated or cannot be tolerated, a cardio-selective beta-blocker (Grade B) or non-dihydropyridine CCB(Grade B) can be substituted.For persons with diabetes and albuminuria, an ACE inhibitor or anARB is recommended as initial therapy (Grade A).
33. ACEIs Vs ARBs
34. ADA Guidelines on Management of Diabetic Nephropathy Hypertensive Type 2 Diabetic Patients* ARBs are the initial agents of choice Type 1 Diabetics with or without hypertension* ACEIs are the initial agents of choice If one class is not tolerated the other should be substituted* With microalbuminuria and clinical proteinuria. Adapted from American Diabetes Association. Diabetes Care. 2002;25:S85-S89.
35. ACEIs VS ARBs,Trials and Guidelines In Diabetes
36. Jikei Heart Study: Valsartan-based TherapyImproved Outcomes in Patients withHypertension, Coronary Heart Disease and/or HeartFailure CV mortality and morbidity Hospitalization Hospitalization (primary endpoint) Stroke/TIA for heart failure for angina 0 Risk reduction (%) 39% 40% 47% 65% 20 40 Mochizuki et al. Lancet 2007;369:1431–9 48 60
38. Further results from JIKEI Heart studyStudy JIKEI Heart Study Kyoto Heart StudyBase line characteristic Population 3,081 Japanese patients > 3,031 Japanese patients BP Average 139/ 80 mmHg ≥ 140/ 90 mmHg (Uncontrolled (controlled BP) with high risk CV patient) with high risk CV disease diseasesStudy design Add on Diovan 80 mg OD to Add on Diovan 160 mg OD to conventional therapy vs conventional therapy vs Conventional therapy Conventional therapyPrimary endpoint Combine endpoint of CV Composite of cardio- or mortality and morbidity cerebro-vascularSecondary endpoint Stroke All cause mortality Hospitalization HF/ angina Worsening cardiac function MI New onset AF or DMKey Results 39% risk reduction in combine 45% risk reduction in CV CV event events 40% risk reduction incidence 45% risk reduction in stroke of new or recurrent stroke 33% risk reduction in new onset DM 50
39. CONCLUSION• Diabetes, the metabolic syndrome and hypertension constitute a particularly dangerous combination as regards cardiovascular morbidity and mortality.• The primary therapeutic goal is to reduce blood pressure.• The ACE inhibitors and ARBs may have additional properties that warrant their use in diabetes and the metabolic syndrome, whereas thiazide diuretic monotherapy may not.
40. Evidence for use of ARB in type 1 and type II Diabetes mellitus
41. 1-ARB in Type I DM withmicroalbuminuria No well conducted studies2-ARB in Normotensive type 2DM with microalbuminuria : Irbesartan in patients with type 2 diabetes and microalbuminuria study group.(IRMA) 2001 Losartan reduces microalbuminuria in hypertensive microalbuminuric type 2 diabetics 2001 MicroAlbuminuria Reduction With VALsartan (MARVAL) Study Investigators. Circulation 2002;106(6):672-8
42. Benefit of Angiotensin Receptor Blockers in Diabetes with overt nephropathy:3 Major Clinical Trials RENAAL (2001) • The angiotensin receptor blocker losartan compared to placebo reduced the risk of diabetic nephropathy developing to renal failure. IRMA II (2001) • Higher doses of the angiotensin receptor blocker irbesartan reduced the risk of progression of renal insufficiency. IDNT (2001) • The angiotensin receptor blocker irbesartan compared to the calcium channel blocker amlodipine provided better renal protection in hypertensive type 2 diabetics, reducing the chance of diabetic nephropathy developing to renal failure. www.hypertensiononline.org
43. Microalbuminuria Reduction With Valsartan in Patients With Type 2 Diabetes Mellitus Blood Pressure–Independent Effect (MARVAL) StudyMethods 332 patients with type 2 diabetes and microalbuminuria, with or without hypertension, Randomly assigned to 80 mg/d valsartan or 5 mg/d amlodipine for 24 weeks. The primary end point was the percent change in UAER from baseline to 24 weeks.Results The UAER at 24 weeks was 56% of baseline with valsartan and 92% of baseline with amlodipine, (P0.001). Valsartan lowered UAER similarly in both the hypertensive and normotensive subgroups. More patients reversed to normoalbuminuria with valsartan (P0.001).
44. Conclusions For the same level of attained BP and the same degree of BP reduction, valsartan lowered UAER more effectively than amlodipine in patients with type 2 diabetes and microalbuminuria, including the subgroup with baseline normotension. This indicates a BP-independent antiproteinuric effect of valsartan. (Circulation. 2002;106:672-678.)
45. Combination Therapy
46. Highly Compliant Patients Are 45% More Likely To Achieve BP Control Odds ratio = 1.45 Patients with BP control* (%) p=0.026 (controlling for age, gender and comorbidities) 50 43 40 34 33 30 20 10 0 High Medium Low (≥80%) (50–79%) (<50%) Adherence (measured using MPR)*According to JNC VI definitions 58 Bramley et al. J Manag Care Pharm 2006;12:239–45
47. Improved Compliance with Fixed-doseCombination Therapy Compared with Free- combination Therapy Fixed-dose combination (RAS blockers +CCB) (n=2,839) 88.0% p<0.0001 Free combination (RAS blockers +CCB) 69.0% (n=3,367) 0% 20% 40% 60% 80% 100% Medication possession ratio (MPR)††Defined as the total number of days of therapy formedication dispensed/365 days of study follow-up 59 Wanovich et al. Am J Hypertens 2004;17:223A (poster)
48. Advantages of Fixed Versus Free Combinations of Two Antihypertensive Drugs Fixed Free Simplicity of + – treatment Compliance + – Efficacy + + Tolerability +* – Price + –*Lower doses generally used in fixed-dose combinations+ = potential advantage 60
49. Take Home Message Before Initiating Antihypertensive Therapy, Thefollowing should be considered:• Age• Metabolic Profile• Renal FunctionFor Patients with Type II Diabetes & RenalImpairment, ARB are on the top of the list ofAntihypertensive medications 61
50. Management of diabetes in hypertensives
51. Number (%) of patients with clinically significant adverse events confirmed by the cardiovascular and cerebrovascular (CCV) adjucation committee Vildagliptin Glimepiride (50 mg twice daily) (up to 6 mg/day) CCV event category n=1389, n (%) n=1383, n (%) Any CCV event 12 (0.9) 22 (1.6) Acute coronary syndrome 5 (0.4) 7 (0.5) Cardiac arrythmia 3 (0.2) 5 (0.4) Congestive heart failure 2 (0.1) 2 (0.1) Death 2 (0.1) 1 (0.1) Peripheral vascular disease 0 (0.0) 1 (0.1) Stroke 0 (0.0) 7 (0.5) Syncope 1 (0.1) 0 (0.0) Ferrannini E. Fonseca V, Zinman B et al. Diabetes, Obesity and Metabolism 2009; 11:157-166
52. SafetyA. J. Garber et al. Diabetes, Obesity and Metaboli
53. The Incretins’ advantageThe incretins provide a global management ofdiabetesThey decrease both fasting and postprandial bloodglucoseThey decrease body weight or BW neutral.They do not cause hypoglycemia provided they arenot used with SUThey preserve beta cells and maintain glucosecontrol if used from the startThey can be combined with any other anti diabeticmedication even insulin
54. Take Home Message Combination of ARB & diuretic is a logic combination supported by guidelines & Morbidity – Mortality Mega Trials Using FDC* in Hypertension Management, Assures compliance and Improves BP Control*FDC: Fixed Dose 72
55. JNC 7 Compelling Indications for Specific Antihypertensive Agents Based on Favorable Outcome Data From Clinical Trials Diuretic BB ACEI ARB CCB AA CHF Post-MI CAD risk Diabetes mellitus Renal disease Recurrent stroke prevention BB, beta blocker; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker;CCB, calcium channel blocker; AA, aldosterone antagonist; CHF, chronic heart failure;MI, myocardial infarction; CAD, coronary artery disease; DM, diabetes mellitusChobanian AV et al. JAMA. 2003;289:2560–2572.
56. ADA Guidelines For Management of Hypertension in Adults With Diabetes Systolic Diastolic Goal (mmHg) <130 <80 Behavioral therapy alone 130–139 80–89 (maximum 3 months) then add pharmacologic treatment Behavioral therapy + 140 90 pharmacologic treatmentArauz-Pacheco C et al. Diabetes Care. 2003;26(suppl):S80–S82.
57. CONCLUSION• Diabetes, the metabolic syndrome and hypertension constitute a particularly dangerous combination as regards cardiovascular morbidity and mortality.• The primary therapeutic goal is to reduce blood pressure.• The ACE inhibitors and ARBs may have additional properties that warrant their use in diabetes and the metabolic syndrome, whereas thiazide diuretic monotherapy may not.