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.

Diabetes: the growing global burden

1Adapted from IDF. E-Atlas. Available at: www.eatlas.idf.org (accessed 05.03.07).2Diabetes Atlas, third edition © International Diabetes Federation, 2006.

IDF:2 • Diabetes currently affects 246 million people worldwide• It is expected to affect 380 million by 2025

No data

< 2%

2–5%

5–8%

8–11%

11–14%

14–17%

> 17%

20002000Prevalence estimates of diabetes mellitusPrevalence estimates of diabetes mellitus 20012001

No data

< 2%

2–5%

5–8%

8–11%

11–14%

14–17%

> 17%

Prevalence estimates of diabetes mellitus 2003200320032003

No data

< 2%

2–5%

5–8%

8–11%

11–14%

14–17%

> 17%

1

Prevalence of diabetes in Eastern Mediterranean and Middle East Region in 2003

International Diabetes Federation. Diabetes Atlas. 2nd Edition. www.eatlas.idf.org. Accessed 27 October, 2006.

Egypt9.8%3.9 million

Pakistan8.5%6.2 million

Saudi Arabia9.4%1 million

United Arab Emirates20.1%0.4 million

Afghanistan8.2%0.9 million

Sudan3.1%0.5 million

Yemen7.7%0.6 million

Total cases > 19 million adults

PREVELANCE OF HYPERTENSION

12.08

13.6

26.3

6.07

20.4

22

0

5

10

15

20

25

30

India China Egypt Bangladesh USA Candada

%

Global Rates (%) of HTN Control<140/90 mm Hg

United States 34

France24

Canada22

Italy 9

Egypt 8

England 6

Korea 5

China 3

Poland 2

<160/95 mmHg

Germany 23

Finland 21

Spain 20

Australia 19

Scotland 18

India 9

Zaire 3

1. JNC VlI. Hypertension ,2003 .2. Joffres et al. Am J Hypertens 1997;10:1097

3. Colhoun et al. J Hypertens 1998;16:7474. Chamontin et al. Am J Hypertens 1998;11(6pt 1):7595. Marques-Vidal et al. J Hum Hypertens 1997;11:213

Diabetes-Hypertension Relationship

Kieran McGlade Nov 2001 Department of General Practice QUB

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.

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.

Slide 26

Percent Chance of Percent Chance of Cardiovascular Event in 5 YearsCardiovascular Event in 5 Years

No DiabetesNo Diabetes

>20%>20%15%15%--20%20%10%10%--15%15%5%5%--10%10%2.5%2.5%--5%5%<2.5%<2.5%

44 55 66 77 88 44 55 66 77 88 44 55 66 77 88 44 55 66 77 88

MenMenNonsmokerNonsmoker SmokerSmokerTotal Chol.:HDLTotal Chol.:HDL--Chol.Chol.

WomenWomenNonsmokerNonsmoker SmokerSmokerTotal Chol.:HDLTotal Chol.:HDL--Chol.Chol.

AgeAge7070

AgeAge6060

AgeAge5050

180/105180/105160/95160/95140/85140/85120/75120/75

180/105180/105160/95160/95140/85140/85120/75120/75

180/105180/105160/95160/95140/85140/85120/75120/75

Slide 27

Percent Chance of Percent Chance of Cardiovascular Event in 5 YearsCardiovascular Event in 5 Years

DiabetesDiabetes

44 55 66 77 88 44 55 66 77 88 44 55 66 77 88 44 55 66 77 88

MenMenNonsmokerNonsmoker SmokerSmokerTotal Chol.:HDLTotal Chol.:HDL--Chol.Chol.

WomenWomenNonsmokerNonsmoker SmokerSmokerTotal Chol.:HDLTotal Chol.:HDL--Chol.Chol.

AgeAge7070

AgeAge6060

AgeAge5050

180/105180/105160/95160/95140/85140/85120/75120/75

180/105180/105160/95160/95140/85140/85120/75120/75

180/105180/105160/95160/95140/85140/85120/75120/75

>20%>20%15%15%--20%20%10%10%--15%15%5%5%--10%10%2.5%2.5%--5%5%<2.5%<2.5%

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.

Hypertension

Hyperinsulinemia can enhance renal sodium reabsorption and vascular reactivity

Angiotensinogen from fat cells can increase angiotensin II and thus blood pressure

Both systolic and diastolic blood pressure increase with increasing body mass index

Diabetes-Hypertension CVS Burden

Hypertension & Diabetes; A major risk for CVD

The relationship between BP and risk of CVD events is continuous, consistent, and independent of other risk factors. The higher the BP, the greater the chance of heart attack, HF, stroke, and kidney diseases.

Hypertension

Associated with up to 80% chance of premature death from CVD and stroke.

Type 2 Diabetes

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.

Coexistence of Hypertension in Diabetes

Even in newly diagnosed diabetes . . .

hypertension is associated with a doubling of the presence of

MicroalbuminuriaLeftventricularhypertrophy

ECG signs of MI and a prior history of overt CV events

Kaplan, 1997.

CV Mortality Risk Doubles withEach 20/10 mm Hg BP Increment*

*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.

CVmortality

risk

SBP/DBP (mm Hg)

0

1

2

3

4

5

6

7

8

115/75 135/85 155/95 175/105

Association of SBP and CV Mortalityin Men With Type 2 Diabetes

250

200

150

100

50

0<120 120-139 140-159 160-179 180-199

SBP (mm Hg)

CVmortality

rate/10,000

person-yr

NondiabeticDiabetic

CV, cardiovascular; SBP, systolic blood pressure.Stamler J et al. Diabetes Care. 1993;16:434-444.

≥200

24.4

18.6

11.9

0

5

10

15

20

25

30

< 90 mm Hg < 85 mm Hg < 80 mm Hg (targetDBP)

Significant benefits from intensive BP reductionin diabetic patients

Major CV events / 100 patient-yr

Increased risk of cardiac complications in 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.

There is a strong linkage of the two conditions (Hypertension & Diabetes) with progression of renal disease.1

Incident rates of end-stage renal disease, by primary diagnosis*

Increased risk of kidney problems in diabetic hypertensives

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood 1. Pressure. NIH Publication 2004.

According to JNC 7# Guidelines;

Renin Angiotensin SYSTEM (RAS)

pathophysiologicphenomena induced by activation of RAAS:

– Increased oxidative stress– Increased vasoconstriction– Promotion of• Proinflammatory• Procoagulatory• Proliferative environment• Endothelial dysfunction– Disruption of insulin signaling pathways

ACE-Is in diabetic hypertension management

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

ABCD, CAPPP & FACET Meta-Analysis

To assess whether ACE inhibitors are superior to other agents in the prevention of cardiovascular events in hypertensive type 2 diabetics

Review and meta-analysis of randomized controlled trials of patients treated with ACEIs or other agents, followed for 2 years, with adjudicated cardiovascular events

3 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.

CV risk reduction with ACEIs in type 2 diabetes:ABCD, CAPPP, and FACET

ACEI (n=733) vs other antihypertensive agents (n=689)

-63

-51

-62

-24

-70

-60

-50

-40

-30

-20

-10

0Acute MI CV events All-cause

mortalityStroke

%

%

%

%

P < 0.001

P < 0.001P = 0.001

P = 0.3

Relative riskreduction

((%)

Pahor M et al. Diabetes Care. 2000;23:888-892.

Prevention of Type 2 Diabetes by Inhibition of the RASResults• Study Treatment Control RR (fixed) 95% CI RR (fixed)

95% CI

0.1 0.2 0.5 1 2 5 10

Favors Treatment Favors Control

ALLHAT 2002 119/5840 302/9733ALPINE 2003 1/196 8/196CAPP 1999 227/5184 280/5229CHARM 2003 163/2715 202/2721HOPE 102/2837 155/2883LIFE 2002 241/4006 319/3592SCOPE 2003 99/2160 125/2170 SOLVD 2003 9/153 31/138STOP-HTN-2 1999 99/1969 97/1961

Total (95% CI) 25060 29023

Total events 1158 (Treatment), 1609 (Control)Test for heterogeneity Chi2 =22.39, df = 8 (p = 0.004), P = 64.3%Test for overall effect Z = 6.73 (p < 0.00001)

.66 [0.53, 0.81]0.13 [0.02, 0.97]0.09 [ 0.70, 1.03]0.01 [0.66, 0.97]0.69 [0.52, 0.85]0.75 [0.64, 0.88]0.81 [0.62, 1.06]0.26 [0.13, 0.53]0.95 [0.72, 1.26]

0.78 [0.72, 0.84]

Scheen A. Diabetes 2004;53(S2);A169.

Conditions favouring use of some antihypertensive drugs versus others (cont)

ACE Inhibitors

Heart FailureLV dysfunctionPost MIDiabetic nephropathyNon- diabetic nephropathyLV hypertrophyCarotid atheroscelerosisProteinuria/MicroalbuminuriaAtrial fibrillationMetabolic syndrome

Angiotensin receptor antagonists

Heart FailurePost MIDiabetic nephropathyProteinuria/MicroalbuminuriaLV hypertrophyAtrial fibrillationMetabolic syndromeACEI- induced cough

European Guidelines on Treatment of Hypertension,Journal of Hypertension,Vol 25 No 6,2007

Angiotensin ConvertingEnzyme (ACE) Inhibitors

•Increased NO at vessel for vasodilatation

•Improved glucose disposal

•Reduction in LV geometry changes

Red 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 mortality

JAMA. 2003:289:2560-2577.

2008 CHEP Recommendations for

the Management of Hypertension

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),

ARB (Grade A for persons with LVH and age greater than or equal to 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 an ARB is recommended as initial therapy (Grade A).

ACEIs Vs ARBs

ADA Guidelines on Management of

Diabetic NephropathyHypertensive Type 2 Diabetic Patients*

ARBs are the initial agents of

choiceType 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.

ACEIs VS ARBs, Trials and Guidelines

In Diabetes

48

40%

Stroke/TIA

Jikei Heart Study: Valsartan-based Therapy Improved Outcomes in Patients with Hypertension, Coronary Heart Disease and/or Heart Failure

Ris

k r

ed

ucti

on

(%

)

65%

Hospitalization for angina

47%

Hospitalization for heart

failure

39%

CV mortality and morbidity

(primary endpoint)0

20

40

60

80

Mochizuki et al. Lancet 2007;369:1431–9

49

Kaplan-Meier’s curves

0 6 12 18 24 30 36 42 48Number at riskValsartan 1,517 1,335 1,289 1,210 1,084 900 759 680 380 220Non-ARB 1,514 1,347 1,262 1,182 1,048 868 749 631 351 178

15

10

5

0

Eve

nt

rate

(%

)

HR=0.55, p=0.0148895% CI 0.3–0.9

Stroke 45% Risk reduction

Non-ARB 46 pts (3.0%)

Valsartan 25 pts (1.7%)

50

Further results from JIKEI Heart study

Study JIKEI Heart Study Kyoto Heart StudyBase line characteristic Population BP

3,081 Japanese patients Average 139/ 80 mmHg (controlled BP) with high risk CV disease

> 3,031 Japanese patients ≥ 140/ 90 mmHg (Uncontrolled patient) with high risk CV diseases

Study design Add on Diovan 80 mg OD to conventional therapy vs Conventional therapy

Add on Diovan 160 mg OD to conventional therapy vs Conventional therapy

Primary endpoint Combine endpoint of CV mortality and morbidity

Composite of cardio- or cerebro-vascular

Secondary endpoint Stroke Hospitalization HF/ angina MI

All cause mortality Worsening cardiac function New onset AF or DM

Key Results 39% risk reduction in combine CV event 40% risk reduction incidence of new or recurrent stroke

45% risk reduction in CV events45% risk reduction in stroke33% risk reduction in new onset DM

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.

Evidence for use of

ARB in

type 1 and type IIDiabetes mellitus

1-ARB in Type I DM with microalbuminuria

No well conducted studies

2-ARB in Normotensive type 2 DM 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

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

Microalbuminuria Reduction With Valsartan in Patients With Type 2 Diabetes MellitusBlood Pressure–Independent Effect

(MARVAL) Study

Methods 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.

ResultsThe 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).

ConclusionsFor 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.)

Combination Therapy

58

0

10

40

50

30

20

Highly Compliant Patients Are 45% More Likely To Achieve BP Control

*According to JNC VI definitions Bramley et al. J Manag Care Pharm 2006;12:239–45

Patients with BP control* (%)

High(≥80%)

Medium(50–79%)

Low(<50%)

43

34 33

Odds ratio = 1.45p=0.026 (controlling for age, gender and comorbidities)

Adherence (measured using MPR)

59†Defined as the total number of days of therapy formedication dispensed/365 days of study follow-up

Fixed-dose combination(RAS blockers +CCB)

(n=2,839)

Free combination(RAS blockers +CCB)

(n=3,367)

Medication possession ratio (MPR)†

Wanovich et al. Am J Hypertens 2004;17:223A (poster)

p<0.0001

Improved Compliance with Fixed-dose Combination Therapy Compared with Free-

combination Therapy

88.0%

69.0%

0% 20% 40% 60% 80%100%

60*Lower doses generally used in fixed-dose combinations+ = potential advantage*Lower doses generally used in fixed-dose combinations+ = potential advantage

Advantages of Fixed Versus Free Combinations of Two Antihypertensive Drugs

Fixed Free

Simplicity of treatment

+ –

Compliance + –

Efficacy + +

Tolerability +* –

Price + –

61

Take Home Message

Before Initiating Antihypertensive Therapy, The following should be considered:• Age• Metabolic Profile• Renal Function

For Patients with Type II Diabetes & Renal Impairment, ARB are on the top of the list of Antihypertensive medications

Management of diabetes in hypertensives

Number (%) of patients with clinically significant adverse events confirmed by the cardiovascular and cerebrovascular (CCV) adjucation committee

Ferrannini E. Fonseca V, Zinman B et al. Diabetes, Obesity and Metabolism 2009; 11:157-166

Glimepiride (up to 6

mg/day)

Vildagliptin (50

mg twice daily) n=1383, n (%)n=1389, n (%)CCV event category

0 (0.0)

22 (1.6)

7 (0.5)

5 (0.4)

2 (0.1)

1 (0.1)

1 (0.1)

7 (0.5)

Syncope

Any CCV event

Acute coronary syndrome

Cardiac arrythmia

Congestive heart failure

Death

Peripheral vascular disease

Stroke

1 (0.1)

12 (0.9)

5 (0.4)

3 (0.2)

2 (0.1)

2 (0.1)

0 (0.0)

0 (0.0)

Safety

A. J. Garber et al. Diabetes, Obesity and Metabolism, 9, 2007, 166–174

The Incretins’ advantage

The incretins provide a global management of diabetes

They decrease both fasting and postprandial blood glucose

They decrease body weight or BW neutral.

They do not cause hypoglycemia provided they are not used with SU

They preserve beta cells and maintain glucose control if used from the start

They can be combined with any other anti diabetic medication even insulin

72

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 Combination

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 mellitus

Chobanian AV et al. JAMA. 2003;289:2560–2572.

CHF

Post-MI

CAD risk

Diabetes mellitus

Renal disease

Recurrent strokeprevention

BB

ACEI

ARB

CCB

AADiuretic

JNC 7 Compelling Indications for Specific Antihypertensive Agents

Based on Favorable Outcome Data From Clinical Trials

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 90pharmacologic treatment

Arauz-Pacheco C et al. Diabetes Care. 2003;26(suppl):S80–S82.

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.