This document discusses the management of hypertension in patients with diabetes. It begins by outlining the magnitude of the problem globally, noting that diabetes currently affects 246 million people worldwide and is expected to affect 380 million by 2025. It then discusses the strong relationship between diabetes and hypertension, and the cardiovascular burden associated with the coexistence of the two conditions. The renin angiotensin system and its role in hypertension is explained. The document recommends the use of ACE inhibitors in the management of diabetic hypertension due to evidence from clinical trials demonstrating their efficacy in reducing cardiovascular events and mortality compared to other agents. It also discusses the benefits of ACE inhibitors versus angiotensin receptor blockers.

2. 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. Diabetes: the growing global burden
1
IDF:2
• Diabetes currently affects 246 million people worldwide
• It is expected to affect 380 million by 2025
1Adapted from IDF. E-Atlas. Available at: www.eatlas.idf.org (accessed 05.03.07).
2Diabetes Atlas, third edition © International Diabetes Federation, 2006.

4. Prevalence of diabetes in Eastern Mediterranean
and Middle East Region in 2003
Saudi Arabia Afghanistan
9.4% 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.

6. PREVELANCE OF
HYPERTENSION
30
25
20
% 15
26.3
20.4
22
10
13.6
12.08
5
6.07
0
India China Egypt Bangladesh USA Candada

7. Global Rates (%) of HTN Control
<140/90 mm Hg <160/95 mmHg
Germany 23
United States 34
France24
Finland 21
Canada22 Spain 20
Italy 9
Egypt 8 Australia 19
England 6 Scotland 18
Korea 5
India 9
China 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

8. Diabetes-Hypertension Relationship

9. 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

10. 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.

11. 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
120/75
Slide 26

12. 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
120/75
Slide 27

13. 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.

14. 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

16. Diabetes-Hypertension CVS Burden

20. 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.

21. Coexistence of Hypertension in Diabetes
Even in newly diagnosed diabetes . . .
hypertension is associated with
a doubling of the presence of
Left ECG signs of MI
Microalbuminuria ventricular and a prior history
hypertrophy
of overt CV events
Kaplan, 1997.

22. CV Mortality Risk Doubles with
Each 20/10 mm Hg BP Increment*
8
7
6
CV 5
mortality 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 pressure
Lewington S, et al. Lancet. 2002; 60:1903-1913.
JNC VII. JAMA. 2003.

23. 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.

24. Significant benefits from intensive BP reduction
in diabetic patients
Major CV events / 100 patient-yr
30
24.4
25
20 18.6
15
11.9
10
5
0
< 90 mm Hg < 85 mm Hg < 80 mm Hg (target
DBP)

25. 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.

26. Increased risk of kidney problems
in 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.

27. Renin Angiotensin SYSTEM (RAS)

30. 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

31. ACE-Is in diabetic hypertension
management

34. 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

35. 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.

36. 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 mortality
Relative 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.

37. Prevention of Type 2 Diabetes by Inhibition of
the RAS
Results
• Study Treatment Control RR (fixed) 95% CI RR
(fixed) 95% CI
ALLHAT 2002 119/5840 302/9733 .66 [0.53, 0.81]
ALPINE 2003 1/196 8/196 0.13 [0.02, 0.97]
CAPP 1999 227/5184 280/5229 0.09 [ 0.70, 1.03]
CHARM 2003 163/2715 202/2721 0.01 [0.66, 0.97]
HOPE 102/2837 155/2883 0.69 [0.52, 0.85]
LIFE 2002 241/4006 319/3592 0.75 [0.64, 0.88]
SCOPE 2003 99/2160 125/2170 0.81 [0.62, 1.06]
SOLVD 2003 9/153 31/138
0.26 [0.13, 0.53]
STOP-HTN-2 1999 99/1969 97/1961
0.95 [0.72, 1.26]
Total (95% CI) 25060 29023 0.78 [0.72, 0.84]
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)
0.1 0.2 0.5 1 2 5 10
Favors Treatment Favors Control
Scheen A. Diabetes 2004;53(S2);A169.

38. Conditions favouring use of some
antihypertensive drugs versus others (cont)
ACE Inhibitors Angiotensin receptor antagonists
Heart Failure Heart Failure
LV dysfunction Post MI
Post MI Diabetic nephropathy
Diabetic nephropathy Proteinuria/Microalbuminuri
Non- diabetic nephropathya
LV hypertrophy LV hypertrophy
Carotid atheroscelerosis Atrial fibrillation
Proteinuria/Microalbuminuria
Metabolic syndrome
Atrial fibrillation ACEI- induced cough
Metabolic syndrome
European Guidelines on Treatment of Hypertension,Journal of Hypertension,Vol 25 No 6,2007

39. Angiotensin Converting
Enzyme (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.

40. 2008 CHEP Recommendations for the
Management of Hypertension

41. 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),

42. 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).

44. ACEIs Vs ARBs

45. 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.

46. ACEIs VS ARBs,
Trials and Guidelines
In Diabetes

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

48. Kaplan-Meier’s curves
15 Stroke 45% Risk reduction
Event rate (%)
10
HR=0.55, p=0.01488
95% CI 0.3–0.9
5 Non-ARB 46 pts (3.0%)
0
Valsartan 25 pts (1.7%)
0 6 12 18 24 30 36 42 48
Number at risk
Valsartan 1,517 1,335 1,289 1,210 1,084 900 759 680 380 220
Non-ARB 1,514 1,347 1,262 1,182 1,048 868 749 631 351 178
49

49. Further results from JIKEI
Heart study
Study JIKEI Heart Study Kyoto Heart Study
Base 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 diseases
Study design Add on Diovan 80 mg OD to Add on Diovan 160 mg OD to
conventional therapy vs conventional therapy vs
Conventional therapy Conventional therapy
Primary endpoint Combine endpoint of CV  Composite of cardio- or
mortality and morbidity cerebro-vascular
Secondary endpoint  Stroke  All cause mortality
 Hospitalization HF/ angina  Worsening cardiac function
 MI  New onset AF or DM
Key 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

50. 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.

51. Evidence for use of
ARB
in
type 1 and type II
Diabetes mellitus

52. 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

53. 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

54. Microalbuminuria Reduction With Valsartan in Patients With Type 2 Diabetes Mellitus
Blood 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.
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).

55. 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.)

56. Combination Therapy

57. 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

58. Improved Compliance with Fixed-dose
Combination 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 for
medication dispensed/365 days of study follow-up 59
Wanovich et al. Am J Hypertens 2004;17:223A (poster)

59. 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

60. 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
61

61. Management of diabetes in
hypertensives

64. 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

65. Safety
A. J. Garber et al. Diabetes, Obesity and Metaboli

70. 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

71. 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

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

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

74. 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.