1. The concept of Diabetes & CV risk: A lifetime risk challenge
Cardio Diabetes Master Class
European chapter
Munich, Germany
May 6-8, 2011
Presentation topic
Targeting Blood Pressure : What are the Optimal Targets in CV Risk and Diabetes?
Slide lecture prepared and held by:
Gordon McInnes, MD
Professor of Clinical Pharmacology
University of Glasgow,
Western Infirmary
Glasgow, United Kingdom

2. Global Mortality 2000: Impact of Correctable Risk Factors
PACE Munich 2011
Global Mortality 2000: Impact of Correctable Risk Factors
High BP
Tobacco
High cholesterol
Underweight
Unsafe sex
High BMI
Physical inactivity
Developing region
Developed region
This slide highlights the contribution of some of the leading health risk factors to global mortality, e.g. high BP, tobacco use, high cholesterol, and under-nutrition.
In both developed and developing regions, high BP was among the major causes of disease burden and a leading cause of global mortality.
Intensive strategies to target leading global health risk factors such as hypertension are therefore necessary.
Reference
Ezzati M, et al. Selected major risk factors and global and regional burden of disease. Lancet 2002;360:1347–60.
Alcohol 1 2 3 4 5 6 7 8
Attributable mortality in millions (total: 55,861,000)
Adapted from The Lancet, 360, Ezzati et al. pp. 1347–60. Copyright © 2002, with permission from Elsevier
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3. CHD mortality rate in each decade of age
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Meta-analysis of individual Blood Pressure data for 1million adults in 61 prospective studies Prospective Studies Collaboration Lancet
CHD mortality rate in each decade of age
versus
usual blood pressure
at the start of
that decade
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4. Diabetes – CHD Risk Equivalent
British Regional Heart Study
Risk of major CHD event
No MI or diabetes
Diabetes diagnosed > 60 years 1.54
Diabetes diagnosed < 60 years 2.39
Prior MI
Wannamethee SG et al, Arch Intern
Med 2011; 171:

5. PACE Munich 2011
Benefits of antihypertensive treatment proportional to reduction in blood pressure
Systolic blood pressure difference
between randomised groups (mmHg)
Relative risk of stroke
CA/plac
ACE/plac
More/less
ARB/other
ACE/CA
CA/DBB
ACE/DBB
Results of prospectively-designed overviews of randomised trials.
Lancet 2003; 362:
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6. Benefits of Antihypertensive Treatment Absolute Risk Reduction

7. UKPDS : Tight Glucose vs Tight BP Control and CV Outcomes in UKPDS
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UKPDS : Tight Glucose vs Tight BP Control and CV Outcomes in UKPDS
Stroke
Any Diabetic
Endpoint DM
Deaths
Microvascular
Complications 5%
10%
-10
12%
-20
24%
Diabetes: Tight Glucose vs Tight BP Control and CV Outcomes in UKPDS
Talking Points: A comparison of tight glucose control, HbA1c=7% (achieved was 8.2%) vs tight blood pressure control <150/85 mmHg (achieved 144/82 mmHg) revealed that blood pressure reduction contributed to a greater extent to the relative reduction of cardiovascular events.
References:
Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ. 1998;317(7160):
Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ. 1998;317(7160): *
-30
% Reduction In Relative Risk
32%
32% *
37%
*P <0.05 compared to tight glucose control
-40 *
44% *
Tight Glucose Control
(Goal <6.0 mmol/l or 108 mg/dL)
Tight BP Control
(Average 144/82 mmHg)
-50
UKPDS 1998
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8. HOT Study: Effects of blood pressure on cardiovascular events
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HOT Study:
Effects of blood pressure on cardiovascular events
Minimum blood pressures around which the maximum benefits of treatment can be expected are
systolic between 130mmHg-140mmHg
diastolic between 80mmHg- 85mmHg
Between 5-10 cardiovascular events can be prevented in every 1000 patients successfully treated for 1 year
Conclusion:
The principal results of the HOT Study demonstrate the benefits of lowering blood pressure in patients with hypertension to 140mm Hg systolic and 85 mm Hg diastolic, or lower. Efforts to lower blood pressure further, down to 120mm Hg systolic and 70mm Hg diastolic, appear to give little further benefit, but do not cause any significant additional risk. Active lowering of blood pressure was particularly beneficial in the subgroup of patients with diabetes mellitus.
Quote
“The HOT study is a triumph in that the diastolic blood pressure was reduced by over 20mm Hg in most of the nearly 19,000 patients, far beyond the average 5-6mm Hg reductions achieved in many other randomised controlled trials”
Lancet 1998; 351: 1748–1753 -Commentary Norman Kaplan, University of Texas
Hansson L, et al. Lancet 1998;351:
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10. Hypertension Optimal Treatment (HOT) Study
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Hypertension Optimal Treatment (HOT) Study
Intensive BP-lowering decreases cardiovascular risk in patients with hypertension, especially among those with diabetes
Major CV events per 1000 patient years 30
24.4 25
All patients (n=18 790)
Diabetics (n=1501) 20
18.6 15
11.9
9.9
10.0 10
9.3 5
90 mm Hg
85 mm Hg
80 mm Hg
Target DBP group
Lancet 1998;351:1755–1762
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11. UKPDS: Microvascular Endpoints, MI, and SBP
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8.Reducing CV risk in diabetes.Multifactorial approach.Prof J Betteridge.pptx - 20 May 2009
UKPDS: Microvascular Endpoints, MI, and SBP
Incidence of microvascular endpoints and MI by updated mean SBP* Adjusted for age, sex, and ethnic group Expressed for white men, 50–54 years old at baseline and with mean diabetes duration of 10 years 50 MI
Microvascular endpoints 40 30
Adjusted incidence per patient years (%) 20 10
UKPDS data were used to evaluate the relationship between systolic blood pressure (SBP) over time and the development of macrovascular and microvascular complications. SBP was measured at baseline and as an updated mean of annual measurements, calculated for each year of follow-up (i.e., average of the baseline and all available annual levels).25
The slide shows results, adjusted for age, sex, and ethnic group, for men 50 to 54 years old with a mean diabetes duration of 10 years at baseline. The risk of both macrovascular (MI) and microvascular complications of type 2 diabetes was strongly associated with increasing SBP. There was no evidence of a threshold effect.25
110
120
130
140
150
160
170
*Updated mean SBP = average of the baseline and all available annual measurements
SBP = systolic blood pressure
Updated mean SBP (mmHg)*
Adler et al BMJ 2000;321:
8.Reducing CV risk in diabetes.Multifactorial approach.Prof J Betteridge.pptx - 20 May 2009
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12. Reduced blood pressure slows the rate of GFR decline
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Reduced blood pressure slows the rate of GFR decline
Mean arterial pressure (mmHg) 95 98
101
104
107
110
113
116
119 -2
r = 0.69; P < 0.05 -4 -6
This meta-analysis of clinical trials in diabetic and non-diabetic renal disease shows the direct and continuous relationship between the achieved blood pressure and the decline in GFR.1
In patients with proteinuria >1 g/day and renal insufficiency (GFR 13–55 mL/min/1.73 m2), optimal blood pressure is <125/75 mmHg.2
Bakris GL, et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis 2000;36:646–661.
Lazarus JM, et al. Achievement and safety of a low blood pressure goal in chronic renal disease. The Modification of Diet in Renal Disease Study Group. Hypertension 1997;29:641–650.
Decline in GFR (mL/min/year)
Untreated
hypertension -8
-10
-12
130/85
140/90
-14
Bakris et al. Am J Kidney Dis 2000;36:646–661
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13. More Versus Less Intensive BP Control Meta-analysis : RR
DM No DM All
BP diff 6.0/ /3.3
Stroke
CHD HF
Major CV event
CV deaths
Total mortality
BPLTTC, Arch Intern Med 2005; 165:

14. Blood Pressure Targets
Uncomplicated DM CRF
US (2003 ) < 140/ < 130/ < 130/80
Europe (2007) < 140/ < 130/ < 130/80
WHO/ISH (2004) SBP < < 130/ < 130/80
UK (2004) < 140/ < 130/ < 130/80
China (2005) < 140/ < 130/ < 130/80

15. Incidence (%) of MI or Stroke
INVEST: Incidence of Myocardial Infarction (MI) and Stroke by Diastolic Blood Pressure Strata
DBP (mm Hg) 25 30 20 15 10 5
≤60
>60 to
≤70
>70 to
≤80
>80 to
≤90
>90 to
≤100
>100 to
≤110
>110
Incidence (%) of MI or Stroke 35 MI
Stroke
Messerli FH et al Ann Intern Med 2006; 144:

16. ESH guidelines - Reappraisal
Rigorous control of BP (< 130 mmHg) in diabetes or prior CV disease not supported by trial evidence
J-curve phenomenon unlikely except perhaps in advanced occlusive disease
Mancia G, Blood Pressure 2009

17. Recommendations for BP Goals
Nairobi Meeting_Showfile_20 Sept 2010.pptx - 23 September 2010
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Recommendations for BP Goals
BHS-IV1
ESH-ESC2
Type of hypertension
BP goal (mmHg)
Uncomplicated
<140/85
130–139/80–85
Complicated
Diabetes mellitus
<130/80
Kidney disease
<130/80*
Other high risk (stroke, myocardial infarction)
Based on published evidence, the ESHESC guidelines1 and the JNC 7 guidelines2 have made recommendations for target BP goals that should be achieved in order to maximize the reduction in the long-term risk of cardiovascular (CV) disease and death.
In the US JNC7 guidelines, target BP goals are <130/80 mmHg for patients with hypertension complicated by diabetes or renal disease. The same is true for those patients considered high risk (e.g. history of stroke or previous myocardial infarction). A re-appraisal of the ESH-ESC guidelines has suggested BP goals of 130–139/80–85 mmHg for these patients.1 Achievement of BP goals is thought to be particularly necessary for such patients because the presence/history of these diseases may compound their total CV risk.
References
1. Mancia G, et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. Blood Pressure 2009;18:308–347.
2. Chobanian AV, et al. Seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 2003;42:1206–1252.
*Lower if proteinuria is >1 g/day
1. Williams B et al J Human Hypertension Mancia et al. Blood Pressure 2009
Valsartan Family Scientific Slide Resource Item code: DIO10.168; Release Date: May 2010
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Nairobi Meeting_Showfile_20 Sept 2010.pptx - 23 September 2010 17

18. 18 ADVANCE: Primary Outcomes Combined Macro & Microvascular Events
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ADVANCE: Primary Outcomes
number of events
Per-Indap
(n=5569)
Placebo
(n=5571)
RR reduction
(95%CI)
Combined Macro & Microvascular Events
9% (0 to 17%)
861
938
Macrovascular Events
480
520
8% (-4 to 19%)
Microvascular Events
439
477
9% (-4 to 20%)
favours per-indap
favours placebo
0.5
1.0
2.0
Hazard Ratio
Average BP during follow-up
140.3 / 77.0 mmHg Placebo
137.4 / 74.8 mmHg Peridopril-Indapamide
ADVANCE Collaborative Group 2007
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19. ADVANCE & ACCORD in context - UKPDS
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ADVANCE & ACCORD in context - UKPDS
Incidence of myocardial infarction & microvascular end points by mean systolic BP, adjusted for age, sex, & ethnic group expressed for white men aged 50­54 yrs at diagnosis & mean duration of diabetes of 10 yrs 50
ACCORD
ADVANCE
UKPDS 40
Myocardial Infarction 30
Microvascular Endpoints
incidence/1000patient. yrs (%)
This relates the study population in the ACCORD Trial to that of UKPDS and ADVANCE 20 10
110
120
130
140
150
160
170
mean systolic BP (mmHg)
UKPDS 36: 2000
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20. Risk of Stroke in DM or Impaired FBS
Messerli FH, Bangalore S
JACC 2011; 57: