1. MANAGEMENT OF HYPPERTENSION IN T2DM
TRIALS, TRIBULATIONS, GUIDELINES AND
GOALS
Dr.Dr. RajeevRajeev AgarwalaAgarwala
Jaswant Rai Speciality Hospital Meerut.Jaswant Rai Speciality Hospital Meerut.
Email : rajeev_jrsh@yahoo.co.inEmail : rajeev_jrsh@yahoo.co.in

2. Rev. Stephen Hales
(1677-1761)
BP = 8 feet 3 inches of water

7. April 12, 1945

9. PROFILE OF THE DISEASE

10. How Common is this Duo?
HTN is twice as common in DMHTN is twice as common in DM
New onset DM is 2.5 times in HTN
20 to 40% of IGT pts have HTN20 to 40% of IGT pts have HTN
40 to 50% of Type 2 DM have HTN40 to 50% of Type 2 DM have HTN
Only 1/4 of HTN in DM is controlledOnly 1/4 of HTN in DM is controlled
DM + HTN –  CV Risk 3 foldDM + HTN –  CV Risk 3 fold

11. Relative Risk of DM + HTN
Diabetes + HTN versus Diabetes
• Neuropathy 1.6
• Nephropathy 2.0
• Retinopathy 2.0
• Stroke 4.0
• CHD 3.0
• Mortality 2.0

12. MRFIT: Association of Systolic BP and
Cardiovascular Death in Type 2 Diabetes
250
225
200
175
150
125
100
75
50
0
25
< 120 120–
139
140–159 160–179 180–199 ≥ 200
Systolic blood pressure (mm Hg)
Cardiovascular
mortality
rate/10,000
person-yr
Nondiabetic
Diabetic
Stamler J et al. Diabetes Care. 1993;16:434-444./
hypertensiononline.org

13. Meta-analysis of 61 prospective, observational studies
One million adults, 12.7 million person-years
2 mmHg
decrease in
mean SBP
10% reduction in risk
of stroke mortality
7% reduction in
risk of ischaemic
heart disease
mortality
Lowering BP reduces cardiovascular risk
Lewington et al. Lancet. 2002;360:1903–1913
Small SBP reductions yield significant benefit
Lesson learned ……
Community based approach & Individual Approach

14. UKPDS: Tight blood control and risk of
macrovascular and microvascular complications in
T2DM
 1148 patients randomized to right control or less tight
control
 Tight control defined as < 150/85 mm Hg
 Less tight control defined as < 180/105 mm Hg
 Half of tight control to ACE inhibitors (captopril) and
half to beta blockers (atenolol)
 Mean follow-up of 8.4 years
 Part of larger UKPDS with follow-up every 3-4
months

15. UKPDS 38: tight control had a greater
effect on blood pressure
Bloodpressure(mmHg)
Baseline 9 years
0
140
145
150
155
160
165
Tight
Less tight
Systolic BP
0
78
80
82
84
86
88
90
92
94
96
Baseline 9 years
Diastolic BP
UKPDS 38: BMJ 1998;317:703–13

16. UKPDS: Results
• Mean blood pressure during follow-up
– Tight control: 144/82 mm Hg
– Less tight control: 154/87 mm Hg
• 1/3 patients in tight control group required 3 or
more medications
• 24% decrease in diabetes-related endpoints
• 32% decrease in deaths related to diabetes
• 37% decrease in microvascular endpoints
– Mostly related to reduced risk of laser treatment
• 44% decrease in strokes
BMJ 317: 703, 1998

17. UKPDS 38: relative risk reduction
with tight blood pressure control
-60
-50
-40
-30
-20
-10
0
Relativeriskreductiontightvs
lesstightBPcontrol(%)
M
icrovascular
endpoint
D
iabetes
death
M
I
All-cause
m
ortality
Stroke
Peripheralvascular
disease
Any
diabetes
endpoint
** * p <
0.05
** p <
0.01
**
*
*
UKPDS 38: BMJ 1998;317:703–13

18. Risk reduction (%) in the UKPDS Participants: Initial
results & 10-years follow-up
UKPDS 38: BMJ 1998;317:703–13
NEJM 2008;359:1565-76

19. UKPDS 38: Antihypertensive requirements for
tight BP control
UKPDS Study Group. BMJ. 1998;317:703-13.
0
20
40
60
80
100
% of patients
Number of antihypertensive agents
≥3
2
1
0
Mean BP in “tight” control group:
144/82 mm Hg
1 2 3 4 5 6 7 8
Years from randomization

20. HOT: Hypertension Optimal Treatment
• 18,790 patients from 26 countries, age 50 -80, and
diastolic blood pressure 100-115 mm Hg were recruited
• Patients were randomized to 3 groups based on diastolic
pressure goal (< 90, < 85, and < 80 mm Hg)
• Primary endpoint was composite macrovascular outcome
of non-fatal MI, non-fatal stroke, or CV death
• Major finding was that patients with diabetes had a 51%
reduction in primary endpoint
• No increase in side effects.
Hansson et al. Lancet 351:1755, 1998

21. HOT Trial: Effect of targeted DBP
on CV events over 4 years

22. Clinical Trials of Blood Pressure Lowering in
Diabetic Patients: Systolic (SBP)
Trial N
Mean SBP,
less intense
Mean SBP,
more intense
CVD Risk
Reduction
SHEP 583 155* 146* 22-56%
Syst-Eur 492 162 153 62-69%
HOT 1,501 148 144 30-67%
UKPDS 1,148 154 144 32-44%
ABCD 470 138 132
No CVD
reduction
Cushman, et al. Am J Cardiol 2007;99:44i-
55i

23. ADVANCE
215 centers in 20 countries with 11,140 patients with
type 2 diabetes randomized to fixed combination of
perindopril and indapamide or matching placebo,
Primary endpoints were composites of major macro-
and microvascular events
Death from CV disease, non-fatal stroke or non-fatal MI
New or worsening renal or diabetic eye disease

24. ADVANCE: a factorial randomised trial
of blood pressure lowering and
intensive glucose control in
11,140 patients with type 2 diabetes
Effects of a fixed combination of the ACE inhibitor,
perindopril, and the diuretic, indapamide on major
vascular events
Lancet 2007 Sept 8;370:829-40
Presented at European society of Cardiology, Vienna, 9/2/07

25. ADVANCE RESULTS
 4.3 years of follow-up
 Compared to placebo, there was a drop in pressure of
5.6/2.2 mm Hg
 There was not a significant decrease in macrovasular (p
= 0.16) events or microvascular events (p = 0.16)
separately
 There was a 9% decrease in combination(p=0.04)
 There was a decrease in CV death (p = 0.03) and death
from any cause (p = 0.03)
Lancet 370:829, 2007

26. ADVANCE: BLOOD PRESSURE REDUCTION
Δ 2.2 mmHg (95% CI 2.0-2.4); p<0.001
Δ 5.6 mmHg (95% CI 5.2-6.0); p<0.001
Diastolic
Systolic
Placebo
Perindopril-Indapamide
MeanBloodPressure(mmHg)
65
75
85
95
105
115
125
135
145
155
165
Follow-up (Months)
R 6 12 18 24 30 36 42 48 54 60
140.3 mmHg
134.7 mmHg
Average BP during
follow-up
77.0 mmHg
74.8 mmHg
BP = 145/81 mm Hg @ baseline
Lancet 2007;370:829-40

27. Macrovascular 480 520 8% (-4 to 19)
Microvascular 439 477 9% (-4 to 20)
Combined macro+micro 861 938 9% (0 to 17)
Number of events
Per-Ind Placebo
(n=5,569) (n=5,571)
Relative risk
reduction (95% CI)
Favours
Per-Ind
Favours
Placebo
Hazard ratio
0.5 1.0 2.0
*
*2P=0.04
Primary outcomes
Major macro or microvascular event
Lancet 2007;370:829-40

28. SBP
ADVANCE BP reduction in context:
UK Prospective Diabetes Study
UKPDSADV
UK Prospective Diabetes Study

30. JNC Guideline Recommendations in
Patients with Diabetes
Nat Rev Cardiol 2011;8:42-49

31. “Usual blood pressure is strongly and directly
related to vascular (and overall) mortality
without any evidence of a threshold down
to at least 115/75 mmHg.”
Prospective Studies Collaboration
Lancet 2002;360:1903-1913

32. The ACCORD Study Group,(2010) NEJM.362:1575-1585

33. ACCORD
Hypothesis: Targeting normal systolic blood pressure (
<120 mm Hg) in patients with type 2 diabetes and at
high risk for cardiovascular events reduces major
cardiovascular events
4733 patients were randomized to intensive therapy
(systolic BP < 120 mm Hg) or standard therapy
(systolic BP < 140 mm Hg)
Primary composit outcome was nonfatal MI, nontatal
storke, or death from CV causes
Mean follow-up time was 4.7 years

34. Mean Systolic Pressure levels at each study visit
(mean + 95% CI)
Average after 1st
year: 133.5 Standard vs. 119.3 Intensive, Delta = 14.2
Mean # Meds
Intensive: 3.2 3.4 3.5 3.4
Standard: 1.9 2.1 2.2 2.3

35. ACCORD Results
• There was no difference between groups, in terms of
reaching the primary outcome composite
• There was a decrease in rates of stroke and lesser rates
of progression of albuminuria
• Benefit to those who have HbAIC >6%
N Engl J Med 362: 1575, 2010

36. Primary & Secondary Outcomes
Intensive
Events (%/yr)
Standard
Events (%/yr) HR (95% CI) P
Primary 208 (1.87) 237 (2.09) 0.88 (0.73-1.06) 0.20
Total Mortality 150 (1.28) 144 (1.19) 1.07 (0.85-1.35) 0.55
Cardiovascular
Deaths
60 (0.52) 58 (0.49) 1.06 (0.74-1.52) 0.74
Nonfatal MI 126 (1.13) 146 (1.28) 0.87 (0.68-1.10) 0.25
Nonfatal
Stroke
34 (0.30) 55 (0.47) 0.63 (0.41-0.96) 0.03
Total Stroke 36 (0.32) 62 (0.53) 0.59 (0.39-0.89) 0.01
Also examined Fatal/Nonfatal HF (HR=0.94, p=0.67), a composite of fatal coronary
events, nonfatal MI and unstable angina (HR=0.94, p=0.50) and a composite of the
primary outcome, revascularization and unstable angina
(HR=0.95, p=0.40)
NEJM 2010

37. Kaplan-Meier Analysis of Selected Outcomes
NEJM 2010

38. SBP
ACCORD BP reduction in context ofACCORD BP reduction in context of
UK Prospective Diabetes Study and ADVANCEUK Prospective Diabetes Study and ADVANCE
UKPDSADV
UK Prospective Diabetes Study
ACCORD

39. ACCORD: Conclusions
“In patients with type 2 diabetes at high risk for
cardiovascular events, targeting a systolic blood
pressure of less than 120 mm Hg, as compared
with less than 140 mmHg, did not reduce the rate
of a composite outcome of fatal and nonfatal
major cardiovascular events.”
Cushman et al. NEJM 2010

40. ACCORD BP INTENSIVE BP
LOWERING
FUTILE IN DIABETES
• No benefit to be gained in diabetes by
intensive lowering (<120mmHg)

41. BP CONTROL IN DIABETES
HOW LOW SHOULD WE GO?
INVEST – Calcium antagonist Vs B Blocker

42. INVEST Trial:Methods
JAMA 2010;304:61-68

43. CONCLUSIONS
There is no data that supports the use of ACE inhibitors orThere is no data that supports the use of ACE inhibitors or
ARBs prior to the development of hypertension (BP >ARBs prior to the development of hypertension (BP >
130/80 mm Hg) or microalbuminuria130/80 mm Hg) or microalbuminuria
Further lowering of blood pressure to values < 120/80 mmFurther lowering of blood pressure to values < 120/80 mm
Hg is not associated with an improvement in cardiovascularHg is not associated with an improvement in cardiovascular
events and is associated with increased side effectsevents and is associated with increased side effects

44. JNC Guideline Recommendations
in Patients with Diabetes
Nat Rev Cardiol 2011;8:42-49

45. CIMT regression better in mean systolic
BP <117 mmHg to
mean <129 mmHg
Haword BV et al
JAMA 2008:299

46. Nihilistic Conclusions from the 3 major recent studies
in diabetes or impaired fasting glycemia
• -Blood pressure was significantly lower by 2.8/1.4 mm Hg in
the valsartan arm when compared with placebo”… but it did not
reduce the rate of cardiovascular events…” NAVIGATOR
• The use of ramipril for 3 years did not significantly reduce the
incidence of diabetes or death…” nor did it “reduce the risk of
the cardiorenal composite outcome.” DREAM
• In 4,733 patients with type 2 diabetes targeting systolic BP to
<120 mm Hg as compared with <140 mmHg “did not reduce the
rate of a composite outcome of fatal and nonfatal major
cardiovascular events.” ACCORD
JACC 2011;57:114-115

48. All Cause Mortality
Circulation 2011;123:2799-2810

49. CV Death
Circulation 2011;123:2799-2810

50. Overt Nephropathy
Circulation 2011;123:2799-2810

51. Stroke
Circulation 2011;123:2799-2810

52. Serious Adverse Events
(SAEs)
Circulation 2011;123:2799-2810

53. • ………in patients with diabetes a systolic
BP goal of 130-135 mmHg is acceptable.
However, with more aggressive goals (<130
mmHg) we observed target organ
heterogeneity in that risk of stroke
continued to fall, but there was no benefit
regarding the risk of other
macro/microvascular (cardiac, renal and
retinal) events and the risk of serious
adverse events increased……..
Circulation 2011;123:2799-2810

54. Achieved SBP and CV Event Reduction in trials on
Antihypertensive Treatment in diabetes
J Hypertension 2009;27:923-934

55. BP targets in Latest guideline

56. JNC Guideline Recommendations in
Patients with Diabetes
JNC 7
EuroPrevention
Guidelines
2012

57. BP TARGETS IN VARIOUS GUIDELINES

58. WHAT WENT WRONG

59. RELATIONSHIP BETWEEN CV
THERAPY AND CV RISK

60. Sleight et al. J Hypertens 27:1360, 2009

61. DBP: Risk for All-Cause Death
DBP (mm Hg)
INVEST Subanalysis: BP and Risk
Total patients 176 2253 11339 7367 1201 240
70< to
≤8060< to
≤70≤60
80< to
≤90 90< to
≤100 100<
0
2
4
6
EstimatedHazardRatio
Hazard Ratio
Nadir = 85.8 mm Hg
1
3
5

62. DBP: Risk for Primary Outcome
DBP (mm Hg)
Total patients 176 2239 11306 7376 1230 248
INVEST Subanalysis: BP and Risk
70< to ≤80
60< to ≤70
≤60
80< to ≤90
90< to
≤100 100<
0
1
2
3
4
5
6
EstimatedHazardRatio
Hazard Ratio
Nadir = 84.1 mm Hg

65. Stroke / MI and DBP Strata
INVEST Subanalysis: BP and Risk
70< to ≤80
60< to ≤70
≤60
80< to ≤90
90< to ≤100
100< to ≤110
110< to ≤120
DBP (mm Hg)

66. CONCLUSIONS
• The preponderance of MIs over strokes at
low diastolic pressures suggests that
excessive diastolic hypotension associated
with antihypertensive therapy increased
CAD risk
INVEST Subanalysis: BP and Risk

67. CHOICE OF AGENTS
A SIMPLER CHOICE

68. Treatment recommendation by various guidelines
for BP lowering in diabetics
Guidelines First Line antihypertensives
in diabetic
Other Recommended
antihypertensives
JNC -7(1) ACE inhibitor or ARB or HCTZ ACEI, ARB, BB, CCB,
or combination
NICE(2) ACE inhibitor or ARB. Calcium-channel blocker
(CCB),Thiazide-like diuretic
ESH(3) ACEI, ARB diuretics, CA
Canadian Hypertension
2012(4)
ACE Inhibitor
or ARB
Long-acting CCB or
Thiazide diuretic
Japanese Society of
Hypertension (5)
ACE inhibitors or ARBs Ca channel blockers,
diuretics
ICMR(6) ACE inhibitors and ARB CCBs, Beta blockers
ADA(7) ACE inhibitor or an ARB diuretics
1.JNC –7, 2.Hypertension: NICE guideline Feb,2011, 3.Journal of Hypertension 2007, 25:1751–1762
4. 2012 Canadian Hypertension Education Program Recommendations
5. Hypertension Research 32, 40-50 (January 2009), 6. Indian J Med Res 132, November 2010, pp 531-542
7. Diabetes Care January 2012; l( 35). Supplement 1 S11-S63

69. HOLISTIC GOALS

70. BP IS UNCONTROLLED IN MOST
DIABETICS

73. Risk factors for 335 CHD events in 3055Risk factors for 335 CHD events in 3055
type 2 diabetic patients followed 7.4 yearstype 2 diabetic patients followed 7.4 years
UKPDS, BMJ 1998
∆ risk of CHD
HbA1c (1 %) x 1.11 (1.02 to 1.20)
SBP (10 mmHg) x 1.15 (1.02 to 1.20)
LDL-chol (1 mmol/l) x 1.57 (1.37 to 1.79)
HDL-chol (0.1 mmol/l) x 0.15 (0.08 to 0.22)
(Smoking vs. no smoking: x 1.6)

75. CONCLUSIONS
• Hypertension and Diabetes are twin
enemies of heart, kidney and brain.
• Aggressive control of BP is out
• J curve is defining diastolic BP bottom
• Choice of agent is simple ACEI/ARBS

76. THANK YOU