BLOOD PRESSURE
LOWERING
UKPDS design
Aim
To determine whether intensified blood glucose
control , with either sulphonylurea or insulin ,
reduces the risk of macrovascular or microvascular
complications in type 2 diabetes. To determine the
effect of aggressive blood pressure control .
Study Population
3867 newly diagnosed type 2 diabetic patients who
were asymptomatic after 3 months of diet ; fasting
glucose 6.1–15 mmol/l (110–270 mg/dl) ; treat for 10
years .
Adapted from UK Prospective Diabetes Study (UKPDS) Group Lancet 1998;352:837-853;
Turner R et al Ann Intern Med 1996;124(1 pt 2):136-145.
UKPDS : diabetes related
endpoints
•
•
•
•
•
•
•
Diabetes related death
Non fatal myocardial infarction , heart failure or
angina
Non fatal stroke
Amputation
Renal failure
Retinal photocoagulation or vitreous haemorrhage
Cataract extraction or blind in one eye
UKPDS 38 : 154/87 versus 144/82
-21
Non significant
MI
-34
Significant
Microvascular endpoint –34%
Significant
Heart failure –35%
-35
-37
Significant
-44 Significant
Stroke –37%
All macrovascular endpoints –44%
Retinal photocoagulation –56%
-56 Significant
Any diabetes-related endpoint –24%
-24
0
-10
-20
Significant
-30
-40
-50
UK Prospective Diabetes Study (UKPDS) Group (38). BMJ 1998;317:703–713
UKPDS : diabetes-related deaths
% of patients with events
20%
Less tight blood pressure control (390)
Tight blood pressure control (758)
15%
10%
5%
Risk reduction
32% ( p=0.019 )
0%
0
3
6
Years from randomisation
9
UKPDS : microvascular endpoints
25%
% patients with event
Less Tight Blood Pressure Control (390)
Tight Blood Pressure Control (758)
20%
15%
10%
5%
Risk reduction
37% ( p=0.0092 )
0%
0
3
6
Years from randomisation
9
UKPDS blood pressure control study
In 1148 type 2 diabetic patients a tight blood pressure
control policy which achieved blood pressure of 144 / 82
mm Hg gave reduced risk for :
Any diabetes-related endpoint
Diabetes-related deaths
Stroke
Microvascular disease
Heart failure
Retinopathy progression
Deterioration of vision
24%
32%
44%
37%
56%
34%
47%
p=0.0046
p=0.019
p=0.013
p=0.0092
p=0.0043
p=0.0038
p=0.0036
Risk of Diabetes Complications by
BP and HbA1c%
BP Treatment Targets:
Moving the Goalposts
QOF
145 / 85
Alphabet
Strategy
140 / 80
JBS2
130 / 80
Blood pressure lowering agents
What will you use?
Blood pressure lowering agents
ALLHAT
•
•
•
•
•
•
33,357 subjects : > 55 years with BP+ and at
least one other CHD risk factor .
Randomised to chlorthalidone, amlodipine
or lisinopril .
Target BP < 140 / 90 : achieved 135 / 75 .
Primary endpoint : combined fatal CHD or
nonfatal MI .
Mean follow-up 4.9 years .
No major differences between agents .
ASCOT-BPLA Study
•
•
•
•
•
•
19,257 subjects : 40-79 years with BP+ and
at least three other CHD risk factors .
Randomised to amlodipine + perindopril or
atenolol + bendroflumethiazide .
Target BP < 140 / 90 : 130 / 80 in diabetes .
Mean follow-up 5.5 years .
Fewer strokes, CV events & procedures and
deaths in amlodipine group . . .
… and 30% less new diabetes.
Angiotensin II may play a
central role in organ damage
Atherosclerosis
Vasoconstriction
Vascular hypertrophy
Endothelial dysfunction
A II
AT1
receptor
LV hypertrophy
Fibrosis
Remodeling
Apoptosis
GFR
Proteinuria
Aldosterone release
Glomerular sclerosis
Stroke
Hypertension
Heart failure
MI
DEATH
Renal failure
LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate
Adapted from Willenheimer R et al Eur Heart J 1999; 20(14): 9971008, Dahlöf B J Hum Hypertens 1995; 9(suppl 5):
S37S44, Daugherty A et al J Clin Invest 2000; 105(11): 16051612, Fyhrquist F et al J Hum Hypertens 1995; 9(suppl 5):
S19S24, Booz GW, Baker KM Heart Fail Rev 1998; 3: 125130, Beers MH, Berkow R, eds. The Merck Manual of
Diagnosis and Therapy. 17th ed. Whitehouse Station, NJ: Merck Research Laboratories 1999: 16821704, Anderson S
Exp Nephrol 1996; 4(suppl 1): 3440, Fogo AB Am J Kidney Dis 2000; 35(2):179188
HOPE Study
•
•
•
•
•
•
9300 high-risk subjects : 3500 with diabetes
Ramipril 10 mg versus placebo
CV death, MI, stroke  25% in diabetic
subjects
Difference in BP between groups = 3/1
Mechanism uncertain
• ? Specific effect of ACE inhibition
• ? BP lowering
Specific to ramipril or a class effect ?
HOPE Study Investigators, Lancet 2000; 355:253
HOPE : MI rate ramipril vs placebo in diabetics
0.16
ramipril
Kaplan-Meier Rates
0.14
Placebo
RRR = 22% (6 - 36) p= 0.01
0.12
0.10
0.08
0.06
0.04
0.02
0.00
0
500
1000
Days of Follow-up
1500
2000
HOPE : stroke rate ramipril vs placebo in diabetics
Kaplan-Meier Rates
0.08
ramipril
Placebo
0.06
RRR = 33% (10 - 50) p=0.0074
0.04
0.02
0.00
0
500
1000
Days of Follow-up
1500
2000
HOPE : CV death ramipril vs placebo in diabetics
Kaplan-Meier Rates
0.12
ramipril
Placebo
0.10
RRR = 37% (21 - 51) p=0.0001
0.08
0.06
0.04
0.02
0.00
0
500
1000
1500
Days of Follow-up
2000
LIFE Study
• 9200 patients with hypertension and LVH : 1200
•
•
•
•
•
•
with diabetes
Losartan versus atenolol (with add-on
medications)
Target BP 140/90 : BP lowering similar in both
groups
In diabetics 10 endpoint  25%, CV mortality 
37%
More LVH regression in losartan group
Fewer losartan patients developed albuminuria
(7% versus 13%)
Cannot extrapolate to subjects without LVH ?
Lindholm LH et al (2002) Lancet 359, 1004 - 1010.
LIFE : study design
Titration to target blood pressure: <140 / <90 mmHg
Losartan 100 mg + HCTZ 12.5-25 mg + others*
Losartan 100 mg + HCTZ 12.5 mg
Losartan 50 mg + HCTZ 12.5 mg
Placebo
Losartan 50 mg
Atenolol 50 mg
Atenolol 50 mg + HCTZ 12.5 mg
Atenolol 100 mg + HCTZ 12.5 mg
Atenolol 100 mg + HCTZ 12.5-25 mg + others*
Day
14
Day Day
7
1
Mth
1
Mth Mth
2
4
Mth
6
Yr
1
Yr
1.5
Yr
2
Yr
2.5
Yr
3
Yr
3.5
Yr
4
Yr
5
* Other antihypertensives excluding ACEIs, AII antagonists, beta-blockers.
Dahlöf B et al (1997) Am J Hypertens 10:705713.
Adverse events
Losartan
Atenolol
P
Withdrawals
2 (0.3%)
9 (2%)
0.065
Bradycardia
6 (1%)
50 (8%)
< 0.0001
Albuminuria
43 (7%)
79 (13%)
0.002
Lindholm LH et al (2002) Lancet 359, 1004 - 1010.
LIFE: New Onset Diabetes by
Treatment Group
Proportion of patients, %
10
Atenolol
Losartan
8
6
4
2
0
0
6
12
18
24
30
36
Study Month
42
48
54
60
66
The Alphabet Strategy
• Advice
• Blood pressure
• Cholesterol
Smoking , diet , exercise
< 140/80
TC < 4.0 mmol/l , LDL ≤ 2.0 mmol/l
HDL > 1.0 mmol/l, TGs < 1.7 mmol/l
• Diabetes control
• Eye examination
• Feet examination
• Guardian drugs
HbA1c ≤ 7%
Annual examination
Annual examination
Aspirin, ACEI, ARB, statins