Diabetes subgroup analyses

1
Diabetes subgroup analyses

• Is there a difference in the treatment effect of
  commonly used blood pressure lowering regimens
  between patients with and without diabetes?

2
Diabetes contributing trials
Second cycle (27 trials, N 158,709)
IDNT INSIGHT JMIC-B LIFE NICOLE NICS-EH NORDIL PAR
T-2 PREVENT PROGRESS
QUIET RENAAL SCAT SCOPE SHELL STOP-2 SYST-EUR UKPD
S-HDS VHAS
AASK ABCD (H) ABCD (N) ALLHAT ANBP2 CAPPP CONVINC
E ELSA HOPE HOT
3
Diabetes data
4
Diabetes characteristics
5
Active vs. control comparisons
6
Stroke
?BP (mmHg)
Favours active
Favours placebo
RR(95CI)
ACE-I vs. placebo
0.69 (0.55,0.86)
-3.6/-1.9
Diabetes
0.72 (0.62,0.85)
-5.8/-2.7
No diabetes
p homog0.74
Overall
CA vs. placebo
0.47 (0.28,0.78)
-5.9/-3.1
Diabetes
0.70 (0.49,0.99)
-9.3/-3.9
No diabetes
p homog0.22
Overall
More vs. less
-6.0/-4.6
0.64 (0.46,0.88)
Diabetes
-3.7/-3.3
0.89 (0.70,1.13)
No diabetes
p homog0.11
Overall
0.25
0.5
1
2
Risk ratio
7
CHD
?BP (mmHg)
Favours active
Favours placebo
RR(95CI)
ACE-I vs. placebo
-3.6/-1.9
0.91 (0.62,1.34)
Diabetes
-5.8/-2.7
0.78 (0.69,0.88)
No diabetes
p homog0.46
Overall
CA vs. placebo
-5.9/-3.1
Diabetes
0.60 (0.41, 0.89)
-9.3/-3.9
No diabetes
0.89 (0.67,1.20)
p homog0.12
Overall
More vs. less
-6.0/-4.6
0.84 (0.60,1.17)
Diabetes
-2.9/-3.0
1.13 (0.90,1.43)
No diabetes
p homog0.14
Overall
0.25
0.5
1
2
Risk ratio
8
Heart Failure
?BP (mmHg)
Favours active
Favours placebo
RR(95CI)
ACE-I vs. placebo
0.88 (0.67,1.16)
-3.6/-1.9
Diabetes
0.78 (0.62,0.98)
-5.8/-2.7
No diabetes
p homog0.49
Overall
CA vs. placebo
1.29 (0.97,1.72)
-5.9/-3.1
Diabetes
1.07 (0.43,2.62)
-9.3/-3.9
No diabetes
p homog0.66
Overall
More vs. less
-6.0/-4.6
0.69 (0.38,1.25)
Diabetes
-3.7/-3.3
No diabetes
1.31 (0.81, 2.11)
p homog0.10
Overall
0.25
0.5
1
2
Risk ratio
9
Major CVD
?BP (mmHg)
Favours active
Favours placebo
RR(95CI)
ACE-I vs. placebo
0.80 (0.71,0.89)
-3.6/-1.9
Diabetes
0.76 (0.70,0.84)
-5.8/-2.7
No diabetes
p homog0.59
Overall
CA vs. placebo
0.72 (0.34,1.53)
-5.9/-3.1
Diabetes
0.79 (0.63,0.98)
-9.3/-3.9
No diabetes
p homog0.83
Overall
More vs. less
-6.0/-4.6
0.75 (0.61,0.94)
Diabetes
-3.7/-3.3
1.01 (0.87,1.17)
No diabetes
Overall
p homog0.03
0.25
0.5
1
2
Risk ratio
10
CV Deaths
?BP (mmHg)
Favours active
Favours placebo
RR(95CI)
ACE-I vs. placebo
0.67 (0.55,0.82)
-3.6/-1.9
Diabetes
0.86 (0.75,0.99)
-5.8/-2.7
No diabetes
p homog0.05
Overall
CA vs. placebo
-5.9/-3.1
0.54 (0.21,1.42)
Diabetes
-9.3/-3.9
0.64 (0.24,1.68)
No diabetes
p homog0.81
Overall
More vs. less
0.67 (0.40,1.12)
-6.0/-4.6
Diabetes
1.30 (1.01,1.66)
-3.7/-3.3
No diabetes
p homog0.02
Overall
0.25
0.5
1
2
Risk ratio
11
All Deaths
?BP (mmHg)
Favours active
Favours placebo
RR(95CI)
ACE-I vs. placebo
0.76 (0.65,0.89)
-3.6/-1.9
Diabetes
0.94 (0.84,1.05)
-5.8/-2.7
No diabetes
p homog0.03
Overall
CA vs. placebo
0.83 (0.65,1.06)
-5.9/-3.1
Diabetes
0.93 (0.74,1.18)
-9.3/-3.9
p homog0.50
No diabetes
Overall
More vs. less
-6.0/-4.6
0.73 (0.56,0.95)
Diabetes
-3.7/-3.3
1.07 (0.80,1.42)
No diabetes
Overall
p homog0.06
0.25
0.5
1
2
Risk ratio
12
Cause-specific outcomesAny active (ACE-I, CA or
more intensive) compared with less active
(placebo or less intensive) regimen
?BP (mmHg)
Favours active
Favours less active
Trials
RR(95CI)
STROKE
0.65 (0.54,0.77)
Diabetes -5.0/-3.1
0.75 (0.68,0.84)
No diabetes -5.8/-2.7
p homog0.2
CORONARY HEART DISEASE
Diabetes -5.0/-3.1
0.81 (0.67,0.97)
No diabetes -4.9/-3.0
0.86 (0.74,1.00)
p homog0.7
HEART FAILURE
Diabetes -4.9/-3.1
0.88 (0.65,1.18)
No diabetes -5.2/-3.2
0.87 (0.71,1.07)
p homog0.9
0.25
0.5
1.0
2.0
Risk ratio
13
Composite outcomesAny active (ACE-I, CA or more
intensive) compared with less active (placebo or
less intensive) regimen
?BP (mmHg)
Favours active
Favours less active
RR(95CI)
Trials
MAJOR CARDIOVASCULAR EVENTS
0.78 (0.68,0.89)
Diabetes -4.9/-3.1
0.86 (0.78,0.95)
No diabetes -5.2/-3.2
p homog0.3
CARDIOVASCULAR DEATHS
0.68 (0.56,0.83)
Diabetes -4.9/-3.1
0.92 (0.76,1.12)
No diabetes -5.3/-3.2
p homog0.03
TOTAL MORTALITY
0.75 (0.67,0.85)
Diabetes -4.9/-3.1
0.99 (0.91,1.07)
No diabetes -5.2/-3.2
p homoglt0.001
0.25
0.5
1.0
2.0
Risk ratio
14
Comparisons of different active agents
15
Stroke
?BP (mmHg)
Favours first listed
Favours second listed
RR(95CI)
ACE-I vs. D/BB
1.02 (0.88,1.19)
2.2/0.3
Diabetes
1.11 (0.96,1.29)
1.4/0.2
No diabetes
p homog 0.49
Overall
CA vs. D/BB
0.7/-0.8
0.94 (0.81,1.09)
Diabetes
1.1/-0.4
0.92 (0.83,1.01)
No diabetes
p homog 0.84
Overall
ACE-I vs. CA
1.09 (0.88,1.36)
1.6/1.2
Diabetes
1.12 (0.92,1.35)
1.3/0.9
No diabetes
p homog 0.88
Overall
0.25
0.5
1
2
Risk ratio
16
CHD
?BP (mmHg)
Favours first listed
Favours second listed
RR(95CI)
ACE-I vs. D/BB
0.83 (0.62,1.12)
2.2/0.3
Diabetes
0.98 (0.88,1.09)
1.5/0.2
No diabetes
p homog 0.33
Overall
CA vs. D/BB
1.00 (0.88,1.13)
0.7/-0.8
Diabetes
1.01 (0.93,1.10)
1.1/-0.4
No diabetes
p homog 0.86
Overall
ACE-I vs. CA
0.76 (0.51,1.12)
1.6/1.2
Diabetes
0.98 (0.84,1.15)
1.3/0.9
No diabetes
p homog 0.22
Overall
0.25
0.5
1
2
Risk ratio
17
Heart Failure
?BP (mmHg)
Favours first listed
Favours second listed
RR(95CI)
ACE-I vs. D/BB
2.5/0.4
0.94 (0.55,1.59)
Diabetes
1.8/0.3
1.09 (0.95,1.25)
No diabetes
p homog 0.59
Overall
CA vs. D/BB
0.5/-0.8
1.27 (1.01,1.61)
Diabetes
1.33 (1.16,1.52)
0.5/-0.5
No diabetes
p homog 0.83
Overall
ACE-I vs. CA
0.92 (0.67,1.27)
1.6/1.2
Diabetes
0.86 (0.73,1.01)
1.3/0.9
No diabetes
p homog 0.67
Overall
0.25
0.5
1
2
Risk ratio
18
Major CVD
?BP (mmHg)
Favours first listed
Favours second listed
RR(95CI)
ACE-I vs. D/BB
2.2/0.3
0.90 (0.74,1.11)
Diabetes
1.04 (0.98,1.04)
1.4/0.2
No diabetes
p homog 0.20
Overall
CA vs. D/BB
0.7/-0.8
1.02 (0.95,1.10)
Diabetes
1.1/-0.4
1.04 (0.99,1.10)
No diabetes
p homog 0.83
Overall
ACE-I vs. CA
1.6/1.2
0.92 (0.79,1.07)
Diabetes
1.3/0.9
0.99 (0.92,1.07)
No diabetes
p homog 0.37
Overall
0.25
0.5
1
2
Risk ratio
19
CV Deaths
?BP (mmHg)
Favours first listed
Favours second listed
RR(95CI)
ACE-I vs. D/BB
0.96 (0.75,1.24)
2.2/0.3
Diabetes
1.04 (0.94,1.14)
1.4/0.2
No diabetes
p homog 0.58
Overall
CA vs. D/BB
0.96 (0.80,1.14)
0.7/-0.8
Diabetes
1.1/-0.4
1.07 (0.96,1.18)
No diabetes
p homog 0.30
Overall
ACE-I vs. CA
1.03 (0.83,1.27)
1.6/1.2
Diabetes
1.06 (0.94,1.19)
1.3/0.9
No diabetes
p homog 0.81
Overall
0.25
0.5
1
2
Risk ratio
20
All Deaths
?BP (mmHg)
Favours first listed
Favours second listed
RR(95CI)
ACE-I vs. D/BB
2.2/0.3
0.94 (0.80,1.11)
Diabetes
1.01 (0.95,1.08)
1.4/0.2
No diabetes
p homog 0.46
Overall
CA vs. D/BB
0.95 (0.87,1.03)
0.7/-0.8
Diabetes
1.1/-0.4
1.00 (0.94,1.07)
No diabetes
p homog 0.29
Overall
ACE-I vs. CA
1.6/1.2
1.04 (0.94,1.15)
Diabetes
1.04 (0.96,1.13)
1.3/0.9
No diabetes
p homog 0.99
Overall
.025
05
1
2
Risk ratio
21
Comparison of ARB vs. Other
22
ARB vs. other
?BP (mmHg)
Favours ARB
Favours Other
RR(95CI)
Stroke
-2.1/-0.9
Diabetes
0.96 (0.77,1.19)
-1. 4/-0.6
No diabetes
0.74 (0.63,0.86)
p homog0.05
CHD
0.92 (0.72,1.17)
-2. 1/-0.9
Diabetes
1.05 (0.89,1.24)
-1.4/-0.6
No diabetes
p homog0.37
Heart failure
-2.0/-0.9
0.70 (0.59,0.83)
Diabetes
-0.8/0.0
1.13 (0.87,1.46)
No diabetes
p homog0.002
Major CVD
-2.1/-0.9
0.90 (0.82,0.99)
Diabetes
-1.4/-0.6
0.90 (0.81,1.00)
No diabetes
p homog0.94
CV deaths
-2.1/-0.9
Diabetes
0.99 (0.77,1.28)
-1.4/-0.6
No diabetes
0.95 (0.81,1.12)
p homog0.79
Total mortality
-2.1/-0.9
Diabetes
0.91 (0.75,1.10)
-1.4/-0.6
No diabetes
0.97 (0.86,1.09)
p homog0.55
0.25
0.5
1
2
Risk ratio
23
Conclusions (1)

• Similar proportional risk reductions achieved
  with regimens based on ACE inhibitors, calcium
  antagonists and diuretics/beta-blockers (from
  both placebo controlled and head-to-head
  comparisons)
• More intensive blood pressure lowering regimens
  may, however, be of particular benefit in
  patients with diabetes

24
Conclusions (2)

• Little evidence from these analyses that any drug
  class provides special protection against
  macrovascular events among patients with diabetes
• Clinicians might reasonably use any agent for
  first line therapy in patients with diabetes
• Many patients are likely to require two or more
  agents

25
Acknowledgements

• Collaborating Trialists L Agodoa, C Baigent, H
  Black, B Brenner, M Brown, C Bulpitt, R Byington,
  J Chalmers, R Collins, J Cutler, B Dahlof, B
  Davis, J Dens, R Estacio, R Fagard, K Fox, L
  Hansson (deceased), R Holman, L Hunsicker, Y
  Imai, J Kostis, K Kuramoto, E Lewis, M Lièvre, L
  H Lindholm, J Lubsen, S MacMahon, E Malacco, G
  Mancia, B Neal, C Pepine, M Pfeffer, B Pitt, P
  Poole-Wilson, G Remuzzi, A Rodgers, P Ruggenenti,
  R Schrier, P Sever, P Sleight, J Staessen, K Teo,
  P Whelton, L Wing, Y Yui, S Yusuf, A Zanchetti.
• Writing Committee F Turnbull, B Neal, C Algert,
  J Chalmers, N Chapman, J Cutler, M Woodward, S
  MacMahon.
• Coordinating Centre C Algert, J Chalmers, S
  MacMahon, B Neal, V Perkovic, F Turnbull, M
  Woodward.
• Financial support Central coordination of
  project supported by the National Health and
  Medical Research Council of Australia.