Transcript Lowering sugars in diabetes – a cardiovascular waste of time?

Lowering sugars in diabetes – a
cardiovascular waste of time?
Hamish Courtney
Regional Endocrine Centre
Royal Victoria Hospital
Belfast
OASIS Study: Total Mortality
0.25
Diabetes/CVD (n = 1148)
RR=2.88 (2.37–3.49)
Diabetes/No CVD (n = 569)
0.20
No Diabetes/CVD (n = 3503)
Event Rate
No Diabetes/No CVD (n = 2796)
RR=1.99 (1.52–2.60)
0.15
RR=1.71 (1.44–2.04)
0.10
RR=1.00
0.05
0.00
3
6
9
12
15
18
21
24
Months
Malmberg K et al. Circulation 2000;102:1014-1019.
Estimates of Diabetes
Prevalence in World Regions
80
1995
2000
2025
70
60
50
40
30
20
10
0
Africa
Americas
Eastern
Europe
Mediterranean
WHO Report 1997. World Health Organization. Geneva;1997.
Southeast
Asia
Western
Pacific
How low can you go.....safely?
UKPDS
United Kingdom
Prospective Diabetes
Study
UKPDS
Main Randomisation
n=4209 (82%)
342 allocated
to
metformin
3867
Conventional Policy
30% (n=1138)
Intensive Policy
70% (n=2729)
Sulphonylurea
n=1573
Insulin
n=1156
HbA1c
9
HbA1c (%)
Conventional
8
Intensive
7
6.2% upper limit of normal range
6
0
0
3
6
9
12
Years from randomisation
15
UKPDS Microvascular Endpoints
% of patients with an event
30%
Conventional
Intensive
p=0.0099
20%
10%
Risk reduction 25%
(95% CI: 7 % to 40%)
0%
0
3
6
9
12
Years from randomisation
15
OASIS Study: Total Mortality
0.25
Diabetes/CVD (n = 1148)
RR=2.88 (2.37–3.49)
Diabetes/No CVD (n = 569)
0.20
No Diabetes/CVD (n = 3503)
Event Rate
No Diabetes/No CVD (n = 2796)
RR=1.99 (1.52–2.60)
0.15
RR=1.71 (1.44–2.04)
0.10
RR=1.00
0.05
0.00
3
6
9
12
15
18
21
24
Months
Malmberg K et al. Circulation 2000;102:1014-1019.
Fatal and Non-Fatal Myocardial Infarction
Hazard ratio
5
p<0.0001
1
14% change per 1% change in HbA1c
0.5
0 5
6
7
8
9
Updated mean HbA1c
UKPDS 35. BMJ 2000; 321: 405-12
10
11
UKPDS and myocardial infarction
% of patients with MI
30
Conventional
Intensive
p=0.06
20
10
Risk reduction 16%
(CI 95%: 0-29%)
0
0
3
6
Years after randomisation
9
12
15
UKPDS 33 Lancet. 1998;352:837-853
UKPDS and myocardial infarction
% of patients with MI
40
Conventional (896)
Chlorpropamide (619)
Glibenclamide (615)
Insulin (911)
30
20
10
CvGvI
P =0.66
0
0
3
6
9
Years after randomisation
12
15
Proportion of patients with events
Myocardial Infarction
0.4
Conventional (411)
Intensive (951)
Metformin (342)
0.3
MvC
p=0.010
0.2
0.1
MvI
p=0.12
0.0
0
3
6
9
12
Years from randomisation
15
University Group Diabetes Program
(UGDP)
North-American multicentre study
Duration: 8 years (1961-1969)
1027 patients randomised into 5 groups
Placebo
Tolbutamide
Phenformin
Insulin
- diet
- fixed dosage 1.5 g/d
- fixed dosage 100 mg/d
- fixed dosage
Insulin
- adjusted dosage
Klimt et al. Diabetes. 1970;19(suppl 2):747-783
UGDP
Meinert et al. Diabetes. 1970;19(suppl 2):789-830
Intensive glycaemic control
Does intensive glycaemic control reduce
cardiovascular outcomes in T2DM?
- ACCORD
- ADVANCE
- VADT
- UKPDS follow up
ACCORD
ADVANCE
VADT
Number
10251
11140
1791
Age (±SD)
62 ± 7yrs
66 ± 6yrs
60 ± 9yrs
Duration
10yrs
8yrs
11yrs
HbA1c
8.1%
7.5%
9.4%
Glycaemic
intervention
Agents
<6 vs 77.9%
Any
<6.5% vs
<6% vs
local targets local targets
Gliclazide
Any
ACCORD
Glycaemic intervention
Intensive (HbA1c <6%)
vs
Standard (HbA1c 7.0-7.9%)
Primary end point
nonfatal MI, stroke or cardiovascular death
Glycaemic Control
N Engl J Med 2008;358:2545-2559
ACCORD: Glucose-lowering drugs
Patients (%)
Intensive therapy
(n = 5128)
Standard therapy
(n = 5123)
Metformin
94.7
86.9
SU
86.6
73.8
Thiazolidinedione
α-Glucosidase
inhibitor
Incretin
91.7
58.3
23.2
5.1
17.8
4.9
Insulin
77.3
55.4
N Engl J Med 2008;358:2545-2559
ACCORD Primary Outcome
N Engl J Med 2008;358:2545-2559
ADVANCE
Glycaemic intervention
Intensive using gliclazide (HbA1c <6.5%)
vs
Standard (HbA1c to local guidelines)
Primary end point
composite macrovascular and microvascular
events
ADVANCE: Glucose-lowering drugs
Patients (%)
Intensive therapy
(n = 4828)
Standard therapy
(n = 4741)
Gliclazide (modified
release)
90.5
1.6
Other sulphonylurea
1.9
57.1
Metformin
73.8
67.0
Thiazolidinedione
16.8
10.9
Acarbose
19.1
12.6
Glinide
1.2
2.8
Insulin
40.5
24.1
ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-72.
ADVANCE: primary macrovascular outcome
CV death, MI, stroke
25
20
Cumulative
incidence (%)
HR 0.94 (0.84-1.06)
P = 0.32
15
Standard
control
10
Intensive
control
5
0
0
6
12 18 24 30 36 42 48 54 60 66
Follow-up (months)
ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-72.
ADVANCE: all-cause mortality
25
20
Cumulative
incidence (%)
HR 0.93 (0.83-1.06)
P = 0.28
15
Standard
control
10
Intensive
control
5
0
0
6
12 18 24 30 36 42 48 54 60 66
Follow-up (months)
ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-72.
ADVANCE: primary microvascular outcome
New/worsening nephropathy, retinopathy
25
20
Cumulative
incidence (%)
HR 0.86 (0.77-0.97)
P = 0.01
15
Standard
control
10
Intensive
control
5
0
0
6
12 18 24 30 36 42 48 54 60 66
Follow-up (months)
ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-72.
VADT
Glycaemic intervention
Intensive (HbA1c <6.0%)
vs
Standard (HbA1c to local guidelines)
Primary end point
composite macrovascular event
VADT
Duckworth W et al. N Engl J Med 2009;360:129-139
VADT
Duckworth W et al. N Engl J Med 2009;360:129-139
Reasons?
Drugs used?
ACCORD: Glucose-lowering drugs
Patients (%)
Intensive therapy
(n = 5128)
Standard therapy
(n = 5123)
Metformin
94.7
86.9
SU
86.6
73.8
Thiazolidinedione
α-Glucosidase
inhibitor
Incretin
91.7
58.3
23.2
5.1
17.8
4.9
Insulin
77.3
55.4
N Engl J Med 2008;358:2545-2559
Reasons?
Drugs used?
Increase in hypoglycaemia?
Increase in weight?
Too rapid reduction in HbA1c?
Glycaemic Control
N Engl J Med 2008;358:2545-2559
Reasons?
Drugs used?
Increase in hypoglycaemia?
Increase in weight?
Too rapid reduction in HbA1c?
Chance?
UKPDS and myocardial infarction
% of patients with MI
30
Conventional
Intensive
p=0.06
20
10
Risk reduction 16%
(CI 95%: 0-29%)
0
0
3
6
Years after randomisation
9
12
15
UKPDS 33 Lancet. 1998;352:837-853
Post-Trial Changes in HbA1c
UKPDS results
presented
Mean (95%CI)
Any Diabetes-related Endpoint
Intervention Trial
Intervention Trial + Post-trial monitoring
Median follow-up 10.0 years
Median follow-up 16.8 years
RR=0.88 (0.79-0.99)
P=0.029
Conventional
Sulfonylurea/
Insulin
Conventional
Sulfonylurea/
Insulin
Myocardial Infarction Hazard Ratio
(fatal or non-fatal myocardial infarction or sudden death)
Intensive (SU/Ins) vs. Conventional glucose control
HR (95%CI)
All-cause Mortality Hazard Ratio
Intensive (SU/Ins) vs. Conventional glucose control
HR (95%CI)
Legacy Effect of Earlier Glucose Control
Aggregate Endpoint
1997
2007
12%
0.029
9%
0.040
Any diabetes related endpoint
RRR:
P:
Microvascular disease
RRR:
25%
P: 0.0099
Myocardial infarction
RRR:
P:
16%
0.052
15%
0.014
All-cause mortality
RRR:
P:
6%
0.44
13%
0.007
RRR = Relative Risk Reduction, P = Log Rank
24%
0.001
Age
ACCORD
ADVANCE
VADT
~60s
Diabetes
duration
~10yrs
Macrovascular
disease
~1/3
Length of
follow-up
~5yrs
ACCORD
ADVANCE
VADT
~60s
UKPDS
Diabetes
duration
~10yrs
New onset
Macrovascular
disease
~1/3
~1/15
Length of
follow-up
~5yrs
17yrs
Age
53
ACCORD/ADVANCE
25
N Engl J Med 2008;358:2545-2559
Cumulative
incidence (%)
20
Standard
control
15
10
Intensive
control
5
0
0
6
12 18 24 30 36 42 48 54 60 66
Follow-up (months)
N Engl J Med. 2008;358:2560-72.
Glucose lowering?
1. Glucose lowering reduces
microvascular complications
2. Intensive glucose lowering with
complex regimens in patients with
“established” diabetes is unlikely to
have a short term cardiovascular
benefit and may indeed be harmful
Glucose lowering?
3. The presence of a legacy effect
argues for early intensive glucose
lowering
4. Target HbA1c to 6.5% except where
this requires complex treatment
regimens or life expectancy is less
than 5 years
Patients Reaching Intensive-Treatment
Goals at Mean 7.8 y, (%)
Steno-2 Study
Intensive Therapy
80
Conventional Therapy
P=0.21
P<0.001
70
P=0.19
60
P=0.001
50
40
30
20
P=0.06
10
0
Glycosylated
haemoglobin
<6.5%
Cholesterol
<175 mg/dl
Triglycerides Systolic BP Diastolic BP
<150 mg/dl <130 mm Hg <80 mm Hg
Gæde P et al. N Engl J Med 2003;348:383-393
Slide Source
Lipids Online Slide Library
www.lipidsonline.org
Primary Composite Endpoint
(%)
Steno-2 primary outcome
60
P=0.007
50
Conventional
Therapy
Hazard ratio = 0.47 (95%
CI, 0.24–0.73; P=0.008)
40
30
20
Intensive
Therapy
10
0
0
12
24 36 48 60 72
Months of Follow-up
Gæde P et al. N Engl J Med 2003;348:383-393
84
96
Slide Source
Lipids Online Slide Library
www.lipidsonline.org
Steno-2 Follow up
Gaede P et al. N Engl J Med 2008;358:580-591
Slide Source
Lipids Online Slide Library
www.lipidsonline.org
Steno-2 follow up primary endpoint
Gaede P et al. N Engl J Med 2008;358:580-591
Steno-2 follow up secondary endpoint
Gaede P et al. N Engl J Med 2008;358:580-591
Glucose lowering – waste of
time?
 Glucose lowering, started early, may have
long term cardiovascular benefits
 Multifactorial risk reduction is imperative