Lowering sugars in diabetes – a cardiovascular waste of time? Hamish Courtney Regional Endocrine Centre Royal Victoria Hospital Belfast
Feb 25, 2016
Lowering sugars in diabetes – a cardiovascular waste of time?
Hamish CourtneyRegional Endocrine Centre
Royal Victoria HospitalBelfast
0.00
0.05
0.10
0.15
0.20
0.25
OASIS Study: Total MortalityOASIS Study: Total MortalityE
vent
Rat
e
Months6 9 153 18 2112
RR=2.88 (2.37–3.49)
Malmberg K et al. Circulation 2000;102:1014-1019.
24
RR=1.99 (1.52–2.60)
RR=1.71 (1.44–2.04)
RR=1.00
Diabetes/CVD (n = 1148)
No Diabetes/CVD (n = 3503)Diabetes/No CVD (n = 569)
No Diabetes/No CVD (n = 2796)
01020304050607080
Esti
ma t
ed p
r eva
len c
e (m
illio
n s)
Estimates of Diabetes Prevalence in World Regions
2025202519951995 20002000
Africa Americas EasternMediterranean
Europe SoutheastAsia
WesternPacific
WHO Report 1997. World Health Organization. Geneva;1997.
How low can you go.....safely?
UKPDS
United Kingdom Prospective Diabetes Study
UKPDS
342 allocated to
metformin
Conventional Policy30% (n=1138)
Intensive Policy70% (n=2729)
Sulphonylurean=1573
Insulinn=1156
Main Randomisationn=4209 (82%)
3867
HbA1c
06
7
8
9
0 3 6 9 12 15
HbA
1c (%
)
Years from randomisation
Conventional
Intensive
6.2% upper limit of normal range
UKPDS Microvascular Endpoints
p=0.0099
0%
10%
20%
30%
0 3 6 9 12 15
% o
f pat
ient
s w
ith a
n ev
ent
Years from randomisation
IntensiveConventional
Risk reduction 25%(95% CI: 7% to 40%)
0.00
0.05
0.10
0.15
0.20
0.25
OASIS Study: Total MortalityOASIS Study: Total MortalityE
vent
Rat
e
Months6 9 153 18 2112
RR=2.88 (2.37–3.49)
Malmberg K et al. Circulation 2000;102:1014-1019.
24
RR=1.99 (1.52–2.60)
RR=1.71 (1.44–2.04)
RR=1.00
Diabetes/CVD (n = 1148)
No Diabetes/CVD (n = 3503)Diabetes/No CVD (n = 569)
No Diabetes/No CVD (n = 2796)
Fatal and Non-Fatal Myocardial Infarction
14% change per 1% change in HbA1c
p<0.0001
0.5
1
5
0 5 6 7 8 9 10 11Updated mean HbA1c
Haz
ard
ratio
UKPDS 35. BMJ 2000; 321: 405-12
UKPDS and myocardial infarctionUKPDS and myocardial infarction
0
10
20
30
0 3 6 9 12 15
% o
f pat
ient
s w
ith M
I
Years after randomisation
IntensiveConventional
p=0.06
Risk reduction 16% (CI 95%: 0-29%)
UKPDS 33 Lancet. 1998;352:837-853
0
10
20
30
40
0 3 6 9 12 15
% o
f pat
ient
s w
ith M
I
Years after randomisation
Conventional (896)
Chlorpropamide (619)Glibenclamide (615)Insulin (911)
C v G v IP =0.66
UKPDS and myocardial infarctionUKPDS and myocardial infarction
Myocardial Infarction
M v Ip=0.12
0.0
0.1
0.2
0.3
0.4
0 3 6 9 12 15
Pro
porti
on o
f pat
ient
s w
ith e
vent
s
Years from randomisation
Conventional (411)Intensive (951)Metformin (342)
M v Cp=0.010
University Group Diabetes Program (UGDP)
North-American multicentre study Duration: 8 years (1961-1969)1027 patients randomised into 5 groups
Placebo - dietTolbutamideTolbutamide - fixed dosage 1.5 g/d- fixed dosage 1.5 g/dPhenformin - fixed dosage fixed dosage 100 mg/dInsulin - fixed dosagefixed dosage
Insulin - adjusted dosagedosage
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
<6 vs 7-7.9%
<6.5% vs local targets
<6% vs local targets
Agents Any Gliclazide Any
ACCORD
Glycaemic interventionIntensive (HbA1c <6%)
vs Standard (HbA1c 7.0-7.9%)
Primary end pointnonfatal MI, stroke or cardiovascular death
N Engl J Med 2008;358:2545-2559
Glycaemic Control
ACCORD: Glucose-lowering drugs
55.477.3Insulin
4.917.8Incretin
5.123.2α-Glucosidase inhibitor
58.391.7Thiazolidinedione
73.886.6SU
Patients (%)
86.994.7Metformin
Standard therapy(n = 5123)
Intensive therapy(n = 5128)
N Engl J Med 2008;358:2545-2559
N Engl J Med 2008;358:2545-2559
ACCORD Primary Outcome
ADVANCE
Glycaemic interventionIntensive 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
ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-72.
CV death, MI, stroke
Cumulative incidence (%)
Follow-up (months)
25
20
15
10
5
00 6 12 18 24 30 36 42 48 54 60 66
HR 0.94 (0.84-1.06)P = 0.32 Standard
control
Intensive control
ADVANCE: all-cause mortality
ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-72.
Cumulative incidence (%)
Follow-up (months)
Standard control
Intensive control
25
20
15
10
5
00 6 12 18 24 30 36 42 48 54 60 66
HR 0.93 (0.83-1.06)P = 0.28
ADVANCE: primary microvascular outcome
ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-72.
New/worsening nephropathy, retinopathy
66
Cumulative incidence (%)
Follow-up (months)
HR 0.86 (0.77-0.97)P = 0.01 Standard
control
Intensive control
25
20
15
10
5
00 6 12 18 24 30 36 42 48 54 60
VADT
Glycaemic interventionIntensive (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
55.477.3Insulin
4.917.8Incretin
5.123.2α-Glucosidase inhibitor
58.391.7Thiazolidinedione
73.886.6SU
Patients (%)
86.994.7Metformin
Standard therapy(n = 5123)
Intensive therapy(n = 5128)
N Engl J Med 2008;358:2545-2559
Reasons?
Drugs used?
Increase in hypoglycaemia?
Increase in weight?
Too rapid reduction in HbA1c?
N Engl J Med 2008;358:2545-2559
Glycaemic Control
Reasons?
Drugs used?
Increase in hypoglycaemia?
Increase in weight?
Too rapid reduction in HbA1c?
Chance?
UKPDS and myocardial infarctionUKPDS and myocardial infarction
0
10
20
30
0 3 6 9 12 15
% o
f pat
ient
s w
ith M
I
Years after randomisation
IntensiveConventional
p=0.06
Risk reduction 16% (CI 95%: 0-29%)
UKPDS 33 Lancet. 1998;352:837-853
Post-Trial Changes in HbA1c
UKPDS resultspresented
Mean (95%CI)
Any Diabetes-related Endpoint
Intervention TrialMedian follow-up 10.0 years
Intervention Trial + Post-trial monitoringMedian 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)
Aggregate Endpoint 1997 2007
Any diabetes related endpoint RRR: 12% 9% P: 0.029 0.040
Microvascular disease RRR: 25% 24% P: 0.0099 0.001
Myocardial infarction RRR: 16% 15% P: 0.052 0.014
All-cause mortality RRR: 6% 13% P: 0.44 0.007
RRR = Relative Risk Reduction, P = Log Rank
Legacy Effect of Earlier Glucose Control
ACCORDADVANCEVADT
Age ~60s
Diabetes duration
~10yrs
Macrovascular disease
~1/3
Length of follow-up
~5yrs
ACCORDADVANCEVADT
UKPDS
Age ~60s 53
Diabetes duration
~10yrs New onset
Macrovascular disease
~1/3 ~1/15
Length of follow-up
~5yrs 17yrs
ACCORD/ADVANCE
N Engl J Med 2008;358:2545-2559
N Engl J Med. 2008;358:2560-72.
Cum
ulat
ive
inci
denc
e (%
)
Follow-up (months)
25
20
15
10
5
00 6 12 18 24 30 36 42 48 54 60 66
Standard control
Intensive control
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
Slide SourceLipids Online Slide Librarywww.lipidsonline.org
0
10
20
30
40
50
60
70
80
Glycosylatedhaemoglobin
<6.5%
Steno-2 StudySteno-2 StudyP
atie
nts
Rea
chin
g In
tens
ive-
Trea
tmen
t G
oals
at M
ean
7.8
y, (%
)
Intensive Therapy
Cholesterol<175 mg/dl
Triglycerides<150 mg/dl
Systolic BP<130 mm Hg
Diastolic BP<80 mm Hg
Conventional Therapy
P=0.06
P<0.001
P=0.19P=0.001
P=0.21
Gæde P et al. N Engl J Med 2003;348:383-393
Slide SourceLipids Online Slide Librarywww.lipidsonline.org
0
10
20
30
40
50
60
Steno-2 primary outcomeSteno-2 primary outcomeP
rimar
y C
ompo
site
End
poin
t (%
)
Months of Follow-up0 24 48 60 9636 847212
Conventional Conventional TherapyTherapy
Intensive Intensive TherapyTherapy
P=0.007P=0.007
Hazard ratio = 0.47 (95% Hazard ratio = 0.47 (95% CI, 0.24–0.73; P=0.008)CI, 0.24–0.73; P=0.008)
Gæde P et al. N Engl J Med 2003;348:383-393
Slide SourceLipids Online Slide Librarywww.lipidsonline.org
Steno-2 Follow up
Gaede P et al. N Engl J Med 2008;358:580-591
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