lowering sugars in diabetes – a cardiovascular waste of time?

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


IntensiveConventional

Risk reduction 25%(95% CI: 7% to 40%)

0.00

0.05

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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


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

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I


Conventional (896)

Chlorpropamide (619)Glibenclamide (615)Insulin (911)

C v G v IP =0.66


Myocardial Infarction

M v Ip=0.12

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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


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 (%)



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

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



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


New/worsening nephropathy, retinopathy

66


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

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



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?


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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

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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


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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


Steno-2 Follow up

Gaede P et al. N Engl J Med 2008;358:580-591

Steno-2 follow up primary endpoint


Steno-2 follow up secondary endpoint


Glucose lowering – waste of time?

Glucose lowering, started early, may have long term cardiovascular benefits

Multifactorial risk reduction is imperative

lowering sugars in diabetes – a cardiovascular waste of time?

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