Cardiovascular disease in childhood

onset type 1 diabetes

Current knowledge and future directions
Knut Dahl-Jrgensen
Oslo Diabetes Research Centre
Oslo University Hospital
University of Oslo
Norway

Presenter disclosure information

Knut Dahl-Jrgensen

Disclosed no conflict of interest

Outline of my talk

Impaired prognosis due to CVD in T1D

Risk of CVD in childhood onset T1D
Lifestyle and lipids
CVD and inflammation
The importance of blood glucose control
Glycemic memory effect
New preventive treatments ?

Microangiopathy causes disability and suffering

Atherosclerosis causes early death

How early does atherosclerosis develop ?

Studies in healthy adolescents

Pathobiological Determinants of Atherosclerosis

in Youth Study (PDAY):
2786 autopsies of adolescents and young adults who died of
external causes.
Youngest age group 15-19 years:
Fibrous plaques >5% of surface vessel area in
13% of the aortas
23% of the right coronary arteries
Strong JP for PDAY group. JAMA 1999;281:727-35.

Coronary IVUS studies in adolescents

In a group of newly heart transplanted patients.
Age of donor hearts 13-19 years
17 % had intima thickening > 0.5 mm

Murat Tuzcu E et al. Circulation 2001; 103: 2705-2710

Atherosclerosis and Childhood Diabetes Study

Population based, prospective study
All patients from one region invited
Participation rate 40%
314 diabetic patients
118 healthy control subjects
Mean age 13 years (8-18 years)
Mean diabetes duration 5 years
All using intensified insulin therapy
60 % on insulin pumps
Representative for all diabetic patients
in Norwegian Childhood Diabetes
Registry (participation rate of 98%)
CVD Imaging studies every 5th year
Biobank

Baseline Results Carotid Intima Media Thickness

More diabetic patients had elevated cIMT values;
19.5% were above the 90th centile
13.1% above the 95th centile of the healthy control
subjects for cIMT (p<0.01).
The mean cIMT was significantly higher among diabetic
boys than in age-matched healthy controls (0.46 /SD 0.06 vs.
0.44/SD 0.05, p=0.04) but not in diabetic girls.
No plaque formation was observed
Margeirsdottir HD et al. Diabetes Care 2010; 33:2043-48

How severe is the problem ?

Mortality from CHD in a UK Cohort of 23,000

T1D before 30 years of age ( 1972-1993), followed until 2000

Laing SP, Swerdlow AJ, Slater SD et al. Diabetologia 2003; 46: 760-765.

Observed Kaplan-Meier survival function comparing EDC study type 1 diabetes diagnosis
year subcohorts (19501964 vs. 19651980) and the ACR cohort.

Miller R G et al. Diabetes 2012;61:2987-2992

Copyright 2014 American Diabetes Association, Inc.

CVD mortality
Norwegian Childhood Diabetes Registry

All patients <14 yrs of age diagnosed in 1973-1982

Follow-up until 2003, n=1906
103 died, 28 from CVD
Overall Standardized Mortality Rate 4,0
SMR for CVD: 23 in men and 18 in women
Skrivarhaug T, et al. Diabetologia. 2006;49:298-305

Risk factors of atherosclerosis in

diabetic children and adolescents

Population based studies

Norwegian Childhood Diabetes Registry

Benchmarking of quality indicators since 2001.

2500 patients (98%) included in 2013
All 26 Norwegian Pediatric Departments participated
Standardized yearly examination
WHO-DiabCare Basic Information Sheet
Standardized screening of vascular complications
HbA1c from the same reference laboratory -DCCTstandard
Stored blood samples
Margeirsdottir HD, Dahl-Jrgensen K et al. Pediatr Diabetes 2010 11(2):88-95

Focus on cardiovascular risk factors

Lipids:
Non-fasting screening
Fasting lipid profile when values above risk limits
BP and AER - standardized
BMI
Smoking
Family history in 1. and 2.degree relatives: early
CVD, type-2 diabetes, treatment of BP, statins
In 2004 Survey of diet and physical activity

High prevalence of cardiovascular risk factors in T1D children and adolescents

a population-based study
Risk factors

All patients (n=1,658) (%)

Positive Family history of early CVDa

295 (17.8)

Positive Family history of Diabetes

369 (22.3)

HbA1c above the ADA target levelb

1,149 (71.4)

LDL-cholesterol >2.6 mmol/l

453 (34.5)

HDL-cholesterol <1.1 mmol/l

94 (6.9)

Blood pressure >90th percentile

152 (6.9)

BMI >95th percentile

71 (4.4)

Persistent microalbuminuria

9 (0.8)

Smokersc

31 (3)

1 of the risk factors above

1,420 (86)

2 of the risk factors above

750 (45)

3 of the risk factors above

250 (15)

4 of the risk factors above

39 (2.4)
Margeirsdottir HD, Larsen JR, Dahl-Jrgensen K et al. Diabetologia 2008

Suggested limits for intervention

Microalbuminuria: ACE inhibitors

BP > 90th centile: Lifestyle intervention

BP > 90th centile despite Lifestyle interv: ACE inhibitor
BP > 95th centile: Lifestyle intervention and ACE inhibitor

ACE inhibitors are considered first choice, but Angiotensin II receptor

blockers, diuretics and betablockers may be indicated

ISPAD Consensus Guidelines 2014.

ADA Position Statement. Diabetes Care 2010; 33 (Suppl 1): S4-S42.
Dahl-Jorgensen K, Larsen JR, Hanssen KF. Review. Diabetologia 2005; 48:1445-53

Suggested limits for intervention

LDL-Chol > 2.6 mmol/l: Dietary intervention

LDL-Chol > 4.1 mmol/l and no CVD risk factors: Statins*
LDL-Chol > 3.4 mmol/l and > one CVD risk factor: Statins*
* Above 10 years of age.
ISPAD Consensus Guidelines 2014.
*ADA Position Statement. Diabetes Care 2010; 33 (Suppl 1): S4-S42.
Dahl-Jorgensen K, Larsen JR, Hanssen KF, Review. Diabetologia 2005; 48:1445-53

Consensus Guidelines for treatment are not followed

BP>90 perc
BP>95 perc

7%
2%

LDL-Chol >2.6 mmol/l

LDL-Chol>3.4 mmol/l+ risk factor
LDL-Chol>4.2 mmol/l

42%
6%
3%

Statin treatment
Anti-hypertensive treatment

0.2%
0.3%

Margeirsdottir HD, Larsen JR, Dahl-Jrgensen K et al. Diabetologia 2008

Patients > 15 years of age smoking cigarettes

2001

18 %

2002

16 %

2003

12 %

2004

9%

2005

5%

2006

7%

2007

6%

2008

8%

2009

7%

2010

6%

2011

6%

2012

3%

2013

3%

Norwegian Childhood Diabetes Registry (NCDR)

Diet and Physical Activity

Nationwide, population based study
655 children and adolescents (34 %) aged 2-19 years
Healthy Controls : n= 1809

Recorded all food intake for 4 days

Precoded food diaries
Validated questionnaire of physical activity
Clinical data from National Diabetes Registry
verby NC, Margeirsdottir HD, Dahl-Jrgensen K et al. Diabetologia 2007

Physical activity
54 % of the participants did not fulfill the CDC
recommendation of more than 60 minutes
moderate physical activity daily.
43 % watch TV for more than 2 hours per day.

verby NC, Margeirsdottir HD, Dahl-Jrgensen K et al. Pediatr Diabetes 2009

Diet
higher intake of saturated fat and a lower
intake of fiber.
90% did not fulfill dietary recommendations

higher intake of total fat (+3,4E%) and

saturated fat (+1,0E%) compared to healthy
controls (p<0,001)
verby NC, Margeirsdottir HD, Dahl-Jrgensen K et al. Diabetologia 2007

Obesity and metabolic syndrome

Increasing problem in T1D

Prevalence of obesity and overweight 30-50%
8-40% have metabolic syndrome
Insulin resistance poor HbA1c
Dyslipidemia
Hypertension
Endothelial dysfunction
Increased risk of CVD

CARDIA Study
Coronary Artery Risk Development
in Young (non-diabetic) Adults
20 Years prospective study. Age 18-30 years. N=3500
Health Life Style Factors (HLFs): Score 0-5.
1. Not currently smoking
2.

Physical activity >60th percentile

3.

BMI<25

4.

Alcohol intake <15g/d (female), <30g/d(male)

5.

Healthy diet (low saturated fat, high fiber)

Spring B et al. Circulation. 2014;130:10-17.

Graded relationship observed between healthy lifestyle factor (HLF) change (from year 0 to
year 20 [Y20]) and incidence of coronary artery calcium (CAC) at year 20.

Spring B et al. Circulation. 2014;130:10-17

Copyright American Heart Association, Inc. All rights reserved.

CARDIA Study
Coronary Artery Risk Development
in Young (non-diabetic) Adults

Adopting a healthier lifestyle during early life

or midlife may reduce the risk of developing
coronary artery disease;
conversely, discontinuing healthy behaviors
may increase risk.
Spring B et al. Circulation. 2014;130:10-17.

MRC/BHF Heart Protection Study. Diabetes

N=5963, 5 years follow-up. 10% type-1 diabetes
Simvastatin safe and well tolerated
Reduction in LDL Cholesterol 1 mmol/l
Reduction of about one quarter of first event rate for major
coronary event, stroke and limb revascularisation
Independent of type of diabetes, age, duration, glycemic
control, blood pressure and cholesterol levels.
HPS collaborative group. Lancet 2003; June 14, 361:2005-16.

MRC/BHF Heart Protection Study. Diabetes

HPS collaborative group. Lancet 2003; June 14, 361:2005-16.

Cholesterol Treatment Trialists Collaboration 2012

Meta-analysis from 27 randomised trials of statin therapy
Risk reduction for each 1 mmol/L reduction in LDL cholesterol:
Major coronary events:
24%
Stroke:
15%
Coronary revascularisation: 24%

Mihaylova B et al. Lancet 2012; 380: 58190.

Efficacy and safety of statin therapy in children

Familial hypercholesterolemia
Double-blind, randomized trial,
Age 8-18 years, n=214
Statin Pravastatin 20- 40 mg daily for 2 years
LDL reduced from 6 to 4,5 mmol/l
Improvement of carotid IMT on statins, progression
in controls.
No adverse effects on growth, sexual maturation,
liver or muscle tissue.
Wiegman A, et al JAMA 2004; 292: 331-337.

Adolescent T1D cardio-renal intervention trial

(AdDIT)

n=500 high risk adolescents

Age 11-16 years
Albumin-Creatinin-Ratio upper tertile.
Randomized placebo-controlled trial to receive either:
ACE inhibitor (Qiunapril) or
Statin (Atorvastatin) or
Both.
Follow-up 3-4 years
n=400 low-risk patients for observational study
Diabetes Care 2014 July 28 (e-pup)

What pharmacological strategies

for LDL reduction beyond statins are emerging?

Mipomersen
PCSK9 inhibitors
Dual AMPK activation and ACL inhibition
(ETC-1002)

Mipomersen
Newly approved agent for homozygous hypercholesterolaemia

Apolipoprotein B synthesis inhibitor

Three phase 3 trials:
2535% mean reduction in LDL cholesterol and concomitant
reductions in triglycerides and lipoprotein(a).

E Wong E et al. P T, 39 (2014), pp. 119122

Raal FJ et al. Lancet, 375 (2010), pp. 9981006
Stein EA et al. Circulation, 126 (2012), pp. 22832292
McGowan MP PLoS One, 7 (2012), p. e49006

PCSK9 inhibitors
Proprotein convertase subtilisin kexin type 9 (PCSK9),
a protein secreted by hepatocytes that binds to the LDL receptor, leading to
its cellular internalisation and subsequent lysosomal degradation.
AMG 145, a human monoclonal antibody against PCSK9, monotherapy
Phase 2 trial n=406
40-60% reduction in LDL-cholesterol

REGN727, a monoclonal antibody to PCSK9, added to statins,

Phase 2 trial n=77
30-60% reduction in LDL-cholesterol
MJ Koren et al. Lancet, 380 (2012), pp. 19952006
EA Stein et al. Lancet, 380 (2012), pp. 2936

Dual mechanism of action of ETC-1002 AMP-activated protein kinase (AMPK) activation and
ATP-citrate lyase (ACL) inhibition.

Gutierrez M J et al. Arterioscler Thromb Vasc Biol.

2014;34:676-683

Copyright American Heart Association, Inc. All rights reserved.

Dual AMPK activation and ACL inhibition (ETC-1002)

2 Short term Phase 2 Trials
LDL-cholesterol reduced by 27% in patients with
hypercholesterolaemia.
LDL-cholesterol reduced by 43% in those with type 2
diabetes
CRP was reduced by 41%
No clinically meaningful safety findings were observed.
Ballantyne CM. J Am Coll Cardiol. 2013 Sep 24;62(13):1154-62
Gutierrez MJ. Arterioscler Thromb Vasc Biol. 2014 Mar;34(3):676-83

Efficacy and safety data from hard endpoint trials will

be available soon for several novel therapeutic approaches
that reduce LDL cholesterol well below the concentrations
that are currently achievable with statins alone.

From a biological perspective, lifelong, early reduction in LDL

cholesterol is likely to result in the largest absolute risk
reductions. Thus, public health programmes emphasising
diet and lifestyle changes in youth and young adulthood
must also be aggressively implemented.
Ridker PM, Lancet; 384, 943, 1622 August 2014, Pages 607617

How important is blood glucose control ?

Glycemic control
and microvascular complications
Intervention trials

Steno Studies
Oslo Study
Stockholm Study
DCCT / EDIC

Start Trial

Follow-up

1980
1981
1985
1983

30 yrs
10 yrs
30 yrs

2 yrs
4 yrs
7 yrs
7 yrs

Coronary IVUS image

The Oslo Study

Summary - The Oslo Study 18 years follow-up

Angiography (>50% Stenosis): 34%
3 times more than age-matched nondiabetics
IVUS: Normal intima : none
3-4 times more severe than in healthy donor hearts
Coronary vessel area stenosis significantly associated with
18 years HbA1c and total cholesterol.
Each % increase in HbA1c increase cornary stenosis by 6.8%
Carotid IMT: values as in nondiabetic persons 30 years older
Larsen J, Dahl-Jrgensen K et al Diabetes 51:2637-2641, 2002

The cumulative incidence of clinical CVD outcomes during DCCT/EDIC.

Lachin J M et al. Dia Care 2014;37:39-43

Copyright 2014 American Diabetes Association, Inc.

Risk reduction of CVD

DCCT/EDIC 30 years follow-up
21% reduction in the risk of CVD events
per 10% lower mean HbA1c during the DCCT

P < 0.001

DCCT/EDIC Research Group. Diabetes Care 2014; 37:39-43

ACCORD study 2014

Adult Type 2 diabetes. N=10 251
Randomized trial. 5 years follow-up.
Intensive treatment group target HbA1c < 6%
Standard treatment group target HbA1c 7-8%
Hard endpoint: Myorcardial infarction
Risk reduction 20%
Gerstein HC et al. Lancet 2014, July 31.

How important is blood glucose control ?

Glycemic memory effect

Periods of poor glycemic control in adolesence

may have serious consequences

DCCT/EDIC: long-term follow-up and glycemic memory effect

Glucose
similar
BUT CV
events
still
higher

HbA1C (%)

Conventional treatment
8
Intensive treatment
7
0

Cumulative incidence of
non-fatal MI, stroke or
death from CVD

1
0.06

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Years
DCCT (intervention period)
EDIC (observational follow-up)
57% risk reduction in non-fatal MI, stroke or CVD death*

0.04

0.02

Conventional
treatment

Intensive
treatment

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
DCCT (intervention period)
EDIC (observational follow-up)
*Intensive vs conventional treatment.

Years

DCCT Research Group. N Engl J Med 1993; 329:977986.

Nathan DM, et al. N Engl J Med 2005; 353:26432653.
Copyright Massachusetts Medical Society.

Lind et al, Diabetologia,2010;53:1093-1098

Implications of glycemic memory effect

The present HbA1c value is not the most important.
Values from 2 to 3 years ago contribute the greatest risk.
Values from up to 8 years ago still have an important impact.
When reducing HbA1c, it will take several years before substantial
preventive effects appear
Patients with current good control can develop retinopathy due to
earlier poor glycemic control.
The common high HbA1c in adolescents may have serious
consequences.

(Sell, Monnier,2012)

Berg TJ et al Diabetes Care 1998;21: 1997-2002

Aker sykehus 00/148

Summary of the multiple causes and locations of

arterial stiffness

Zieman, S. J. et al. Arterioscler Thromb Vasc Biol 2005;25:932-943

Copyright 2005 American Heart Association

Atherosclerosis and Childhood Diabetes Study

AGE methylglyoxal-derived hydroimidazolone
MG-H1

CRP

Atherosclerosis and Childhood Diabetes Study

Aortic vessel stiffness assessed by CMR PWV.
Diabetes duration mean 10 years

Diabetes group

mean 4.10 (SD 4.6) m/s

Controls

mean 3.90 (SD 4.0) m/s

p = .045.

CRP measured 5 years previously predicted aortic stiffness

Heier M et al. 2014 (submitted)

Atherosclerosis and Childhood Diabetes Study

AGEs and Inflammation
MG-H1 is an independent risk factor for low grade
inflammation measured by CRP, indicative of an
accelerated early atherosclerotic process
Heier M et al. 2014(submitted)

The relationship between traditional risk factors for atherosclerosis and inflammation.

Libby P Arterioscler Thromb Vasc Biol. 2012;32:2045-2051

Copyright American Heart Association, Inc. All rights reserved.

Atherosclerosis and Childhood Diabetes Study

Markers of inflammation are increased at an early stage
Marker of

Diabetes

Control

p-value

VCAM-1 (ng/ml)

704 (184)

667 (175)

.056

ICAM-1 (ng/ml)

212 (75)

208 (76)

.614

E-selectin (ng/ml)

27.0 (10.2)

24.2 (8.6)

.006

P-selectin (ng/ml)

34.2 (10.3)

30.2 (9.9)

< .001

TNF (pg/ml)1

2.21 (1.67, 2.80)

1.98 (1.63, 2.67)

.295

IL-6 (pg/ml)1

0.95 (0.68, 1.40)

0.88 (0.68, 1.23)

.125

CRP (mg/L)1

0.51 (0.27, 1.77)

0.31 (0.19, 0.68)

< .001

MCP-1 (pg/ml)

339 (112)

317 (97)

.043

IL-18 (pg/ml)1

232 (185, 282)

205 (173, 264)

.018

MMP-9 (ng/ml)1

201 (138, 277)

179 (127, 259)

.071

TIMP-1 (ng/ml)

166 (27)

158 (25)

.004

inflammation

Heier M, Margeirsdottir HD, Seljeflot I, Dahl-Jrgensen et al. Atherosclerosis 2014

Inflammatory pathways as potential targets for atherosclerotic therapies.

Ridker P M , and Lscher T F Eur Heart J 2014;35:17821791

Published on behalf of the European Society of Cardiology. All rights reserved. The Author
2014. For permissions please email: Journals.permissions@oup.com

Phase III trials of anti-inflammatory agents under evaluation in cardiovascular disease.

Ridker P M , and Lscher T F Eur Heart J 2014;35:17821791

Published on behalf of the European Society of Cardiology. All rights reserved. The Author
2014. For permissions please email: Journals.permissions@oup.com

Conclusions- current knowledge

CVD is the major lifethreatening complication of
childhood onset T1D
CVD risk factors should be assessed regularely from
diagnosis and lifestyle changes introduced
Healthy diet and regular physical activity. No smoking
Preventing obesity and insulin resistance
HbA1c target <7,5% without hypoglycemia. All efforts
BP target < 90 centile. Active treatment.
LDL Cholesterol target <2.6mmol/l (100mg/dl).
Active treatment with diet and statins.

Conclusions future direction

Lower HbA1c targets possible with new treatment
(Pumps, CGM, closed loop systems, new long acting
insulin analogs) ?
Starting statins from diagnosis of T1D ?
Lower LDL targets possible with new drugs ?
Additional new drugs addressing
Obesity and metabolic syndrome
Glycation of proteins
Endothelial dysfunction
Inflammation
Pending safe and effective in children

We have to focus all this work at

an early age

-and never give in !

Thanks
Kristian F. Hanssen
Hanna Dis Margeirsdottir
Martin Heier
Jakob R Larsen
Kari Anne Sveen
Torild Skrivarhaug
Magne Brekke
Knut Hkon Stensth
Ingebjrg Seljeflot
Harald Arnesen
Ketil Steine
Peter Abusdal Torjesen

Nina Cecilie verby

Ingunn Bergstad
Lene Frost Andersen
Sigmund Andersen
Leiv Sandvik
Cathrine Brunborg
Siv Janne Kummernes
Eva Lindstad
Beth Tyrdal
The Norwegian Study Group for
Childhood Diabetes