Risk Factors for CVD

in Type 1 Diabetes

Marian Rewers, MD, PhD

Professor & Clinical Director, BDC

Duality of Interest DeclarationI have no conflict of interest in the field covered by my lecture

but I’d rather be there today

Type 1 diabetes = a disease of adults1.4 million of adults with T1D in the U.S.

0

25,000

50,000

75,000

100,000

125,000

150,000

5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80Age [yrs]

Number of patients, 2005

Survival among T1 D patients is improving

Allegheny County IDDM Registry 1965-1999

Nishmura R, et al. Diabetes Care 2001

Duration of diabetes (yrs)

0.5

0.6

0.7

0.8

0.9

1

0 5 10 15 20 25 30 35

1975-79 SMR =235

1970-74 SMR =367

1965-69 SMR =497

Duration of diabetes (yrs)

0.5

0.6

0.7

0.8

0.9

1

0 5 10 15 20 25 30 35

1975-79 SMR =235

1970-74 SMR =367

1965-69 SMR =497

General Population SMR =100

The incidence of microvascular complications in T1D

is decliningSteno Clinic, Denmark, 600 Patients diagnosed 1965-84

Hovind P, et al. Diabetes Care 2003

1961-65

1966-70

1966-70

1971-751971-75

1976-80 1976-80

Diabetic nephropathyProliferative diabetic retinopathy

1965-691965-69

1970-741970-74

1975-791975-79

1980-841980-84

30

20

10

40

0

10

20

30

40

50

60

70

80

90

100

20 yrs` 25 yrs 30 yrs 35 yrs 40 yrs 45 yrs 50 yrs

1950-59

1960-69

1970-80

The incidence of coronary artery disease in T1D

is increasing684 Patients diagnosed 1950-1980

%

Orchard T, Pittsburgh EDC StudyDiabetes duration

Coronary Artery Disease in T1DEDC T1D Patients vs. General Population

0

1

2

3

4

20-29 30-39 40-49 50+

DM Men

DM Women

non-DM Men

non-DM Women

Incidence of CAD /100 p-yr

Age

• Vast majority of the U.S. T1D patients are middle-aged

• Survival has improved, due to prevention of acute

complications and nephropathy

• CAD is the leading cause of death in people with T1D

and poorly responds to prevention efforts

• Women with T1D have 10-30 times higher risk of CAD,

and men have 4-10 times higher risk, compared to the

general population.

Summary 1

Standards of Medical Care, ADA 2010Non-pregnant adults (T1D and T2D)

• A1c: <7% (eAG <154 mg/dl)

– pre-prandial BG 70-130 mg/dl

– post-prandial peak BG <180 mg/dl

– avoid severe hypoglycemia

• BP: 130/80 mm/Hg

– antihypertensives if micro-/macroalbuminuria

• LDL-Ch: <100 mg/dl (non-HDL-ch<130, apoB<90)

– TG <150 mg/dl, HDL-ch >40(M) >50(F)

• No smoking

• BMI <25• Aspirin M>50, F>60 and high risk CVD

Standards of Medical Care, ADA 2010Adults with T1D

• A1c: <7% (eAG <154 mg/dl)

– pre-prandial BG 70-130 mg/dl

– post-prandial peak BG <180 mg/dl

– avoid severe hypoglycemia

• BP: 130/80 mm/Hg

– antihypertensives if micro-/macroalbuminuria

• LDL-Ch: <100 mg/dl (non-HDL-ch<130, apoB<90)

– TG <150 mg/dl, HDL-ch >40(M) >50(F)

• No smoking

• BMI <25• Aspirin M>50, F>60 and high risk CVD

<10% of T1D patients meet the ‘ABC’ goals:

A1c<7%, LDL<100 mg/dl, BP<130/80CACTI, N=652 age 20-55, duration 23 ± 8 yr

P=0.001

%

Snell-Bergeon J et al 2011

01020

3040506070

8090

100

DN DR PDR Neuropathy

%

Met all goals Met some goals Met no goals

p<0.0001 p=0.008 p=0.032 p=0.009

Meeting the ADA ‘ABC’ goals

helps to prevent microvascular complications:CACTI, N=459 age 20-55, duration 23 ± 8 yr

A1c<7%, LDL<100 mg/dl, BP<130/80

6-yr

cumulative

incidence

[%]

Snell-Bergeon J et al 2011

Figure 2.

Compliance with ADA Goals and CAC Progression in T1DCAC progresses regardless of meeting the ADA goals:

CACTI, N=459 age 20-55, duration 23 ± 8 yr

% CAC

progressed

in 6 yrs

Snell-Bergeon J et al 2011A1c<7%, LDL<100 mg/dl, BP<130/80

EBT CACIncreased calcium

in the LAD and CFX

Angiography & IVUS

Each magnified image demonstrates focal

regions of LAD intimal artery architecture

viewed by IVUS.

CAC strongly predicts future coronary events

in asymptomatic subjects

Pletcher MJ, Arch Intern Med 2004

OR=2.1 (1.6-2.9)

OR=5.4 (2.2-13)

OR=10.0 (3.1-34)

• Few T1D patients meet the ADA ‘ABC’ goals

– those who do, lower their risk of microvascular disease,

– but remain at high risk of CVD

• We need to find additional important risk factors and interventions

• Non-invasive monitoring of progression of subclinical CVD and effects of treatment will help

Summary 2

Risk factors for CVD in T1D

Non-modifiable predictors of CVD

in T1D

• Age

• Duration of diabetes

• Male gender (less than in the general population)

• Lack of residual insulin secretion

• Genetic markers, e.g.:– family history of MI in parents

– apolipoprotein A-IV Gln360His

– hepatic lipase (LIPC-480C>T)

– ACE I/D, angiotensin type 1 receptor (1166A), angiotensinogen (235M>T)

– VDR

– Matrix metalloproteinase-3 (MMP3-5A/6A)

Risk factors for CVD in T1D

• Hypertension

• Renal dysfunction

– tubular markers, MA, GFR

Independent Baseline Predictors of CAD EventsBoth Sexes, Cox PH Model

Orchard TJ. EDC 2004

Type of CAD Variables HR (95% CI) p

Total CAD Duration 2.18 (1.74-2.73) <0.001

Hypertension 2.16 (1.40-3.32) <0.001

WBC 1.35 (1.11-1.59) 0.002

HDLc 0.72 (0.58-0.91) 0.005

non-HDLc 1.33 (1.08-1.59) 0.007

Ever Smoke 1.58 (1.05-2.38) 0.028

HR yes/no or change per standard deviation (SD):WBC=1.92x103, Duration=7.5 y, HDLc=12.4 mg/dl, non-HDLc=43.0 mg/dl

Baseline DCCT Predictors of CVD in T1DNathan DM et al. DCCT/EDIC 2006

With CVD

N=83

No CVD

N=1358 p-value

Intensive insulinotherapy (%) 37 50 0.02

HbA1c (%) 9.5 9.0 0.014

Current smoking (%) 33 18 <0.001

LDL (mg/dl) 127 109 <0.001

Albuminuria (mg/24h) 19 16 0.02

Triglicerides (mg/dl) 88 81 0.04

Coronary Artery Calcification in Type 1 Diabetes

6-yr follow-up exam (N=1,173)

N=543 (83%)

3-yr follow-up exam (N=1,215)

N=559 (86%)

Baseline examination (N=1,416)

652 T1D patients + 764 non-diabetic controls 20-55 yr old, 10+ yr diabetes duration

Baseline characteristics of T1D participants

with CAC progression from baseline to 6 years

CACTI 2000-08 Progressors

(n = 192)

Non-Progressors

(n = 249)

Sex (%male) 57.8** 37.8

Age (yrs) 40.6±8.3** 34.3±8.4

Duration of Diabetes (yrs) 26.7±8.8** 20.3±7.9

Hypertension (%) 57.8** 27.42

Systolic Blood Pressure 121±14** 113±12

Diastolic Blood Pressure 78±9* 76±8

Means ± SD, percent, or median. ŧSquare root transformed. *p<0.05, **p<001

Maahs, CACTI. J Diab Comp, 2006

62% lower risk of CAC progression

with

ACE/ARB Tx

Risk factors for CVD in T1D

• Hypertension

• Renal dysfunction

– tubular markers, MA, GFR

• Hyperglycemia and glycemic variability

Conventional

Intensive

Cardiovascular Events

Non-Fatal MI, Stroke or CVD Death

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Number at Risk

Intensive: 705 686 640 118

Conventional: 721 694 637 96

Years from Study Entry

0.00

0.02

0.04

0.06

0.08

0.10

0.12

Cu

mu

lati

ve I

ncid

en

ce

Risk reduction 57%

95% CI: (12-79%)

Log-rank P = 0.018

DCCT/EDIC

Snell-Bergeon et al. Diabetes Care 20030.0

0.1

1.0

10.0

100.0

< 6.0 6- 6.8 6.8-7.5 >7.5

HbA1c

OR

fo

r p

rog

ressio

n o

f C

AC

A1c predicts progression of coronary calcium

in T1D CACTI participants

Adjusted for age, gender, duration of diabetes and baseline CAC

RR 7.1 p=0.02

<6.0% 6-6.8% 6.8-7.5% >7.5% HbA1c

Mixed-effects models for 6-yr progression of CAC,

best models in T1D patients

Estimate (95% CI) p-value

Age (yrs) 0.97 (0.50 , 1.44 ) .0001

Baseline CAC>0 3.39 (2.53 , 4.25 ) .0000

Diabetes Duration (yrs) 1.10 (0.63 , 1.57 ) .0000

Hypertension 1.74 (0.94 , 2.53 ) .0000

HbA1c 0.54 (0.08 , 1.01 ) .0224

Estimates per SD: age 9 yr, duration 9 yr, HbA1c 1.5%

CACTI 2010

Good glycemic control & low variability

CGM CACTI ID 2013; 3443 observations in 15 days

0

100

200

300

400

12:00 AM 6:00 AM 12:00 PM 6:00 PM 12:00 AM

Time of Day

Glu

cose (

mg/d

L)

Grand mean 117 mg/dl

Overall standard

deviation33 mg/dl

% within 70 – 180 96%

MODD_ave 31 mg/dl

HbA1c 6.4%

Good glycemic control & high variability

CGM CACTI ID 1049; 2805 observations in 15 days

0

100

200

300

400

12:00 AM 6:00 AM 12:00 PM 6:00 PM 12:00 AM

Time of Day

Glu

cose (

mg/d

L)

Grand mean 131 mg/dl

SD 72 mg/dl

% within 70 – 180 78%

MODD_ave 67 mg/dl

HbA1c 5.8%

Glycemic variability is associated with

CAC in men with T1DOdds Ratios (95% CI)

Men

(n=29)

Women

(n=40)

p-value

interaction

by sex

Mean glucose 5.0 (1.1-21.6) 1.2 (0.6-2.2) 0.07

SDT 7.2 (1.6-32.6) 1.2 (0.6-2.4) 0.04

% of time <70 mg/dl 1.3 (0.4-3.7) 0.9 (0.4-1.7) 0.52

% of time >180 mg/dl 9.0 (1.5 – 54.5) 1.1 (0.6 – 2.2) 0.03

Snell-Bergeon J et al Diabet Med 2010

Risk factors for CVD in T1D

• Hypertension

• Renal dysfunction

– tubular markers, MA, GFR

• Hyperglycemia and glycemic variability

• Insulin resistance

– central obesity

– ↓HDL, ↑triglycerides, impaired FFA suppression

T1D Subjects are Insulin ResistantCACTI N=87

Glu

co

se D

isp

osal

mg

/kg

/min

LS Mean ± SE, adjusted for age, BMI, fasting glucose, final clamp glucose and insulin

0

2

4

6

8

10

12

14

16

T1DWomen

ControlWomen

T1D Men ControlMen

p<0.005p<0.0001

Interventions to improve insulin sensitivity

• Optimal timing of insulin delivery

• Weight loss if BMI>23;

no gain in those with BMI<23

• Aerobic exercise intervention

• Metformin

• ?? TZD, acipimox ??

Estimation of insulin sensitivity using clinical

parameters

Group Equation Mean

eGDR± SD

T1D

Men

23.91 +(adiponectin*0.139) –(triglycerides*0.003)

- (insulin dose/kg/day*4.29) - (waist*0.184)

6.0 ± 2.8

T1D

Women

6.92 + (adiponectin*0.139) - (triglycerides * 0.003)

- (insulin dose/kg/day*4.29)

6.7 ± 1.8

Equations derived from clamp studies in 40 adults with T1D

Validated in CACTI cohort (n=652)

Snell-Bergeon J, CACTI 2010

Risk factors for CVD in T1D

• Hypertension

• Renal dysfunction

– tubular markers, MA, GFR

• Hyperglycemia and glycemic variability

• Insulin resistance

– central obesity

– ↓HDL, ↑triglycerides, impaired FFA suppression

• LDL-cholesterol

• smoking

Baseline characteristics of T1D participants

with CAC progression from baseline to 6 years

CACTI 2000-08 Progressors

(n = 192)

Non-Progressors

(n = 249)

Sex (%male) 57.8** 37.8

Age (yrs) 40.6±8.3** 34.3±8.4

Duration of Diabetes (yrs) 26.7±8.8** 20.3±7.9

LDL Cholesterol 101.8±27.6* 96.1±28.0

HDL Cholesterol 53.9±15.7* 57.7±16.7

Log Triglycerides 4.5±0.5** 4.3±0.5

Means ± SD, percent, or median. ŧSquare root transformed. *p<0.05, **p<001

CACTI 2010

Effects of Simvastatin

on First Major CVD Event in Diabetes

HPS Collaborative Group, Lancet 361:2010, 2003

Practical implications

• Take care of the ABCs:

A1c, Blood pressure, LDL-Cholesterol

• Screen all asymptomatic diabetic patients older than 30 for

increased plaque burden = high or rapidly increasing CAC score

• Patients with high or rapidly increasing CAC score ->

myocardial perfusion tests, angiography, IVUS

•Intensive interventions

Emerging CVD risk factors in T1D

• Dysfunctional (high/normal) HDL

• Inflammation (markers of response to injury?)

– ↓ adiponectin

– ↑ sIL-2r, WBC, hsCRP, IL-1, IL-1ra, IL-6, IL-6r, TNF- TNF-rII, IL18,

ICAM-1, VCAM-1, E-selectin, P-selectin, Lp-PLA2, CD40L

• Hypovitaminosis

– Vitamin E in subjects with haptoglobin 1/1 ?

– Vitamin D in subjects with VDR Fok I T allele ?

– Folate in subjects with MTHFR-677 C>T ?

• Impaired fibrinolysis

– ↑ fibrynogen, PAI-1

Rewers M. 4/2010

University of ColoradoBarbara Davis Center:

Marian Rewers, P.I., Janet Snell-Bergeon

David Maahs, Franziska Bishop

Greg Kinney, Paul Wadwa

Ram Naik, Satish Garg

Nicole Gendelman, Katherine Pratte

Colorado School of Public Health:

John Hokanson, Lorri Ogden

Dana Dabelea, Kim McFann

Medicine: Robert Eckel

Robert Quaife, Marcus Chen

Irene Schauer, Bryan Bergman

Colorado Heart Imaging: James Ehrlich

Roche Molecular Systems:

Suzanne Cheng, Henry Erlich

Univ. Bialystok: Adam Kretowski

Univ. Vermont: Russell Tracy

Wake Forest Univ. Ronald Prineas

Porto Alegre Univ. Ticiana Rodirigues

Univ. de Chile: Rossana Roman

UCLA: Matthew Budoff

Univ. Pittsburgh: Trevor Orchard

Tina Costacou

LDL HDL

ApoB ApoAI

The Bad and the Good Cholesterol

Alan Chait, ADA 2011

Can HDL become dysfunctional

so as not to be atheroprotective or anti-inflammatory?

Altered HDL composition and function

“Inflammatory HDL” bind avidly to vascular proteoglycans

Oxidized HDL functions poorly in reverse cholesterol transport

CE

HDL

INFLAMMATION

CE ↓ HDL level

CE

↓ApoA-I

↓PON1

↑SAA1/2

↓cholesterol efflux

↓anti-oxidant activity

Khovidhunkit J Lipid Res 2004; Navab J Lipid Res 2009; Han ATVB 2006; Shao J Lipid Res2010