Type 2 diabetes and cardiovascular disease Christopher D. Byrne FRCPath FRCP PhD Professor of Endocrinology & Metabolism Director of Wellcome Trust Clinical.

Type 2 diabetes and cardiovascular disease

Christopher D. Byrne FRCPath FRCP PhD

Professor of Endocrinology & Metabolism

Director of Wellcome Trust Clinical Research Facility

Southampton University Hospitals Trust

Impact of diabetes on the average annual age-adjusted incidence/1,000 cardiovascular events in men and

women aged 45-74 years from the Framingham study

Men Women

Diabetes Control Diabetes Control

Cardiovascular disease 39.1 19.1 27.2 10.2Cardiovascular mortality 17.4 8.5 17.0 3.6Coronary heart disease 24.8 14.9 17.8 6.9Congestive heart failure 7.6 3.5 11.4 2.2Claudication 12.6 3.3 8.4 1.3Stroke 4.7 1.9 6.2 1.7

Kannel WB, McGee DL, JAMA 1979; 241: 2035 - 2038.

CHD mortality in type 2 diabetes

No DM type 2 DM

MI no MI MI no MI

(n=69) (n=1304) (n=169) (n=890)

% events (p.a.)

fatal/non-fatal MI 3.0 0.5* 7.8# 3.2**

fatal/non-fatal stroke 1.2 0.3* 3.4# 1.6**

CV death 2.6 0.3* 7.3# 2.5**

*p<0.001 prior MI versus no prior MI no DM#p<0.001 prior MI versus no prior MI DM**p<0.001 DM versus no DM Haffner et al NEJM 1998 339: 229-234

STABLE ATHEROSCLEROTIC PLAQUE

fibrous cap(smooth muscle cells & matrix)

lipid core

adventitia

endothelial cellsintimal smooth muscle cells

(repair phenotype)

medial smooth muscle cells(contractile phenotype)

adventitia

lipid corelipid core

UNSTABLE CORONARY ARTERY DISEASE

Accumulation of modified lipid

Endothelial cell activation

Inflammatory cell migration

Inflammatory cell activation

Smooth muscle cell recruitment

Proliferation and matrix synthesis

Fibrous cap formation

Plaque rupture

Platelet aggregation

Thrombosis

Smooth musclecell apoptosis

Matrix degradation

PATHOGENESIS OF ATHEROSCLEROSIS

Growthfactors

Growthfactors

Insulinresistance

-celldysfunction

Type 2diabetes

Adapted from: Beck-Nielson H et al. J Clin Invest 1994;94:1714–1721 and Saltiel AR, Olefsky JM. Diabetes 1996;45:1661–1669

What is Type 2 diabetes?

A progressive metabolic disordercharacterised by:

Insulin resistance and insulinhypersecretion precede type 2 diabetes

Insulin Insulin Macrovascularsensitivity secretion disease

30% 50% 50%

50% 70–100% 40%

70% 150% 10%

100% 100%

Adapted from: Beck-Nielsen H, Groop LC. J Clin Invest 1994;94:1714–1721

IGT

Impaired glucose

metabolism

Normal glucose metabolism

Type 2 diabetes

Clinical indicators ofthe Insulin Resistance Syndrome

• + Insulin resistance

• + Type 2 diabetes or IGT

• + Dyslipidaemia ( TG, LDLc, HDLc)

• + Central obesity

• + Hypertension

• + Hyperinsulinaemia (initially)

• + Atherosclerosis

DeFronzo RA, Ferrannini E. Diabetes Care 1991;14(3):173–194

Glucose uptake in insulin-resistant subjects: impaired in patients with type 2 diabetes

Adapted from Baron AD. Am J Physiol 1994;267:E187–E202

Serum insulin (pmol/L)

Who

le-b

ody

gluc

ose

upta

ke(µ

mol

/m2 /

min

)3,000

1,500

1,000

500

0

2,000

2,500

10 100 1,000 10,000 100,000

Lean

Obese

Type 2 diabetes

Pancreatic -cell Insulin resistance

Liver

HYPERGLYCAEMIA

Islet -cell degranulationReduced insulin content

Muscle(PKC Adipose tissue

Decreased glucose transport& activity (expression) of GLUT-4

Increased lipolysis

Elevated plasma NEFA

+ -

Low plasmainsulin

Increased glucose output

ElevatedTNF

Insulin resistance and -cell dysfunctionproduce hyperglycaemia in type 2 diabetes

Modified from: Turner N, Clapham JC. Prog Drug Res 1998;51:34–94

Why is the prevalence of insulin resistance increasing?

Health Survey for England:Cardiovascular disease 1998

• 16 - 24 year age group

• ~50% overweight BMI > 25kg/m2

or obese BMI > 30kg/m2

• 17% men and 21% women are obese

NB: increased from 14% men and 17% women - 1994

Relative risk of death due to cardiovascular disease according to BMI among non-smoking women aged 30 to 55 years

0.0

1.0

2.0

3.0

4.0

5.0

Manson, J.E. et al. New England Journal of Medicine 1995; 333: 677-85.

Body mass index (kg/m2)

Rel

ativ

e ri

sk o

f de

ath

P<0.001

Relative risk of type 2 diabetes according to BMI in US women aged 30 to 55 years

0102030405060708090

100

Body mass index (kg/m2)

Age

-adj

uste

d re

lativ

e ris

k

Colditz GA et al. Annals of Internal Medicine 1995; 122: 481-86.

Why does obesity cause type 2 diabetes?

• high levels of free fatty acids found in obese or overweight patients, interfere with

glucose metabolism

Mechanisms of insulin resistance linking fatty acid and glucose metabolism

Increased adipocyte lipolysis (central obesity)

FFAs

acetyl CoA (cellular)

hepaticgluconeogenesis

NADH/NAD citrate

glycogen synthase

pyruvate dehydrogenase

plasmaglucose

glucose transport

hexokinase glucose 6-P

phosphofructokinase

glycogen content

Differences between visceral and subcutaneous fat

Visceral fat Subcutaneous fat

6-20% of total body fat 80% of total body fat

Greater number of smaller cells Smaller number of large cells with richer blood supply with poorer blood supply

Intra-abdominal with direct Extra-abdominal drainage to portal vein

Greater catecholamine-induced Reduced catecholamine-induced lipolysis lipolysis

Reduced insulin inhibition of Increased insulin inhibition of lipolysis lipolysis

How can the impact of diabetes and metabolic syndrome

to cause vascular disease be reduced?

TM

© 1999 Professional Postgraduate Services®

UKPDS: Intensive Blood-Glucose vs ConventionalTreatment in Patients With Type 2 Diabetes

RR=relative risk.PVD=peripheral vascular disease.

UKPDS Group. Lancet. 1998;352:837-853.

Any diabetes-related end point 0.88 (0.79–0.99) 0.029

Diabetes-related deaths 0.90 (0.73–1.11) 0.34

All-cause mortality 0.94 (0.80–1.10) 0.44

MI 0.84 (0.71–1.00) 0.052

Stroke 1.11 (0.81–1.51) 0.52

Amputation or death from PVD 0.65 (0.36–1.18) 0.15

Microvascular disease 0.75 (0.60–0.93) 0.0099

Favors Favors Log-rank RR (95% CI) intensive conventional P value

Clinical End Point0.1 1 10

TM

© 1999 Professional Postgraduate Services®

Any diabetes-related end point 0.76 (0.62–0.92) 0.0046

Diabetes-related deaths 0.68 (0.49–0.94) 0.019

All-cause mortality 0.82 (0.63–1.08) 0.17

MI 0.79 (0.59–1.07) 0.13

Stroke 0.56 (0.35–0.89) 0.013

Peripheral vascular disease 0.51 (0.19–1.37) 0.17

Microvascular disease 0.63 (0.44–0.89) 0.0092

UKPDS: Tight Blood Pressure Control vs LessTight Control in Patients With Type 2 Diabetes

RR=relative risk.

UKPDS Group. BMJ. 1998;317:703-713.

RR for Favors Favors tight control tight less tight P

(95% CI) control control value

Clinical End Point10.1 10

August 1999

How can insulin resistance be How can insulin resistance be reduced?reduced?

How can insulin resistance be How can insulin resistance be reduced?reduced?

LifestyleLifestyleWeight reduction - optimum BMI in Weight reduction - optimum BMI in Caucasians?Caucasians?Increasing levels of energy expenditureIncreasing levels of energy expenditure

MedicationMedicationMetformin & GlitazonesMetformin & Glitazones

LifestyleLifestyleWeight reduction - optimum BMI in Weight reduction - optimum BMI in Caucasians?Caucasians?Increasing levels of energy expenditureIncreasing levels of energy expenditure

MedicationMedicationMetformin & GlitazonesMetformin & Glitazones

Reduction in risk of various clinical endpoints with metformin (n=342) compared with a conventional policy

in overweight patients (BMI=31) with type 2 diabetes

Clinical endpoint Risk reduction p value

Any diabetes-related endpoint 32% 0.002

Diabetes-related deaths 42% 0.017

All-cause mortality 36% 0.011

Myocardial infarction 39% 0.010

Data taken from UK Prospective Diabetes Study (UKPDS) group. Lancet 1998; 352: 854-65.

How does activation of PPAR enhance insulin action and normalise blood glucose?

Glitazoneand insulin

PPAR

Pre-adipocyte

Adipocyte

Increaseddifferentiation

Reversal of TNF-inducedinsulin resistance

Increased insulin sensitivity and capacity for glucose

disposal/lipid storage

Reduced lipolysis and free fatty

acid availability

Skeletal muscle

Liver

Euglycaemia

Increasedglucose disposal

Reducedhepatic glucose output

PPAR

GLUT-4

TG & PKC

Treatment with glitazones

Diagnosis

Diet and Exercise

Sulphonylurea

HbA1c > 7%

Can’t use Metformin

Metformin

HbA1c > 7%

Obese

Add Glitazone

HbA1c > 7%

OverweightNormal weight

Combination therapy?

PPAR gamma andPPAR alpha agonists

Future challenges for type 2 diabetes management

Glucose control

Adverse experiences

ComplicationsDrug

interactions

-cell function

Insulin resistance