Targeting Insulin Resistance for Vascular Protection

Contents

I. Vascular Consequences of Diabetes and Insulin Resistance

II. CV Risk Reduction, Diabetes Prevention, and TZDs

III. Clinical Imperatives When Treating Patients with Diabetes

Vascular Consequences of Diabetes and Insulin Resistance

One third of adults with diabetes are undiagnosed

• ~10% of US adults have diabetes/~20 million persons in 2005

• Nearly one third don’t know they have diabetes

• 26% of US adults have impaired fasting glucose (IFG)*

*100–125 mg/dLCowie CC et al. Diabetes Care. 2006;29:1263-8.

NIDDK. National Diabetes Statistics. www.diabetes.niddk.nih.gov.

Total: 35% of US adults with diabetes or IFG~73.3 million persons

Rising prevalence of diabetes

Steinbrook R. N Engl J Med. 2006;354:545-8.

Diagnosed diabetes in US, 1980–2004

Persons with diagnosed diabetes (millions)

15

10

5

01980 1984 1988 1992 1996 2000 2004

Year

CDC. www.cdc.gov.

Parallel epidemics of diabetes and obesity

Diabetes

Obesity(BMI ≥30 kg/m2)

<4% 4%–4.9% 5%–5.9% >6%

10%–14% 15%–19% 20%– 24% >25%

2004 1994

90% of patients with newly diagnosed diabetes are overweight or obese

30

60

0

20

40

60

80

100

Geiss LS et al. Am J Prev Med. 2006;30:371-7.

Obese (BMI ≥30)

Overweight(BMI 25 to <30)

Diabetes patients with

BMI ≥25 kg/m2

(%)

National Health Interview Survey, 2003; N ≈ 31,000 aged 18 to 79 years

90%

IFG/IGT: Challenge for prevention

41

0

5

10

15

20

25

30

35

40

45

US population (millions)

NIDDK. National Diabetes Statistics. www.diabetes.niddk.nih.gov.ADA. Diabetes Care. 2006;29(suppl I):S4-48.

Ages 40 to 74 years; US population estimates 2000

IGT = impaired glucose toleranceOGTT = oral glucose tolerance test

Fasting plasma glucose (FPG) 100–125 mg/dLand/or 2-hr OGTT 140–199 mg/dL

“Ticking clock” hypothesis: Glucose abnormalities increase CV risk

1.0

2.8

3.7

5.0

0

1

2

3

4

5

6

Nurses’ Health Study, N = 117,629 women, aged 30–55 years; follow-up 20 years (1976–1996)

Hu FB et al. Diabetes Care. 2002;25:1129-34.

Relative risk of MI or stroke*

No diabetes Before diabetes

diagnosis

After diabetes

diagnosis

Diabetes atbaseline

*Adjustedn = 1508 diabetes at baselinen = 5894 new-onset diabetes

DECODE: IGT increases mortality risk

Diagnosed diabetes (n = 1275)Undiagnosed diabetes (n = 3071)Impaired glucose tolerance (n = 2766)*Normal glucose tolerance (n = 18,252)*

Follow-up (years)

Mortalityhazard

(%)

DECODE Study Group. Lancet. 1999;354:617-21.*2-hour OGTT

Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in EuropeN = 25,364 aged ≥30 years

20

10

00 2 4 6 8 10

CHD risk appears to begin at low blood glucose levelsN = 17,869 men, aged 40–64 years; follow-up 33 years

Brunner EJ et al.Diabetes Care. 2006;29:26-31.

*Relative to baseline group of all men with blood glucose <83 mg/dL

83 mg/dL

OGTT blood glucose (mg/dL)

54 72 108 90 126 144 162 180

1.6

1.2

0.8

0.4

0.0

-0.4

CHD mortality

(log hazard ratios)*

Continuum of CV risk: Reason for early intervention in patients with IFG/IGTCardiovascular Health Study; N = 4014, age ≥65 years

Smith NL et al. Arch Intern Med. 2002;162:209-16.

CV events(hazardratio*)

↑42%

↑36%

↑17%

↑54%

↑90%

*Adjusted for age, sex, and race†Reference

1.6

1.4

1.2

1

0

2

1.6

1.2

1

0

1.8

1.4

†

†

≤92 93–97 98–103 104–111 ≥112 ≤103 104–124 125–146 147–181 ≥182

FG (mg/dL) 2-h glucose (mg/dL)

Even mild glucose elevations increase mortality in patients undergoing PCI

1.9

6.6

9.5

11.2

0

2

4

6

8

10

12

NFG IFG Undx DM2 DM2

Muhlestein JB et al. Am Heart J. 2003;146:351-8.

N = 1612 with CAD; mean age 62 years

Mortality(%)

P-trend < 0.001

FG (mg/dL) <110 110–125 ≥126

NFG = normal FGUndx DM2 = undiagnosed type 2 diabetes

IGT and undiagnosed DM2 are common in acute MI and stroke

3523

31

16

0

10

20

30

40

50

60

70

Norhammar Matz

Patients(%)

Norhammar A et al. Lancet. 2002;359:2140-4.Matz K et al. Diabetes Care. 2006;792-7.

2-hour OGTT

66

39

(n = 181) (n = 238)

Myocardial infarction Stroke

IGT Undiagnosed DM2

Risk of endothelial dysfunction increases at FG 110–125 mg/dLN = 579 without diabetes or prior CV disease

Rodriguez CJ et al. Am J Cardiol. 2005;96:1273-7.

*UnadjustedFMD = flow-mediated dilation

%

FG (mg/dL)

<900

2

4

6

8

90–99 100–109 110–125

P < 0.05

100

10

1

0

90–99 100–109 110–125

Odds ratio (95% Cl)*

FG (mg/dL)(Referent = FG <90 mg/dL)

FMD change Endothelial dysfunction

Impaired macrovascular reactivity in people at risk for type 2 diabetes

0

5

10

15

Controls Relatives IGT Diabetes

Caballero AE et al. Diabetes. 1999;48:1856-62.*vs relatives, IGT, diabetes

Increase from baseline after cuff occlusion

(%)

13.7

10.59.8

8.4

P < 0.01*

Insulin resistance: Risk factor for CV disease

Kim J-a et al. Circulation. 2006;113:1888-904.Ridker P, Libby PJ. In Braunwald’s Heart Disease. 7th ed.

• Important feature of diabetes, obesity, glucose intolerance, and dyslipidemia

• Key component of CV disorders: hypertension, CAD, and atherosclerosis

• Independent risk factor for atherosclerosis

Insulin resistance promotes atherosclerosiseven before it produces diabetes

Insulin resistance and atherosclerosis

Insulin resistance

Genetic factors Acquiredconditions

VasoconstrictionINFLAMMATION

Thrombosis

ACCELERATED ATHEROSCLEROSIS

Kim J-a et al. Circulation. 2006;113:1888-904.

Who has insulin resistance?

90 88

50 5045

50

40

0

20

40

60

80

100

DM21 HTN3 Stroke4 CHD5 Refer to cardiol.6

Age40 to 747

1Haffner et al. Diabetes. 1997. 2McLaughlin et al. Am J Cardiol. 2005.3Reaven et al. N Engl J Med. 1996. 4NIH. www.clinicaltrials.gov.

5Lankisch et al. Clin Res Cardiol. 2006.6Savage et al. Am Heart J. 2005. 7www.diabetes.niddk.nih.gov/.

%Patients

↓HDL+ ↑TG2

I II III IV

Insulin resistance is an independent predictor of HF N = 1187 men, aged ≥70 years; follow-up 8.9 years

Ingelsson E et al. JAMA. 2005;294:334-41.

Inverse relationship between HF incidence and insulin sensitivity

HF incidence/1000

person-years at risk*

*Adjusted for HF risk factors†Quartiles of clamp glucose disposal rate (mg/kg body weight per min)

Insulin resistance quartiles†

25

20

15

10

0

5

Insulin resistance increases risk of chronic kidney disease (CKD)

4.0

2.7

0

1

2

3

4

5

Serum insulin HOMA-IR

N = 6453 without diabetes

Odds ratio (highest vs

lowest quartiles*)

Chen J et al. J Am Soc Nephrol. 2003;14:469-77.

*Multivariate adjustedCKD = GFR <60 mL/min per 1.73 m2

HOMA-IR = Homeostasis model assessment of insulin resistance

P = 0.001

P = 0.008

Development of insulin resistance in obesity-induced inflammation and stress

Adapted from de Luca C, Olefsky JM. Nat Med. 2006;12:41-2.

Macrophage

Endocrine inflammatory

signals

Paracrine and autocrine

inflammatory signals

Fatinsulin resistance

Muscle insulin resistance

Liver insulin resistance

Systemicinsulin resistance

Overnutrition and genetics

Dyslipidemia, hypertension, hyperglycemia

Accelerated atherosclerosis

Visceral obesity CT scans from men matched for BMI and total body fat White = visceral fat area (VFA); black = subcutaneous fat

Després J-P. Eur Heart J Suppl. 2006;8(suppl B):B4-12.

Subcutaneous obesity

Fat mass: 19.8 kgVFA: 96 cm2

Visceral obesity

Fat mass: 19.8 kgVFA: 155 cm2 Visceral obesity

drives CV risk progression independent of BMI

Visceral fat independently predicts mortalityN = 291 men, mortality follow-up 2.2 years

Kuk JL et al. Obesity. 2006;14:336-41.*Adjusted for age, follow-up time, and other fat measures

Subcutaneous fat mass

Visceral fat mass

P

0.04

0.98

Mortalityodds ratio (95% CI)*

Waist circumference 0.26

Liver fat

0.60 (0.25–1.44)

0.87 (0.56–1.37) 0.55

0.99 (0.63–1.58)

1.81 (1.04–3.14)

CRP levels show positive correlation with visceral obesity

P < 0.0001 vs *quintile 1; †quintile 2; ‡quintile 3Lemieux I et al. Arterioscler Thromb Vasc Biol. 2001;21:961-7.

Després J-P. Eur Heart J Suppl. 2006;8(suppl B):B4-12.

N = 159 men, mean age 43 yr; BMI 21.0–41.0 kg/m2

0

50

100

150

200

250

I II III IV V I II III IV V

Visceral fat area Waist circumference

CRP quintiles CRP quintiles

**

* *

*

*

**‡ ‡ †

† ‡

cm2 cm

90

95

100

105

110

Shared CV risk between insulin resistance and visceral obesity

Hypertension↑SBP/DBPAbsent nocturnal

BP dipping

Altered hemostasis↑Fibrinogen ↑PAI-1↑Blood viscosity

Renal changesMicroalbuminuria↑Uric acid

Inflammation↑CRP + other

markers

Endothelial dysfunction

Insulin resistance and

visceral obesity

McFarlane SI et al. J Clin Endocrinol Metab. 2001;86:713-8.

Dyslipidemia↓HDL-C↑Apo BSmall dense LDL↑TG

Metabolically active molecules link obesity and atherosclerosis

CRP

IL-6

PAI-1

Angiotensinogen

Leptin

Resistin

MCP-1

TNFα

Adiponectin

Lau DCW et al. Am J Physiol Heart Circ Physiol. 2005;288:H2031-41.Wellen KE, Hotamisligil GS. J Clin Invest. 2005;115:1111-9.

Atherogenic Antiatherogenic

Adipocytokines (adipokines)

Antiatherogenic effects of adiponectin

↑ Endothelial vasodilation

↑ Nitric oxide

↑ Angiogenesis

↓ VCAM-1

↓ TNF level and proinflammatory effects

↓ Oxidized LDL effects on EC

↓ EC proliferation/migration

↓ Growth factor effects on SMC

↓ Neointimal thickening

↓ SMC proliferation

EC = endothelial cellsSMC = smooth muscle cellsVCAM = vascular cell adhesion molecule Goldstein BJ, Scalia R. J Clin Endocrinol Metab. 2004;89:2563-8.

Visceral obesity and adiponectin

Manigrasso MR et al. J Clin Endocrinol Metab. 2005;90:5876-9.

Plasma adiponectin

(µg/mL)

30

25

20

15

10

5

0Non-obese Android

(visceral)

Obesity* status

Gynoid(nonvisceral)

P < 0.0001

P < 0.0001

P < 0.01

N = 104 women; 12-week follow-up

Median*BMI > 28 kg/m2

Inverse relationship between baseline adiponectin level and MI risk

Pischon T et al. JAMA. 2004;291:1730-7.

Multivariate adjusted (PTrend < 0.001) Multivariate + lipid adjusted (PTrend = 0.02)

n = 798, case-control study; follow-up 6 years*

I II III IV V0

0.2

0.4

0.6

0.8

1.0

1.2

Quintile of adiponectin7.9 12.6 16.5 21.1 29.2Median adiponectin (mg/L)

Relative risk of MI

(95% CI)

*Health Professionals Follow-up Study

Shared metabolic abnormalities with insulin resistance and endothelial dysfunction

Glucotoxicity Lipotoxicity Inflammation

Insulin resistance

Endothelialdysfunction

Adapted from Kim J-a et al. Circulation. 2006;13:1888-904.

• Oxidative stress• AGE formation• Pro-inflammatory signaling

• Oxidative stress• Pro-inflammatory signaling

• Pro-inflammatory factors• Kinases/transcription factors

AGE = advanced glycation end product

PPAR activation and atherosclerosis: A hypothesis

Plutzky J. Science. 2003;302:406-7.Blunts atherosclerosis

IndirectFat, liver, skeletal muscle cells

Ligand:Endogenousor synthetic

Activated PPAR

Reducesinflammation

DirectVascular and inflammatory cells

FFA Glucose Insulin sensitivity Triglycerides HDL Atherogenic LDL

Cytokines Chemokines Cholesterol efflux Adhesion molecules

– –

– –

Peroxisome proliferator-activator receptors (PPARs)

• PPAR , , and belong to the nuclear hormone receptor superfamily

• PPAR agonists appear to play a critical role in regulating inflammation, lipoprotein metabolism, and glucose homeostasis

• Studies suggest that PPAR agonists exert antiatherogenic effects by inhibiting proinflammatory gene expression and enhancing cholesterol efflux

• PPAR agonists have potential in the treatment of obesity, diabetes, and atherosclerosis

Li AC et al. J Clin Invest. 2004;114:1564-76. Blaschke F et al. Arterioscler Thromb Vasc Biol. 2006;26:28-40.

PPARs: Overview

PPARreceptor Main tissue location Regulates

Alpha

Liver, skeletal muscle, heart, kidney

Lipid metabolism (dyslipidemia)Inflammation/atherosclerosis

Gamma

Fat cells, macrophages Insulin sensitivity/glucose metabolism

Inflammation/atherosclerosisAdipocyte differentiation

Delta

Widespread, includingskeletal muscle andfat cells

Fatty acid oxidationInflammation

Blaschke F et al. Arterioscler Thromb Vasc Biol. 2006;26:28-40.Semple RK et al. J Clin Invest. 2006;116:581-9.

Beyond fat and glucose: Potential for CV benefits with PPAR agonists

• PPAR is expressed incell types associated withCV disease– Vascular endothelial

cells (EC)– Vascular smooth

muscle cells (VSMC)– T-lymphocytes– Monocyte/macrophages– Cardiac myocytes– Renal tubule cells

Monocytes

Necrotic core

Lumen

VSMC

Adapted from Marx N et al. Arterioscler Thromb Vasc Biol. 1999;19:546-51.

Lumen

EC

Obesity induces inflammatory changes in adipose tissue

Wellen KE, Hotamisligil GS. J Clin Invest. 2003;112:1785-8.

Macrophage and adipocyte similarities

Adipocyte• Energy/lipids

• Inflammation

Macrophage• Inflammation

• Lipid storage

• Insulin resistance

PPAR and LXR oppose these actions in both macrophages and adipocytes

Wellen KE, Hotamisligil GS. J Clin Invest. 2005;115:1111-9.LXR = liver X receptor

Castrillo A, Tontonoz P. J Clin Invest. 2004;114:1538-40.

PPAR signaling pathways influence macrophage gene expression and foam-cell formation

Atherogenicinflammation

PPAR PPAR PPAR/

ABCG1ABCA1

Cholesterol efflux HDL acceptor

Cholesterol efflux ApoA1 acceptor

ApoE,PLTP

Atheroscleroticblood vessel

Macrophage

LXRα = liver X receptor α PLTP = phospholipid transfer protein

LXR ?

Campia U et al. Circulation. 2006;113:867-75.

N = 80 with hypertension or hypercholesterolemia and no diabetes; change after 16 weeks

PPAR agonists improve endothelial vasodilation and decrease inflammation

Pioglitazone 45 mg/dPlacebo

100 200 400

600

500

400

300

0

Forearm blood flow(% from baseline)

Bradykinin (ng/min)

All subjects

Insulin resistant

Insulin sensitive

CRP (mg/L)

7

5

3

1

0

6

4

2

P = 0.0001

P = 0.38

P = 0.0008

P = 0.01

0

PPAR agonists impact inflammatory markers and adiponectinN = 54 adults with metabolic syndrome and no diabetes; change after 12 weeks

Samaha FF et al. Arterioscler Thromb Vasc Biol. 2006;26:624-30.*P = 0.002; †P = 0.027; ‡P < 0.001

Change from

baseline (%)

*

†

0

50

100

150

200‡

Placebo Rosiglitazone 8 mg/d

-40

-20

0

20

40IL-6CRP

Adiponectin

Added benefit of BP reduction with PPAR agonistsN = 87 with diabetes; PPAR agonist added to glimepiride 4 mg/d; change after 12 months

*P < 0.05 vs baseline Derosa G et al. Hypertens Res. 2005;28:917-24.

-3.8

-3.2

-4.4-4.8

-6

-5

-4

-3

-2

-1

0

Change in BP(mm Hg)

Systolic Diastolic

*

*

*

*

Pioglitazone 15 mg/d Rosiglitazone 4 mg/d

PPAR agonists increase collagen content – potentially improving plaque stability

3.7

7.7

0

2

4

6

8

10

Collagen (% in carotid artery plaque

area)

Meisner F et al. Arterioscler Thromb Vasc Biol. 2006;26:845-50.

N = 24 without diabetes; change after 4 weeks in carotid endarterectomy samples

P = 0.04

Placebo Rosiglitazone8 mg/d

Potential vascular benefits of PPAR activation

PPAR agonists

Thrombosis

Plaque stability Cell recruitment

and activation Inflammatory

response Vasoconstriction

Cell migration

Foam cell formation

Cholesterol efflux

Atherogenesis

Cariou B et al. Br J Diabetes Vasc Dis. 2005;5:126-32.

Improved substrate metabolism