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Metabolic Syndrome and Dyslipidemia: Effective Strategies for Lipid Management. Peter W. F. Wilson, M.D. Emory University School of Medicine. Outline Insulin Resistant Patients Lipids and CVD Risk . Pathophysiology Observational Studies Clinical Trials Specific Medications

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metabolic syndrome and dyslipidemia effective strategies for lipid management

Metabolic Syndrome and Dyslipidemia:Effective Strategies for LipidManagement

Peter W. F. Wilson, M.D.

Emory University School of Medicine

outline insulin resistant patients lipids and cvd risk
OutlineInsulin Resistant PatientsLipids and CVD Risk
  • Pathophysiology
  • Observational Studies
  • Clinical Trials
  • Specific Medications
  • Multivariable concepts
slide3

Risk Variables for a Metabolic Syndrome

Fasting

Fasting

Body

Insulin

Glucose

Mass

Waist/Hip

Index

2-Hour

Insulin

BP

Diastolic

2-Hour

Glucose

BP

HDL-C

Trig

Systolic

Meigs Diabetes 1997; 46:1594

slide4

Risk Variables for a Metabolic Syndrome

Impaired

Glucose

Tolerance

Hypertension

Central

Metabolic Syndrome

Meigs Diabetes 1997; 46:1594

lipid metabolism and insulin resistance
Lipid Metabolism and Insulin Resistance

Ginsberg JCI 2000; 106: 453

serum lipoprotein size and density
Serum Lipoprotein Size and Density

VLDL

1.140 --

Chylomicrons

1.100 --

1.060 --

LDL

Density (g/ml)

HDL-1

IDL

1.020 --

Chylomicron

Remnants

1.006 --

HDL-2

HDL-3

0.950 --

Nascent HDL

60

100

140

200

280

400

600

800

1000

Diameter (Angstroms)

slide7

LDL Cholesterol and LDL Particle Numbers in T2DM Patients with LDL-C < 100 mg/dL (n=2,355)

5th 20th 50th 80th percentile

37%

(n=870)

63%

(n=1485)

LDL-C

Percent

of

Subjects

70 100 130 160 (mg/dL)

7%

(n=162)

31%

(n=741)

38%

(n=891)

16%

(n=383)

8%

(n=178)

Percent

of

Subjects

LDL-P

700 1000 1300 1600 (nmol/L)

Cromwell Amer J Cardi 2006; 98: 1599

slide8

Diabetes and CVD Risk in Framingham Cohort

Age 35-64 Years--30 Year Follow-up

10

P<0.001

P<0.001

8

Men

Women

P<0.001

6

Risk Ratio

P<0.001

P<0.001

4

P<0.001

P<0.001

P<0.05

P<0.001

2

0

CHD

Stroke

Int.

Cardiac

CVD

Claudication

Failure

Total

Wilson Am J Kidney Dis 1998

slide9

Diabetes and Lipid Extremes

Framingham Offspring

Men

60

p<0.001

50

Non-Diabetic

40

Diabetic

Per cent

30

p<0.001

20

p<0.001

10

0

HDL-C<35

Total-C 240+

LDL-C 160+

Trig 250+

HDL-C<35

Total-C 240+

Siegel Metabolism 1996; 96: 1267

slide10

Diabetes and Lipid Extremes

Framingham Offspring

Women

50

p<0.001

Non-Diabetic

p<0.001

40

Diabetic

p<0.001

30

Per cent

p<0.001

20

10

0

HDL-C<35

Total-C 240+

LDL-C 160+

Trig 250+

HDL-C<35

Trig 250+

Siegel Metabolism 1996; 96: 1267

chd death risk by non hdl c ldl c and diabetes aric framingham mrfit usual care
CHD Death Riskby non HDL-C, LDL-C, and DiabetesARIC, Framingham, MRFIT Usual Care

Relative Risk

>100

LDL-C

(mg/dL)

<100

Non HDL-C (mg/dL)

Diabetes Present

Diabetes Absent

Liu Diabetes Care 2006; 28: 1916

slide12
Prevalence of NCEP Metabolic Syndrome TraitsNHANES III, Framingham Offspring Study, San Antonio Heart Study

Prevalence

Meigs Diabetes 2003: 53 2160

slide13

Nutrient Intake in Various Diets

Sat Fat

Mono & Poly Fat

Protein

Carbo

25

35

22

18

Atkins

7

33

15

45

Reaven

15

25

15

45

US Diet

10

20

15

55

AHA Step I

7

23

15

55

AHA Step 2

7

18-23

15

50-60

ATP III

6

24

30

40

The Zone

6

21

18

55

Dash

5

25

15

65

Connor

3

7

18

72

Ornish

0%

20%

40%

60%

80%

100%

Per cent

effects of fibrates on vascular events va hit
Effects of Fibrates on Vascular Events: VA-HIT

Percent Difference vs Placebo

Rubins N Engl J Med. 1999;341:410

gemfibrozil and chd risk va hit diabetes results
Gemfibrozil and CHD RiskVA-HIT Diabetes Results

-24% risk

-24% risk

Vascular Event Rate (%)

Diabetic Patients

N=627, P=0.05

Nondiabetic Patients

N=1904, P=0.004

Rubins N Engl J Med 1999.

slide16

CHD Prevention Trials with Statins in Diabetic Subjects: LDL-C Lowering

*LDL-C values for overall group

Downs JR et al. JAMA 1998;279:1615-1622. | HPS Investigators. Presented at AHA, 2001. |

Goldberg RB et al. Circulation 1998;98:2513-2519. | Pyorala K et al. Diabetes Care

1997;20:614-620. | Haffner SM et al. Arch Intern Med 1999;159:2661-2667. | LIPID

Study Group. N Engl J Med 1998;339:1349-1357.

slide17

CHD Prevention Trials with Statins in Diabetic Subjects: CHD Risk Reduction

Downs JR et al. JAMA 1998;279:1615-1622. | HPS Investigators. Presented at AHA, 2001. |

Goldberg RB et al. Circulation 1998;98:2513-2519. | Pyorala K et al. Diabetes Care

1997;20:614-620. | LIPID Study Group. N Engl J Med 1998;339:1349-1357. |

Haffner SM et al. Arch Intern Med 1999;159:2661-2667.

slide18
Summary of Intervention Studies Risk Reduction with Individual TreatmentsPersons with Diabetes Mellitus

Blood pressure treatment 30-50%

Lipid treatment 25-55%

Glucose treatment 10-20%per 1% HbA1c

Macrovascular

Event Reduction

cad risk factors in type 2 diabetes based on time to first event ukpds
CAD Risk Factors in Type 2 Diabetes Based on Time to First Event: UKPDS

Variable Increment in Increment in risk

variable of CAD

LDL-C 1.0 mmol/L + 57 %

(39 mg/dL)

HDL-C 0.1 mmol/L - 15 %

(3.9 mg/dL)

SBP 10 mm Hg + 15 %

HBA1C 1.0 % + 11 %

Multivariate Cox proportional hazard model containing age, sex, and smoking as significant categorical risk factors.

Turner RC et al, for the UKPDS Group. BMJ. 1998;316:823-828

ukpds order of baseline risk factors for cad based on time to first event
UKPDS: Order of Baseline Risk Factors for CAD Based on Time to First Event*

Risk Factor P Value+

LDL-C <0.0001

HDL-C 0.0001

HbA1C 0.0022

SBP 0.0065

Smoking 0.056

*Fatal or nonfatal MI or clinical angina

+Significance of risk factor after considering all other risk factors

Turner RC BMJ. 1998;316:823-828

steno 2 study outcomes
Steno-2 Study: Outcomes

60

50

40

30

20

10

0

Conventional

Primary Composite Endpoint (%)

Intensive

ASA, statins, ACE, ARB, exercise, low fat diet, smoking cessation, tight glucose control, and blood pressure control

0 12 24 26 48 60 72 84 96

Months of Follow-up

Gaede N Eng J Med 2003;348:383-393.

rio lipids percent change in hdl c and tg levels at 1 year

10

5

0

-5

-10

-15

-20

30

25

20

15

10

5

0

P<0.001

22.9

+0.4

P=0.017

Change in TG (%)

Change in HDL-C (%)

-3.6

15.6

11.8

P<0.001

-15.7

0 12 24 36 52

Week

0 12 24 36 52

Week

RIO-LipidsPercent Change in HDL-C and TG Levels At 1 Year

Completers

Rimonabant 20 mg

Rimonabant 5 mg

Placebo

Despres N Engl J Med. 2005;353:2121

combination lipid altering drug therapy with statins
Combination Lipid-Altering Drug Therapy with Statins
  • Medications used in combinations
    • Ezetimibe
    • Bile acid sequestrants
    • PPAR alpha (fibrates)
    • Fish oils
    • Niacin
summary metabolic syndrome insulin resistance lipid therapy
SummaryMetabolic Syndrome/Insulin ResistanceLipid Therapy
  • Lipid Abnormalities

HDL

Triglycerides

LDL particle characteristics

  • Lipid Goals

Aggressive lowering of LDL, nonHDL,

Lowering of triglycerides

  • Lipid Treatment Adjuvants

Weight loss (diet, drug, surgery)

Diet

Monotherapy, combination therapy