Dyslipidemia in the Metabolic Syndrome:Can 1 agent treat all?

Brian Tulloch, M.D. Diagnostic ClinicHouston, Texas

The Metabolic Syndrome in Middle-Aged Men in Finland

CHD Mortality

RR (95% CI)3.77 (1.74–8.17)

20

15

10

5

0

0 2 4 6 8 10 12

CVD Mortality

RR (95% CI)3.55 (1.96–6.43)

0 2 4 6 8 10 12

All-Cause Mortality

RR (95% CI)2.43 (1.64–3.61)

0 2 4 6 8 10 12

Metabolic SyndromeYesNo

Cum

ulat

ive

haza

rd (

%)

Lakka et al. JAMA. 2002;288:2709-2716.

Follow-up (yr)

Number at risk for metabolic syndrome

20

15

10

5

0

20

15

10

5

0

Yes 866 852 834 292 866 852 834 292 866 852 834 292 No 288 279 234 100 288 279 234 100 288 279 234 100

Metabolic Syndrome - AKA … Syndrome X Dysmetabolic syndrome Insulin resistance syndrome Polymetabolic syndrome Central obesity syndrome Deadly quartet Coronary risk syndrome Visceral adiposity syndrome Atherogenic lipoprotein phenotype

“Ticking Clock” Hypothesis

WHO. Diabetologia. 1985;28:615-640. Haffner SM et al. JAMA. 1990;263:2893-2898.

For

Microvascular complications

Macrovascular complications

The “clock starts ticking”

At onset of hyperglycemia

Before the diagnosis of Before the diagnosis of hyperglycemiahyperglycemia

Conditions Associated with the Metabolic Syndrome-

Measurable indices Central obesity (increased waist

circumference) Atherogenic dyslipidemia

High triglycerides Low HDL, increased small dense LDL

Increased ApoB Increased blood pressure

Conditions Associated with the Metabolic Syndrome-2

Insulin resistance Hyperinsulinemia Glucose intolerance Increased uric acid

Prothrombotic state Increased plasminogen activator

inhibitor (PAI-1) Increased blood viscosity Increased plasma fibrinogen

Proinflammatory state (increased C-reactive protein)

Who Has the Metabolic Syndrome?

In 2000: over 47 million Americans Prevalence increases with age &

Wt. Age-adjusted prevalence = 23.7%. More common in Mex-Americans.

Major risk factor for- DM, CHD & Stroke. PCOS. NASH.

Diagnosis of Metabolic Syndrome-NCEP

Any three or more of 5 components: abdominal adiposity (>40in for men,>35ins for women)103,88cms

TG >150 mg/dL HDL-C <40 mg/dL (men), <50 mg/dL (women)

impaired fasting glucose (110–125 mg/dL)

BP >130/85 mm Hg

Pathogenesis of the Metabolic Syndrome

Abdominal Adiposity

Metabolic Syndrome

Enlarging adipocytes

Increased adipocytokines

and FFA

Inflammatory(IL-6, coagulation factors)

Liver

Increased glucose

Insulin resistance

When Should Physicians Intervene?

Prevention ofweight gain

Weight gainOverweightand obesity

Insulin resistanceMetabolicsyndrome

Impairedglucosetolerance

DiabetesHypertensionHyperlipidemia

CVD

Siz

e o

f p

op

ula

tion

need

ing

tre

atm

en

t

NCDP-ATP III Guidelines: Clinical Management of the Metabolic

Syndrome Management of underlying cause

Weight control (enhances LDL lowering and reduces all risk factors)

Physical activity (reduces VLDL, increases HDL and may lower LDL)

Management of lipid and nonlipid risk factors

Treat hypertension Use of aspirin in CHD patients Treat elevated triglycerides, lower LDL

–(Raise HDL)

New Treatment Paradigm

Dyslipidemia Hypertension IGT

WeightManagement of weightfirst, followed by anintegrated treatmentapproach

New Agents for Wt loss

1-Endocannabinoid Blockers: Rimonabant.

2- Incretins: Byetta.

Goal To assess the efficacy of rimonabant, a

selective cannabinoid receptor blocker, against placebo in prediabetes (IFG)

Methods Patients randomized to a daily dose of

rimonabant 5mg (n=492), rimonabant 20mg (n= 508) or plcbo (n= 290)

Results from three trials were pooled at one year.

Rimonabant in Prediabetes-Analysis from RIO-Lipids, RIO-Europe and RIO-North America

Study Design

Rosenstock, J. Late Breaking Clinical Trial. EASD Annual Meeting, September 2005.

Rimonabant in Prediabetes-Analysis from RIO-Lipids, RIO-Europe and

RIO-North America Results

End Point Placebo

Rimonabant 5mg

Rimonabant

20 mgWeight loss

(kg)- 1.7 - 3.2

(P=0.002)

- 6.9(P<0.001

)Decrease in

waist circumference (cm)

- 2.1 - 3.8 (P=0.001)

- 6.7 (P<0.001

)

Rosenstock, J. Late Breaking Clinical Trial. EASD Annual Meeting, September 2005.

Glucose-dependent Glucose-dependent Acute EffectsAcute Effects Glucagon secretion (Glucagon secretion (αα--

cell)cell)

• GLP-1 onlyGLP-1 only

Insulin secretion (Insulin secretion (ββ-cell)-cell)

Chronic EffectsChronic Effects• Rejuvenation of pancreasRejuvenation of pancreas

-cell proliferation-cell proliferation

-cell death-cell death ββββ ββββ

ββ

ββ

FoodFoodintakeintake

GLP-1GLP-1

GIPGIP

αα-Cell-Cellββ-Cell-Cell

GLP-1 and GIP are GLP-1 and GIP are secreted in secreted in response to food response to food intakeintake

IsletIsletIsletIslet

Incretin Hormones Improve Acute and Chronic Aspects of

Pancreatic Islet Function

Gault, et al,Gault, et al, Neuropeptide Neuropeptide , GIP: Anti-diabetic and Anti-obesity Potential? 2003 (37), 253-63., GIP: Anti-diabetic and Anti-obesity Potential? 2003 (37), 253-63.

Exenatide vs. Glargine in Treated Type 2 Diabetes

ResultsGlargine 10 μg

ExenatideHbA1C (%)* -1.0% -1.1%% Achieving HbA1C < 7%*

46% 48%

Weight Change §

+1.8 kg -2.3 kg

Fasting Glucose§

-2.9mmol/L -1.2mmol/L* No difference* No difference §§P <0.0001P <0.0001

Heine RJ. Oral Presentation. EASD Annual Meeting, September 2005

NCDP-ATP III Guidelines: Clinical Management of the Metabolic

Syndrome Management of underlying cause

Weight control enhances LDL lowering and reduces all risk factors

Physical activity reduces VLDL, increases HDL and may lower LDL

Management of lipid risk factors: Treat elevated TG and lower LDL,

raise HDL ? C-RP. Treat H/T- ACE/ARB, Beta blockers. Aspirin

Treating the Lipid Triad in the Metabolic Syndrome

Available drugs: 1-Statins

-New data,(HPStudy)-New statin-more potent

2-Fibric acids3-Nicotinic acids

Combinations: (watch for myalgias)

MRC/BHF Heart Protection Study. HPS info:slideshow presentation. Available at: http://www.lipidsonline.org. MRC/BHF Heart Protection Study. HPS info:slideshow presentation. Available at: http://www.lipidsonline.org.

358(21.0%)

358(21.0%)

282(16.4%)

282(16.4%)<100<100

871(24.7)871

(24.7)668

(18.9%)668

(18.9%)100–130100–130

1356(26.9%)

1356(26.9%)

1083(21.6%)

1083(21.6%)≥130≥130

2585(25.2%)

2585(25.2%)

Placebo n=10,267Placebo

n=10,267

2033(19.8%)

2033(19.8%)

All patientsAll patients

Statin n=10,269

Statin n=10,269

Baseline LDL (mg/dl)

Baseline LDL (mg/dl)

Vascular EventVascular Event

24% SE 3reduction(2P<0.00001)

24% SE 3reduction(2P<0.00001)

0.40.4 0.60.6 0.80.8 1.01.0 1.21.2 1.41.4

Risk ratio and 95% CIRisk ratio and 95% CI

StatinbetterStatinbetter

Statin worseStatin worse

Heart Protection StudyStatin Benefit Independent of

LDL-C Level

Heart Protection StudyStatin Benefit Independent of

LDL-C Level

Lipoprotein Effects of Lipid-modifying Therapy

Statins Nicotinic acid

Fibrates

LDL 18%-55% 5%-25% 5%-20%HDL 5%-15% 15%-35% 10%-20%Triglycerides

7%-30% 20%-50% 20%-50%

Small, dense LDL

No effect Decrease Decrease

Effect on insulin resistance

None May increase

May increase

STELLAR: LDL-C Percentage Change from Baseline at Week 6

LS

mean

% c

han

ge f

rom

baselin

e

-60

-50

-40

-30

-20

-10

0

10 20 40 80

Dose (mg)

RosuvastatinAtorvastatin

Simvastatin

Pravastatin

Log scale

Jones PH et al. Am J Cardiol 2003;92:152–160..

STELLAR: Percentage of Patients Achieving NCEP ATP-III LDL-C

Goals at Week 6

0

20

40

60

80

100

10 10 20 40 10 20 40 10 20 40

rosuvastatin atorvastatin simvastatin pravastatin

Pati

en

ts a

ch

ievin

g L

DL-C

goal (%

)

Dose (mg)808020 40

*

# ‡

* p<0.001 vs rosuvastatin 10mg# p<0.001 vs rosuvastatin 20mg‡ p<0.001 vs rosuvastatin 40mg

82

6975

85

51

6367

31

44

89

82

55

8982

n=156 n=158n=154n=156 n=165n=162 n=158 n=159n=164n=159n=157 n=160n=163n=165

*#

*

#

*#

*# ‡

STELLAR: HDL-C Percentage Change from Baseline at Week 6

0

2

4

6

8

10

12

10 20 40 80

Dose (mg)

LS

mean

% c

han

ge f

rom

baselin

e

Log scale

Rosuvastatin

Atorvastatin

Simvastatin

Pravastatin

Jones PH et al. Am J Cardiol 2003;92:152–160.

Percentage Change From Baseline in Triglycerides at

Week 6 by Dose (ITT)Simvastatin

(mg)Simvastatin

(mg)

*P<.002 vs pravastatin 10 mg, 20 mg**P<.002 vs simvastatin 40 mg; pravastatin 20 mg, 40 mg† P<.002 vs simvastatin 40 mg; pravastatin 40 mgJones PH, Davidson MH, Stein EA, et al. Am J Cardiol. 2003; 93:152-160.

*P<.002 vs pravastatin 10 mg, 20 mg**P<.002 vs simvastatin 40 mg; pravastatin 20 mg, 40 mg† P<.002 vs simvastatin 40 mg; pravastatin 40 mgJones PH, Davidson MH, Stein EA, et al. Am J Cardiol. 2003; 93:152-160.

-20-20

-22.6-22.6

-26.8-26.8-28.2-28.2M

ean

Perc

en

t C

han

ge F

rom

B

ase

line in

TG

Levels

Mean

Perc

en

t C

han

ge F

rom

B

ase

line in

TG

Levels

Rosuvastatin(mg)

Rosuvastatin(mg)

Atorvastatin(mg)

Atorvastatin(mg)

Pravastatin(mg)

Pravastatin(mg)

-11.9-11.9

-17.6-17.6

-14.8-14.8

-18.2-18.2

10 10 20 20 40 40 80 80

-23.7**

-23.7**

-26.1†

-26.1†

-19.8*

-19.8*

10 10 20 20 40 40 10 10 20 20 40 40 80 80

-8.2-8.2 -7.7-7.7

-13.2-13.2

10 10 20 20 40 40

-30-30

-25-25

-20-20

-15-15

-10-10

00

-5-5

Sideaffects: Muscle & Liver

E. Bryan Brewer, Amer Jrnal of Cardiology 92:4B23K-29K

Protein Handling by the Kidney

Glomerularproteinuria

TubularproteinuriaNormal

Plasmaconcentration,mg/L

Filtered load, mg/dayif GFR – 150L/day

% reabsorbed

40,000 4

360 360

40,000 4 40,000 4

360360 360

2 2 2 222000

360,000

Daily excretion, mg 18 18 18 180 18018,000

95 95 95 95 50 50

AlbuminLow molecular weight proteins

Inhibition of Albumin Uptake and

Cholesterol Synthesis

0

20

40

60

80

100

0 10 20 30 40 50 60 70 80 90 100

Inhibition of Cholesterol Synthesis (%)

Inh

ibit

ion

of

Alb

um

in U

pta

ke (

%)

SimvastatinPravastatin

Rosuvastatin

Preclinical data: proximal tubule-derived opossum kidney cell line.Sidaway et al. Poster presented at: 41st Congress of the European Societies of Toxicology;September 28-October 1, 2003; Florence, Italy.

Preclinical data: proximal tubule-derived opossum kidney cell line.Sidaway et al. Poster presented at: 41st Congress of the European Societies of Toxicology;September 28-October 1, 2003; Florence, Italy.

Effects of Rosuvastatin on Proteinuria in Patients† With

Baseline Proteinuria ≥40 mg Rosuvastatin for ≥96 Wk (n =

53)

0

10

20

30

40

50

60

70

80

90

100

Decrease No Change Increase

Data on file, (DA-CRS-07) AstraZeneca Pharmaceuticals LP, Wilmington, DE.

Pati

en

ts (

%)

Change in Urine Protein—Baseline to Last Visit

Changes in Plasma Creatinine in Patients TreatedWith 40 mg of

Rosuvastatin for 96 Weeks:

Renal function N

Creatinine %

change*

Normal 456 –5.9

Impaired 415 –5.3 Mild 366 –5.3 Moderate 46 –4.9Severe 3 –13.7

*Last visit compared to baseline. Data on file, (DA-CRS-07) AstraZeneca Pharmaceuticals LP, Wilmington, DE.*Last visit compared to baseline. Data on file, (DA-CRS-07) AstraZeneca Pharmaceuticals LP, Wilmington, DE.

Fibrate Mechanisms of Action

FibrateFibrate

PPARPPAR↑HDL Synthesis↑HDL Synthesis

↓Triglycerides↓Triglycerides

↑Reverse Cholesterol Transport↑Reverse Cholesterol Transport

↑LDL Particle Size↑LDL Particle Size

↓Inflammation↓Inflammation

0

2

4

6

8

10

125-

Yea

r In

cide

nce

of C

HD

, %

Type 2(n = 135)

Other(n = 3946)

Type 2 on Placebo(n = 76)

Type 2 on Gemfibrozil

(n = 59)

P<.02P<.19

Koskinen P, et al. Diabetes Care. 1992;15:820-825.Mean baseline characteristics: Total-C 291 mg/dL;LDL-C 200 mg/dL; HDL-C 46 mg/dL; TG 236 mg/dL.

Helsinki Heart Study: Enhanced Reduction of CHD Events in Patients

With Type 2 Diabetes

Rubins HB, et al. Arch Intern Med. 2002;162:2597-2604.

40

35

30

25

20

15

10

5

0

Cu

mu

lativ

e E

ven

t Ra

te C

han

ge, %

Combined End Point

Nonfatal MI CHD Death Stroke

45

18

21

10

3

No DM

P=.67

P=.88

P=.09

P=.07 22P=.17

32

4041

P=.004

P=.046P=.02P=.26

DM

VA-HIT: CVD Risk Reduction in Diabetics Compared With

Nondiabetics

15.3%

17.1%

12.2%

10.4%11.5%

5.6%

0

2

4

6

8

10

12

14

16

18

Nonfatal MI Any MI Cardiac Death

Event

Rate

, %

Placebo (n = 287)

Bezafibrate (n = 288)

BIP: Enhanced Event Rate Reduction in Patients With Augmented Features of the

Metabolic Syndrome*

54% ReductionP=.005

P=NS 33% ReductionP=.05

*Patients with 4-5 risk factors for the metabolic syndrome Tenenbaum A, et al. Arch Intern Med. 2005;165:1154-1160.

Adjustment for Statin Use

-11%

-19%-20

-18

-16-14

-12

-10

-8

-6-4

-2

0

Nonadj Adj

Re

lati

ve

Ris

k,

%

P=.16 P=.01

Primary End Point:CHD Events

-25%

-30

-25

-20

-15

-10

-5

0

Re

lati

ve

Ris

k,

%

P=.004

Adjusted Primary End Point in Patients With No Prior

CVD

Abbreviations: Adj, adjusted for statin use; Nonadj, nonadjusted risk

-11%

-15%-16

-14

-12

-10

-8

-6

-4

-2

0

Nonadj Adj

Re

lati

ve

Ris

k,

%

P=.035 P=.004

Secondary End Point:Total CVD Risk

The FIELD Study Investigators. Lancet [Early Online Publication]. November 14, 2005.

Outcomes in Fibrate Trials:Diabetic or Metabolic Syndrome

Primary Prevention HHS* 29

213.0 3.9% 71% <.0

05 FIELD† 76

6410.8 8.9% 19% .00

4Secondary Prevention BIP‡ 14

7018.4 14.1 25% .03

VA-HIT§ 769

29.4 21.2%

32% .004

Major CVDEvent Rate

Combo Therapy HIGH LDL: Water-soluble statin

+Resin/Zetia+Fibrate+ Niaspan

?Vytorin?-(Zetia+Zocor) E-mycin/Grpefruit/Ca-

Channel blockers-Myositis

Combo Therapy

HIGH T/G’s:Statin(Water-sol) + Fibrate Statin(w/s) + Fibrate + Niaspan

SUPER-HI T/G’s (>2,000- Danger of Pancreatitis):

Fish Oil + Fibrate + Niaspan(?+ Crestor)

Metabolic Syndrome - Goals for Therapy

Control Weight +promote excercise

LDL-C <100 mg/dL, raise HDL Triglycerides < 150 mg/dL Control BP <130/80 Control sugar, HbA1c <6.5 Clotting-Aspirin (81 or 325 mg) Microalbuminuria ACE-inhibition Previous MI -blocker ? Treat CRP: -Statin/Fibrate

When to Measure hs-CRP Measure hs-CRP when it influences decision to

initiate or intensify lipid-lowering treatment:

primary prevention in young individuals with strong family history

secondary prevention with LDL-C <100 mg/dL,

No need to measure in: secondary prevention and type 2 diabetes

with LDL-C >100 mg/dL or non–HDL-C >130 mg/dL

Measurements of hs-CRP: perform twice (2 weeks apart) results averaged, fasting or nonfasting, in metabolically stable

patients if level >10 mg/L, repeat test, examine for

sources of infectionRelative risk categories for hs-CRP levels:

low <1 mg/L average 1.0–3.0 mg/L high >3.0 mg/L

AHA/CDC Panel: Recommendations for hs-CRP Testing

Pearson TA et al. Circulation. 2003;107:499-511.

National Cholesterol Education

Program (NCEP)Adult Treatment Panel III

(ATP-III) Guidelines:

Metabolic Syndrome is a HIGH RISK equivalent:

Conclusions NCEP ATP III guidelines:

intensity of lipid treatment depends global CHD risk.

HIGH-RISK patients are CHD/CVD equivalents, including METABOLIC SYNDROME , DM, +those with 2 RF & hi (>3 mg/L) hs-CRP.

Lipid monotherapy, esp. a statin, is effective and safe;

consider combo therapy to reach HI RISK pt goals.

New ICD Codes for Metabolic Syndrome

414.00-414.05 Cardiovascular disease

250.01 Diabetes272.0 Dyslipidemia278.01 Morbid obesity for

surgical tx

277.7 Dysmetabolic Syndrome XUse additional codes for associated manifestations,As follows:

Thank You !!!

B R TullochDiagnostic Clinic.

Manninen V, et al. Circulation. 1992;85:37-45.

0

5

10

15

20

25

30

TG ≤204 TG >204 TG ≤204 TG >204

Incid

en

ce

of

Ca

rdia

c E

ve

nts

pe

r 1

00

0 P

ers

on

-Ye

ars Placebo

Gemfibrozil

71% Reduction

P<.005

LDL/HDL >5LDL/HDL ≤5

Triglyceride values are in mg/dL

HHS: Significant Reduction of CHD Events in Patients With High

Triglyceride and LDL/HDL Ratio

18%

14%15%

12%

14%

10%

11%

9%

0

2

4

6

8

10

12

14

16

18

20

Primary EndPoint*

Nonfatal MI Any MI Cardiac Death

Event

Rate

, %

PlaceboBezafibrate

23% Reduction

P=.03

BIP: Event Rate Reduction in Patients With the Metabolic

Syndrome

*Fatal MI, Nonfatal MI, and Sudden Death

33% ReductionP=.009

29% ReductionP=.02

26% Reduction

P=.056

Tenenbaum A, et al. Arch Intern Med. 2005;165:1154-1160.

Fenofibrate Versus Placeboin Patients With Mixed

Dyslipidemia

Mea

n C

han

ge,

%

Baseline LDL-C >160 mg/dL and TG 150 mg/dL (Type IIb)

0

5

10

15

20+15%*

+2%

Increases in HDL-C

*P<.05

TriCor(n=126)

Placebo(n=116)

Mean HDL-C baseline: 47 mg/dL

-40-30-20-10

010

-36%*

+1%

Reductions inTriglycerides

*P<.05

TriCor(n=126)

Placebo(n=116)

Mean TG baseline: 232 mg/dL

-30

-20

-10

0

-20%*

-7%

Reductions in LDL-C

TriCor(n=126)

Placebo(n=116)

*P<.05

Mean LDL-C baseline: 220 mg/dL

TriCor was assessed in multicenter clinical trials of 3 to 6 months duration in Type IIa and Type IIb patients with mean baseline LDL-C of 213.8 mg/dL

The independent effect of raising HDL-C or lowering TG on the risk of cardiovascular morbidity and mortality has not been determined

TriCor package insert. Abbott Laboratories.

Please see accompanying full prescribing information

Why Do Physicians Not Treat Obesity?

Compensation issues

Difficult to change behavior

Not taught in medical school

Only recently thought of as legitimate disease

Have a Dietary and Physical Activity Plan Available

Food diaries Based on ?fat/CHO

Physical activity plan ACSM:* walking program: 5 min out, 5 min back, gradually increase

Handouts, staff included* American College of Sports Medicine

Effect of Exercise on Metabolic Syndrome

Increases insulin sensitivity and glucose control

Increases HDL Chol Decreases TG large,

buoyant LDL Decreases blood pressure Decreases fibrinogen Decreases risk of CAD Assists in weight loss

Combination Therapy- Lipids Lipid Profile Single agent Combination

1-Elev. LDL-C, Statin Statin + resin TG < 200 mg/dL

Ezetimibe Statin + ezetimibe

Niacin Statin + niacin + resin

Resin Statin + niacin + ezetimibe

2-Elev. LDL-C, Statin Statin + niacin

TG 200-500 Niacin Statin + fibrate

Fibrate Ezetimibe + niacin/ fibrate

3-TG >>500 Niacin + fibrate + fish oil