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

1
Dyslipidemia in the Metabolic SyndromeCan 1
agent treat all?

• Brian Tulloch, M.D.
• Diagnostic Clinic
• Houston, Texas

2
The Metabolic Syndrome in Middle-Aged Men in
Finland
CHD Mortality
CVD Mortality
All-Cause Mortality
20 15 10 5 0
20 15 10 5 0
20 15 10 5 0
RR (95 CI) 3.77 (1.748.17)
RR (95 CI) 3.55 (1.966.43)
RR (95 CI) 2.43 (1.643.61)
Metabolic Syndrome Yes No
Cumulative hazard ()
0 2 4 6 8 10 12
0 2 4 6 8 10 12
0 2 4 6 8 10 12
Follow-up (yr)
Number at risk for metabolic syndrome
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
Lakka et al. JAMA. 20022882709-2716.
3
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

4
Ticking Clock Hypothesis
For Microvascular complications Macrovascular
complications
The clock starts ticking
At onset of hyperglycemia
Before the diagnosis of hyperglycemia
WHO. Diabetologia. 198528615-640. Haffner SM
et al. JAMA. 19902632893-2898.
5
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

6
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)

7
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.

8
Diagnosis of Metabolic Syndrome-NCEP

• Any three or more of 5 components
• abdominal adiposity (gt40in for men,gt35ins for
  women)103,88cms
• TG gt150 mg/dL
• HDL-C lt40 mg/dL (men), lt50 mg/dL (women)
• impaired fasting glucose (110125 mg/dL)
• BP gt130/85 mm Hg

9
Pathogenesis of the Metabolic Syndrome
Abdominal Adiposity
Liver
Enlarging adipocytes
Increased glucose
Increased adipocytokines and FFA
Insulin resistance
Inflammatory(IL-6, coagulation factors)
Metabolic Syndrome
10
When Should Physicians Intervene?
Prevention ofweight gain Weight
gain Overweight and obesity Insulin
resistance Metabolic syndrome Impaire
d glucose tolerance Diabetes
Hypertension Hyperlipidemia CVD
Size of populationneeding treatment
11
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)

12
New Treatment Paradigm
Weight
Management of weightfirst, followed by
anintegrated treatmentapproach
Dyslipidemia Hypertension IGT
13
New Agents for Wt loss

• 1-Endocannabinoid Blockers Rimonabant.
• 2- Incretins Byetta.

14
Rimonabant in Prediabetes-Analysis from
RIO-Lipids, RIO-Europe and RIO-North
AmericaStudy Design

• 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 (n492), rimonabant 20mg (n 508) or plcbo
  (n 290)
• Results from three trials were pooled at one year.

Rosenstock, J. Late Breaking Clinical Trial.
EASD Annual Meeting, September 2005.
15
Rimonabant in Prediabetes-Analysis from
RIO-Lipids, RIO-Europe and RIO-North America
Results
End Point Placebo Rimonabant 5mg Rimonabant 20 mg
Weight loss (kg) - 1.7 - 3.2 (P0.002) 6.9 (Plt0.001)
Decrease in waist circumference (cm) - 2.1 - 3.8 (P0.001) 6.7 (Plt0.001)
Rosenstock, J. Late Breaking Clinical Trial.
EASD Annual Meeting, September 2005.
16
Incretin Hormones Improve Acute and Chronic
Aspects of Pancreatic Islet Function

• Glucose-dependent Acute Effects
• ? Glucagon secretion (a-cell)
• GLP-1 only
• ? Insulin secretion (ß-cell)
• Chronic Effects
• Rejuvenation of pancreas
• ? ?-cell proliferation
• ? ?-cell death

GLP-1 and GIP are secreted in response to food
intake
Foodintake
a-Cell
ß-Cell
GLP-1
ß
?
Islet
GIP
Gault, et al, Neuropeptide , GIP Anti-diabetic
and Anti-obesity Potential? 2003 (37), 253-63.
17
Exenatide vs. Glargine in Treated Type 2
DiabetesResults
Glargine 10 µg Exenatide
HbA1C () -1.0 -1.1
Achieving HbA1C lt 7 46 48
Weight Change 1.8 kg -2.3 kg
Fasting Glucose -2.9mmol/L -1.2mmol/L
No difference P lt0.0001
Heine RJ. Oral Presentation. EASD Annual
Meeting, September 2005
18
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

19
Treating the Lipid Triad in the Metabolic Syndrome

• Available drugs
• 1-Statins
• -New data,(HPStudy)
• -New statin-more potent
• 2-Fibric acids
• 3-Nicotinic acids
• Combinations (watch for myalgias)

20
Heart Protection StudyStatin Benefit Independent
of LDL-C Level
Risk ratio and 95 CI
Vascular Event
Placebo n10,267
Statin n10,269
Baseline LDL (mg/dl)
Statin better
Statin worse
lt100
358 (21.0)
282 (16.4)
100130
871 (24.7)
668 (18.9)
1356 (26.9)
1083 (21.6)
130
24 SE 3 reduction(2Plt0.00001)
2585(25.2)
2033(19.8)
All patients
0.4
0.6
0.8
1.0
1.2
1.4
MRC/BHF Heart Protection Study. HPS
infoslideshow presentation. Available at
http//www.lipidsonline.org.
21
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
22
STELLAR LDL-C Percentage Change from Baseline at
Week 6
Dose (mg)
10
20
40
80
Log scale
0
-10
-20
Pravastatin
-30
LS mean change from baseline
-40
Simvastatin
-50
Atorvastatin
Rosuvastatin
-60
Jones PH et al. Am J Cardiol 200392152160.
23
STELLAR Percentage of Patients Achieving NCEP
ATP-III LDL-C Goals at Week 6
100
89
89
85
80

82
82
82
75


69
67
60

63

Patients achieving LDL-C goal ()
55

51
40
44

31
20
n156
n158
n154
n156
n165
n162
n159
n164
n159
n157
n160
n163
n165
n158
Dose (mg)
0
10
10
20
40
10
20
40
10
20
40
80
80
20
40
rosuvastatin
atorvastatin
simvastatin
pravastatin
plt0.001 vs rosuvastatin 10mg plt0.001 vs
rosuvastatin 20mg plt0.001 vs rosuvastatin 40mg
24
STELLAR HDL-C Percentage Change from Baseline at
Week 6
12
10
Rosuvastatin
8
Simvastatin
LS mean change from baseline
6
4
Pravastatin
2
Atorvastatin
0
10
20
40
80
Log scale
Dose (mg)
Jones PH et al. Am J Cardiol 200392152160.
25
Percentage Change From Baseline in Triglycerides
at Week 6 by Dose (ITT)
Simvastatin (mg)
Rosuvastatin (mg)
Atorvastatin (mg)
Pravastatin (mg)
-8.2
-7.7
Mean Percent Change From Baseline in TG Levels
-13.2
Plt.002 vs pravastatin 10 mg, 20 mg Plt.002 vs
simvastatin 40 mg pravastatin 20 mg, 40 mg
Plt.002 vs simvastatin 40 mg pravastatin 40
mg Jones PH, Davidson MH, Stein EA, et al. Am J
Cardiol. 2003 93152-160.
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(No Transcript)
27
Sideaffects Muscle Liver
E. Bryan Brewer, Amer Jrnal of Cardiology
924B23K-29K
28
Protein Handling by the Kidney
Albumin Low molecular weight proteins
Tubular proteinuria
Glomerular proteinuria
Normal
Plasmaconcentration,mg/L
40,000
4
40,000
4
40,000
4
2
2
2
2
2
2000
Filtered load, mg/dayif GFR 150L/day
360,000
360
360
360
360
360
50
50
95
95
95
95
reabsorbed
Daily excretion, mg
18
18
18
180
180
18,000
29
Inhibition of Albumin Uptake andCholesterol
Synthesis
100
Rosuvastatin
Simvastatin
80
Pravastatin
60
Inhibition of Albumin Uptake ()
40
20
0
0
10
20
30
40
50
60
70
80
90
100
Inhibition of Cholesterol Synthesis ()
Preclinical data proximal tubule-derived opossum
kidney cell line. Sidaway et al. Poster presented
at 41st Congress of the European Societies of
ToxicologySeptember 28-October 1, 2003
Florence, Italy.
30
Effects of Rosuvastatin on Proteinuria in
Patients With Baseline Proteinuria 40 mg
Rosuvastatin for 96 Wk (n 53)
Patients ()
Change in Urine ProteinBaseline to Last Visit
Data on file, (DA-CRS-07) AstraZeneca
Pharmaceuticals LP, Wilmington, DE.
31
Changes in Plasma Creatinine in Patients
TreatedWith ?40 mg of Rosuvastatin for ?96 Weeks

Renal function N Creatinine change
Renal function N Creatinine change
Normal 456 5.9
Impaired 415 5.3
Mild 366 5.3
Moderate 46 4.9
Severe 3 13.7

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

32
Fibrate Mechanisms of Action
?Triglycerides
?LDL Particle Size
?Triglycerides
?LDL Particle Size
?HDL Synthesis
?Inflammation
?HDL Synthesis
?Inflammation
?Reverse Cholesterol Transport
?Reverse Cholesterol Transport
33
Helsinki Heart Study Enhanced Reduction of CHD
Events in Patients With Type 2 Diabetes
12
Plt.19
Plt.02
10
8
5-Year Incidence of CHD,
6
4
2
0
Type 2 (n 135)
Other (n 3946)
Type 2 on Placebo (n 76)
Type 2 on Gemfibrozil (n 59)
Mean baseline characteristics Total-C 291
mg/dLLDL-C 200 mg/dL HDL-C 46 mg/dL TG 236
mg/dL.
Koskinen P, et al. Diabetes Care. 199215820-825.
34
VA-HIT CVD Risk Reduction in Diabetics Compared
With Nondiabetics
Combined End Point
Nonfatal MI
CHD Death
Stroke
0
5
3
10
P.88
10
15
P.67
20
18
Cumulative Event Rate Change,
P.07
22
21
25
P.17
P.09
30
32
35
P.004
DM
40
No DM
40
41
P.26
45
P.046
P.02
Rubins HB, et al. Arch Intern Med.
20021622597-2604.
35
BIP Enhanced Event Rate Reduction in Patients
With Augmented Features of the Metabolic Syndrome
PNS
33 Reduction P.05
54 Reduction P.005
Patients with 4-5 risk factors for the metabolic
syndrome
Tenenbaum A, et al. Arch Intern Med.
20051651154-1160.
36
Adjustment for Statin Use
Adjusted Primary End Point in Patients With No
Prior CVD
Primary End Point CHD Events
Secondary End Point Total CVD Risk
P.16
P.01
P.004
P.035
P.004
Abbreviations Adj, adjusted for statin use
Nonadj, nonadjusted risk
The FIELD Study Investigators. Lancet Early
Online Publication. November 14, 2005.
37
Outcomes in Fibrate TrialsDiabetic or Metabolic
Syndrome
Major CVD Event Rate

Primary Prevention
HHS 292 13.0 3.9 71 lt.005
FIELD 7664 10.8 8.9 19 .004
Secondary Prevention
BIP 1470 18.4 14.1 25 .03
VA-HIT 769 29.4 21.2 32 .004
38
Combo Therapy

• HIGH LDL
• Water-soluble statin
• Resin/Zetia
• Fibrate
• Niaspan
• ?Vytorin?-(ZetiaZocor)
• E-mycin/Grpefruit/Ca- Channel
  blockers-Myositis

39
Combo Therapy

• HIGH T/Gs
• Statin(Water-sol) Fibrate
• Statin(w/s) Fibrate Niaspan
• SUPER-HI T/Gs
• (gt2,000- Danger of Pancreatitis)
• Fish Oil Fibrate Niaspan
• (? Crestor)

40
(No Transcript)
41
Metabolic Syndrome - Goals for Therapy

• Control Weight promote excercise
• LDL-C lt100 mg/dL, raise HDL
• Triglycerides lt 150 mg/dL
• Control BP lt130/80
• Control sugar, HbA1c lt6.5
• Clotting-Aspirin (81 or 325 mg)
• Microalbuminuria ? ACE-inhibition
• Previous MI ? ?-blocker
• ? Treat CRP -Statin/Fibrate

42
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 lt100 mg/dL,
• No need to measure in
• secondary prevention and type 2 diabetes with
  LDL-C gt100 mg/dL or nonHDL-C gt130 mg/dL

43
AHA/CDC Panel Recommendations for hs-CRP Testing

• Measurements of hs-CRP
• perform twice (2 weeks apart)
• results averaged,
• fasting or nonfasting, in metabolically stable
  patients
• if level gt10 mg/L, repeat test, examine for
  sources of infection
• Relative risk categories for hs-CRP levels
• low lt1 mg/L
• average 1.03.0 mg/L
• high gt3.0 mg/L

Pearson TA et al. Circulation. 2003107499-511.
44
National Cholesterol Education Program
(NCEP)Adult Treatment Panel III(ATP-III)
GuidelinesMetabolic Syndrome is a HIGH RISK
equivalent
45
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 (gt3 mg/L) hs-CRP.
• Lipid monotherapy, esp. a statin, is effective
  and safe
• consider combo therapy to reach HI RISK pt goals.

46
New ICD Codes for Metabolic Syndrome
277.7 Dysmetabolic Syndrome X
Use additional codes for associated
manifestations, As follows
414.00-414.05 Cardiovascular disease
250.01 Diabetes
272.0 Dyslipidemia
278.01 Morbid obesity for surgical tx
47
Thank You !!!B R TullochDiagnostic Clinic.
48
HHS Significant Reduction of CHD Events in
Patients With High Triglyceride and LDL/HDL Ratio
LDL/HDL gt5
LDL/HDL 5
Triglyceride values are in mg/dL
Manninen V, et al. Circulation. 19928537-45.
49
BIP Event Rate Reduction in Patients With the
Metabolic Syndrome
23 Reduction P.03
29 Reduction P.02
33 Reduction P.009
26 Reduction P.056
Fatal MI, Nonfatal MI, and Sudden Death
Tenenbaum A, et al. Arch Intern Med.
20051651154-1160.
50
Fenofibrate Versus Placeboin Patients With
Mixed Dyslipidemia
Baseline LDL-C gt160 mg/dL and TG ?150 mg/dL (Type
IIb)
Reductions in Triglycerides
Increases in HDL-C
Reductions in LDL-C
Plt.05
Plt.05
Plt.05
1
15
-7
Mean Change,
2
-20
-36
TriCor (n126)
Placebo (n116)
TriCor (n126)
Placebo (n116)
TriCor (n126)
Placebo (n116)
Mean HDL-C baseline 47 mg/dL
Mean LDL-C baseline 220 mg/dL
Mean TG baseline 232 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
51
Why Do Physicians Not Treat Obesity?

• Compensation issues
• Difficult to change behavior
• Not taught in medical school
• Only recently thought of as legitimate disease

52
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
53
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

54
Combination Therapy- Lipids
Lipid Profile Single agent Combination
1-Elev. LDL-C, Statin Statin resin
TG lt 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 gtgt500 Niacin fibrate fish oil