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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
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