Transcript Metabolic Syndrome: Outline

Dyslipidemia in the
Metabolic Syndrome:
Can 1 agent treat all?
Brian Tulloch, M.D.
Diagnostic Clinic
Houston, Texas
The Metabolic Syndrome in Middle-Aged
Men in Finland
CHD Mortality
CVD Mortality
Cumulative hazard (%)
20
20
RR (95% CI)
3.77 (1.74–8.17)
15
10
20
RR (95% CI)
3.55 (1.96–6.43)
15
Metabolic Syndrome
Yes
No
All-Cause Mortality
15
10
10
5
5
5
0
0
0
0
2
4
6
8 10 12
0
2
4
6
RR (95% CI)
2.43 (1.64–3.61)
8 10 12
0
2
4
6
8 10 12
Follow-up (yr)
Number at risk for metabolic syndrome
Yes
No
866
288
852
279
834
234
292
100
Lakka et al. JAMA. 2002;288:2709-2716.
866
288
852
279
834
234
292
100
866
288
852
279
834
234
292
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
For
The “clock starts ticking”
Microvascular
complications
At onset of hyperglycemia
Macrovascular
complications
Before the diagnosis of
hyperglycemia
WHO. Diabetologia. 1985;28:615-640.
Haffner SM et al. JAMA. 1990;263:2893-2898.
Conditions Associated with the
Metabolic SyndromeMeasurable 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
Liver
Enlarging adipocytes
Increased
glucose
Increased adipocytokines
and
FFA
Inflammatory
Insulin resistance
(IL-6, coagulation factors)
Metabolic Syndrome
When Should Physicians Intervene?
Prevention of
weight gain
Weight gain
Overweight
and obesity
Insulin resistance
Metabolic
syndrome
Impaired
glucose
tolerance
Diabetes
Hypertension
Hyperlipidemia
CVD
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
Weight
Management of weight
first, followed by an
integrated treatment
approach
Dyslipidemia
Hypertension
IGT
New Agents for Wt loss
 1-Endocannabinoid Blockers:
Rimonabant.
 2- Incretins: Byetta.
Rimonabant in Prediabetes-Analysis
from RIO-Lipids, RIO-Europe and RIONorth America
 Goal
Study Design
 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.
Rosenstock, J. Late Breaking Clinical Trial. EASD Annual Meeting, September 2005.
from RIO-Lipids, RIO-Europe and RIONorth America
Results
Rimonab
End Point
Placeb
ant
o
5mg
Weight loss
- 1.7
- 3.2
(kg)
(P=0.0
02)
Decrease in
- 2.1
- 3.8
waist
(P=0.0
circumferenc
01)
e (cm)
Rosenstock, J. Late Breaking Clinical Trial. EASD Annual Meeting, September 2005.
Rimonaba
nt
20 mg
- 6.9
(P<0.001)
- 6.7
(P<0.001)
Incretin Hormones Improve Acute
and Chronic Aspects of Pancreatic
Islet Function
Glucose-dependent Acute
Effects
GLP-1 and GIP are
secreted in response to
food intake
Food
intake
α-Cell
β-Cell
GLP-1
Islet
GIP
•  Glucagon secretion (α-cell)
• GLP-1 only

•  Insulin secretion (β-cell)
Chronic Effects
• Rejuvenation of pancreas
•  -cell proliferation
•  -cell death
Gault, et al, Neuropeptide , GIP: Anti-diabetic and Anti-obesity Potential? 2003 (37), 253-63.
β
β
β
β
β
Exenatide vs. Glargine in Treated Type
2 Diabetes
Results
Glargine
HbA1C (%)*
-1.0%
% Achieving
46%
HbA1C < 7%*
Weight
+1.8 kg
Change §
Fasting
-2.9mmol/L
Glucose§
* No difference
§P
<0.0001
Heine RJ. Oral Presentation. EASD Annual Meeting, September 2005
10 μg
Exenatide
-1.1%
48%
-2.3 kg
-1.2mmol/L
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 acids
3-Nicotinic acids
Combinations: (watch for myalgias)
Heart Protection Study
Statin Benefit Independent of LDLC Level
Risk ratio and 95% CI
Vascular Event
Baseline LDL
(mg/dl)
Statin
n=10,269
Placebo
n=10,267
<100
282
(16.4%)
668
(18.9%)
358
(21.0%)
871
(24.7)
1083
(21.6%)
1356
(26.9%)
2033
All patients
(19.8%)
2585
(25.2%)
100–130
≥130
Statin
better
Statin
worse
24% SE 3
reduction
(2P<0.00001)
0.4 0.6 0.8
MRC/BHF Heart Protection Study. HPS info:slideshow presentation. Available at:
http://www.lipidsonline.org.
1.0 1.2 1.4
Lipoprotein Effects of Lipidmodifying Therapy
LDL
HDL
Triglycerides
Small, dense
LDL
Effect on
insulin
resistance
Statins
Nicotinic
acid
Fibrates
18%-55%
5%-15%
7%-30%
No effect
5%-25%
15%-35%
20%-50%
Decrease
5%-20%
10%-20%
20%-50%
Decrease
None
May
increase
May
increase
STELLAR: LDL-C Percentage Change
from Baseline at Week 6
Dose (mg)
LS mean % change from baseline
10
20
40
80
0
Log scale
-10
-20
-30
Pravastatin
-40
Simvastatin
-50
-60
Jones PH et al. Am J Cardiol 2003;92:152–160.
Atorvastatin
Rosuvastatin
Patients achieving LDL-C goal (%)
STELLAR: Percentage of Patients
Achieving NCEP ATP-III LDL-C Goals
at Week 6
100
80
89 89
#
82
85
82
82
75
*#
69
60
*
63
#‡
67
*# 55
51
40
*
n=156 n=159n=157
10 20
40
rosuvastatin
*
#
‡
44
31
20
0
*# ‡
n=158n=154n=156n=165
10
20
40
80
atorvastatin
p<0.001 vs rosuvastatin 10mg
p<0.001 vs rosuvastatin 20mg
p<0.001 vs rosuvastatin 40mg
n=165n=162 n=158 n=163
10
20 40 80
simvastatin
n=159n=164n=160
10
20
40
pravastatin
Dose (mg)
LS mean % change from baseline
STELLAR: HDL-C Percentage Change from
Baseline at Week 6
12
10
Rosuvastatin
8
Simvastatin
6
4
Pravastatin
2
Atorvastatin
0
10
20
40
Dose (mg)
Jones PH et al. Am J Cardiol 2003;92:152–160.
80
Log scale
Percentage Change From
Baseline in Triglycerides at
Week 6 by Dose (ITT)
Rosuvastatin
Mean Percent Change From
Baseline in TG Levels
(mg)
0
10
20
40
Atorvastatin
Simvastatin
Pravastatin
10
10
10
(mg)
20
40
80
(mg)
20
40
80
(mg)
20
40
-5
-10
-8.2 -7.7
-11.9
-15
-20
-25
-30
-14.8
-17.6
-19.8
*
-23.7
**
-20
-22.6
-26.1
†
-26.8
-28.2
*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 mg
Jones PH, Davidson MH, Stein EA, et al. Am J Cardiol. 2003; 93:152-160.
-18.2
-13.2
Sideaffects: Muscle & Liver
E. Bryan Brewer, Amer Jrnal of Cardiology 92:4B23K-29K
Protein Handling by the Kidney
Albumin
Low molecular weight proteins
Glomerular
proteinuria
Normal
Plasma
concentration,
mg/L
40,000 4
2
Filtered load, mg/day
if GFR – 150L/day
% reabsorbed
Daily excretion, mg
40,000 4
2
2000
95
95
18 18
40,000 4
2
360,000
360
360 360
95
18,000 18
Tubular
proteinuria
95
2
2
360
360
50
50
180 180
Inhibition of Albumin Uptake and
Cholesterol Synthesis
Inhibition of
Albumin Uptake (%)
100
Rosuvastatin
Simvastatin
Pravastatin
80
60
40
20
0
0
10
20
30
40
50
60
70
80
90
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 Toxicology;
September 28-October 1, 2003; Florence, Italy.
100
Effects of Rosuvastatin on Proteinuria in
Patients† With Baseline Proteinuria
≥40 mg Rosuvastatin for ≥96 Wk (n = 53)
100
90
80
70
60
50
40
30
20
10
0
Decrease
No Change
Increase
Change in Urine Protein—Baseline to Last Visit
Data on file, (DA-CRS-07) AstraZeneca Pharmaceuticals LP, Wilmington, DE.
Changes in Plasma Creatinine in
Patients TreatedWith 40 mg of
Rosuvastatin for 96 Weeks:
Renal
function
N
Creatinine
%
change*
Normal
456
–5.9
Impaired
Mild
Moderate
Severe
415
366
46
3
–5.3
–5.3
–4.9
–13.7
*Last visit compared to baseline.
Data on file, (DA-CRS-07) AstraZeneca Pharmaceuticals LP, Wilmington, DE.
Fibrate Mechanisms of Action
Fibrate
↑LDL Particle Size
↑HDL Synthesis
↓Triglycerides
PPAR
↑Reverse Cholesterol Transport
↓Inflammation
Helsinki Heart Study: Enhanced Reduction
of CHD Events in Patients With Type 2
Diabetes
5-Year Incidence of CHD, %
12
P<.19
P<.02
10
8
6
4
2
0
Type 2
(n = 135)
Other
Type 2 on Placebo
(n = 3946)
(n = 76)
Mean baseline characteristics: Total-C 291 mg/dL;
LDL-C 200 mg/dL; HDL-C 46 mg/dL; TG 236 mg/dL.
Type 2 on
Gemfibrozil
(n = 59)
Koskinen P, et al. Diabetes Care. 1992;15:820-825.
VA-HIT: CVD Risk Reduction in
Diabetics Compared With
Nondiabetics
Combined
Nonfatal
MI
CHD
Cumulative Event Rate Change, %
End Point
Stroke
Death
0
5
3
10
P=.88
10
15
P=.67
20
18
P=.07
25
22
P=.17
21
P=.09
30
35
32
P=.004
40
45
P=.26
DM
No DM
41
P=.02
40
P=.046
Rubins HB, et al. Arch Intern Med. 2002;162:2597-2604.
BIP: Enhanced Event Rate Reduction in Patients
With Augmented Features of the Metabolic
Syndrome*
Placebo (n = 287)
Bezafibrate (n = 288)
18
16
P=NS
15.3%
17.1%
33% Reduction
P=.05
Event Rate, %
14
12
11.5%
10.4%
12.2%
54% Reduction
P=.005
10
8
5.6%
6
4
2
0
Nonfatal MI
*Patients with 4-5 risk factors for the
metabolic syndrome
Any MI
Cardiac Death
Tenenbaum A, et al. Arch Intern Med. 2005;165:1154-1160.
Adjustment for Statin Use
Secondary End Point:
Total CVD Risk
0
0
-2
-5
-11%
-10
-15
-20
-25
-19%
Nonadj
P=.16
Adj
P=.01
Relative Risk, %
0
-2
-4
-6
-8
-10
-12
-14
-16
-18
-20
Relative Risk, %
Relative Risk, %
Primary End Point:
CHD Events
Adjusted Primary End Point
in Patients With No Prior
CVD
-4
-6
-8
-10
-12
-11%
-14
-25%
-30
P=.004
-16
-15%
Nonadj
Adj
P=.035
P=.004
Abbreviations: Adj, adjusted for statin use; Nonadj, nonadjusted risk
The FIELD Study Investigators. Lancet [Early Online Publication]. November 14, 2005.
Outcomes in Fibrate Trials:
Diabetic or Metabolic Syndrome
Major CVD
Event Rate
Primary
Prevention
HHS*
FIELD†
Secondary
Prevention
BIP‡
VA-HIT§
292 13.0
766 10.8
4
147 18.4
0
769 29.4
3.9% 71% <.0
05
8.9% 19% .00
4
14.1
25% .03
21.2
%
32% .00
4
Combo Therapy
 HIGH LDL:
Water-soluble statin
 +Resin/Zetia
 +Fibrate
 + Niaspan
 ?Vytorin?-(Zetia+Zocor)
E-mycin/Grpefruit/CaChannel 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
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 >10 mg/L, repeat test, examine for
sources of infection
 Relative risk categories for hs-CRP levels:
 low
<1 mg/L
 average 1.0–3.0 mg/L
 high
>3.0 mg/L
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
277.7 Dysmetabolic Syndrome X
Use additional codes for associated manifestations,
As follows:
414.00-414.05
250.01
272.0
278.01
Cardiovascular disease
Diabetes
Dyslipidemia
Morbid obesity for surgical
tx
Thank You !!!
B R Tulloch
Diagnostic Clinic.
Incidence of Cardiac Events
per 1000 Person-Years
HHS: Significant Reduction of CHD Events
in Patients With High Triglyceride and
LDL/HDL Ratio
30
Placebo
Gemfibrozil
25
71%
Reduction
P<.005
20
15
10
5
0
TG ≤204
TG >204
LDL/HDL ≤5
Triglyceride values are in mg/dL
TG ≤204
TG >204
LDL/HDL >5
Manninen V, et al. Circulation. 1992;85:37-45.
BIP: Event Rate Reduction in Patients
With the Metabolic Syndrome
23%
Reduction
P=.03
20
33% Reduction
P=.009
18%
18
Event Rate, %
16
29% Reduction
P=.02
26%
Reduction
P=.056
15%
14%
14
14%
11%
12
10%
10
Placebo
Bezafibrate
12%
9%
8
6
4
2
0
Primary End
Point*
Nonfatal MI
*Fatal MI, Nonfatal MI, and Sudden Death
Any MI
Cardiac Death
Tenenbaum A, et al. Arch Intern Med. 2005;165:1154-1160.
Fenofibrate Versus Placebo
in Patients With Mixed Dyslipidemia
Baseline LDL-C >160 mg/dL and TG 150 mg/dL (Type IIb)
Reductions in
Triglycerides
Increases in HDL-C
Mean Change, %
*P<.05
20
15
+15%*
10
+2%
5
0
TriCor
(n=126)
Placebo
(n=116)
Mean HDL-C baseline: 47 mg/dL
Reductions in LDL-C
*P<.05
10
0
-10
-20
-30
-40
*P<.05
+1%
0
-10
-7%
-20
-30
-36%*
TriCor
(n=126)
Placebo
(n=116)
Mean TG baseline: 232 mg/dL
-20%*
TriCor
(n=126)
Placebo
(n=116)
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
Niacin
Resin
Statin + ezetimibe
Statin + niacin + 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