therapeutic lifestyle therapy for...
TRANSCRIPT
Therapeutic Lifestyle Therapy for Dyslipidemia
R. La Forge
Lessons Learned from 10+ year-old
Diet-Heart Intervention Trials ?
OSLO DHS 1966
LAVA 1968
FMHS 1968-72
DART 1988
CLAS 1990
LHT 1990-92
Heidelberg 1992
STARS 1992
SCRIP 1994
LYON 1994
GISSI 1999
PORTFOLIO 2003
Angiographic CAD
lesion regression
CV events 22-33%
CVD mortality 26-65%
Exercise and Dyslipidemia
500 1000 1500 2000 2500+
kcal/week of physical activity
(added to a relatively sedentary baseline)
Functional and metabolic
benefits (glucose transport,
AMPK, PPAR, insulin
sensitization…)
Measurable body fat
alterations, weight
loss,
↓ LDL-C, …
Weight loss
maintenance
Weekly Physical Activity Energy Expenditure
and Cardiometabolic Benefit
*
Sattelmair 2012 ACSM 2009 Wannamethee 2000 Haskell 1994;2007 Ohkawara 2007
LDL-C ↓ 0-4 %
LDL-P ↓ 4-10+ %
HDL-C ↑4-25%
TG ↓4-37%
Non HDL ↓5-12%
Mestek 2008 LaForge 2007 Fletcher 2005 Durstine 2002 Kraus 2002
Overall Lipid/Lipoprotein Response to Aerobic Exercise Training of Sufficient Quantity
The sum of the literature seems to indicate that TGs are
consistently, reproducibly, and robustly responsive to exercise training at volumes that are comparable to those that induce changes in HDL (700–1,500 kcal/week)
LDL cholesterol generally is found not to be very
responsive to exercise training interventions unless there is significant fat weight loss.
LDL-Pnmr is more responsive to a given exercise energy
expenditure dose of exercise therapy (non-HDL-C also)
Kraus/Slentz 2009
2013
Based on known therapeutic effects of habitual physical activity, ACSM makes the following recommendations regarding exercise prescription of persons with dyslipidemia: *
Primary activity: aerobic exercise
Intensity: 40-75% aerobic capacity (V02R)
Frequency: 5 or more days a week
Duration: 30-60+ minutes
ACSM 2013
* This amount of physical activity is consistent with recommendations for long-
term weight control: 200-300 minutes/wk mod. PA or ≥ 2,000 kcal/wk). This
volume may be accumulated with repeated exercise bouts of 10 minutes.
Summary Box/Key Points on Exercise & Adiposity • Exercise training of sufficient quantity can reduce adiposity
with or without weight loss • In general, fat weight reduction is required for exercise
generated total cholesterol and LDL-C reduction but not always
• There are advantages of exercise intervention in contrast to
dietary-only intervention. • Exercise training can significantly reduce intramuscular
adipose tissue, likewise inactivity can significantly increase IMAT
• Overweight and obese adults should progress to a minimum of
150 min of moderate intensity exercise per week and, when possible, progress to >200 min of moderate intensity exercise per week.
Bays H, LaForge R et.al. JCL 2013
Primary Triglycerides NonHDL-C* Sys BP Secondary FPG &/or A1C Subscap SF Waist circumference
Lifestyle Lab Panel
* Non HDLC = TC-HDL
Bankoski, A. Sedentary Activity Associated With Metabolic Syndrome Independent of Physical Activity Diabetes Care February 1, 2011 34:497-503 NIH and GMUSe
SEDENTARY TIME, Dyslipidemia, & Metabolic Response
Inactivity, exercise training and detraining, and plasma lipoproteins Cris A. Slentz et.al. J Appl Physiol 103: 432–442, 2007.
Sedentary, overweight subjects (n =240) were randomized to 6-mo control or one of three exercise groups: 1) high-amount/vigorous-intensity exercise; 2) low-amount/vigorous-intensity exercise; or 3) low-amount/moderate-intensity exercise. - 6 mo. training followed by 14 days of detraining.
Sustained physical inactivity resulted in statistically
significant increases in LDL particle number, small dense LDL, and LDL-C and in significant decreases in LDL particle size.
A modest amount of exercise training prevented this
deterioration. Moderate-intensity but not vigorous- intensity exercise resulted in a sustained reduction in very-lowdensity lipoprotein (VLDL)-triglycerides over 15 days of detraining (P 0.05).
Minimal Intensity Physical Activity (Standing and Walking) of
Longer Duration Improves Insulin Action and Plasma Lipids
More than Shorter Periods of Moderate to Vigorous Exercise
(Cycling) in Sedentary Subjects When Energy Expenditure Is
Comparable Bernard M. F. M. Duvivier, et.al. PLOS One 2013, February 2013; e55542 Netherlands Methodology/Principal Findings: 18 healthy subjects, age 21.62 year, BMI 22.6 followed randomly three physical activity regimes for four days. Participants were instructed to sit 14 hr/day (sitting regime); to sit 13 hr/day and to substitute 1 hr of sitting with vigorous exercise 1 hr (exercise regime); to substitute 6 hrs sitting with 4 hr walking and 2 hr standing (minimal intensity physical activity (PA) regime). The sitting and exercise regime had comparable numbers of sitting hours; the exercise and minimal intensity PA regime had the same daily energy expenditure Conclusions: One hour of daily physical exercise cannot compensate the negative effects of inactivity on insulin level and plasma lipids if the rest of the day is spent sitting. Reducing inactivity by increasing the time spent walking/standing is more effective than one hour of physical exercise, when energy expenditure is kept constant.
Metabolic responses to reduced daily steps in healthy nonexercising men
Olsen RH et.al. JAMA 2008;299, 1261–1263
6203 to 1394
6203 to 1394
10, 501 to 1344
3 weeks of dec. PA
INACTIVITY: EVERY DAY COUNTS
Also increase in abdominal fat mass (CT) by 7 % (p .04).
Fat free mass (muscle) decreased 5% (p= <.001)
Olsen, et al. JAMA. 2008;299(11):1261-1263.
Baseline 1 2 30
500
1000
1500
Weeks of Inactivity
Insu
lin
Resis
tan
ce (
Insu
lin
AU
C)
* *
*
* p<0.05 compared to baseline 6203 to 1394 steps
The Physiology of Inactivity i.e., Prolonged Sitting
Increased platelet “stickiness”
Decreased lipoprotein lipase activity
The clinical utility of pedometry in deferring metabolic risk
Muscle contraction – AMPK activation – Stepcount
Accusplit® AX2720
• Step counter with tilt-proof sensor
• 5-second delay function prevents
recording false steps
• Hibernate mode
www.accusplit.com
Just get your patients to move and move
often !
You too !!
Post prandial Lipid and Lipoprotein Responses
Postprandial Lipemia (TG) Issues
• TG time/area under the curve
is greater with T2D, visceral ob,
& MetSyn
• Decreased arterial endothelial function
• Decreased HDL-C response
• Increased IDL- VLDL remnant exposure
EXERCISE AND POSTPRANDIAL LIPEMIA
TG
Hours after high fat meal
0 2 4 6 8
400
300
200
100
TG
mg/dL
Exercise and Postprandial Lipemia
Petitt D & Cureton K Metabolism. 2003;4:418
Zhang J et. al. JAP 1998;85:1516
1.20
1.10
1.06
1.02
1.006
0.95
5 10 20 40 60 80 1000
Chylomicron Remnants
VLDL
IDL
LDL
HDL2
HDL3
Diameter (nm)
De
nsit
y (
g/m
l)
Chylo- microns
Lp(a)
Lipoprotein (Sub)Classes
Fat load (12 - 22 grams)
and/or glycemic load
+
Caffeine load (40-200 milligrams)
0
10
20
30
40
50
60
70
80
90
100
400+ kcal
exercise
Immed. Post
Exercise
4 hrs post 8 hrs post 12 hrs post
LPL
TG
HDL
Post Exercise Peak Lipoprotein Lipase Activity
and Postprandial TG
Thomas T & La Fontaine T ACSM Res. Man., 2001
Relative Value
LPL
HDL
TG
N = 10 healthy males (25yrs)
Supplementation consisted of 4.0 g of n-3FA per day for 5 weeks.
Results: TG peak 38% by n-3FA supplementation and 50% by the
combination of exercise and n-3FA supplementation.
When compared with the exercise trial, the TG-AUCT during the
combined trial was significantly lower.
Exercise: 40%
n-3FAs: 42%
Ex + n3: 58%
Exercise plus n-3 fatty acids: Additive
effect on postprandial lipemia Smith BK et. al. Metabolism 2004;53:1365 (Univ. of Kansas)
Practical Implications
1. For those patients who plan on eating occasional
high fat but especially very high fat (>100g) evening
meals, it may be advantageous to plan a ≥50 minute
morning exercise session
2. Moderate exercise every other day for 45-60 (~400
kcal) minutes also may help blunt excessive increases
in postprandial TG and help maintain a higher mean
24-hour HDL-cholesterol
PHARMACOTHERAPY
Mipomersen (antisense Apo B inhibitor) PCSK9 inhibitors
I. Elevated LDL-C
II. Elevated LDL & TG
III. Elevated TG (>500mg/dl)
IV. Isolated low HDL-C
Statin monotherapy
Niacin
Ezetimibe
BAS
Statin-niacin
Statin-ezetimibe
Vytorin
Statin-resin
Mipomersen
Statin monotherapy
Statin-niacin
Advicor-Simcor
Statin-fish oil
Statin-fibrate orTLX
Fibrate-ezetimibe
Vytorin-fibrate
Vytorin-niacin
Niacin
Fibrate or TLX
Fish oil Rx
Niacin-fish oil
Fibrate-niacin
Fibrate-niacin-FO
Niacin
Fibrate
Niacin-fibrate
D
i
e
t
E
x
e
r
c
i
s
e
►LDL reduced 15-63%
►Triglycerides reduced 10-40%
►HDL increased 5-15%
Obtain baseline liver
enzymes
Myalgia, myopathy
Statins
HMG CoA Reductase
(More Than Cholesterol Synthesis)
Acetyl CoA
HMG CoA
Mevalonate
Farnesyl Pyrophosphate
Cholesterol
HMG CoA Reductase Isopentenyl
adenine
(transfer RNA)
Prenylation of
signalling peptides
(Ras, Raf, Rho) Ubiquinones
(CoQ-10, etc.) Dolichols
Inhibition of other key products of mevalonate may relate to
nonlipid effects & rare side effects of statins.
Statin
Eckel JCEM, 2010
Statin Pharmacokinetic Comparisons
Jupiter
Brown WV, Curr Opin Lipid 19:558, 2008
Thompson P, 2012
Golomb B, 2012
Statins: The Down Side
• Abnormal AST and ALT (liver toxicity) < 3X ULN: ~1.3% > 3X ULN: <1.0%
Dose related
• Myopathy: Any disease of muscles Myalgias: pain in a muscle of group of muscles
~10%++ Myositis: muscle symptoms with CK
~2.5% Rhabdomyolysis: > 50 fold in CK + renal impairment
<0.1%
• Exercise intolerance/fatigue
• Statin dose (esp. moderate high)
• Small body frame (gender ?)
• Decreased statin metabolism – increased statin exposure
to muscle:
- Drug-drug interactions (CYP3A4 drugs)
- Grapefruit juice (pomergranate, starfruit ?)
- Hypothyroidism
- Advanced age
- Liver and renal disease
• Alcohol consumption
• Heavy eccentric exercise
• Heat loads
• Baseline muscular disease
• SLCO1B1*5 genotype
• Vitamin D deficiency ?
Risk factors for Statin Induced Myopathy
18
The Majority of Statin LDL-C Efficacy Is at Starting Doses
*P<0.001 vs atorvastatin 10 mg and simvastatin 20 mg and 40 mg. †P=0.026 vs atorvastatin 20 mg.
–28%
–46%*,†
–37%
–7%
–6%
–6%
–3%
–5%
–4%
–7%
–3%
Atorvastatin Rosuvastatin Simvastatin
Mean %
Change
in LDL-C
From
Untreated
Baseline
10 mg
20 mg
40 mg
80 mg
Jones PH et al. Am J Cardiol. 2003;92:152–160.
–55%
–45%
–35%
–25%
–15%
–5%
STELLAR EFFICACY RESULTS
*P<.002 vs atorvastatin 10 mg; simvastatin 10 mg, 20 mg, 40 mg; pravastatin 10 mg, 20 mg, 40 mg. **P<.002 vs atorvastatin 20 mg; simvastatin 20 mg, 40 mg, 80 mg; pravastatin 20 mg, 40 mg. †P<.002 vs atorvastatin 40 mg; simvastatin 40 mg, 80 mg; pravastatin 40 mg. Jones et al. Poster presented at: European Society of Cardiology Congress; August 30-September 3, 2003; Vienna, Austria.
-26
-48
-40
-33
-22
-51
-45
-35
-27
-48
-42 -42
-34
-19
*
** †
Mean N
on–H
DL-
C R
eduction
(%)
Percent Reduction in Non–HDL-C
-60
-50
-40
-30
-20
-10
0 10 20 40 80 10 20 40 10 20 40 80 10 20 40
Simvastatin (mg)
Rosuvastatin (mg)
Atorvastatin (mg)
Pravastatin (mg)
PERCENTAGE CHANGE FROM BASELINE IN
HDL-C AT WEEK 6 BY DOSE
Mea
n P
erce
nt
Ch
ang
e F
rom
Bas
elin
e in
HD
L-C
Rosuvastatin
(mg)
Atorvastatin (mg)
Simvastatin (mg)
Pravastatin (mg)
10 20 40
3.2
4.4
5.6
10 20 40 80 10 20 40 0
2
4
6
8
10
12
5.7
4.8 4.4
2.1
*
7.7
**
9.5
†
9.6
10 20 40 80
5.3
6.0
5.2
6.8
*P<.002 vs pravastatin 10 mg
**P<.002 vs atorvastatin 20 mg, 40 mg, 80 mg; simvastatin 40 mg; pravastatin 20 mg, 40 mg
† P<.002 vs atorvastatin 40 mg, 80 mg; simvastatin 40 mg; pravastatin 40 mg
Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93:152-160.
Antisense Apo B Inhibition
Mipomersen (Kynamro)
Rx: add to statin
Indication: Homozygous FH
30% dec. in LDL-C
Lp(a) reduction
►Triglycerides reduced 20-35%
►HDL increased 10-30%
►LDL reduced 10-20%
Immediate release (eg. Niacor)
Extended release (eg. Niaspan)
Sustained release (eg. SloNiacin)
Niacin (nicotinic acid)
Is the agent with largest impact on HDL, and the only
agent that lowers Lp(a) (by ~ 30%)
- Usually employed in combination with fibrate, resin
or statin – this avoids side effects of higher doses
Major side effects
Flushing – prostaglandin mediated
Skin drying & GI intolerance
Nicotinic Acid
Niacin Product Examples
Nicotinic acid (Niacin) Nicotinamide (Niacin)
The term niacin is used in two different ways. As a collective
term, it refers to both nicotinic acid and nicotinamide.
They have identical vitamin activities, but have very different
Pharmacological activities.
Niacin vs Niacin
Nicotinic acid
IH is marketed to reduce niacin-related flushing
►Triglycerides reduced 25-50%
►HDL increased 10-20%
►LDL reduced 10-20% (TG++ - LDL )
Liver enzymes
Skeletal muscle myopathy
Fibric Acid Derivatives (Fibrates)
e.g., gemfibrozil, fenofibrate – trilipix
Promotes action of lipoprotein lipase
Frick MH et al. N Engl J Med. 1987;317:1237-1245. Rubins HB et al. N Engl J Med. 1999;341;410-418. Keech A et al. Lancet. 2005;366:1849–1861. Accord Study Group. N Engl J Med. 2010;362,1563-1574
Reduce LDL Cholesterol 5-25%
Raise Triglycerides Variable
Raise HDL Cholesterol 0-5%
Bile Acid Binding Resins
eg. cholestyramine & colestipol
& Cholesevelam
CHOLESTEROL TRANSPORT
INHIBITORS
Ezetimibe increases LDL receptors by inhibiting cholesterol absorption in the intestine
Ezetimibe (Zetia)
EZETIMIBE ZETIA
-0.4-1.3
-0.2
-5.8
2.9
-18.5
-4.9
3.5
-15.7
-20
-15
-10
-5
0
5
Mean
% C
han
ge f
rom
Baseli
ne
Placebo Ezetimibe 5 mg (n=125) Ezetimibe 10 mg (n=123)
LDL-C Triglyceride HDL-C
* P<0.05 vs placebo
*
*
* *
Lipka et al. J Am Coll Cardiol 2000; 35(supp A):257A
Ezetimibe + Simvastatin
Vytorin
Ezetimibe
Clearly reduces LDL-C
Does it reduce CVD risk ??
Omega 3 Fatty Acid Therapy (Fish Oil)
Marine omega 3 fatty acids
vs.
Plant omega 3 fatty acids
TG + CV risk
CV risk
► Reduced triglycerides & VLDL (at higher doses)
► Ventricular arrhythmia reduction
► Anti-inflammatory properties
► Decrease synthesis of cytokines and mitogens
► Stimulate endothelial-derived NO
► Anti-thrombotic
Kris-Etherton P et al Circ. 2001;103:1823
Omega 3 Fatty Acid Therapy Cardoprotective Mechanisms
1.4 g gel 0.6 g gel
5 ml = 1.4g EPA + DHA
Carlson Fish Oil 1000mg
CHEWABLE ORANGE flavor
SOFTGEL
Vascepa epa concentrate
ANCHOR EPA Trial
N=702, 12 weeks
Ballantyne CM, Bays HE et.al. Am J Cardio. 2012 Oct 1;110(7):984-92
PCSK9 Inhibitors
Investigational
PCSK9 binds to the epidermal growth factor-like repeat A (EGF-A) domain of the LDL-C receptor (LDLR), inducing LDLR degradation. Reduced LDLR levels result in decreased metabolism of LDL-C, which could lead to hypercholesterolemia
Laboratory Assessment and Residual Risk
Not everything that can be counted
counts, and not everything that counts
can be counted.
Albert Einstein
Residual Risk
Residual CVD Risk Beyond LDL-C
Apo B Non-HDL C LDL-P Lp(a) LpPLA2 VLDL-p HDL HDL-P CRP
TLC Rx 1500 kcal PA Reduced CHOhg
Adiposity reduction DASH & Medit. dietary Rx Tobacco cessation
Low HDL High TG
Residual cardiovascular risk despite optimal LDL cholesterol reduction with statins: the evidence, etiology, and therapeutic challenges Sampson UK, Fazio S, Linton MF. Curr Atheroscler Rep. 2012 Feb;14(1):1-10 Vandy
This review captures the existence, cause, and treatment challenges of residual
cardiovascular risk (CVR) after aggressive low-density lipoprotein cholesterol (LDL-C)
reduction. Scientific evidence implicates low high-density lipoprotein cholesterol
(HDL-C) and high triglycerides (TG) in the CVR observed after LDL-C lowering
The optimum approach to long-term lipid-modifying therapies for CVR reduction
remains uncertain.
Absolute risk modulation via lifestyle changes remains the
centerpiece of a strategy addressing the physiologic drivers of CVR
associated with HDL-C/TG, especially in the context of
diabetes/metabolic syndrome.
ADVANCED LABORATORY ASSESSMENTS
Which laboratory and anthropometric tools will you employ for diagnostic and therapeutic assessment ?
LDLp#
Apo B
Apo A1
Apo C II & III
CRP
Lp(a)
LpPla2
Apo E isoforms
TC/HDL
hs-cTnI
Genotypes
Others
TC
LDL
HDL
TG
nonHDL
Primary (Tier I) Secondary (Tier II)
LIPID AND LIPOPROTEIN LABS
Apo B, LDL particle #,
or other assays ?
Determine for which patients or lipoprotein disorders you will
evaluate these and if the results will confirm a differential
lipoprotein diagnosis and/or a significant change in the course
or intensity of therapy.
- Is there a clear evidence base for using this test outcome for
decision making that justify the added costs ?
- Is this test outcome an independent risk predictor and/or a
target of therapy ?
- Does it provide consistent and reproducible results ?
1.20
1.10
1.06
1.02
1.006
0.95
5 10 20 40 60 80 1000
Chylomicron
Remnants
VLDL
IDL
LDL
HDL2
HDL3
Diameter (nm)
Den
sity
(g/m
l)
Chylo-
microns
Lp(a)
Non HDL (ApoB, LDL-P)
Most responsive to lifestyle therapy
Atherogenic Particle Focus
ADA AND ACC CONSENSUS STATEMENT
ON LIPOPROTEIN MANAGEMENT
Brunzell JD, et al. Diabetes Care 2008;31:811-822
Highest-risk patients, including
those with 1) known CVD or 2) Diabetes plus one or more additional CVD risk factor
High-risk patients, including
those with 1) no diabetes or known clinical CVD but 2 or more additional major CVD risk factors or 2) Diabetes but no other CVD risk factors
LDL-C (mg/dL)
Non-HDL-C (mg/dL)
ApoB (mg/dL)
< 70 < 100 < 80
< 100 < 130 < 90
TREATMENT GOALS
Although largely ignored, it is recommended that,
because of analytical and biological variability, at least two
serial samples be measured before clinical decision making,
although even duplicate testing leaves room for
misclassification of patient’s risk:
‘‘Based on the prevailing distributions of LDL-C, with two serial measurements and
considering a cutpoint of 130 mg/dL, a patient’s LDL-C can be confidently assumed
to be above or below the cutpoint when the mean value is >145 mg/dL or <115
mg/dL, respectively …. sufficient to categorize 71% of the general population as
being above or below the 130 mg/dL cutpoint..”
Contois et.al. JCL 2011;5, 264–272
The high day-to-day variability (i.e., 25–30%) of plasma
TG concentration measurements often reported in the
literature could be problematic when evaluating VLDL-TG
kinetics.
For example, Jacobs and Barrett-Connor (38) investigated
the test-retest reliability of fasting plasma TG concentrations
in 7,000 men; the 95% CI for a single plasma TG
measurement with a true mean of 175 mg/dL was reported
to range from 88 to 262 mg/dl.
Magkos et.al. J. Lipid Res., 2007;48:1204
Other Markers of Risk
Lp(a)
CRPhs
LPPLA2
1.20
1.10
1.06
1.02
1.006
0.95
5 10 20 40 60 80 1000
Chylomicron
Remnants
VLDL
IDL
LDL
HDL2
HDL3
Diameter (nm)
Den
sity
(g/m
l)
Chylomicron
VLDL
Remnants
Lp(a)
Lp(a)
LDL-C + apolipoprotein (a)
Lipoprotein(a) consists of an LDL-like particle with
apoprotein B and a side chain of a highly glycosylated
protein.
Lp(a) has a role not only in atherogenesis but also in
thrombogenesis because of its homology with plasminogen.
Lp(a) is associated with increased levels of plasminogen
activator-inhibitor (PAI-1) and decreased activity of tissue
plasminogen activator (t-PA).
These effects all promote thrombosis and inhibit fibrinolysis.
Lipoprotein(a) CPT 83520
Levels of Lp(a) are largely genetically determined, increase
slightly with age, and vary by race. Values are lower in white
populations, but both higher and more normally distributed in
African Americans.
Framingham study cohort mean:
Men: 14 mg/dL
Women: 15 mg/dL for women
High Lp(a): > 80th percentile (>50 mg/dL) European guidelines
Lp(a) levels are higher in patients with chronic renal failure, the
nephrotic syndrome, and diabetic nephropathy.
►Niacin
4 gm/d reduces [Lp(a)] by 30 - 40%
►Omega-3-fatty acids
8 gm/d reduces [Lp(a)] by 25%
►Mipomersen (antisense ApoB inhibitor – phase IV)
►Fenofibrate
201 mg/d reduces [Lp(a)] by 15%
►ASA 350 mg qD reduces Lp(a) ~ 15% (especially drops smaller isoforms)
►Other (anecdotal):
Estrogen, neomycin, acetylcystiene, EtOH, metformin, testosterone
TREATMENT CONSIDERATIONS: DRUG EFFECTS ON
LP(A)
C-Reactive Protein Cut-Points
hs-CRP assay
< 1.0 mg/L Low Risk
1.0 -3.0 mg/L Average Risk
>3.0 mg/L High Risk
>10 mg/L, source of overt inflammation
should be sought
The recommendation is for “optional use” of hs-CRP to identify
patients without documented CVD who may be at higher risk
than indicated by major risk factors.
AHA/CDC Pearson T et.al. Circ. 2003;107:499
Lipoprotein-
associated
Phospholipase A2
LpPLA-2
Lp-PLA2 is an enzyme which circulates primarily in association with LDL and is believed to have a causal role in atherosclerosis. Once within the intima, LDL may be oxidized. Upon oxidation, LDL becomes a viable substrate for the Lp-PLA2 enzyme.
Lp-PLA2 is an inflammatory marker
LpPLA2 normal levels
250 - 350 ug/L normal
>400 ug/L high
Davidson M et.al. JCL 2011;5:338
1. NonHDL TG 2. Select subcutaneous skinfolds 3. LDL-P Apo B FPG Body weight/BMI/WCir 4. LDL-C TC A1C
Most Responsive Lab Measures to TLC
* assumptions
Good decision making – The trick is not to amass information, but to discard it: to know intuitively what one doesn’t need to know. The drugery of pros and cons lists Gigerenzer Gut Feelings 2007
PRACTICAL OFFICE-BASED
ANTHROPOMETRY
FOR LIPID AND CMR PROGRAMS
Anthropometric Measures
(skinfolds and waist circumference)
The Gulick
McArdle, 2010
Anthropometric Measures
Skinfold
Assessment
Skinfold measures
Two utilities
• To estimate body density via a mathmatical equation and calculate body fat % • To assess subcutaneous fatfolds to show change in total body adiposity over time
Assessing Serial Changes in Adiposity
Lange calipers (~ $220)
Recording Serial Skinfold Changes
OPTIONS Subscapular Subscapular + Tricep Subscapular + Tricep + Iliac crest
Children and Adolescents
Although BMI is the recommended measure for determining overweight
and obesity status, the percentiles and z scores of triceps and subscapular
skinfold thicknesses will allow better assessment of adiposity. In children,
skinfold thicknesses are more highly correlated with measures of total body
fat than is BMI.
Reference curves for triceps and subscapular skinfold
thicknesses in US children and adolescents O Yaw Addo and John H Himes Am J Clin Nutr 2010;91:635–42.
www.quickmedical.com/calipers/lange_skinfold.html
On the basis of data from this and previous studies
that evaluated regional fat loss after a prolonged
energy deficit, we suggested a regional hierarchy
of fat mobilization:
Men: abdomen/trunk > arms > legs.
Women: arm > truncal > legs.
J Appl Physiol 88: 2251–2259, 2000.
N=31 DEXA & MRI
For a given reduction in body weight or waist circumference men loose more VAT and less SAT than women; however, the total adipose tissue loss observed for a given reduction in BW or WC in men and women is not different
Kuk JL & Ross R. Int. J Obes. 2009;33:629
Key points • Clinical and anthropometric assessment of CMR is important for programmatic triage as well as group outcomes reporting.
• Key measures include: TG, non HDL, waist circumference, BMI, BP, FPG, A1C, LDL-C.
• Adiposity changes should also be tracked (e.g., SkFss)
Additional assessment will help define residual risk
Clinical/Anthropometric Behavioral Outcomes
Outcomes
LDL-C STC dietary score
HDL-C Daily/weekly step counts
TG Physical activity encounters/wk
Non HDL-C 7-day dietary recall
Fasting glucose Fast food encounters/wk
Waist circumference/SF Fruits and vegetable serv/wk
BMI Minutes of moderate ex/wk
Blood pressure Mediterranean diet score (0-9)
Labs versus Behaviors
Elements of Cardiometabolic
Risk Reduction Program
Organization
Integrated diabetes and CVD prevention programming for high risk metabolic syndrome patients
DEFINING GLOBAL CARDIOMETABOLIC RISK
Global Cardiometabolic Risk
+
Traditional Risk Factors Metabolic Syndrome
Diabetes Hypertension
Smoking
LDL
Cholesterol
HDL
Insulin resistance Insulin
Emerging markers
Visceral Obesity
HDL = high-density lipoprotein; LDL = low-density lipoprotein
Brunzell 2008
CMR – Lipoproteincentric
A coordinated and systematic process whereby patients at
high risk for diabetes and CVD who exhibit the metabolic
syndrome and traditional Framingham CVD risk factors
are identified and expediently managed to acceptable
behavioral, lipid/lipoprotein, blood pressure, blood
glucose, and body fat levels.
Primary focus of IHS: delay the onset of diabetes and
diabetes related costs
Cardiometabolic Risk
Reduction Program
Operational Definition
Preventive
cardiology
* Preventive
endocrinology
* Delaying the onset of diabetes is a priority
Suspected Metabolic Syndrome or Prediabetes
Metabolic
Panel BP, Wcir/BMI, TG, HDL,
LDL, nonHDL, FPG
High Risk
12-15 mo. intensive
MSM program
Low-Int. Risk
Core Ed. Curriculum
Intensive therapy and
individualized f/u
q6-8wks
Core Group
RF Education
Support
Very high risk require triage to specialty clinics
CMR Programming
Must consider and choose one:
1. Integrated CMR programs
(MetSyn + CHD risk factors)
2. Metabolic syndrome program
3. Prediabetes programming
(diabetes prevention priority)
Prediabetes Program Focus
IFG or A1Cpd
+
Adiposity measure
+ Option: TG and/or nonHDL
PRIMARY METABOLIC SYNDROME/CMR RX
15-MONTH INTENSIVE PHASE
1. Lifestyle intervention
1000+ kcal/wk physical activity (weekly baseline +
20,000+ steps/wk)
Dietary substitutions and graduated CHOhg reduction
2. Omega 3 fatty acid therapy for TG >200 mg/dL (1-3g/day)
3. Pharmacotherapy
TG/HDL (marine n3 fatty acids/fibrates/TLX/niacin)
LDL & nonHDL (statin therapy)
Insulin sensitivity (glucophage)
Weight loss drugs
✔ One or two dietary changes for one
food group per return visit (4-6 weeks)
✔ Evaluate weekly physical activity
volume, e.g., increase weekly pedometer step-counts,
minutes per week of moderate activity
Recommended TLC Instruction
Resources
Ballantyne Davidson Davignon
CLINICAL RESOURCES
Obesity, Adiposity, and Dyslipidemia: A Consensus Statement from the National Lipid Association Authors: Harold Bays, MD, FNLA, Chair*; Peter P. Toth MD, PhD, FNLA, Co-Chair; Penny Kris-Etherton, PhD, RD, FNLA, Co-Chair; Nicola Abate, MD; Louis Aronne, MD; W. Virgil Brown, MD, FNLA; J. Michael Gonzalez-Campoy, MD, PhD, FACE; Steven Jones, MD, FNLA; Rekha Kumar, MD; Ralph La Forge, MS, FLNA; Varman Samuel, MD, PhD Journal of Clinical Lipidology Summer 2013
http://www.anthctoday.org/storeoutside/
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Consider inaugurating a IHS DDTP
Lipid Clinic
• Focused clinical care and TLC for 7 categories of high risk lipid disorders
• Dedicated appointments (NPV 25 min, RV 10-15 min)
• Written defined written treatment pathways • RD, CDE, ExPhys • Medical Director
• CPT codes and reasonable third party coverage
• CME training/certification
