Lipoprotein disorders

1. Lipoprotein disorders and cardiovascular diseases
Date-28-03-2017

2. GENERAL STRUCTURE OF LIPO PROTEINSGENERAL STRUCTURE OF LIPO PROTEINS
Lipoproteins consist of a nonpolar core and a single
surface layer of amphipathic lipids
The nonpolar lipid core consists of mainly
triacylglycerol and cholesteryl ester and is surrounded
by a single surface layer of amphipathic phospholipid
and cholesterol molecules
These are oriented so that their polar groups face outward
to the aqueous medium.
The protein moiety of a lipoprotein is known as an
apolipoprotein or apoprotein.
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3. GENERAL STRUCTURE OF LIPO PROTEINSGENERAL STRUCTURE OF LIPO PROTEINS
Some apolipoproteins are integral and cannot be removed, whereas others
can be freely transferred to other lipoproteins.
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5. Classification of LipoproteinsClassification of Lipoproteins
Lipoproteins with high lipid content will have low density, larger
size and so float on centrifugation. Those with high protein
content sediment easily, have compact size and have a high
density.04/02/17 5

6. APOLIPOPROTEINSAPOLIPOPROTEINS
One or more apolipoproteins (proteins or polypeptides)
are present in each lipoprotein.
The major apolipoproteins of HDL (α-lipoprotein) are
designated A.
The main apolipoprotein of LDL (β -lipoprotein) is
apolipoprotein B (B-100), which is found also in VLDL.
Chylomicons contain a truncated form of apo B (B-48)
that is synthesized in the intestine, while B-100 is
synthesized in the liver.
Apo E is found in VLDL, HDL, Chylomicons, and
chylomicron remnants.
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8. LIPOPROTEIN METABOLISM AND TRANSPORTLIPOPROTEIN METABOLISM AND TRANSPORT
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11. LIPOPROTEIN DISORDERSLIPOPROTEIN DISORDERS
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13. Provided a useful conceptual framework.
 This classification had many drawbacks:
A)did not give much emphasis on HDL-C,
B)it does not differentiate severe monogenic lipoprotein
disorders from the more common polygenic disorders.
 World Health Organization, the European
Atherosclerosis Society, and more recently, the National
Cholesterol Education Program (NCEP) classified
lipoprotein disorders on the basis of arbitrary cut points.
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14. GENETIC LIPOPROTEIN DISORDERSGENETIC LIPOPROTEIN DISORDERS
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(TYPE II HYPERLIPIDEMIA)

15. FAMILIAL HYPERCHOLESTEROLEMIAFAMILIAL HYPERCHOLESTEROLEMIA
Affected subjects have an elevated LDL-C level greater
than the 95th percentile for age and sex.
 In adulthood, clinical manifestations include corneal
arcus, tendinous xanthomas over the extensor
tendons (metacarpophalangeal joints, patellar,
triceps, and Achilles tendons), and xanthelasmas.
Transmission is autosomal codominant.
FH affects approximately 1 in 500.
Patients with FH have high risk for the development of
CAD by the third to fourth decade in men and
approximately 8 to 10 years later in women.
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16. PROPROTEIN CONVERTASE, SUBTILISIN/KEXINPROPROTEIN CONVERTASE, SUBTILISIN/KEXIN
TYPE 9 GENETYPE 9 GENE
An autosomal dominant form of hypercholesterolemia
that maps to chromosome 1p34.1 involves a mutation
within the PCSK9 gene.
PCSK9 codes for a proprotein convertase belonging to
the subtilase family of convertases.
Gain-of-function mutations in the PCSK9 gene decrease
surface availability of the LDL-R protein and cause
accumulation of LDL-C in plasma.
 Subjects with a loss-of-function mutation of PCSK9 have
markedly lower LDL-C than do subjects without the
mutation.
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Cohen J et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 354:1264, 2006.
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March 17th
, 2017

18. AUTOSOMAL RECESSIVEAUTOSOMAL RECESSIVE
HYPERCHOLESTEROLEMIAHYPERCHOLESTEROLEMIA
HYPOBETALIPOPROTEINEMIA
Mutations within the APOB gene can lead to
truncations of the mature apo B100 peptide.
 Many such mutations cause a syndrome characterized by
reduced LDL-C and VLDL-C but little or no clinical
manifestations and no known risk for CVD, a condition
referred to as hypobetalipoproteinemia .
04/02/17 Curr Opin Lipidol. 2014 June ; 25(3): 161–168. 18

19. ABETALIPOPROTEINEMIA
Results from a mutation in the gene coding for the
microsomal triglyceride transfer protein (MTP),
required for assembly of apo B–containing
lipoproteins in the liver and the intestine.
Lack of apo B–containing lipoproteins in plasma
causes a marked deficiency of fat-soluble vitamins
(A, D, E, and K) that circulate in lipoproteins.
Results in mental and developmental retardation
in affected children.
04/02/17 Curr Opin Lipidol. 2014 June ; 25(3): 161–168. 19

20. Acanthocytosis in PBF
Oral fat intolerance, steatorrhea, diarrhea, fat
malabsorption, lipid accumulation in enterocytes,
failure to thrive and deficiency of fat-soluble vitamins A
and E.
Deficiency of vitamin E leads to progressive degeneration
of the central nervous system and death.
Unless treated early with vitamin E, subjects develop
atypical retinitis pigmentosa, spinocerebellar
degeneration with ataxia and a bleeding diathesis
secondary to malabsorption of fat-soluble vitamins
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21. SITOSTEROLEMIA
A rare condition of increased intestinal absorption and
decreased excretion of plant sterols (sitosterol and
campesterol) can mimic severe FH with extensive
xanthoma formation.
Premature atherosclerosis,occurs in patients with
sitosterolemia.
Patients with sitosterolemia have homozygous (or
compound heterozygous) mutations in the ABCG5 and
ABCG8 genes.
A defect in either of the genes inactivates the transport
mechanism across the intestinal lumen, and net
accumulation of plant sterols (because of impaired
elimination) ensues .
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22. 04/02/17
Othman et al. Non-cholesterol sterols and
cholesterol metabolism in sitosterolemia. Atherosclerosis.
2013;231(2):291–9.
Quintás-Cardama A et al .Long-term follow-up of a patient
with sitosterolemia and hemolytic anemia with excellent response
to ezetimibe. J Genet Disord Genet Rep. 2013;2:1. 22

23. LIPOPROTEIN(a)LIPOPROTEIN(a)
Lp(a) (pronounced “lipoprotein little a”) consists of an
LDL particle linked covalently with one molecule of apo
(a).
 The apo (a) moiety consists of a protein with a high
degree of homology with plasminogen.
The pathogenesis of Lp(a) may result from an
antifibrinolytic potential and/or ability to bind
oxidized lipoproteins.
Prospective epidemiologic studies have shown a positive
(albeit weak) association between Lp(a) and CAD.
04/02/17
Di Angelantonio E, Gao P, Pennells L, et al: Lipid-related markers and cardiovascular disease
prediction. JAMA 307:2499, 2012.
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24. TRIGLYCERIDE-RICH LIPOPROTEINSTRIGLYCERIDE-RICH LIPOPROTEINS
FAMILIAL HYPERTRIGLYCERIDEMIA (TYPE IV
HYPERLIPOPROTEINEMIA)
Clinical signs such as corneal arcus, xanthoma, and
xanthelasmas are absent.
 Plasma triglycerides, VLDL-C, and VLDL triglycerides
are moderately to markedly elevated; the LDL-C level
is usually low, as is HDL-C.
Total cholesterol is normal or elevated, depending on
VLDL-C levels.
Fasting plasma concentrations of triglycerides are in the
range - 200 to 500 mg/dL.
Weaker relationship with CAD
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25. 04/02/17
(Adult Treatment Panel III): final report. NIH publication
no.: 02-5215. Bethesda, Md.: National Heart, Lung, and
Blood Institute, 2002 25

26. 04/02/17
(Adult Treatment Panel III): final report. NIH publication
no.: 02-5215. Bethesda, Md.: National Heart, Lung, and
Blood Institute, 2002
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27. FAMILIAL HYPERCHYLOMICRONEMIA (TYPE I
HYPERLIPIDEMIA)
Elevations in fasting plasma triglycerides to greater
than >1000 mg/dL.
Patients have recurrent bouts of pancreatitis and
eruptive xanthomas.
Can also be associated with xerostomia, xerophthalmia,
and behavioral abnormalities.
The hypertriglyceridemia results from markedly reduced
or absent LPL activity or, more rarely, absence of its
activator apo C-II
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28. DIAGNOSIS/MANAGEMENTDIAGNOSIS/MANAGEMENT
Based on the assay of LPL enzyme activity in plasma
following intravenous administration of heparin.
Detection of very low or absent LPL enzyme activity in an
assay system that contains either normal plasma or
apoprotein C-II and excludes hepatic lipase is diagnostic of
familial LPL deficiency.
Treatment –
1. Medical nutrition therapy to maintain plasma
triglyceride concentration at less than 1000 mg/dL.
2. Restriction of dietary fat to no more than 20 g/day or
15% of a total energy intake is usually sufficient.
3. The acute pancreatitis episode is treated with standard
care.04/02/17 28

29. TYPE III HYPERLIPOPROTEINEMIA
(Dysbetalipoproteinemia or Broad Beta Disease)
Increased cardiovascular risk.
Pathognomonic tuberous xanthomas and palmar
striated xanthomas are present.
Increased cholesterol and triglyceride levels and reduced
HDL-C.
 Remnant lipoproteins (partly catabolized chylomicrons
and VLDL) accumulate in plasma resulting from abnormal
apo E, which does not bind to hepatic receptors that
recognize apo E as a ligand.
 Ratio of VLDL cholesterol to triglycerides, normally
less than 0.7 is elevated in patients with type III
hyperlipoproteinemia because of cholesteryl ester
enrichment of remnant particles.04/02/17 29

30. Treatment of dysbetalipoproteinemia is the same as for
hypertriglyceridemia.
 Weight loss, diet fat restriction and treatment of
secondary factors, such as diabetes and hypothyroidism
are important for all dysbetalipoproteinemia patients.
Administration of fibrates, statins, omega-3 fatty acids and
niacin or their combinations is very effective.
However, it has to be underlined that fibrates, with or
without statin, seem to comprise the cornerstone of
dysbetalipoproteinemia treatment.
04/02/17 Marais AD, et al. Crit Rev Clin Lab Sci 2014; 51: 46-62 30

31. FAMILIAL COMBINED HYPERLIPIDEMIA
Characterized by the presence of elevated total
cholesterol and/or triglyceride levels .
Prevalence of approximately 1 in 50 .
Accounts for 10% to 20% of patients with premature
CAD.
Corneal arcus, xanthomas, and xanthelasmas occur
infrequently.
Diagnosis of familial combined hyperlipoproteinemia
requires identification of the disorder in at least one
first-degree relative.
 Underlying metabolic disorders appear to include hepatic
overproduction of apo B–containing lipoproteins, delayed
postprandial clearance of TRLs, and increased flux of FFAs
to the liver.04/02/17 31

32. HIGH-DENSITY LIPOPROTEINSHIGH-DENSITY LIPOPROTEINS
Disorders of High-Density Lipoprotein Biogenesis
Apolipoprotein A-I Gene Defects
Primary defects affecting the production of HDL particles
may be caused by mutations in the apo A-I–C-III–A-IV
gene complex.
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33. TANGIER DISEASE AND FAMILIAL HIGH-DENSITY
LIPOPROTEIN DEFICIENCY.
The cellular defect - consists of reduced cellular
cholesterol efflux in skin fibroblasts and
macrophages from affected subjects.
 A more common entity, familial HDL deficiency, was
also found to result from decreased cellular cholesterol.
Tangier disease and familial HDL deficiency result from
mutations in the ABCA1 gene, which encodes the
ABCA1 transporter .
Increased risk for CAD
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34. DIAGNOSISDIAGNOSIS
Other tests:
1. 2D electrophoresis with
subsequent anti-apoA-I
immunoblotting.
2.Cholesterol efflux assay
on cultivated skin
fibroblasts.
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von Eckardstein A, et al.. Atherosclerosis 1998; 138: 25-34
Joyce C, et al.. Arterioscler Thromb Vasc Biol 2003; 23: 965-71
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35. MANAGEMENTMANAGEMENT
To date, the only definite therapeutic intervention for
Tangier patients is a very low fat diet, thus reducing the
potential to develop fatty liver.
CETP Inhibitors-
Torcetrapib(ILLUMINATE), Dalcetrapib(dal-VESSEL).
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36. Niemann-Pick type C disease is a disorder of lysosomal
cholesterol transport.
In patients with Niemann-Pick type C disease, mental
retardation and neurologic manifestations occur
frequently.
 The cellular phenotype involves markedly decreased
cholesterol esterification and a defect in the cellular
transport of cholesterol to the Golgi apparatus.
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37. DISORDERS OF HIGH-DENSITY LIPOPROTEIN–DISORDERS OF HIGH-DENSITY LIPOPROTEIN–
PROCESSING ENZYMESPROCESSING ENZYMES
LECITHIN-CHOLESTEROL ACYLTRANSFERASE
DEFICIENCY
Deficiencies of LCAT, the enzyme that catalyzes the
formation of cholesteryl esters in plasma, cause corneal
infiltration of neutral lipids and hematologic
abnormalities as a result of the abnormal
constitution of red blood cell membranes .
“FISH EYE DISEASE”
No increased risk of cad.
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38. CHOLESTERYL ESTER TRANSFER PROTEIN
DEFICIENCY
 Patients without CETP have very elevated levels of HDL-
C, which is enriched in cholesteryl esters as it facilitates
the transfer of HDL cholesteryl esters into TRLs.
 CETP deficiency is not associated with premature
CAD.
Niemann-Pick type I disease (subtypes A and B), which is
caused by mutations in the sphingomyelin
phosphodiesterase-1 (SMPD1) gene, is associated with a
low HDL-C level .
Decrease in LCAT reaction because of abnormal HDL
constituents.04/02/17 38

39. SECONDARY CAUSES OF DYSLIPOPROTEINEMIASSECONDARY CAUSES OF DYSLIPOPROTEINEMIAS
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40. DYSLIPIDEMIA MANAGEMENTDYSLIPIDEMIA MANAGEMENT
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41. 2013 ACC/AHA Guidelines:2013 ACC/AHA Guidelines:
Statins without any lipid “goals”Statins without any lipid “goals”
Circulation 2014; 129: S1-S45
• Clinical ASCVD*
• LDL-C ≥190 mg/dL, Age ≥21 years
• Primary prevention – Diabetes: Age 40-75 years, LDL-C
70-189 mg/dL
• Primary prevention - No Diabetes†: ≥7.5%‡ 10-year
ASCVD risk, Age 40-75 years, LDL-C 70-189 mg/dL
*Atherosclerotic cardiovascular disease
†
Requires risk discussion between clinician and patient before statin initiation
‡
Statin therapy may be considered if risk decision is uncertain after use of ASCVD risk calculator
Circulation. 2014;129[suppl 2]:S1-S45

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43. INDIAN GUIDELINESINDIAN GUIDELINES
43

44. INDIAN DYSLIPIDEMIAINDIAN DYSLIPIDEMIA

45. RISK FACTORSRISK FACTORS

46. NON TRADITIONAL CV RISKS IN INDIANON TRADITIONAL CV RISKS IN INDIA
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47. CORONARY CALCIUM
Both LDL-C and HDL-C were found to be
independent predictors of CAC
CAC score >400 had 100% specificity

48. CIMT
 For 0.1 mm increase in CIMT the future risk of MI increased by 10-15%
 A 10% reduction in LDL-C per year accounted for a reduction of CIMT by
0.73
 presence of carotid plaques is a marker of already existing ASCVD

49. Lp(a)
 more common
among CAD patients
with existing family
history
 Lp(a) levels in Asian
Indian newborns were
significantly higher than
in Chinese in Singapore
 Level > 20 mg/dL
indicates increased
ASCVD risk in Indians

50. Presence of obesity
and/or metabolic
syndrome in an
individual who is
otherwise at low 10-year
risk of ASCVD should
indicate high lifetime
ASCVD risk.
OBESITY/ MET Syn.OBESITY/ MET Syn.

51. A 5-μmol/L tHcy increment elevates CAD risk by as much
as cholesterol increases of 0.5 mmol/L (20 mg/dL)
Very high prevalence of hyperhomocystinemia (>15
µmol/L) in 75% of subjects in India, which was strongly
correlated with cobalamin deficiency
Impaired cobalamin status appears more important than
folate deficiency among Asian Indians
HOMOCYSTEINEHOMOCYSTEINE

52. CRP
 significant ASCVD risk
reduction with statin in
individuals with elevated CRP
despite relatively normal LDL-C
 A value of > 2 mg/l of hs-CRP
indicates increased ASCVD risk.
 When the value is >10 mg/L, it
usually indicates a non-
atherosclerotic cause of
Inflammation
 But Quality control and proper
standardization of hs-CRP is
challenging in India

53. JBS3: LIFETIME ASCVD RISK CALCULATOR
Estimate lifetime risk
Validated in indians
Non-conventional risk
factors
<30% = LOW RISK
30-44% = MODERATE RISK
>45% = HIGH RISK

54. The Indian ApproachThe Indian Approach

55. 1. History of MI or documented CAD
2. History of ischemic stroke or TIA
3. Hemodynamically significant carotid plaque
4. Atherosclerotic peripheral arterial
disease(ABPI<0.9)
5. Atherosclerotic aortic aneurysms
6. Atherosclerotic renal artery stenosis
Pre-existing ASCVDPre-existing ASCVD

56. 30-44%
risk
>45%
risk
Moderate
risk
High
risk
INDIANINDIAN
RISKRISK
STRATIFICATIONSTRATIFICATION

57. SETTING INDIAN TARGETSSETTING INDIAN TARGETS
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58. Adapted from Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-279

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60. RESIDUAL CVD RISK WITH INTENSIVE STATIN
THERAPY LESS, BUT STILL UNACCEPTABLY HIGH
PatientsExperiencing
MajorCVDEvents,%
PROVE IT-TIMI 222 IDEAL3
TNT4
n
LDL-C* mg/dL
1
Superko HR. Br J Cardiol. 2006;13:131-136.
2
Cannon CP et al. N Engl J Med. 2004;350:1495-1504.
3
Pedersen TR et al. JAMA. 2005;294:2437-2445.
4
LaRosa JC et al. N Engl J Med. 2005;352:1425-1435.
4162 8888 10,001
95
*Mean or median LDL-C after
treatment
62 104 81 101 77
Statistically significant, but clinically inadequate CVD reduction1
Standard statin therapy
Intensive high-dose statin
therapy

61. BEYOND TARGETING LDL
There are several atherogenic
lipoproteins and LDL
accounts for only about 75%
of them
Residual risk of ASCVD in
statin-treated patients
remains as high as 55%-70%.
 It is thus evident that in
order to reduce ASCVD
effectively, we need to
concentrate on all
atherogenic lipoproteins, and
not just LDL alone

63. increased non-HDL-C is associated
with increased risk of future CV events
even if LDL-C is under
control with statin

64. Better correlate of ASCVD than LDL
Includes TG and Lp(a)
Does not need fasting
Can be easily calculated by total cholesterol and HDL
Surrogate for small dense LDL
NON HDL CHOLESTEROLNON HDL CHOLESTEROL
BETTER THAN LDL?BETTER THAN LDL?

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67.  Prevalence of low HDL-C levels was much higherlow HDL-C levels was much higher in the
South Asian populations than in the other populations
(82% vs 60% of acute MI cases)
 Increaseing HDL-C was associated with a mere 13%
reduction in MI risk in South Asians as compared to 23%
risk reduction in the other Asians
 The patients with low HDL-C are three times more likely
to die after an acute coronary event
INTERHEART: HDL IN INDIANSINTERHEART: HDL IN INDIANS

68. THERAPY FOR INDIAN DYSLIPIDEMIATHERAPY FOR INDIAN DYSLIPIDEMIA
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69. Smoking
It is never too late to quit
smoking. After quitting
smoking,
the ASCVD risk decreases by
50% within 2 years.
Alcohol consumption was
not found to be protective
among South Asians
INTERHEARTINTERHEART
Alcohol

70. DIET AND NUTRITIONDIET AND NUTRITION

71. Statin doses
STATINSSTATINS
Statin adr

72. FIBRATESFIBRATES
A meta-analysis of 18 trials
providing data for 45058
participants, including
2870 major CV events,
4552 coronary events, and
3880 deaths.
It was found that fibrates
could reduce the risk of
major CV events
predominantly by
prevention of coronary
events.
Patients with higher
baseline TG and lower
HDL-C levels benefited
from fenofibrate therapy
in addition to pre-existing
simvastatin (ACCORD).

73. Look for reversible causes
Eg.DM, hypothyroidsm, CKD,
immuocomprised
LSM
TG<500 TG>500
Statin
Achieve LDL target
Achieve non HDL cholesterol
Non-statin drugs
Fibrate
Achieve TG target
Statin
Achieve LDL and
non HDL cholesterol target
Hyper
TG

74. CURRENT LAI GUIDELINES – KEY POINTSCURRENT LAI GUIDELINES – KEY POINTS
Enas EA, Dharmarajan T S. The Lipid Association of India Expert Consensus Statement 2016: A sea change for
management of dyslipidemia in Indians. J Clin Prev Cardiol 2016;5:62-6

75. TAKE HOME MESSAGETAKE HOME MESSAGE
LIFE SIMPLE SEVENLIFE SIMPLE SEVEN
1. No tobacco
2. Physical activity: ≥150 min moderate intensity or
equivalent exercise per week
3. Body-mass index <23 kg/m2
4. Healthy diet: achieving at least four of the five important
dietary components, focusing on fruits and vegetables,
fish, fibre, and sodium intake and sweetened beverage
intake
5. LDL-C level should be below 100mg/dl
6.Blood pressure: <120/80 mmHg
7. Fasting plasma glucose level: <100 mg/d
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76. THANKSTHANKS
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