Hypertriglyceridemia

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Hypertriglyceridemia

• Why dont we address it at the next visit?
• Jenny Gordon
• March 26, 2004

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Overview

• Case Presentations
• Pathophysiology- review the lipids
• Triglyceride Disorders
• Secondary causes of Hypertriglyceridemia
• Cardiac Risk factor
• Current guidelines
• Treatment options

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Patient M.B.

• 40 y/o male comes in to establish care, CPE,
  wants to make some healthy changes. H/O ETOH
  abuse, quit 6 months ago. Quit smoking 6 days
  ago. Concerned about cholesterol, heart disease ,
  etc.
• FH-neg for CAD, HTN, DM , CA
• PMH- ETOH x 25 yrs, Smoking-25pack years
• Meds-Nicotine Patch, MVI

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Patient M.B.

• PE-
• BP 153/85, P 84, Wt 181 lb
• Physical exam unremarkable except for partial
  dentures and mild abdominal obesity
• Labs-
• CBC, Chem 7, LFTs wnl
• Tchol 275, HDL 31, LDL 176, TG 34
• Plan- Diet and Exercise, nutrition visit, recheck
  chol 3 months

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Patient M.B.

• Returns 2 months later- he has started smoking,
  wants to quit again. Has seen nutrition and made
  some diet changes-eating oatmeal and fruit for
  breakfast-getting dental surgery, so needs to eat
  soft foods.
• Plan Zyban, Patch , SFGH smoking cessation class
• Returns 1 month later-not smoking ,eating oatmeal
  and bran, wants to focus on diet changes after
  smoking cessation

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Patient M.B.

• Returns 2 mo later- still not smoking or drinking
• BP130/86
• T Chol 258, HDL 49, LDL 129, TG 398
• Not ready to take medication, really wants to try
  diet change wholeheartedly now. Pt wants to try a
  vegetarian diet for 3 months and see if he can
  decrease his TG. Discussed starting lipid
  lowering meds if still high at that point.

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Patient R.P.

• 57 y/o female seen very briefly in ACC for URI
• Review of labs shows TG 620, TSH 15.2, HgA1c 13.9
• What is causing her high TGs?

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Questions I Had

• Were they REALLY fasting or not?
• Is it a risk factor for heart disease or not?
  What do triglycerides do in the body?
• Do I need any other labs? To rule out any other
  things?
• Should I treat with meds? Which ones?
• Why is it so hard to spell Hypertriglyceridemia?
• Maybe we should address this at the next visit
• ???

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Review the Lipids (briefly!)

• Lipids (cholesterol and triglycerides)
• insoluble in plasma
• circulating lipid is bound to lipoprotein
• lipoprotein
• esterified and unesterified cholesterol
• triglycerides
• phospholipids
• Protein -known as apolipoproteins or apoproteins.
  
• serve as cofactors for enzymes and ligands for
  receptors.

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Review the Lipids (briefly!)

• Chylomicrons - Chol and TG
• A-I, A-II, A-IV, B-48, C-I,C-II, C-III, and E.
• VLDL- TG and less chol
• B-100, C-I, C-II, C-III, and E.
• IDL- Chol esters and TG.
• B-100, C-III, and E.
• LDL- chol esters
• B-100.
• HDL- Chol esters.
• A-I, A-II, C-I, C-II, C-III, D, and E.

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Atherogenic lipids

• VLDL
• IDL
• LDL especially small dense LDL

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Elevated Triglycerides

• Normal lt150 mg/dL
• Borderline high 150199 mg/dL
• High 200499 mg/dL
• Very high gt500 mg/dL

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Fredrickson Classification
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Disorders of TG Metabolism
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Borderline High Triglycerides(150199 mg/dL)

• Acquired causes
• Overweight and obesity
• Physical inactivity
• Cigarette smoking
• Excess alcohol intake
• High carbohydrate intake
• (gt60 of total energy)
• Secondary causes
• Genetic causes
• Various genetic polymorphisms

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High Triglycerides(200499 mg/dL)

• Acquired causes
• Same as for borderline high triglycerides
  (usually combined with foregoing causes)
• Secondary causes
• Genetic patterns
• Familial combined hyperlipidemia
• Familial hypertriglyceridemia
• Polygenic hypertriglyceridemia
• Familial dysbetalipoproteinemia

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Very High Triglycerides(gt500 mg/dL)

• Usually combined causes
• Same as for high triglycerides
• Familial lipoprotein lipase deficiency
• Familial apolipoprotein C-II deficiency

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Secondary causes of Hypertriglyceridemia

•  Type 2 diabetes mellitus
•   Cholestatic liver diseases
•   Nephrotic syndrome
•  Chronic renal failure
• Hypothyroidism
• Cigarette smoking
• Obesity
•    Drugs (Tamoxifene, glucocorticoids,
  cyclosporine, Estrogen, Protease inhibitors)

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Additional Labs to order

• Thyroid function tests
• Creatinine
• Fasting glucose

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Chylomicronemia syndrometriglycerides gt2000
mg/dL)

• Eruptive skin xanthomas
• Hepatic steatosis
• Lipemia retinalis
• Mental changes
• High risk for pancreatitis

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Eruptive Xanthoma
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Palmare Striatum
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A Risk Factor for Heart Disease?

• Hokanson and Austins meta-analysis of
  prospective population-based studies
• association between the serum triglyceride
  concentration and cardiovascular disease
• pooled analysis of 46,413 men enrolled in 16
  studies
• univariate risk ratio (RR) for triglyceride of
  1.32 (95 percent CI 1.26 to 1.39) for men
• five studies of nearly 10,800 women were
  associated with a univariate RR of 1.76 (95
  percent CI 1.50 to 2.07).
• With adjustment for HDL and other risk factors,
  correlation was still significant

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A Risk Factor for Heart Disease?

• Physician's Health Study
• The risk of myocardial infarction (MI) was
  highest among men with the highest tertile for
  both triglyceride and the TC/HDL-C ratio
• Helsinki Heart Study
• CHD risk was highest in the cohort with a
  triglyceride level gt201 mg/dL and an
  LDL-cholesterol/HDL-cholesterol ratio gt5.0. A
  benefit from lipid-lowering from gemfibrozol was
  confined to this high-risk subgroup

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A Risk Factor for Heart Disease?

• Copenhagen Male Study
• gradient of CHD risk with increasing serum
  triglycerides
• even after adjustment for other major CHD risk
  factors, including LDL-cholesterol.
• The protective effect of a high HDL-C
  concentration above 68 mg/dL was not seen in the
  highest third of triglyceride levels.

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A Risk Factor for Heart Disease?

• It still remains debated whether treating
  hypertriglyceridemia really independently lowers
  CHD risk, however almost everyone can agree that
  elevated triglycerides are a very important
  marker for
• 1. Metabolic Syndrome
• 2. Atherogenic dyslipidemia ( high small dense
  LDL, low HDL, high atherogenic remnants)

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Associated Abnormalities

• Low levels of HDL-C
• The presence of small, dense LDL particles.
• The presence of atherogenic triglyceride-rich
  lipoprotein remnants  
• Insulin resistance
•  Increases in coagulability and viscosity

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TG and Small dense LDL
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Why High TG causes Low HDL and High small dense
LDL

• High levels of VLDL
• VLDL exchanges its TG for Chol from HDL
• Chol rich VLDL- very atherogenic!
• Chol depleted HDL-can easily dissociate from apo
  A-1 and be cleared
• VLDL exchanges its TG for Chol from LDL
• LDL gets denser and smaller-Very atherogenic

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Identify Metabolic Syndrome

• Any three of the following
• - Triglycerides 150 mg/dL
•  HDL cholesterol lt40 mg/dL in men and lt50 mg/dL
  in women
•  Blood pressure 130/ 85 mmHg
•  Fasting glucose 110 mg/dL
• waist circumference in men gt40 in and in women 35
  in

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TG and Insulin Resistance
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TG and Insulin Resistance
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Treat Metabolic Syndrome

• Treat HTN
• Treat Obesity/Abdominal Obesity
• Weight reduction
• Diet and exercise
• ASA if high CHD risk for prothrombotic state
• Treat lipid abnormalities
• Treat insulin insensitivity (Controversial)

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Treating Lipids in Insulin Resistance
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Guidelines for treatment

• ATP-III focuses on non-HDL( Total Chol- HDL) as
  secondary goal after LDL has been addressed .
  Why?
• TG is more variable day to day than non-HDL
• Non-HDL may actually turn out to be a more
  powerful predictor of CHD risk than LDL
• Reflects highly atherogenic VLDL LDL

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Borderline TG (150-199)

• Primary goal achieve LDL-C goal
• Life-habit changes first-line therapy
• Body weight control
• Regular physical activity
• Smoking cessation
• Restriction of alcohol use (when consumed in
  excess)
• Avoid high carbohydrate intakes
• Drug therapy Triglycerides in this range not a
  direct target of drug therapy

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High TG (200-499)

• Primary goal achieve LDL-C goal
• Secondary goal achieve non-HDL-C goal 30 mg/dL
  higher than LDL-C goal
• First-line therapy for high triglycerides
  TLC-emphasize weight reduction and exercise
• Second-line therapy drugs to achieve non-HDL-C
  goal
• Statins lowers both LDL-C and VLDL-C
• Fibrates lowers VLDL-triglycerides and VLDL-C
• Nicotinic acid lowers VLDL-triglycerides and
  VLDL-C

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High TG (200-499) cont..

• Alternate approaches to drug therapy for lowering
  non-HDL-C
• High doses of statins (lower both LDL-C and
  VLDL-C)
• Moderate doses of statins and triglyceride-lowerin
  g drug (fibrate or nicotinic acid)
• Caution increased frequency of myopathy with
  statins fibrates

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Very High TG (gt500)

• Goals of therapy
• Triglyceride lowering to prevent acute
  pancreatitis (first priority)
• Prevention of CHD (second priority)
• Triglyceride lowering to prevent pancreatitis
• Very low-fat diet when TG gt1000 mg/dL (lt15 of
  total calories as fat)
• Institute weight reduction/physical activity
• Fish oils

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Very High TG (gt500) cont

• Triglyceride-lowering drugs (fibrate or nicotinic
  acid) most effective
• Statins not first-line agent for very high
  triglycerides (statins not powerful
  triglyceride-lowering drugs)
• Bile acid sequestrants contraindicatedtend to
  raise triglycerides

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Summary of Non-Hdl goals
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Lipid Lowering Drugs
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Main Points

• Hypertriglyceridemia is a marker for metabolic
  syndrome, increased CHD, and multiple associated
  lipid abnormalities that further increase CHD
  risk
• Treatment involves
• Review meds
• Look for acquired causes and secondary causes
  (TSH, Cr, Fasting Glucose)
• Therapeutic Lifestyle changes
• Meds- statins, niacin, fibrates,

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References

• ATP-III, Third Report of the National Cholesterol
  education program expert panel. Nhlb.nih.gov
• Gotto,A., et al, High Density lipoprotein
  cholesterol and triglycerides as therapeutic
  targets.., Am Heart Journal, December, 2002.
• Watson,K., et al, Lipid abnormalities in insulin
  resistance states, Rev Cardiovasc Med. 2003, Vol
  4, No 4

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References cont

• Hokansen,J. et al, Plasma triglyceride level is
  a risk factor for cardiovascular disease, Jou
  Cardiovascular Risk April 1996
• Collins, R., et al, Heart protection study of
  cholesterol lowering with simvastatin in 5963
  people with diabetes., Lancet, 2003 Vol 361
  p2005-2016.
• Up To Date online-multiple topics
• Broset, Tom, Lipid clinic SFGH Gladstone
  Cardiovascular Institute

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