Hypertriglyceridemia

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Hypertriglyceridemia

• Jenny Shu, IM PGY-1
• November 28, 2012

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Objectives

• To outline an approach to patients with
  hypertriglyceridemia
• To discuss primary and secondary causes of
  hypertriglyceridemia
• To discuss the non-pharmacologic and
  pharmacologic therapies available for
  hypertriglyceridemia

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Definition

• Serum triglyceride (TG) concentration can be
  stratified in terms of population percentiles
  and/or coronary risk
• Normal 1.7 mmol/L
• Borderline high 1.7 to 2.2 mmol/L
• High 2.3 to 5.6 mmol/L
• Very high 5.7 mmol/L

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Sources of plasma TG

• Exogenous
• From dietary fat
• After meal gt 90 circulating TG originate in
  intestine, secreted in CMs
• Endogenous
• From liver
• During fasting, secreted by liver as VLDL
  predominate hydrolyzed by LPL ? free FA

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Lipid metabolism

• High TG because of either
• Increased production from liver and intestine
  (upregulated synthetic and secretory pathways)
• Decreased peripheral catabolism reduced LPL
  activity

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Why do we care?

• Hypertriglyceridemia has implications for
• Cardiovascular disease
• Directly
• Indirectly
• Pancreatitis
• Cerebrovascular disease

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Incidence

• In US National Health and Nutrition Examination
  Surveys (NHANES) from 1999 to 2004
• adults with TG gt 1.7mmol/L 33
• TG gt 2.3 mmol/L 18
• TG gt 5.7 mmol/L -1.7
• TG gt 11.3 mmol/L 0.4

Data from Genest JJ, McNamara JR, Ordovas JM, et
al. J Am Coll Cardiol 1992 19792.
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Types of hypertriglyceridemia

• Primary (inherited)
• Familial chylomicronemia (type I)
• Primary mixed hyperlipidemia (type V)
• Familial hypertriglyceridemia (type IV)
• Familial combined hyperlipoproteinemia (type IIB)
• Familial dysbetalipoproteinemia (type III)
• Secondary (acquired)
• Medications or exogenous substances
• Other medical conditions

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Primary Hypertriglyceridemia

• Familial chylomicronemia (I) primary mixed
  hyperlipidemia (V)
• Both associated with pathologic presence of CMs
  after 12-14h period of fasting
• Clinical features include eruptive xanthomata,
  lipidemia retinalis, HSM, focal neurological
  deficits (irritability), recurrent epigastric
  pain (pancreatitis risk)
• Typically plasma TG gt 10 mmol/L

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Primary Hypertriglyceridemia

• Familial chylomicronemia (I) vs primary mixed
  hyperlipidemia (V)
• Timing of onset
• Biochemically proven deficiencies in LPL, apo CI
  activity or homozygous gene mutations
• Secondary factors
• Greater elevation of total cholesterol

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Clinical Manifestations
Lipemia retinalis usually TG gt 35 mmol/L
Eruptive cutaneous xanthoma trunk, buttocks,
extremities
Palmar crease xanthomas Type III
Tuberous xanthomas extensors, usually Type III
Yuan G et al. CMAJ 20071761113-1120
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When draw blood, you will see

• Creamy supernatant when refrigerated overnight
• (4 degrees C)

Yuan G et al. CMAJ 20071761113-1120
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Primary Hypertriglyceridemia

• Mixed hypertriglyceridemia (Type IV)
• Isolated elevation VLDL (not as TG rich as CMs),
  5-10 population prevalence
• Likely polygenic
• Mod elevated plasma TG (3-10 mmol/L)
• Low levels HDL-C
• Increased risk CAD, obesity insulin resistance,
  DM, htn, hyperuricemia

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Primary Hypertriglyceridemia

• Familial dysbetalipoproteinemia (type III)
• Increase in TG rich lipoprotein remnants IDL or
  beta-VLDL that produce equimolar elevation plasma
  total cholesterol and TG
• Population prevalence 1-2 in 20 000
• Usually homozygotic for binding defective APOE E2
  isoform phenotypic expression often requires
  other RF such as T2DM, obesity, or hypothyroidism
• Also with elevated LDL (interrupted processing
  VLDL) diagnostic when high VLDL-C TG ratio
  with E2/E2 homozygosity
• Increased risk cardiovascular disease, often have
  tuberous/tuberoeruptive xanthomata on extensor
  surfaces

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Primary Hypertriglyceridemia

• Familial combined hyperlipoproteinemia (Type IIB)
• Increased VLDL and LDL, low HDL
• Autosomal dominant with variable penetrance, 2-5
  population prevalence
• At least one 1st degree relative with abn
  lipoprotein profile
• Affected individuals usually obligate
  heterozygosity for LPL or APO3 gene mutation, but
  unknown molecular basis in most cases, other
  genes implicated include USF1, APOA5, APOC3

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Secondary Hypertriglyceridemia

• Other medical conditions
• Renal disease
• Usually ass. With high LDL-C
• Nephrotic syn ass high apo B containing
  lipoproteins such as VLDL
• Obesity/metabolic/DM
• Excess adipose tissue high TG, low HDL-C
• Part of metabolic syndrome
• NASH
• High TG, low HDL-C are defining components
• Statin treatment may be more effective than
  fibrates

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Secondary Hypertriglyceridemia

• Other Medical conditions
• Pregnancy during T3, plasma TG can go up to 3x
  normal
• Minimal clinical consequence
• Should not always assume due to pregnancy can
  get chylomicronemia (rare) ? complicated
  pancreatitis serious health consequences for
  mother and fetus
• Other
• Sedentary lifestyle
• Diet positive energy intake balance and high
  fat/GI
• Paraproteinemias e.g hypergammaglobuliemia in
  macroglobulinemia, yeloma, lymphoma, lymphocytic
  leukemias), autoimmm (SLE)

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Secondary Hypertriglyceridemia

• Medications or Exogenous Substances
• Medications
• Steroids, estrogens (esp po), tamoxifen, anti-htn
  (non cardioselective BB, thiazides),
  isotretinoin, bile acid-binding resins,
  cyclophosphamide, antiretroviral regiemns
  (HAART), psychotropic (phenothiazines, 2nd gen
  anti psychotics)
• Alcohol
• Due to high VLDL /- chylomicronemia
• Can have normal TG because of adaptive increase
  in lipolytic activity

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Approach to Management

• IF TG gt 10 start FIBRATE right away
• Then lifestyle, rule out secondary causes,
  dysglycemia
• If TG 4.5 10,
• Lifestyle intervention, rule out secondary causes
• Address dysglycemia
• Fibrate, ezetimibe, niacin
• If TG 2 4.5,
• Lifestyle intervention, rule out secondary causes
• Address dysglycemia
• If patient already on statin, can intensify
  statin dose
• Or can try any of fibrate, niacin, fish oil,
  ezetimibe

Yuan G et al CMAJ 20071761113-1120
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Conservative Management

• Non-pharmacological
• Conservative measures such as weight reduction,
  diet modification, exercise
• Goal for dieting is to decrease wt overall intake
  of energy/fat/refined carbs (high GI)
• Fat intake should be 10-15 total energy intake
  (15-20 g/d) if severe hypertriglyceridemia
• Avoid alcohol
• Underlying cause hypothyroid, renal disease
  etc.
• Better glycemic control of DM
• Omega-3 FA component of Mediterranean diet and
  fish oils
• Daily consumption 4g restricted energy and
  saturated fat intake can reduce TG by 20
• Rarely effective when sole TG-lowering therapy

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Pharmacologic agents

• Fibrates
• Mainstay of treatment, generally well tolerated
  (rare hepatitis/myositis), other effects include
  reduction of LDL, increase HDL-C activates
  PPAR-alpha to activate LPL action inducing
  lipolysis and elimination of TG rich particles
• Statins
• Inhibit HMG-CoA reductae, not 1st line with TG gt5
  mmol/L as monotherapy
• Safety profile appropriate combo with fibrate as
  FIELD showed no rhabdomyolysis among more than
  1000 patients taking combination statin
  fenofibrate
• Niacin (daily consumption up to 3g)
• Binds GPCR and inhibits adipose breakdown,
  decreases VLDL, increases HDL, lowers TG up to
  45, start low gradually increase
• Other lipid lowering medications
• Ezetimibe inhibits cholesterol absorption, safe
  in combo with fibrates
• Emerging treatments

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Efficacy of Various Agents

• Fibrates 10-50 ?TG
• Ezetimibe 10-15 ?TG
• Statins 7-30 ?TG
• Niacin 20-50 ?TG
• Omega-3 fatty acids 15-20 ?TG

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Evidence for Omega-3

• Contain EPA and DHA dose dependent TG lowering
  effect through various mechanisms decreased
  VLDL secretion, improved VLDL TG clearance
• JELIS trial (Yokoyama et al Lancet 2007 369
  1090-8) found 1.8g/d EPA supp low dose statin
  decreased rate major coronary events compared
  statin monotherapy (? Related to TG since minimal
  reduction in levels (reduction 9 from baseline
  in EPA group vs. 4 in controls) plt00001
• GISSI-P (Lancet 1999 354, 447-455) showed 1g/d
  as 1 cap Omacor reduced all cause mortality and
  sudden death in patients with previous MIs
• Benefit on mortality?
• Recent JAMA systematic review and meta-analysis
  2012 (Rizo et al) ? overall, omega-3 PUFA
  supplementation was not associated with a lower
  risk of all-cause mortality, cardiac death,
  sudden death, myocardial infarction, or stroke
  based on relative and absolute measures of
  association
• Did not support that higher TG lowering dose was
  more protective than lower TG lowering dose

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Fibrates

• Fenofibrate most commonly prescribed
• Lipidil EZ 145 mg od
• Lipidil (fenofibrate) supra 160 mg od
• Fenofibrate 200 mg od
• Gemfibrozil (lopid) 600-1200 mg od
• Bezafibrate (bezalip) 400 mg od

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Safety concern with fibrates

• Baseline and post-initiation
• CK, creatinine, INR (if receiving anti-coagulants
  potentiates actions) risk myalgias, myopathy,
  rhabdomyolysis
• If using in combination with statin, fenofibrate
  recommended (lower risk rhabdo)
• Be aware of implications of renal dysfunction
• Up to 15-20 increase in Cr acceptable, but may
  need to dose reduce
• Potential increased risk for cholelithiasis
  (clofibrate), follow LFTs

Davidson MH et al Am J Cardiol 200799(6A)3C-18C
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Evidence for fibrates

• Meta-analysis looked at 6 RCTs, showing fibrate
  Tx significantly reduced subsequent vascular
  event risk and effective in lowering TG levels
• FIELD
• ACCORD-Lipid

Lee M et al Atherosclerosis 2011217492-498
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Meta-analysis Fibrates CVD
Trial (drug) population of patients with diabetes Primary endpoint entire cohort (p value) Lipid subgroup criterion Analysis(p value)
HHS (gemfibrozil) 4081 (100 male) 3 -34 (0.02) TG gt 2.26 mmol/L LDL-C/HDL-C gt 5.0 Post-hoc -71 (lt0.005)
VA-HIT (gemfibrozil) 2531 (100 male) 25 -22 (0.006) TG 1.69 mmol/L Post-hoc -27 (0.01)
BIP (bezafibrate) 3090 (91 male) 10 -7.3 (0.26) TG 2.26 mmol/L Post-hoc -39.5 (0.02)
FIELD (fenofibrate) 9795 (63 male) 100 -11 (0.16) TG 2.30 mmol/L HDL-C lt 1.086 mmol/L Post-hoc -27 (0.005)
ACCORD (fenofibrate) 5518 (69 male) 100 -8 (0.32) TG 2.30 mmol/L HDL-C 0.879 mmol/L Prespecified -31 (0.06)
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Evidence for fibrates meta analysis
Lee M et al Atherosclerosis 2011217492-498
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FIELD

• Studied effect of fenofibrate on cardiovascular
  disease events in DM patients (not taking statin
  at entry)
• Allocation to fenofibrate (200 mg daily) resulted
  in reductions relative to placebo in plasma
  total-cholesterol concentration of 11,
  LDL-cholesterol level of 12, and TG of 29, and
  increases in levels of HDL cholesterol of 5
  after 4 months of treatment.
• However no statistically significant reduction in
  combined outcome of all-cause mortality and non
  fatal MIs despite reducing TGs
• Did show reduction in non-fatal MI and coronary
  revascularization rate in fenofibrate arm,
  reduction microvascular complications of DM,
  reductions proteinuria and laser eye
  interventions

FIELD Lancet 20053661849-1861
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FIELD
FIELD Lancet 20053661849-1861
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ACCORD-Lipid

• Whether combination therapy with a statin
  (simvastatin) plus a fibrate (fenofibrate) vs.
  statin alone reduces cardiovascular risk in T2DM
  patients at high risk
• Median plasma triglyceride levels decreased from
  1.85 to 1.38 mmol/L in fenofibrate group and from
  1.81 to 1.63 mmol/L in placebo group
• Conclusion was that combo fenofibrate and
  simvastatin did not reduce the rate of fatal
  cardiovascular events, nonfatal myocardial
  infarction, or nonfatal stroke, as compared with
  simvastatin alone
• However pre-specified subgroup with TG gt11.3
  mmol/L and HDL lt 1.89mmol/L could benefit due to
  improvement of primary outcome (p 0.057)
• FDA May 2011- trial not designed for mixed
  dyslipidemia, inappropriate to infer combo
  therapy ineffective

ACCORD LIPID NEJM 20103621563-1574
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ACCORD-Lipid
ACCORD LIPID NEJM 20103621563-1574
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Conclusion

• Classify hypertriglyceridemia based on severity
  moderate RF for cardiovascular/CVS disease,
  severe RF for pancreatitis
• When thinking about etiology, consider primary
  vs. secondary causes
• Based on severity, consider non-pharmacological
  and pharmacological Tx and dont forget about
  safety profile
• Needs to be more high-powered RCTs looking at
  combination therapy and cardiovascular outcomes

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Discussion/Questions

• Thanks for your attention.