Transcript Hypertriglyceridemia - London Health Sciences Centre

Hypertriglyceridemia
Jenny Shu, IM PGY-1
November 28, 2012
Objectives
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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
Definition
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Serum triglyceride (TG) concentration
can be stratified in terms of population
percentiles and/or coronary risk
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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
Sources of plasma TG
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Exogenous
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From dietary fat
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After meal > 90% circulating TG originate in
intestine, secreted in CMs
Endogenous
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From liver
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During fasting, secreted by liver as VLDL
predominate – hydrolyzed by LPL  free FA
Lipid metabolism
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High TG because of either:
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Increased production from liver and intestine
(upregulated synthetic and secretory pathways)
Decreased peripheral catabolism – reduced LPL
activity
Why do we care?
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Hypertriglyceridemia has implications
for:
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Cardiovascular disease
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Directly
Indirectly
Pancreatitis
Cerebrovascular disease
Incidence
In US National Health and
Nutrition Examination Surveys
(NHANES) from 1999 to 2004
% adults with TG >
1.7mmol/L – 33%
TG > 2.3 mmol/L – 18%
TG > 5.7 mmol/L -1.7%
TG > 11.3 mmol/L – 0.4%
Data from Genest JJ, McNamara JR, Ordovas JM, et al. J Am Coll Cardiol 1992; 19:792.
Types of hypertriglyceridemia
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Primary (inherited)
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Familial chylomicronemia (type I)
Primary mixed hyperlipidemia (type V)
Familial hypertriglyceridemia (type IV)
Familial combined hyperlipoproteinemia (type IIB)
Familial dysbetalipoproteinemia (type III)
Secondary (acquired)
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Medications or exogenous substances
Other medical conditions
Primary Hypertriglyceridemia
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Familial chylomicronemia (I) &
primary mixed hyperlipidemia (V)
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Both associated with pathologic presence
of CMs after 12-14h period of fasting
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Clinical features include eruptive xanthomata,
lipidemia retinalis, HSM, focal neurological
deficits (irritability), recurrent epigastric pain
(pancreatitis risk)
Typically plasma TG > 10 mmol/L
Primary Hypertriglyceridemia
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Familial chylomicronemia (I) vs
primary mixed hyperlipidemia (V)
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Timing of onset
Biochemically proven deficiencies in LPL,
apo CI activity or homozygous gene
mutations
Secondary factors
Greater elevation of total cholesterol
Clinical Manifestations
Eruptive cutaneous
xanthoma – trunk,
buttocks, extremities
Palmar crease
xanthomas – Type
III
Lipemia retinalis –
usually TG > 35
mmol/L
Tuberous xanthomas
– extensors, usually
Yuan G et al. CMAJ 2007;176:1113-1120
Type III
When draw blood, you will see
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Creamy
supernatant when
refrigerated
overnight
(4 degrees C)
Yuan G et al. CMAJ 2007;176:1113-1120
Primary Hypertriglyceridemia
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Mixed hypertriglyceridemia
(Type IV)
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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
Primary Hypertriglyceridemia
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Familial dysbetalipoproteinemia (type III)
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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
Primary Hypertriglyceridemia
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Familial combined hyperlipoproteinemia
(Type IIB)
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Increased VLDL and LDL, low HDL
Autosomal dominant with variable penetrance, 25% population prevalence
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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
Secondary
Hypertriglyceridemia
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Other medical conditions
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Renal disease
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Obesity/metabolic/DM
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Usually ass. With high LDL-C
Nephrotic syn ass high apo B containing lipoproteins
such as VLDL
Excess adipose tissue – high TG, low HDL-C
Part of metabolic syndrome
NASH
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High TG, low HDL-C are defining components
Statin treatment may be more effective than fibrates
Secondary
Hypertriglyceridemia
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Other Medical conditions
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Pregnancy – during T3, plasma TG can go up to
3x normal
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Minimal clinical consequence
Should not always assume due to pregnancy – can get
chylomicronemia (rare)  complicated pancreatitis =
serious health consequences for mother and fetus
Other
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Sedentary lifestyle
Diet – positive energy intake balance and high fat/GI
Paraproteinemias e.g hypergammaglobuliemia in
macroglobulinemia, yeloma, lymphoma, lymphocytic
leukemias), autoimmm (SLE)
Secondary
Hypertriglyceridemia
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Medications or Exogenous Substances
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Medications
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Steroids, estrogens (esp po), tamoxifen, anti-htn (non
cardioselective BB, thiazides), isotretinoin, bile acidbinding resins, cyclophosphamide, antiretroviral regiemns
(HAART), psychotropic (phenothiazines, 2nd gen anti
psychotics)
Alcohol
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Due to high VLDL +/- chylomicronemia
Can have normal TG because of adaptive increase in
lipolytic activity
Approach to Management
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IF TG > 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 2007;176:1113-1120
Conservative Management
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Non-pharmacological
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Conservative measures such as weight reduction, diet
modification, exercise
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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
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Daily consumption 4g + restricted energy and saturated fat
intake can reduce TG by 20%
Rarely effective when sole TG-lowering therapy
Pharmacologic agents
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Fibrates
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Statins
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Binds GPCR and inhibits adipose breakdown, decreases VLDL, increases
HDL, lowers TG up to 45%, start low & gradually increase
Other lipid lowering medications
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Inhibit HMG-CoA reductae, not 1st line with TG >5 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)
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Mainstay of treatment, generally well tolerated (rare hepatitis/myositis),
other effects include reduction of LDL, increase HDL-C – activates PPARalpha to activate LPL action inducing lipolysis and elimination of TG rich
particles
Ezetimibe – inhibits cholesterol absorption, safe in combo with fibrates
Emerging treatments
Efficacy of Various Agents
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Fibrates
Ezetimibe
Statins
Niacin
Omega-3 fatty acids
10-50% ↓TG
10-15% ↓TG
7-30% ↓TG
20-50% ↓TG
15-20% ↓TG
Evidence for Omega-3
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Contain EPA and DHA – dose dependent TG lowering effect
through various mechanisms – decreased VLDL secretion,
improved VLDL TG clearance
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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) p<0·0001
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 MI’s
Benefit on mortality?
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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
Fibrates
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Fenofibrate – most commonly
prescribed
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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
Safety concern with fibrates
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Baseline and post-initiation
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If using in combination with statin,
fenofibrate recommended (lower risk rhabdo)
Be aware of implications of renal dysfunction
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CK, creatinine, INR (if receiving anti-coagulants –
potentiates actions) – risk myalgias, myopathy,
rhabdomyolysis
Up to 15-20% increase in Cr acceptable, but may
need to dose reduce
Potential increased risk for cholelithiasis
(clofibrate), follow LFT’s
Davidson MH et al Am J Cardiol 2007;99(6A):3C-18C
Evidence for fibrates
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Meta-analysis looked at 6 RCT’s,
showing fibrate Tx significantly reduced
subsequent vascular event risk and
effective in lowering TG levels
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FIELD
ACCORD-Lipid
Lee M et al Atherosclerosis 2011;217:492-498
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 > 2.26 mmol/L
LDL-C/HDL-C > 5.0
Post-hoc
-71%
(<0.005)
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 < 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)
Evidence for fibrates
– meta analysis
Lee M et al Atherosclerosis 2011;217:492-498
FIELD
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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 MI’s despite
reducing TG’s
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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 2005;366:1849-1861
FIELD
FIELD Lancet 2005;366:1849-1861
ACCORD-Lipid
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Whether combination therapy with a statin (simvastatin) plus a
fibrate (fenofibrate) vs. statin alone reduces cardiovascular risk
in T2DM patients at high risk
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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
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However pre-specified subgroup with TG >11.3 mmol/L and HDL
< 1.89mmol/L could benefit due to improvement of primary
outcome (p = 0.057)
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FDA May 2011- trial not designed for mixed dyslipidemia, inappropriate
to infer combo therapy ineffective
ACCORD LIPID NEJM 2010;362:1563-1574
ACCORD-Lipid
ACCORD LIPID NEJM 2010;362:1563-1574
Conclusion
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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 don’t forget about safety
profile
Needs to be more high-powered RCT’s looking at
combination therapy and cardiovascular outcomes
Discussion/Questions
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Thanks for your attention.