Hypertriglyceridemia

Jenny Shu, IM PGY-1November 28, 2012

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

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

Sources of plasma TG

Exogenous From dietary fat

After meal > 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

Lipid metabolism

High TG because of either: Increased production from liver and intestine

(upregulated synthetic and secretory pathways)

Decreased peripheral catabolism – reduced LPL activity

Why do we care?

Hypertriglyceridemia has implications for: Cardiovascular disease

Directly Indirectly

Pancreatitis Cerebrovascular disease

Incidence

Data from Genest JJ, McNamara JR, Ordovas JM, et al. J Am Coll Cardiol 1992; 19:792.

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%

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

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 > 10 mmol/L

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

Clinical Manifestations

Eruptive cutaneous xanthoma – trunk, buttocks, extremities

Lipemia retinalis – usually TG > 35 mmol/L

Palmar crease xanthomas – Type III

Tuberous xanthomas – extensors, usually Type III

Yuan G et al. CMAJ 2007;176:1113-1120

When draw blood, you will see

Creamy supernatant when refrigerated overnight

(4 degrees C)

Yuan G et al. CMAJ 2007;176:1113-1120

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

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

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

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

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)

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

Approach to Management 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, ezetimibeYuan G et al CMAJ 2007;176:1113-1120

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

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 >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) 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

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

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) 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? 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 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

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 LFT’sDavidson MH et al Am J Cardiol 2007;99(6A):3C-18C

Evidence for fibrates

Meta-analysis looked at 6 RCT’s, showing fibrate Tx significantly reduced subsequent vascular event risk and effective in lowering TG levels 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/LLDL-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/LHDL-C < 1.086

mmol/L

Post-hoc-27%

(0.005)

ACCORD(fenofibrate)5518 (69% male)

100 -8% (0.32) TG ≥ 2.30 mmol/LHDL-C ≤ 0.879

mmol/L

Prespecified-31% (0.06)

Evidence for fibrates – meta analysis

Lee M et al Atherosclerosis 2011;217:492-498

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 MI’s despite reducing TG’s

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 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 >11.3 mmol/L and HDL < 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 2010;362:1563-1574

ACCORD-Lipid

ACCORD LIPID NEJM 2010;362:1563-1574

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 don’t forget about safety profile

Needs to be more high-powered RCT’s looking at combination therapy and cardiovascular outcomes

Discussion/Questions

Thanks for your attention.