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Hypertriglyceridemia Jenny Shu, IM PGY-1 November 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 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 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 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 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, 25% 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 Obesity/metabolic/DM 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 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 acidbinding 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, ezetimibe Yuan 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 Statins Binds GPCR and inhibits adipose breakdown, decreases VLDL, increases HDL, lowers TG up to 45%, start low & gradually increase Other lipid lowering medications 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) 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 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 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 If using in combination with statin, fenofibrate recommended (lower risk rhabdo) Be aware of implications of renal dysfunction 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 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/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 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.