Hypertriglyceridemia JANEL LIANE CALA, RPH MEDICAL CENTER HOSPITAL - - PowerPoint PPT Presentation

Hypertriglyceridemia

JANEL LIANE CALA, RPH MEDICAL CENTER HOSPITAL

Objectives:

 To define hypertriglyceridemia  To discuss pathophysiology behind hypertriglyceridemia  To identify the diagnostic criteria for hypertriglyceridemia  To tabulate the types of hypertriglyceridemia  To list the common causes of Hypertriglyceridemia  To state the clinical manifestations and physiologic effects of hypertriglyceridemia  To enumerate the possible pharmacologic and non-pharmacologic treatments behind hypertriglyceridemia  To summarize the guideline recommendations in dealing with hypertriglyceridemia

Hypertriglyceridemia (HTG)

 A condition in which the fasting plasma concentration of triglyceride exceeds a threshold value (eg, >1·7 mmol/L [>150 mg/dL])  Proposed definitions of HTG varies (see table below)  Usually asymptomatic until TG >1000-2000 mg/dL

Reference: The polygenic nature of hypertriglyceridemia: implications for definition, diagnosis, and management triglyceridespanel.ajconline.org/Content/PDFs/4-Hegele-Polygenic.pdf

Types of Lipoproteins

Source: http://apoa1.org/2015/10/not-all-hdl-molecules-are-created-equal/

Source: An Update on Hyperlipidemia and its Management http://jpma.org.pk/full_article_text .php?article_id=4665

Apolipoproteins- proteins that bind lipids to form lipoproteins

• act as structural components of lipoproteins, cofactors for

enzymes, and ligand for cell-surface receptors APOLIPOPROTEIN LIPOPROTEIN FUNCTIONS Apo A-I HDL Structural component of HDL Apo B-100 VLDL, IDL, LDL Assembly and secretion

• f VLDL from liver;

Binding protein for LDL-R

• n cells

Apo C-II Chylomicron, VLDL, HDL LPL activator Apo E Chylomicron, VLDL Ligand for receptor mediated clearance of VLDL and Chylomicron in the circulation

APOLIPOPROTEINS

Source: https://www.researchgate.net/figure/278524013_fig2_Figure-13-Schematic-of-the-exogenous-and-endogenous-lipid-metabolism-pathways

Lipid Metabolism Pathway

Causes of HTG

HTG Secondary Drug- Induced Predisposing Conditions Primary Genetic Disorders

Primary Causes of HTG

PRIMARY CAUSES DEFINITION Familial HTG

• High TG (200- 500 mg/dl)
• May be due to VLDL overproduction and/or impaired VLDL catabolism

VLDL overproduced unable to increase VLDL catabolism

• Strongly associated with hyperinsulinemia, hyperglycemia, and

hypertension

Familial Combined Hyperlipidemia (FCHL)

• Overproduction of hepatically derived ApoB-100 associated with VLDL
• Elevated TC and/or TG; Low HDL
• Elevated ApoB and small dense LDL
• Associated with Coronary risk - accounts for 1/3 to ½ of familial causes of

CHD

Primary Causes of HTG

PRIMARY CAUSES DEFINITION Hyperchylomicronemia

• Increased chylomicron and VLDL; Partial LPL deficiency
• Usually presents with hepatosplenomegaly, eruptive xanthomas
• Chylomicronemia Syndrome (TG >1000mg/dl)

+ memory loss, abdominal pain, pancreatitis, lipemia retinalis

• Ultracentrifugal analysis

+ creamy supernatant (Chylomicron); turbid infranatant (VLDL) Familial Dysbetalipoproteinemia

• Presence of two Apo E2 alleles; (N= Apo 3/3 allele);
• Chylomicrons and VLDL with ApoE2- not cleared efficiently
• Beta- VLDL formation (dense VLDL particle)
• Premature CHD and PVD are common
• Tuberoeruptive xanthomas, xanthoma palmare striatum

Clinical Manifestations of Primary HTG

Reference: Hypertriglyceridemia: its etiology, effects and treatment http://www.cmaj.ca/content/176/8/1113.full.pdf+html

• A. Eruptive cutaneous xanthomas
• B. Lipemic plasma
• C. Lipemia retinalis
• D. Tuberous xanthomas
• E. Palmar crease xanthomas

Secondary Causes of HTG

 Obesity, Metabolic Syndrome, Diabetes  increased plasma concentrations of VLDL  deficient lipoprotein lipase activity  increased cholesteryl ester transfer protein activity  increased flux of free fatty acids to the liver  Acromegaly- decreased activity of Hepatic Lipase and LPL; increased insulin resistance  Pregnancy- estrogen-induced stimulation of the secretion of VLDL

• decreased LPL and HL activity

 Hypothyroidism- reduced LPL activity (Thyroid Hormones stimulate LPL)  Renal failure- reduced LPL activity; decreased clearance of TG-rich lipoprotein

Reference: Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3431581/ Hypertriglyceridemia: its etiology, effects and treatment http://www.cmaj.ca/content/176/8/1113.full.pdf+html

Secondary Causes of HTG- Drugs

 Alcohol- increased hepatic FA synthesis + decreased FA oxidation  hepatic VLDL secretion  Oral estrogen therapy – reduces levels of LPL and HL decreased lipoprotein clearance  Tamoxifen- Selective Estrogen Receptor Modulator; reduction of LPL activity  Glucocorticoids - decreased clearance of TG rich lipoproteins

• increased FA synthesis (synthesis of FA synthase)
• insulin resistance
• increased cholesterol production (HMG CoA reductase induction)

Reference: Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3431581/ Hypertriglyceridemia: its etiology, effects and treatment http://www.cmaj.ca/content/176/8/1113.full.pdf+html Hypertriglyceride Induced Pancreatitis http://cdn.intechopen.com/pdfs-wm/26197.pdf

Correlation of HTG with CVD in Obesity

Source: http://www.mdpi.com/1422-0067/15/4/6184/htm

Treatment Goals of Hypertriglyceridemia

HYPERTRIGLYCERIDEMIA Fasting TG level (mg/dl) Treatment Goal Treatment

Mild Moderate 150-199 200-999 Reduction of Cardiovascular risk

• Lifestyle changes
• Statin Therapy
• +/- TG lowering drugs

Severe Very Severe 1000-1999 >2000 Prevent Acute Pancreatitis

• Lifestyle Changes
• Fibrates (1st line)/

Niacin/ Fish Oil

• +/- Statin

Lifestyle Changes = Weight loss (Obese patients), Aerobic Exercise, Strict Glycemic Control, Avoiding Medications that increase TG levels

References: Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline https://www.endocrine.org/~/media/endosociety/Files/Publications/Clinical%20Practice%20Guidelines/082312_Hypertriglyceridemia_FinalA.PDF Hypertriglyceridemia, Journal of the American Board of Family Medicine http://www.jabfm.org/content/19/3/310.full

Source: Hypertriglyceridemia, American Academy of Family Physicians http://www.aafp.org/afp/2007/0501/p1365.html

Treatment Flowchart

Non-Pharmacologic Treatment

 Weight Loss for Obese Patients (BMI >= 30)  Mild-to-moderate weight loss (5 – 10% wt loss)  Reduce TG levels by 22%  Increase HDL-C by 9%.8  Decrease LDL by 40%  Lowers blood glucose  Diet and Exercise are the cornerstones of Weight loss  Excess calories are converted to TG then stored in adipose  To prevent this conversion (and eventually lower TG), decrease the caloric intake and increase physical activity

Source: Hypertriglyceridemia-induced recurrent acute pancreatitis: A case-based review http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3263185/ Hypertriglyceridemia Management in Patients With Diabetes, US Pharmacist http://www.uspharmacist.com/content/s/68/c/13446

 DIET: Reduced calories, fat, and refined carbohydrate intake  Chylomicrons are the product of dietary fat absorption  Reduce fat to 10 – 15% of total energy intake (about 15 – 20 gm / day)  EXERCISE: 30 mins of Moderate Intensity Aerobic Exercise about 4x/wk can decrease TG and increase HDL Walking briskly (>=3mph) Water aerobics Bicycling (<10mph) Ballroom dancing General gardening  Alcohol should be avoided because it raises TG levels

Source: Hypertriglyceridemia-induced recurrent acute pancreatitis: A case-based review http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3263185/ Hypertriglyceridemia Management in Patients With Diabetes, US Pharmacist http://www.uspharmacist.com/content/s/68/c/13446 Measuring Physical Activity Intensity, Center for Disease Control and Prevention http://www.cdc.gov/physicalactivity/basics/measuring/

Pharmacologic Treatment for Hypertriglyceridemia

Source: Hypertriglyceridemia Management in Patients With Diabetes, US Pharmacist http://www.uspharmacist.com/content/s/68/c/13446

Fibrates

 modulate peroxisome proliferator activated receptors-α (PPAR-α) in the liver  Decreased hepatic secretion of VLDL  Increased lipolysis of the plasma triglyceride  PPAR-a activator; upregulate ApoCII and ApoAI  ApoAI- building block of HDL  Increased HDL levels  ApoCII activates LPL  Increased VLDL catabolism  Can lower TG significantly  However, if TG is high, it can increase LDL  Side Effects:  Increased LFTs (Dose Related)  GI disturbances- Abdominal Pain, N/V  Dyspepsia

Source: Hypertriglyceridemia-induced recurrent acute pancreatitis: A case-based review http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3263185/ Hypertriglyceridemia Management in Patients With Diabetes, US Pharmacist http://www.uspharmacist.com/content/s/68/c/13446

Gemfibrozil VS Fenofibrates

 Effect on TG: Both drugs lower TG levels by 20% to 50%  Both gemfibrozil and fenofibrate are taken orally  Fenofibrate is given once daily compared with Gemfibrozil (BID)  Fenofibrate: Peak= 2-8 hr / Half life= 20 hrs  Gemfibrozil: Peak= 1-2 hr/ Half-life= 1.5 hrs  Metabolism:  Gemfibrozil extensively metabolized in liver  CYP3A4 substrate  strong inhibitor of CYP2C9 and CYP2C19; also inhibits CYP2C8  Fenofibrate is minimally metabolized in the liver, which limits its potential for drug-drug interactions

Source: Hypertriglyceridemia-induced recurrent acute pancreatitis: A case-based review http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3263185/ Hypertriglyceridemia Management in Patients With Diabetes, US Pharmacist http://www.uspharmacist.com/content/s/68/c/13446

Fibrates

Fibrates are associated with an increased risk of myopathy and rhabdomyolysis, especially when used in combination with statins National Lipid Association (NLA) Statin Safety Task Statin + Gemfibrozil: should generally be avoided (increased risk of rhabdomyolysis) Gemfibrozil inhibits hepatic glucuronidation of statin Statin + Fenofibrate: lesser DI, less risk of rhabdomyolisis Risk factors that may predispose patients to rhabdomyolysis in Fenofibrate + Statin therapy advanced age female gender - smaller vascular volumes; reduced muscle mass greater tissue drug exposure/ statin dose renal or liver disease hypothyroidism excessive alcohol intake

References: NKF KDOQI Guidelines http://www2.kidney.org/professionals/kdoqi/guidelines_lipids/iii.htm Hypertriglyceridemia Management in Patients With Diabetes, US Pharmacist http://www.uspharmacist.com/content/s/68/c/13446 Statins and their interactions with other lipid-modifying medications: safety issues in the elderly http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110829/

Fibrates: Drug Interactions

 Fibrates + Statins: Fibrates can increase the risk of myopathies and rhabdomyolysis, especially with Gemfibrozil  Monitor LFTs when fibrates are used alone or in combination with statins The NLA or NCEP ATP-III guidelines do not provide specific recommendations for liver function monitoring with fibrate therapy. However, baseline measures, periodic follow-up monitoring, and reduction or discontinuation

• f therapy with transaminase levels ≥3 times the ULN is prudent

 Cholelithiasis: fibrates increase cholesterol secretion in the bile  Fibrate + Colchicine: additive effect; both drugs cause myopathy by themselves  Gemfibrozil + Repaglinide: increased hypoglycemic effects; Repaglinide is CYP2C8 substrate; Gemfibrozil is CYP2C8 inhibitor  Fibrates + Warfarin: Increased effect of warfarin (CYP2C9 inhibition)

References: Management of Hypertriglyceridemia http://www.aafp.org/afp/2007/0501/p1365.html Hypertriglyceridemia Management in Patients With Diabetes, US Pharmacist http://www.uspharmacist.com/content/s/68/c/13446

Niacin (Nicotinic Acid/ Vitamin B3)

 Decreases hepatic synthesis of VLDL and LDL  Increased chylomicron removal in plasma  Side effects:  Flushing, pruritus  N/ V/ diarrhea, GI distress  Hyperglycemia, Hyperuricemia  Hepatotoxicity  SR (Slo-Niacin) has less flushing than IR (Niacor) but more hepatotoxicity.  ER (Niaspan) has the least flushing and least hepatotoxicity but most expensive.  IR, SR, and ER Formulations are not interchangeable.

Source: Hypertriglyceridemia-induced recurrent acute pancreatitis: A case-based review http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3263185/ Hypertriglyceridemia Management in Patients With Diabetes, US Pharmacist http://www.uspharmacist.com/content/s/68/c/13446

Niacin (Nicotinic Acid/ Vitamin B3)

 Take with food. Avoid hot beverages and spicy foods (worsen flushing) while taking Niacin.  Slow dose titration and the use of aspirin taken 30 minutes before the niacin may improve flushing.  Niacin + Lovastatin: Advicor (Max: 2000mg/40mg)  Niacin + Simvastatin: Simcor (Max: 2000mg/40mg)  Monitor LFTs if given concomitantly for other hepatotoxic drugs.  Bile Acid Sequestrants + Niacin: Separate by 4-6 hours  Note:  Check LFTs @ baseline, q6-12 weeks for the first year and then q6months  Monitor  Blood glucose (Diabetes)  Uric Acid (Gout)

Source: Hypertriglyceridemia: its etiology, effects and treatment http://www.cmaj.ca/content/176/8/1113.full Hypertriglyceridemia Management in Patients With Diabetes, US Pharmacist http://www.uspharmacist.com/content/s/68/c/13446

Fish Oil

 Mechanism not completely understood; lower TG levels 20% to 45% by decreasing the production of VLDL and stimulating the oxidation of fatty acids  Indicated as adjunct to diet if TG >500mg/dl  Use with caution to patients with shellfish and/or fish allergy  Adjunct to diet when TG >500 mg/dl  Side effects:  Burping, dyspepsia  Taste perversions  Arthralgias  Prolonged bleeding time: monitor INR if given with warfarin  Omega-3 fatty acids decrease platelet aggregation  FDA has noted that an intake in excess of >3g could result in excessive bleeding in some individuals

References: Hypertriglyceridemia Management in Patients With Diabetes, US Pharmacist http://www.uspharmacist.com/content/s/68/c/13446 Fish Consumption, Fish Oil, Omega-3 Fatty Acids, and Cardiovascular Disease http://circ.ahajournals.org/content/106/21/2747.full

Fish Oil: Lovaza VS Vascepa

 Omega-3 Acid Ethyl esters (Lovaza) 1g cap= 465mg EPA + 375mg DHA  Icosapentethyl (Vascepa) 1g icosapent ethyl (ethyl ester of EPA)  In severe HTG, Lovaza (85% Omega 3 FA) reduced TG by 45% but increased LDL by 31%. Vascepa (>95% Icosapent ethyl) reduced TG by 45% with no LDL increase

References: Hypertriglyceridemia Management in Patients With Diabetes, US Pharmacist http://www.uspharmacist.com/content/s/68/c/13446 Fish Consumption, Fish Oil, Omega-3 Fatty Acids, and Cardiovascular Disease http://circ.ahajournals.org/content/106/21/2747.full

Statins

 HMG- COA reductase inhibitor  Pregnancy Category X  Side effects:  Rhabdomyolisis (dose related), Myopathy  Age >65  Female  Uncontrolled Hypothyroidism  Vitamin D deficiency  Renal Impairment  Cognitive Impairment  Increased LFTs  Increased blood glucose and A1C

Source: Hypertriglyceridemia: its etiology, effects and treatment http://www.cmaj.ca/content/176/8/1113.full Hypertriglyceridemia Management in Patients With Diabetes, US Pharmacist http://www.uspharmacist.com/content/s/68/c/13446

HMG- CoA reductase Inhibitors

Statins

 Monitor LFTs  Lipid panel after 4-6 weeks starting therapy (to assess for dose titration), then q3-12 months thereafter  Renal Dosing:  CrCl < 30ml/min- Use lower doses (Except Lipitor)  Statin + Cochicine: Increased myopathy; P-glycoprotein inhibitor (Colchicine )and additive effect  Simvastatin, Lovastatin: Major CYP3A4 Substrate  Avoid with strong CYP Inhibitors (e.g. Azole antifungals, Macrolides, HIV PI’s, Gemfibrozil)  Statin + Niacin (>1g): Increased myopathy

Source: Hypertriglyceridemia: its etiology, effects and treatment http://www.cmaj.ca/content/176/8/1113.full Hypertriglyceridemia Management in Patients With Diabetes, US Pharmacist http://www.uspharmacist.com/content/s/68/c/13446

 Statins are the most effective hypolipidemic agents for reducing cardiovascular risk; and therefore should be first line in treating mild to moderate hypertriglyceridemia (<500 mg/dl).  In patients with TG level >500mg/dl, Fibrates (1st line), Niacin, or Fish oil are more preferable. After TG level has been lowered, a statin may be added.  ACCORD (Action to Control Cardiovascular Risk in Diabetes) Lipid Study- No significant difference in experiencing a major cardiac event between DM2 patients treated with Fenofibrate + Simvastatin VS Simvastatin alone

Treatment for Hypertriglyceridemia

References: ACCORD Lipid Trial http://care.diabetesjournals.org/content/34/Supplement_2/S107.full.pdf+html Primary Prevention with Statins in Cardiovascular Diseases: A Saudi Arabian perspective http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4481463/

Hypertriglyceridemia- Induced Pancreatitis

 Usually occur when TG >1000  If plasma TG level increases beyond enzymatic capacity of pancreas, free FA accumulates, causes activation of inflammatory mediators and causes injury of acinar cells and surrounding tissue  Hyperviscosity of chylomicronemia alters pancreatic blood flow which makes an acidic environment and become toxic to surrounding tissues  The severity of acute pancreatitis is dependent on the inflammatory response of pancreas and injury cause from lipotoxicity from TG hydrolysis  TG >1000 mg/dl has 5% risk to develop pancreatitis while TG >2000 mg/dl has 10-20% risk

References: Hypertriglyceride Induced Pancreatitis http://cdn.intechopen.com/pdfs-wm/26197.pdf Heparin and Insulin for Hypertriglyceridemia Induced Pancreatitis: Case Report http://www.ncbi.nlm.nih.gov/pubmed/19882092

Hypertriglyceridemia- Induced Pancreatitis

 Clinical features- abdominal pain, N/V  Treatment  Conventional treatment of Acute Pancreatitis  Lowering TG, initial goal TG <500mg/dl  Others  Therapeutic Plasma Exchange- removal of plasma and replacement with a colloid (e.g. albumin, plasma)  Heparin- stimulates release of endothelial LPL  Insulin- activates LPL

Therapeutic Plasma Exchange

 This involves the replacement of TG-rich plasma with salt-free human albumin or fresh-frozen plasma  Removes chylomicrons from circulation, therefore reducing TG  Reports show that Plasmapheresis was shown to decrease TG levels by as much as 70% within several hours  Useful for  Pregnant patients  Rapid reduction of TG levels in Severe HTG  Acute/ Recurrent Pancreatitis that does not respond to conventional therapy  Goal: Reduce TG to <500mg/dl  Cons: Cost ($1000-$2000/procedure), Availability, allergic reactions

References: Hypertriglyceride Induced Pancreatitis http://cdn.intechopen.com/pdfs-wm/26197.pdf Use of apheresis and Insulin for HTGP and DKA http://jdc.jefferson.edu/cgi/viewcontent.cgi?article=1003&context=jeffpharmacypr esgr

Insulin

 Both IV and SC insulin have been used in studies, with IV being more effective in severe cases

• f HTG induced pancreatitis

 Useful in the treatment of poorly controlled diabetic subjects with HTG  Also safe and efficacious in non-diabetic subjects  Many cases show a decrease in TG levels to <500mg/dl within 3.5-4 days  Most studies used IV infusion of regular insulin with 5% dextrose  maintain Blood glucose at150-200mg/dl  No established dosing  Start 0.1- 0.3 u/kg/hr (with adjustment of the insulin dosage as needed)  Stop therapy once TG <500mg/dl  Suggested Monitoring:  Fingerstick glucose levels q4h  TG levels q12-24h

References: Use of apheresis and Insulin for HTGP and DKA http://jdc.jefferson.edu/cgi/viewcontent.cgi?article=1003&context=jeffpharmacypresgr Rapid Reduction of Severely Elevated Serum Triglycerides with Insulin Infusion, Gemfibrozil and Niacin http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3064759/ Hypertriglyceride Induced Pancreatitis http://cdn.intechopen.com/pdfs-wm/26197.pdf

Heparin

 Stimulates the release of lipoprotein lipase (LPL), therefore, increasing its activity.  LPL is normally bound by heparan sulfate proteoglycan chain to the capillary endothelium.  When heparin is given in bolus dose, it has stronger affinity to the LPL binding site than heparan sulfate, making it dissociate to the plasma as heparan-LPL complex  The surge of free LPL can metabolize lipoproteins at an accelerated rate, lowering TG  May cause rebound hypertriglyceridemia after discontinuation of therapy:  The process to synthesize LPL is slow that continued use of heparin may lead to depletion of LPL  Not recommended as monotherapy  No established dosing. (IV bolus 18u/kg q-46 more effective than continuous administration)  Most case reports use weight based infusion to keep the PTT 1.5 - 2 times the ULN and to achieve triglyceride levels of at least < 1,000 mg/dL

References: Hypertriglyceride Induced Pancreatitis http://cdn.intechopen.com/pdfs-wm/26197.pdf

Summary of Recommendations (Endocrine Society of Clinical Practice Guidelines)

 Severe and very severe HTG can increase the risk of Pancreatitis while mild or moderate HTG can increase risk for cardiovascular disease.  Use fasting triglyceride levels to diagnose HTG  Patients with elevations of fasting TG should be evaluated for secondary cause of Hyperlipidemia, to which treatment should be focused on  Patients with primary HTG should be assessed for other cardiovascular risk factors and evaluated with family history of dyslipidemia and cardiovascular disease to assess future cardiovascular risk

References: Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline https://www.endocrine.org/~/media/endosociety/Files/Publications/Clinical%20Practice%20Guidelines /082312_Hypertriglyceridemia_FinalA.PDF

 For Mild to Moderate HTG, Lifestyle changes (Dietary Counseling, Physical Activity, Weight reduction in Obese Patients) should be the initial treatment.  For severe and very severe HTG, drug treatment + diet modifications (Reduction in Dietary fat and simple Carbohydrate) to reduce risk of pancreatitis.  Drug Treatment: Fibrate, Niacin, or Fish Oil +/- Statin  Fibrate as first line agent for TG reduction in hypertriglyceridemia-induced pancreatitis.  Statins not for use in severe and very severe HTG but may be useful in treatment of Mild to Moderate HTG to modify cardiovascular risk

References: Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline https://www.endocrine.org/~/media/endosociety/Files/Publications/Clinical%20Practice%20Guidelines /082312_Hypertriglyceridemia_FinalA.PDF

Q and A