Therapeutic Options for Triglyceride Lowering

Dave L. Dixon, PharmD, BCPS, CDE, CLS, AACC, FNLA Associate Professor and Vice-Chair of Clinical Services Department of Pharmacotherapy & Outcomes Science Disclosures

• Novartis – Speaker’s Bureau • Sanofi – Received speaker honorarium Objectives

• Summarize current guideline recommendations on the management of hypertriglyceridemia.

• Compare and contrast the safety, efficacy, and tolerability of available lipid-lowering therapies that lower triglycerides.

• Discuss emerging triglyceride-lowering therapies. AHA Scientific Statement: Triglycerides and Cardiovascular Disease Fasting Triglyceride Level (mg/dL) Recommendations 150-199 200-499 ≥500* Weight Loss Up to 5% 5-10% 5-10% Carbohydrates 50-60% 50-55% 45-50% • Added sugar <10% 5-10% <5% • Fructose <100g 50-100g <50g Protein 15% 15-20% 20% Fat 25-35% 30-35% 30-35% • Trans Avoid Avoid Avoid • Saturated <7% <5% <5% • Monounsaturated 10-20% 10-20% 10-20% • Polyunsaturated 10-20% 10-20% 10-20% • EPA/DHA 0.5-1 g 1-2g >2g Aerobic Activity At least 2 times weekly

* Drug therapy to prevent pancreatitis Circulation. 2011;123:2292-2333 ACC/AHA Cholesterol Guideline

• Reader directed to the 2011 AHA Scientific Statement on TG (see previous slide) • Treatment of elevated TG listed as a critical question for consideration in future guideline updates…

Circulation. 2014;129[suppl 2]:S1:S45. NLA Recommendations

• TG >1000 mg/dL – Primary goal: reduce pancreatitis risk – TG-lowering therapy  O3FA, fibrates, or niacin

• TG 500-999 mg/dL – Primary goal: reduce pancreatitis risk – Statin monotherapy “OK” if no h/o pancreatitis – O3FA, fibrates, or niacin preferred as initial therapy in patients with h/o pancreatitis

J Clin Lipidol. 2014;8(5):473-488. NLA Recommendations

• TG 200-499 mg/dL – Primary goal: reduce ASCVD risk by reducing atherogenic lipoprotein burden – Statins are preferred as initial therapy – However, if non-HDL-C goals not met, may consider adding O3FA, fibrate, or niacin to statin therapy

J Clin Lipidol. 2014;8(5):473-488. Effects of Lipid-Lowering Classes on TG

Drug Class % change in TG Fibrates ↓ 30-50 Omega-3 fatty acids ↓ 20-50 Nicotinic acid ↓ 20-50 Statins ↓ 10-30 Ezetimibe ↓ 5-10 PCSK9 inhibitors ↓ 0-17 Bile acid sequestrants ↑ 0-10

Circulation. 2011;123(20):2292-2333. European Heart Journal. 2015;36(36):2415-2424. Fibrates: MOA (Gemfibrozil, Fenofibrate) Fibrates

PPARα Activates LPL:  VLDL clearance

 ApoC-III (an LPL inhibitor)

PPARα RXR  β-oxidation of free fatty acids

ApoA1 and ApoA2:  HDL

PPARα: peroxisome proliferator activated receptor α; LPL: lipoprotein lipase; RXR: retinoid x receptor Vasc Health Risk Manag. 2008;4(1):131-41. Fibrates: Role in Therapy

• Indicated for use: – Severe hypertriglyceridemia – Reduce atherogenic lipoproteins and increase HDL-C in primary hypercholesterolemia or mixed dyslipidemia • Contraindications: – Severe renal disease, active liver disease, or gallbladder disease • Common SE: – Increased liver enzymes, myopathy, cholelithiasis • Significant drug-drug interactions – May increase the INR in patients taking warfarin

Tricor® Package Insert. Dixon DL. Pharmacotherapy. 2009;29(6):744-748. Fibrates: Clinical Outcomes • HHS – Reduced CV events in patients with non-HDL-C >200 mg/dl • VA-HIT – Reduced CV events in patients with CHD and low-HDL-C

• FIELD – Primary composite endpoint was not significant, but total CV events and microvascular complications were reduced in patients with type 2 DM • ACCORD – No reduction in CV events when added to statin therapy in patients with type 2 DM NEJM. 1987;317:1237-45; NEJM. 1999;341:410-8; Lancet. 2005;366:1849–1861.; NEJM. 2010;362,1563-1574. Fenofibrate Formulations Take Trade Name (generic) Form: Doses (mg) with food? Antara® (micronized fenofibrate) Capsules: 30, 90 No

Fenoglide® (fenofibrate) Tablets: 40, 120 Yes

Lipofen® (fenofibrate) Capsules: 50, 150 Yes

Tricor® (fenofibrate) Tablets: 48, 145 No

Triglide® (fenofibrate) Tablets: 160 Yes

Trilipix® (fenofibric acid) DR Capsules: 45, 135 No

Generic - fenofibrate Tablets: 48, 54, 145, 160 Yes Generic - micronized fenofibrate Capsules: 43, 67, 130, 134, 200 No Fenofibrate Safety: Renal

Level of Class I Recommendation Evidence • Renal status should be evaluated before fenofibrate initiation, B within 3 months after initiation, and every 6 months thereafter. Assess renal safety with both a serum creatinine level and an eGFR based on creatinine.

Level of Class III Recommendation: Harm Evidence • Fenofibrate should not be used if moderate or severe renal B impairment, defined as eGFR <30 mL/min per 1.73 m2 • If eGFR is between 30 and 59 mL/min per 1.73 m2, the dose of fenofibrate should not exceed 54 mg/day

Circulation. 2014;129[suppl 2]:S1:S45. Renal Dosing of Fibrates

Dose based on GFR (mL/min/1.73 m2) Fibrate >90 60-90 15-59 <15

High Dose Medium Dose Low Dose Fenofibrate* (ex. 200 mg) (ex. 167 mg) (ex. 67 mg) AVOID 600 mg 600 mg 600 mg Gemfibrozil Twice daily Twice daily daily

Adapted from the National Kidney Foundation and National Lipid Association Recommendations; *Multiple fenofibrate formulations exist Gemfibrozil Safety Level of Class III Recommendation: Harm Evidence • Gemfibrozil should not be initiated in patients on statin B therapy because of an increased risk for muscle symptoms and rhabdomyolysis

Fenofibrate resulted in a 15 times lower rhabdomyolysis rate than did gemfibrozil

• Gemfibrozil can reduce the glucuronidation of statins • Inhibition of organic anion transporting polypeptide 1B1 (OATP1B1), rather than CYP3A4

Circulation. 2014;129[suppl 2]:S1:S45. J Clin Lipid. 2014;(3 Suppl):S30-46. Am J Cardiol. 2005;95:120-2 Available at: https://federalregister.gov/a/2016-08887. Accessed July 5, 2016. Omega-3 Fatty Acids: Potential Mechanism of Action

DGAT=diacylglycerol acyltransferase; PA(P)=phosphatidic acid phosphatase/phosphohydrolase. Omega-3 Fatty Acids • Indications for use: – Severe hypertriglyceridemia (≥500 mg/dL) • Precautions: – Patients allergic to fish/shellfish • Common SE: – belching, dyspepsia, taste perversion • Significant drug-drug interactions: – May prolong bleeding time

Am J Cardiol. 2007;99(Suppl 6A):35C–43C. JAMA. 2012;308(10):1024-1033 Omega-3 Fatty Acids: Rx Products

O3FA Take with Product EPA (mg) DHA (mg) Dosing Source food?

Omega-3 acid 4g QD ethyl esters With our Fish 465 375 or (Lovaza®) 2g BID without

Icosapent ethyl (Vascepa®) Fish 1000 -- 2g BID Yes

Omega-3 carboxylic acids 850mg of “O3FA” - With our Fish 2-4g QD (Epanova®) predominantly EPA without

Lovaza® Package Insert Vascepa® Package Insert Epanova® Package Insert Omega-3 Fatty Acids: Clinical Outcomes

• Outcomes data remains unclear… – No evidence of reduced pancreatitis risk – No significant CV event reduction in a 2012 meta- analysis of 20 trials in 68,680 patients with omega-3 fatty acid supplementation – ORIGIN trial found no CV benefit with 1g daily in patients with dysglycemia

NEJM. 2012;367:309-318. JAMA. 2012;308(10):1024-33. Ongoing Clinical Trials with EPA REDUCE-IT STRENGTH (N=8,000) (N=13,000) Patients Mixed dyslipidemia on statin ASCVD Risk High TG Level 200 to <500 mg/dL 180 to <500 mg/dL Intervention Vascepa® Epanova® Primary Endpoint MACE Timeline 2011-2017 2014-2019

Vascepa® = icosapent ethyl Epanova® = omega-3 carboxylic acids

www.vascepahcp.com accessed 7/5/16. www.ClinicalTrials.gov accessed 7/5/16. Over-the-counter “Fish Oil” “Fish Oil” ≠ Omega-3 Fatty Acids OTC “Krill Oil” Niacin: Mechanism of Action Niacin: Role in Therapy • Indications for use: – Reduce triglycerides in severe hypertriglyceridemia – Reduce Apo B and TG, and to increase HDL-C in primary hyperlipidemia and mixed dyslipidemia • Use often limited by poor tolerability – Flushing, hyperglycemia, hyperuricemia, etc. – Varies based on selected product (IR vs. ER vs. SR) • Outcomes data in patients without elevated triglycerides – Limited as monotherapy in secondary prevention – No reduction in CV events with statin therapy (AIM-HIGH, HPS2- THRIVE)

NEJM. 2011;365:2255-67. NEJM. 2014;371:203-12. Reminder…Statins Lower TG • Triglyceride reduction is dose-dependent – Upregulation of LDL receptors enhances clearance of TG-rich VLDL and chylomicrons

Am J Cardiol. 2003;93:152-160. Emerging Therapies • Volanesorsen (formerly ISIS 304801) – Antisense oligonucleotide that targets ApoC-III mRNA in the liver, which is known to inhibit lipoprotein lipase – TG 70% and HDL-C 30% • Angiopoietin-like proteins (ANGPTLs) Inhibitor – ANGPTLs inhibit activity of lipoprotein lipase – REGN1500 is a mAb shown to inhibit ANGPTLs and  TGs – Early human clinical trials ongoing • Pemafibrate (K-877) – Potent and selective inhibitor of Peroxisome proliferator- activated receptor (PPARα) – PROMINENT trial: 10,000 high-risk DM patients with high TG, low HDL-C, on statin therapy Diabetes Care. 2016;39:1408-15. Curr Cardiol Rep. 2016;18:65 Summary • Fibrates, omega-3 fatty acids, niacin, and high- intensity statins significantly lower triglycerides. • Clinical evidence demonstrating a reduction in CV mortality and morbidity in patients with elevated TG remains limited, but key trials are ongoing. • Emerging therapies show potential, but remain in development. Take Home Message • In patients with TG >500, treat to lower risk of acute pancreatitis.

• Treating TG <500 to lower ASCVD risk remains controversial due to limited supportive clinical outcomes data, but may be considered in patients with elevated non-HDL-C despite statin therapy.

• Fenofibrate and Rx omega-3 fatty acid products are preferred in most patients. Thank you