Therapeutic Options for Triglyceride Lowering

Dave L. Dixon, PharmD, BCPS, CDE, CLS, AACC, FNLAAssociate Professor and Vice-Chair of Clinical ServicesDepartment 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• Added sugar• Fructose

50‐60%<10%<100g

50‐55%5‐10%50‐100g

45‐50%<5%<50g

Protein 15% 15‐20% 20%

Fat• Trans• Saturated• Monounsaturated• Polyunsaturated• EPA/DHA

25‐35%Avoid<7%

10‐20%10‐20%0.5‐1 g

30‐35%Avoid<5%

10‐20%10‐20%1‐2g

30‐35%Avoid<5%

10‐20%10‐20%>2g

Aerobic Activity At least 2 times weekly

Circulation. 2011;123:2292-2333* Drug therapy to prevent pancreatitis

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)

PPARα RXR

Fibrates

PPARα

PPARα: peroxisome proliferator activated receptor α; LPL: lipoprotein lipase; RXR: retinoid x receptor

Vasc Health Risk Manag. 2008;4(1):131-41.

Activates LPL: VLDL clearance

ApoC‐III (an LPL inhibitor)

β‐oxidation of free fatty acids

ApoA1 and ApoA2:  HDL

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

Trade Name (generic) Form: Doses (mg)Take 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 - fenofibrateGeneric - micronized fenofibrate

Tablets: 48, 54, 145, 160Capsules: 43, 67, 130, 134, 200

YesNo

Fenofibrate Safety: Renal

Class I RecommendationLevel of

Evidence• Renal status should be evaluated before fenofibrate initiation,

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.

B

Class III Recommendation: HarmLevel of

Evidence• Fenofibrate should not be used if moderate or severe renal

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

B

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

Renal Dosing of Fibrates

FibrateDose based on GFR (mL/min/1.73 m2)

>90 60-90 15-59 <15

Fenofibrate* High Dose(ex. 200 mg)

Medium Dose(ex. 167 mg)

Low Dose(ex. 67 mg)

AVOID

Gemfibrozil 600 mg Twice daily

600 mg Twice daily

600 mg daily

Adapted from the National Kidney Foundation and National Lipid Association Recommendations; *Multiple fenofibrate formulations exist

Gemfibrozil SafetyClass III Recommendation: Harm

Level of Evidence

• Gemfibrozil should not be initiated in patients on statin therapy because of an increased risk for muscle symptoms and rhabdomyolysis

B

• 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

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

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

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

food?

Omega‐3 acid ethyl esters (Lovaza®) Fish oils 465 375

4g QDor

2g BID

With our without

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

Omega‐3carboxylic acids (Epanova®) Fish oils 850mg of “O3FA” ‐

predominantly EPA and DHA 2‐4g QD With our without

Lovaza® Package InsertVascepa® Package InsertEpanova® 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 EPAREDUCE‐IT(N=8,000)

STRENGTH(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 2011‐2016 2014‐2019Vascepa® = icosapent ethylEpanova® = 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• Few clinical guidelines directly address management of hypertriglyceridemia.

• 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 remains controversial due to lack of supportive clinical outcomes data.

• Fenofibrate and Rx omega‐3 fatty acid products are preferred in most patients.

Thank you