Therapeutic Options for Triglyceride Lowering · Class III Recommendation:Harm Level of Evidence...
Transcript of Therapeutic Options for Triglyceride Lowering · Class III Recommendation:Harm Level of Evidence...
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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
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Disclosures
• Novartis – Speaker’s Bureau• Sanofi – Received speaker honorarium
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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.
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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
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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.
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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.
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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.
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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.
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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
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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.
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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.
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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
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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.
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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
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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
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Available at: https://federalregister.gov/a/2016‐08887.Accessed July 5, 2016.
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Omega‐3 Fatty Acids: Potential Mechanism of Action
DGAT=diacylglycerol acyltransferase; PA(P)=phosphatidic acid phosphatase/phosphohydrolase.
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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
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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
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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.
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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.
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Over‐the‐counter “Fish Oil”
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“Fish Oil” ≠ Omega‐3 Fatty Acids
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OTC “Krill Oil”
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Niacin: Mechanism of Action
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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.
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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.
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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
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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.
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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.
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Thank you