Clinical Management of Hypertriglyceridemia: State of the Art 2015 Eliot A. Brinton, MD, FAHA, FNLA President, American Board of Clinical Lipidology Director, Atherometabolic Research Utah Foundation for Biomedical Research President, Utah Lipid Center Salt Lake City [email protected]National Lipid Association Clinical Lipid Update February 28, 2015, Denver, Colorado
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Clinical Management of Hypertriglyceridemia: State of the Art 2015
Eliot A. Brinton, MD, FAHA, FNLAPresident, American Board of Clinical Lipidology
Director, Atherometabolic ResearchUtah Foundation for Biomedical Research
Learning ObjectivesParticipants should be able to:1. Discuss the prevalence and pathophysiology
of hypertriglyceridemia (HTG)2. Appreciate the likely causal connection of
HTG with acute pancreatitis and atherosclerotic cardiovascular disease (ASCVD)
3. Diagnose HTG and its atherogenic sequelae4. Acknowledge TG-lowering medications in
development5. Implement appropriate management of HTG
TG Categories: Names, Disease Risks, and Drug
Approval PathwaysTG Range (mg/dL) NCEP ATP-III 1 AHA Statement 2
NLA Statement 3 Disease Risk FDA
<100Desirable
Optimal None
No Rx interest<150 Normal Dyslipidemia
150-199 Borderline High Borderline More dyslipidemia
200-499 High High ↑CVD Approve if ↓CVD likely
>500 Very High Very High↑CVD & sl
↑pancreatitis 4(esp ↑if >2000)
Approve if reasonable
safety1. Grundy, S, for the NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III). Circulation. 2002;106:3143‐3421.2. Miller, M, et al. AHA Statement, Circulation. 2011;123(20):2292‐2333.3. All but “Optimal” are in the NLA Statement: Jacobson, TA, et al. J Clin Lip 2014;8:473–488.4. ↑Risk of acute pancrea s at this level is mainly due to ↑TG variability.
Prevalence of HTG in US Adults
%
From Christian et al. Am J Cardiol 2011: 107: 891
3.4 million Americans have
very high TG
Triglyceride Level (mg/dL)
42.3
40.6
NHANES II (1976-1980) NHANES III (1988-1994) NHANES (1999-2006)
Adults aged 20-74 years Adults aged 60-74 years
Increasing Prevalence of HTG Parallels Increased Obesity in the US
Cohen J, et al. Poster at 2008 AHA Scientific Sessions. Ford ES, et al. Arch Intern Med. 2009;169:572-8.Christian JB, et al. Am J Cardiol. 2011;107:891-7.
0
5
10
15
Abno
rmal
TG (%
)
2.4 2.3
5.5
3.5
5x
8.7
1.8
2x
Very-High and Severe HTG are Usually Genetic
Adapted from Hegele et al. Lancet Diabetes & Endocrinology 2014; 2: 655. *Miller, M. Circulation 2011.
% o
f Gen
eral
Pop
ulat
ion
885 mg/dL **500 mg/dL *
*“Very High” cutoff per AHA Consensus Panel Statement. **“Severe” cutoff per EAS Consensus Panel.
Metabolism of TG-Rich Lipoproteins
RemnantReceptor
Hepatocyte
Fatty Acids
Small intestine
Chylomicron
ChylomicronRemnant
Liver
Bloodstream
Lipoprotein Lipase
Normal Metabolism of TGRLp: Exogenous (Dietary Origin)
1. Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011;123(20):2292-2333. 2. Grundy SM. Atlas of atherosclerosis and metabolic syndrome. Chapters 4 and 5. 4th edition. Current Medicine LLC. 2005.
Muscle and
adipose tissue
Normal Metabolism of TGRLp: Endogenous (Hepatic Origin)
Glycerol
Fatty Acids
Triglyceride
Cholesteryl ester
VLDLTG:CE =
5:1
Apo B
Apo, apolipoprotein; VLDL, very low-density lipoprotein; CE, cholesteryl ester
Kwiterovich PO. Johns Hopkins Textbook of Dyslipidemia. 2009.; Miller M, et al. Circulation. 2011;123:2292-2333.; Grundy SM. Atlas of atherosclerosis and metabolic syndrome. 2005.
TG within VLDL:• derived from glycerol + fatty acids from plasma• newly synthesized in the liver (fructose driven)
LDLreceptor
Hepatocyte
Normal Plasma Metabolism of TGRLp: Hepatic Origin
Fatty Acids
Bloodstream Muscle and
adipose tissueLipoprotein
Lipase
Lipoprotein Lipase
IDL
LDL
Normal Size VLDL
• LDL receptor clears VLDL remnants, IDL & LDL
IDL, intermediate-density lipoproteins; LDL, low-density lipoproteinKwiterovich PO. Johns Hopkins Textbook of Dyslipidemia. 2009. Miller M, et al. Circulation. 2011;123:2292-2333. Grundy SM. Atlas of atherosclerosis and metabolic syndrome. 2005.
BloodstreamMuscle
and adipose tissue
Cholesterol Enrichment of VLDL and Shrinkage of LDL & HDL Promoted by CETP in HTG
Hepatic TG Lipase
Hepatic TG Lipase
LDL
Increased Triglycerides
HDL
Small,DenseHDL
VLDL
• CETP-mediated exchange affects composition and metabolism of VLDL, LDL, and HDL
• Occurs at all TG levels but is greatly increased w/ HTG, causing “Atherogenic Dyslipidemia”
HDL, high-density lipoprotein; LDL, low-density lipoprotein; CETP, cholesteryl ester transfer proteinMiller M, et al. Circulation. 2011;123:2292-2333. Ginsberg HN. J Clin Invest. 2000;106(4):453-458.
Small,DenseLDL
Cholesterol-enriched
VLDL
Lipid Measurements in HTG Patients
Increasing Inaccuracy of Friedewald LDL-C with Increasing TG
LDL-C = Total Cholesterol – HDL-C –TG/5
On routine lipid panel, LDL-C is calculated using the Friedewald Formula:
0
10
20
30
40
50
0-100 101-200 201-300 301-400
Absolute underestimation of LDL-C (by Friedewald) by Fasting TG level
Triglyceride Level (mg/dL)
Abso
lute
diff
eren
ce (
mg/
dL)
Even modest increases in TG result in LDL-C underestimation using Friedewald formula
Lindsey CC, et al. Pharmacotherapy. 2004;24:167-172.
Increasing Inaccuracy of Friedewald LDL-C with Increasing TG
LDL-C = Total Cholesterol – HDL-C –TG/5
On routine lipid panel, LDL-C is calculated using the Friedewald Formula:
0
10
20
30
40
50
0-100 101-200 201-300 301-400
Absolute underestimation of LDL-C (by Friedewald) by Fasting TG level
Triglyceride Level (mg/dL)
Abso
lute
diff
eren
ce (
mg/
dL)
Even modest increases in TG result in LDL-C underestimation using Friedewald formula
Lindsey CC, et al. Pharmacotherapy. 2004;24:167-172.
Direct LDL-C solves this problem, but there may be a better solution…
What is Non-HDL-C?
16
HDL LDL IDL VLDL Chylomicron remnant
Apo AI Apo B100 Apo B100 Apo B Apo B48
CholesterolTriglyceride
All atherogenic lipoproteins
non-HDL
Non-HDL-C = Total cholesterol – HDL-C
Liu J, et al. Am J Cardiol. 2006;98:1363-1368. (Framingham Study)
0
0.5
1
1.5
2
2.5
Rel
ativ
e C
HD
Ris
k
LDL-C, mg/dL
Non-HDL-C, mg/dL
<130 130-159 ≥160
≥190160-189
<160
Non–HDL-C Is Stronger than LDL-C in Predicting CHD Risk
Non-HDL-C Advantagesvs other Lipid Parameters
• Stronger CVD risk predictor than TG (less variable, less loss w/ adjustments)
• Measures chol content of TG-rich lipos• Stronger CVD risk predictor than LDL-C• More stringent than LDL-C (only ~ ½ of pts at
LDL-C goal also at Non-HDL-C goal)• Valid non-fasting (not true for LDL-C)• Valid in HTG (not true for LDL-C)• ~Comparable to apo B/LDL-P, yet• Free with basic lipid panel• Guideline goal consensus (IAS, NLA, etc.)
TG Measurement: Summary• Fasting TG is standard (12 hr, water ok)• Non-fasting TG predicts CVD risk in
populations1 but too variable in individuals?• If NF TG <200 mg/dL fasting TG not neces.2• SD LDL remains important (see below)• Remnant particle testing controversial
– Post-prandial (cumbersome, no standards)– RLP-C—easy but ?accuracy ?validation– DGUC—apo A-I/Rem ratio?3
– Beta-quant best to R/O type III4– Other: NMR? ion mobility?– Friedewald VLDL-C (=TG/5) is NOT remnants!5
• Non-HDL-C incl. all, is free, has consensus1. Langsted A, et al. J Intern Med. 2011 Jul;270(1):65-75.2. Miller, M, et al. Circulation. 2011;123(20):2292-2333.3. May, HT. Lipids Health Dis. 2013 Apr 26;12:55. 4. Hopkins, PN. Current Athero Reports. 2014 in press.5. Varbo, A. Circulation. 2013 epub August 7.
Does HTG Cause Disease?
*After adjustment for covariates and removal of patients hospitalized for gallstones, chronic pancreatitis, alcohol-related morbidities, renal failure, and other biliary disease.1. Cybulska B, Klosiewicz-Latoszek L. Kardiol Pol. 2013;71(10):1007-1012; 2. Miller M et al. Circulation. 2011;123(20):2292-2333; 3. Murphy M et al. JAMA Intern Med. 2013;173(2):162-164. N=n=31,740, 31,887 and 3,642 for 3 TG strata w/ cutpoints150 and 500 mg/dL
Crud
e Incide
nce
(Cases/100
0 Patie
nt‐Years)
Group 1
Group 2
Group 3
• HTG is the 3rd
biggest cause of acute pancreatitis (~10%) after alcohol & gallstones1,2
Conclusion: “In mild-to moderate [HTG], intervention can be indicated to prevent cardiovascular disease, dependent on triglyceride concentration, concomitant lipoprotein disturbances, and overall cardiovascular risk.”2
Genetic Causes of HTGSomewhat Common but Controversial• Familial combined hyperlipidemia (FCH)
– ↑TG and Cholesterol levels (possibly also w/ HBP) believed due to genetic defects in one or more factors of lipoprotein metabolism (including Apo C-II, Apo C-III & CETP?)
• Familial hypertriglyceridemia (FHT)– ↑TG levels only (nl cholesterol), related to ↑ hepatic VLDL
production and/or polygenic vs environmental ↓LPL activityRelatively Rare to Very Rare• Familial dysbetalipoproteinemia (Fredrickson Type III)• Lipoprotein lipase (LPL) deficiency• Apo C-II deficiency• GPIHBP1 deficiency• Others
CETP=cholesteryl ester transfer proteinAfter Bays HE. Chapter 21 in The Johns Hopkins Textbook of Dyslipidemia. Kwiterovich, PO, Jr., ed. 2010; p 245-57.
Note: genetic testing for HTG is rarely usefulclinically and is not recommended for routine use
SD LDL SummaryBiology: SD LDL is pro-atherogenic• Easier into subendothelial space• Stickier to subendothelial matrix• More readily oxidized• Carries atherogenic proteins (e.g. apo C-III)• Harder to clear via LDL-REpidemiology: SD LDL predicts ASCVD• SD LDL was discounted since not predictive of ASCVD
w/ LDL-P; however,• Discordance between LDL-P and LDL-C makes sense
only re: LDL size, and• LDL-P is “weighted” towards SD LDL, and• SD LDL by new assay strongly predicts ASCVD;
however,• Non-HDL-C captures much of this assoc.
Bottom line: LDL size is important mechanisticallyHow to measure? Non-HDL-C, LDL-P, LDL sizing, new assay?
Management of HTG Patients
Statins do NOT Prevent All CHD Events (Residual Risk ~50-70%)
4HPS Collaborative Group. Lancet. 2002;360:7-22. 5Shepherd J et al. N Engl J Med. 1995;333:1301-7.6 Downs JR et al. JAMA. 1998;279:1615-22.
14S Group. Lancet. 1994;344:1383-9.2LIPID Study Group. N Engl J Med. 1998;339:1349-57. 3Sacks FM et al. N Engl J Med. 1996;335:1001-9.
0
10
20
30
40
4S1 LIPID2 CARE3 HPS4 WOSCOPS5 AFCAPS/TexCAPS6
N 4444 4159 20,536 6595 66059014Secondary High Risk Primary
Patie
nts
Expe
rienc
ing
Maj
or C
HD
Eve
nts,
%
PlaceboStatin
19.4
12.310.2 8.7
5.5 6.8
28.0
15.913.2 11.8
7.910.9
CHD events occur frequently in patients taking statins
Statins Reduce CVD Events in HTG PatientsHOWEVER…
CARE=Cholesterol and Recurrent Events Trial; CTT=Cholesterol Treatment Trialists; JUPITER=Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin; NS=not significant; PPP=Prospective Pravastatin Pooling; 4S=Scandinavian Simvastatin Survival Study; WOSCOPS=West of Scotland Coronary Prevention Study. Ballantyne et al. Circulation. 2001;104:3056-51. CTT Collaborators. Lancet. 2005;366:1267-78. Maki et al. J Clin Lipidol. 2012;6:413-26.
thiazide diuretics, etc.)After Bays HE. In The Johns Hopkins Textbook of Dyslipidemia. Kwiterovich, PO Jr., ed. 2010;245-57.
TG-Lowering Medications
Drug/class ↓TriglyceridesFenofibrate 20-50%Omega-3 oil (EPA +/- DHA; EE vs FFA) (pharmacologic doses)
20-45%
Niacin 20-50%Statins** 7-30%
After:• *Expert Panel on Detection, Evaluation & Treatment of High Blood Cholesterol in Adults. JAMA 2001: 285:
2486-97. • Robinson JG, Stone NJ. Am J Cardiol 2006; 98(suppl):39i-49i.• Robinson JG, Davidson MH. Expert Rev Cardiovasc Ther 2006; 4: 461-76.• Briel M, et al. BMJ 2009: 338:b92.• Miller M et al. Circulation. 2011;123:2292-2333• *Chapman MJ et al. Eur Heart J. 2011;32(11):1345-1361.
“TG-Lowering”1o for TG ≥500
2o for TG 200-499
1o for TG 200-4992o for TG ≥500
**High-intensity statin Rx will ↓TG 20-50% in pts with HTG
TG Medications: Which? When?
• If TG 200-499 mg/dL: consider Rx to prevent ASCVD*• If TG ≥500 mg/dL: Rx all to prevent pancreatitis (& ASCVD)
eruct, dyspeps±Arthralgia only Fishy eruct, dyspeps,
diarrhea, nauseaTG-lowering ++++ +++ +++LDL-C effects ↑↑/± ±/↓ ↑/±HDL-C effects ↑ ±/↓ ↑↓CVD? Not at low dose,
no ongoing trialsProbably (mid-
dose) +ongoing trialNo data,
but ongoing trial
*Lovaza PI. Davidson MH et al Clin Ther 2007;29:1354–1367. ORIGIN Investigators. N Engl J Med. 2012;367:309-18. 4. Risk & Prevention Investigators N Engl J Med 2013;358:1800-8.**Vascepa PI. Yokoyama M et al. Lancet. 2007;369:1090-8. Bays HE, et al. Am J Cardiol. 2011;108:682-90.Ballantyne CM et al Am J Cardiol 2012;110:984-992.***Epanova PI. Davidson MH, J Clin Lipidology, 2012, 6:573. Offman E, Vasc Health Risk Manag. 2013; 9; 563–573. Kastelein, JJP; J Clin Lip 2013 epub 10 Oct. . Maki KC et al Clin Ther 2013;35:1400–1411.
Fenofibrate Rx Omega-3 NiacinΔ TG ↓↓↓ ↓↓↓ ↓↓Δ LDL-C ↑↑↑ to → ↑↑↑ to → to ↓ ↓ to ↓↓Δ Non-HDL-C → to ↓ → to ↓ ↓ to ↓↓Δ HDL-C → to ↑ → to ↑ ↑ to ↑↑↓ CVD Efficacy 0 to + 0 to +++ 0 to +↓ Mortality 0 ++ +Non-CVD Benefits 0 to ++ 0 to ++? 0Access (cost/month) $60-250 $90-300 $10-400“Natural” 0 ++ +Safety + to – +++ – – – to 0Tolerability ++ to – ++ to – – – – to 0Ease of use +++ +++ – – to ++
71
Fenofibrate vs Om-3 vs Niacin as TG/HDL Statin Adjuncts
Fenofibrate Rx Omega-3 NiacinΔ TG ↓↓↓ ↓↓↓ ↓↓Δ LDL-C ↑↑↑ to → ↑↑↑ to → to ↓ ↓ to ↓↓Δ Non-HDL-C → to ↓ → to ↓ ↓ to ↓↓Δ HDL-C → to ↑ → to ↑ ↑ to ↑↑↓ CVD Efficacy 0 to + 0 to +++ 0 to +↓ Mortality 0 ++ +Non-CVD Benefits 0 to ++ 0 to ++? 0Access (cost/month) $60-250 $90-300 $10-400“Natural” 0 ++ +Safety + to – +++ – – – to 0Tolerability ++ to – ++ to – – – – to 0Ease of use +++ +++ – – to ++
72
Fenofibrate vs Om-3 vs Niacin as TG/HDL Statin Adjuncts
Fenofibrate Rx Omega-3 NiacinΔ TG ↓↓↓ ↓↓↓ ↓↓Δ LDL-C ↑↑↑ to → ↑↑↑ to → to ↓ ↓ to ↓↓Δ Non-HDL-C → to ↓ → to ↓ ↓ to ↓↓Δ HDL-C → to ↑ → to ↑ ↑ to ↑↑↓ CVD Efficacy 0 to + 0 to +++ 0 to +↓ Mortality 0 ++ +Non-CVD Benefits 0 to ++ 0 to ++? 0Access (cost/month) $60-250 $90-300 $10-400“Natural” 0 ++ +Safety + to – +++ – – – to 0Tolerability ++ to – ++ to – – – – to 0Ease of use +++ +++ – – to ++
73Bottom line: Feno or Om-3 are 1st line for TG, Niacin for HDL, combos good.
Fenofibrate vs Om-3 vs Niacin as TG/HDL Statin Adjuncts
HTG: Should We Treat? Yes!• TG>~100: assume ↑ASCVD risk (statin Rx)• TG 200-500—↑ASCVD risk even w/ statin!
– Test for remnants if TC≈TG & both > ~250– Diet: ↓calories, ↓fructose, ↓EtOH (in ~all)– ↑Physical activity (in ~all)– ↓Glycemia (if DM or IR)– Rx w/ medications: