Uncomfortable rash and recurrent pancreatitis in 40 yo man Daniel Soffer MD FNLA University of Pennsylvania Division of Internal Medicine, Translational Medicine and Human Genetics FINANCIAL DISCLOSURE: Consultant Akcea Therapeutics, Kaneka (apheresis), Novartis Investigator Amgen Inc, Akcea Therapeutics, Novartis, Regeneron, RegenXBio, Astra-Zeneca UNLABELED/UNAPPROVED USES DISCLOSURE: none Outline • Brief case oBackground: severe hypertriglyceridemia oMaking the diagnosis oTreatment considerations oFuture direction Joe • 37 yo obese (BMI 50) nonsmoker; referred bc of severe hyperTG. • h/o pancreatitis x3 (1st at 35 yo) • t2dm (A1C 8-10%) • h/o gout, arthritis, OSA, fatty liver oNormal thyroid; no nephrotic syn oNo EtOH 3 Joe • Choline fenofibrate 135 mg Lipids 2011 daily (mg/dL) • Niacin ER 500 mg daily TC 592 • Omega-3-acid ethyl esters 1 TG 4565 gm twice daily HDL-C 34 • Rosuvastatin calcium 20 mg daily • Metformin 500 mg 2 times daily • Saxagliptin hcl 5 mg daily • Valsartan 160 mg daily 4 Joe’s pedigree Hyperlipidemia Joe Developed painful xanthomas • 40 yo; conditions unchanged • Deferring bariatric surgery (BMI 50) Lab Results Units 12/2013 12/2013 1/2014 CHOL 946 852 970 TRIG 6,922 6,100 8,860 CHOLHDL 13 8 10 mg/dL CREATININE 0.73 GLUCOSE 204 HEMOGLOBIN % A1C 10.0 6 Images shared with permission from patient Joe Lab Results TRIG Ref Rng & Units mg/dL 7/15/2014 >10,000 (H) 7/17/2014 7,719 (H) 7/21/2014 5,450 (H) 7/24/2014 5,758 (H) 7/24/2014 2,861 (H) 7/28/2014 6,016 (H) 8/1/2014 4723 8/4/2014 5,055 (H) 8/7/2014 5,682 (H) 8/11/2014 6,384 (H) 8/14/2014 5226 8/25/2014 5,729 (H) 8/28/2014 3,375 (H) 9/4/2014 9/8/2014 >10,000 (H) 9/15/2014 1,863 (H) 9/18/2014 2,909 (H) 9/19/2014 9/25/2014 1,879 (H) 9/29/2014 2,381 (H) 10/2/2014 2,775 (H) 10/6/2014 1390 7 Images shared with permission from patient Overall Prevalence of Hypertriglyceridemia 2014 National Lipid Association (NLA) by Age in NHANES (representative sample) Classification of TG Levels 1999-2008 Triglycerides (mg/dL) Demographic TG ≥150 mg/dL <150 Normal Overall (age 150–199 Borderline high 25.0% ≥20 y) 200–499 High Men 28.7% ≥500 Very high Women 21.5% U.S. Census Age 20 and above, July 1, 2010, was 226,113,653. Jacobson TA, Maki KC, Orringer CE, et al. J Clin Lipidol. Carroll MD et al. NCHS Data Brief, No 198. National Center for Health 8Statistics. 2015. 2015. 9(6) S1-S122.e1. doi:10.1016/j.jacl.2015.09.002 https://www.cdc.gov/nchs/products/databriefs/db198.htm Plasma TG concentrations and expected genetic variants associated from ~70 000 adults (>20 years of age) from the Copenhagen General Population Study. 1 mmol/L = 88.57 mg/dL 2 mmol/L = 177.14 9 Hegele RA et al. Lancet Diabetes & Endocrinology.2014;2(8):655-666 Very Severe Hypertriglyceridemia in a Large US County Health Care System (n ~70 000): Associated Conditions and Management very severe hyperTG % pts w/lipid profile 0.14% 103 of 71 495 TG > 2000 mg/dL (<0.1%) the rest 99.86% Maria Isabel Esparza MI, et al. Journal of the Endocrine Society, 2019. 3(8): 1595–1607, https://doi.org/10.1210/js.2019-00129 Hypertriglyceridemia: etiology Acquired/environmental (post- transcriptional) “Most cases of HTG are felt to be • Diet, EtOH polygenic, with strong influence by environmental factors.” • Meds • Metabolic conditions • Medical conditions Gary F. Lewis, Changting Xiao, Robert A. Hegele; Hypertriglyceridemia in the Genomic Era: A New Paradigm, Endocrine Reviews, Volume 36, Issue 1, 2 February 2015, Pages 131–147, https://doi.org/10.1210/er.2014-1062 Inherited syndromes • Monogenic (FCS, FDBL) • Polygenic (MCS, FCH, FHTG) 11 MCS multifactorial CM syndrome, FCH familial combined hyperlipidemia, FHTG familial hypertriglyceridemia, FDBL familial dysbetalipoproteinemia High TGs Acute ASCVD pancreatitis TG risk >440 vs <88 mg/dL (women>men) MI IHD MI Myocardial infarction IHD Ischemic heart disease ischemic stroke all cause mortality 0 5 10 15 20 (MEN) Copenhagen Heart Study (WOMEN) from WHI Freiberg JJ, Tybjaerg-Hansen A, Jensen JS, Nordestgaard BG. JAMA. 2008;300:2142–2152. doi: 10.1001/jama.2008.621 Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM. JAMA. 2007;298:309–316. doi: 10.1001/jama.298.3.309. TG/TRL atherosclerosis direct, indirect, bystander B48 B FA A1 TRLr HDL Lipolysis Vascular lumen Endothelium Subendothelial B Macrophage space/GP matrix Remnant Foam cells Uptake ABCA1, SRB1 B Apolipoprotein B A1 ABCA1 ATP binding cassette A1 Cholesterol efflux SRB1 Scavenger receptor class B, type 1 HDL HDL High density lipoprotein A1 Apolipoprotein A1 Adapted from Watts GF et al. Nat Rev Cardiol. 2013;10(11):648-61. TRLr TG rich lipoprotein remnant High TG/CM, genetic association Acute pancreatitis Stroes E et al. Atherosclerosis Supplements 2017;23:1-7 400 361.4 350 High TRL/CMexposed to lipase in 300 pancreatic capillaries 250 200 150 Inflammatory FFAtrypsin pancreatitis OR acute 100 55.8 50 activation/pancreatic necrosis 15.8 0 moderate TG (5-9 mmol/L severe TG (>9 mmol/L LPLd; n=28 [442-797 mg/dL]), n=487 [>797 mg/dL]); n=354 LipaseFFA release from TRL/CM; moderate TG (5-9 mmol/L [442-797 mg/dL]), n=487 vicious cycle severe TG (>9 mmol/L [>797 mg/dL]); n=354 LPLd; n=28 15 TRL lifecycle: synthesis clearance/atherosclerosis HL VLDL LRP E TRL TRLr LDL CM LPL LPL ER Endoplasmic reticulum LMF1 Lipase maturation factor 1 SEL1L Sel1-Suppressor of Lin-12-Like 1-HRD1 ER-associated degradation HSPG Heparan sulfate proteoglycan GPIHBP1 glycophosphatidyl-inositol HDL binding protein 1 Young SG, Davies BS, Fong LG, et al. Curr Opin Lipidol. 2007;18(4):389-396. doi:10.1097/MOL.0b013e3281527914 Wu SA, Kersten S, Qi L. Trends Endocrinol Metab. 2020. 32(1):48-61. doi:10.1016/j.tem.2020.11.005 Apos Apolipoproteins Schematic representation (Venn diagram) of associated conditions for serum triglyceride levels ≥2000 mg/dL ... 103 of 71 495 patients who had lipid testing in 2016, had TG > 2000 mg/dL (<0.1%) Maria Isabel Esparza MI, et al. Journal of the Endocrine Society, 2019. 3(8): 1595–1607, https://doi.org/10.1210/js.2019-00129 Genetic testing in dyslipidemia: a scientific statement from the NLA Genetic testing in severe hypertriglyceridemia (SHTG) is III C-EO generally not indicated because most SHTG is polygenic or multifactorial. Genetic testing in severe hypertriglyceridemia may be IIb C-EO reasonable if a monogenic disorder is suspected clinically such as familial chylomicronemia syndrome (eg, young age, failure to thrive, relapsing pancreatitis, and absence of secondary causes). Brown, E. E et al. Journal of Clinical Lipidology, 2020.14(4), 398–413. https://doi.org/10.1016/j.jacl.2020.04.011 Is it FCS? Images used with patient permission Moulin P et al. Atherosclerosis, 2018. 275:265-272. ISSN 0021-9150. https://doi.org/10.1016/j.atherosclerosis.2018.06.814. Joe •Pathogenic mutations in LPL, APOC2, APOA5, LMF1, GP1HBP1, GCKR, CREBH; APOE2/3 •Polygenic TG risk score 21/28 21 Images shared with permission from patient Should TGs be treated? Nordestgaard BG. Circ Res. 2016 Feb 19;118(4):547-63. doi: 10.1161/CIRCRESAHA.115.306249. PMID: 26892957. Severe Hypertriglyceridemia Recommendations for Hypertriglyceridemia COR LOE Recommendations In adults 40 to 75 years of age with severe hypertriglyceridemia (fasting triglycerides ≥500 mg/dL [≥5.6 mmol/L]) or higher, IIa B-R and ASCVD risk of 7.5% it is reasonable to address reversible causes of high triglyceride and to initiate statin therapy. In adults with severe hypertriglyceridemia (fasting triglycerides ≥500 mg/dL [≥5.7 mmol/L]), and especially fasting triglycerides ≥1000 mg/dL (11.3 mmol/L)), it is reasonable to identify and address other causes of hypertriglyceridemia), and if triglycerides are persistently elevated or increasing, IIa B-NR to further reduce triglycerides by implementation of a very low-fat diet, avoidance of refined carbohydrates and alcohol, consumption of omega-3 fatty acids, and, if necessary to prevent acute pancreatitis, fibrate therapy. 23 Grundy et al. Circulation 2018. VERY LOW-FAT DIET The main focus for CM clearing is very low-fat meal plan with no more than 20-30 g of fat per day. https://www.lipid.org/sites/default/files/when_your_tgs_are_over_1000_mgdl.pdf Joe’s future Complications from… • Plasma exchange • Bariatric surgery • HyperCM/TG o Recurrent AP o Recurrent xanthomas o ASCVD risk ASO-APOC3 • obesity, diabetes and OSA Anti-AngPTL3 (ASO, mAb) o Arthritis o Neuropathy o CKD o Optho o ED o Cor pulmonale o Liver dz o Etc… Severe hypertriglyceridemia • …the consequence of combined impact from genes and environment • …associated with ASCVD and acute pancreatitis • Tx o ASCVD risk: environment and lifestyle modification/statins o AP risk: environment and lifestyle modification/TG-lowering Rx • Genetic testing may inform expectations and novel therapy 26 Uncomfortable rash and recurrent pancreatitis in 40 yo man Daniel Soffer MD FNLA University of Pennsylvania Division of Internal Medicine, Translational Medicine and Human Genetics FINANCIAL DISCLOSURE: Consultant Akcea Therapeutics, Kaneka (apheresis), Novartis Investigator Amgen Inc, Akcea Therapeutics, Novartis, Regeneron, RegenXBio, Astra-Zeneca UNLABELED/UNAPPROVED USES DISCLOSURE: none Severe Hypertriglyceridemia – Pharmacotherapy Allison Hester, PharmD, BCACP Disclosures Allison Hester, PharmD, BCACP has no financial relationships to disclose in relation to this presentation. Outline Medications TG Current Pipeline that treatment medications medications contribute goals to treat HTG for HTG to HTG HTG: hypertriglyceridemia; TG: triglyceride Medications that can contribute to hypertriglyceridemia Beta-blockers Tamoxifen, Thiazides Corticosteroids (non-selelctive) raloxifene Estrogens Retinoic acid, Immunosuppressants Protease inhibitors (oral, not topical) isotretinoin (i.e., sirolimus) Antipsychotics L-Asparaginase Bile acid resins Phenothiazines (second generation) Curr Cardiol Rev.