STATE OF THE ART REVIEW Management of hypertriglyceridemia BMJ: first published as 10.1136/bmj.m3109 on 12 October 2020. Downloaded from Vinaya Simha ABSTRACT Hypertriglyceridemia is one of the most common lipid abnormalities encountered in clinical practice. Many monogenic disorders causing severe hypertriglyceridemia have been identified, but in most patients triglyceride elevations result from a Division of Endocrinology, Mayo combination of multiple genetic variations with small effects and environmental Clinic, Rochester, MN 55905, USA factors. Common secondary causes include obesity, uncontrolled diabetes, alcohol Correspondence to: misuse, and various commonly used drugs. Correcting these factors and optimizing [email protected] Cite this as: BMJ 2020;371:m3109 lifestyle choices, including dietary modification, is important before starting http://dx.doi.org/10.1136/bmj.m3109 drug treatment. The goal of drug treatment is to reduce the risk of pancreatitis in Series explanation: State of the Art Reviews are commissioned patients with severe hypertriglyceridemia and cardiovascular disease in those on the basis of their relevance with moderate hypertriglyceridemia. This review discusses the various genetic and to academics and specialists in the US and internationally. acquired causes of hypertriglyceridemia, as well as current management strategies. For this reason they are written predominantly by US authors. Evidence supporting the different drug and non-drug approaches to treating hypertriglyceridemia is examined, and an easy to adopt step-by-step management strategy is presented. Introduction independent risk factor for ASCVD and optimal drug Hypertriglyceridemia is a fairly common clinical treatment, including novel and emerging therapies, condition, but it continues to evoke considerable to mitigate this will be examined in greater detail. http://www.bmj.com/ debate about its ramifications and management. Consider the clinical vignette in box 1. Even as the Sources and selection criteria diagnosis of hypertriglyceridemic acute pancreatitis I searched PubMed for English language articles (HTG-AP) seems relatively straightforward, the published in peer reviewed journals over the clinician is confronted by quite a few conundrums. past two decades. Search terms used included Is hypertriglyceridemia a cause or a consequence hypertriglyceridemia management, hypertriglyceri- of acute pancreatitis? Are previous non-fasting demic pancreatitis, hypertriglyceridemia and cardio- on 24 September 2021 by guest. Protected copyright. serum triglyceride values valid for diagnosing vascular risk, drug-induced dyslipidemia, and hypertriglyceridemia and assessing future risk? What genetic hypertriglyceridemia. I included consensus is the cause of the patient’s hypertriglyceridemia: statements, guidelines, and systematic reviews primary genetic abnormality or secondary to un- from 2010 to 2020 and also considered randomized controlled diabetes and estrogen use? Would genetic controlled trials (RCTs) and human pathophysiology testing have any benefit? What is the optimal studies from earlier (from 1970). I prioritized RCTs, treatment plan for the elevated triglycerides, both systematic reviews with meta-analyses, and large acutely to relieve pancreatitis and in the long term case series, in that order, when evaluating treatment to prevent its recurrence? Does hypertriglyceridemia effects. Case reports were excluded, but some increase her long term risk of atherosclerotic observational studies detailing the epidemiology cardiovascular disease (ASCVD)? What is the optimal and pathophysiology of the disease were included. diet that should be recommended, especially in view of her preference for a “ketogenic” diet? Which drug Diagnosis and classification treatment will benefit her the most: statins, fibrates, The mean age adjusted serum triglyceride omega-3 fatty acids, niacin, or a combination? concentrations of US adult men and women were This review summarizes relevant data to help to reported to be 128 (5th-95th percentile 52-361) answer some of these questions. The target audience mg/dL and 110 mg/dL (48-270), respectively, in the is general internists, hospital based physicians, 1999-2008 National Health and Nutrition Examina- endocrinologists, and cardiologists. It outlines the tion Survey (NHANES).1 Serum triglycerides tend epidemiology and changing trends of dyslipidemia in to increase with age and are lower in children. the general population, the different classifications Hypertriglyceridemia is commonly defined as fasting of the severity of hypertriglyceridemia, and the serum triglycerides of 150 mg/dL (1.7 mmol/L) or pathophysiology of hypertriglyceridemia and its above, although the “optimal” fasting triglyceride complications. The role of hypertriglyceridemia as an concentration, which confers the lowest risk of incident the bmj | BMJ 2020;371:m3109 | doi: 10.1136/bmj.m3109 1 STATE OF THE ART REVIEW Furthermore, non-fasting serum triglycerides have BMJ: first published as 10.1136/bmj.m3109 on 12 October 2020. Downloaded from Box 1: Clinical vignette also been shown to be associated with risk of acute A 46 year old woman with recently diagnosed type 2 diabetes was admitted with pancreatitis, with a hazard ratio exceeding that for severe abdominal pain, nausea, and vomiting. Abdominal imaging and elevated ASCVD.8 Non-fasting triglycerides may better reflect serum lipase concentrations confirmed the diagnosis of acute pancreatitis. At the postprandial accumulation of atherogenic presentation, her plasma glucose was 306 mg/dL and her serum triglycerides were triglyceride-rich remnant lipoprotein particles 1850 mg/dL. Two months previously, her fasting plasma glucose was 155 mg/dL, her and thus better predict the risk for ASCVD than do hemoglobin A1c was 7.6%, and she had been treated with metformin monotherapy. fasting triglyceride concentrations. Accordingly, She had also been given hormone replacement therapy for menopausal symptoms the European and Canadian guidelines do not and moderate intensity statin therapy for primary prevention of atherosclerotic advocate a fasting lipid profile,5 9 and the recent cardiovascular disease. She had generalized obesity with a body mass index of 35. AHA/ACC guidelines recommend either a fasting or Review of previous medical records showed serum triglyceride concentrations ranging a non-fasting lipid profile for screening, although from 265 to 440 mg/dL, although some measurements were obtained in a non-fasting a follow-up fasting lipid profile is recommended if state. Her family history was significant for hypercholesterolemia and premature serum triglycerides are above 400 mg/dL.3 These coronary artery disease but not for pancreatitis or severe hypertriglyceridemia. recommendations are intended to simplify screening procedures, as an elevation of only 15-20% in serum triglycerides is seen after a regular low fat meal (about and recurrent ASCVD, may be below 100 mg/dL.1 15 g fat), which would be inconsequential in people Different guidelines and expert committees have with normal triglyceride concentrations. However, designated different cut-off values for classification in the absence of established normal standards for of the severity of hypertriglyceridemia (table 1). postprandial triglyceride concentrations, fasting The US National Cholesterol Education Program triglycerides are still recommended for the diagnosis (NCEP) Adult Treatment Panel,2 and the subsequent and classification of hypertriglyceridemia. The American Heart Association/American College of postprandial triglyceride responses to a standardized Cardiology (AHA/ACC) guidelines on lipid treatment,3 test meal that would best predict future ASCVD or considered serum triglycerides of 500 mg/dL or above pancreatitis remain to be determined. as severe hypertriglyceridemia indicative of risk for pancreatitis, with lesser elevations (borderline and Epidemiology borderline high) associated with increased ASCVD Hypertriglyceridemia is the most common form of risk. They note that patients with triglycerides dyslipidemia observed in the general population. 10 in the 500-999 mg/dL (5.6-11.2 mmol/L) range On the basis of the NHANES 2003-06 data, an http://www.bmj.com/ are at risk of developing unrecognized marked estimated 53% of US adults have dyslipidemia, increases in triglycerides, leading to pancreatitis. As 27% have elevated low density lipoprotein (LDL) pancreatitis is rarely seen with serum triglycerides cholesterol, 23% have low high density lipoprotein below 1000 mg/dL, the Endocrine Society and (HDL) cholesterol, and 30% have elevated serum European Atherosclerosis Society/European Society triglycerides (>150 mg/dL). However, encouraging of Cardiology classify severe hypertriglyceridemia as trends have been noted, with a steady decline in the concentrations of at least 1000 mg/dL or 10 mmol/L prevalence of hypertriglyceridemia from 33.3% in the .4 5 on 24 September 2021 by guest. Protected copyright. (880 mg/dL), respectively 2001-04 survey to 25.1% in the 2009-12 survey.11 The above classifications are based on fasting According to the 2007-14 NHANES data, the overall serum triglyceride concentrations, but non-fasting prevalence of hypertriglyceridemia is 25.9%, and the serum triglycerides are perhaps more indicative prevalence in people treated with statins is 31.6%.12 of health risk. Many large epidemiologic studies The overall prevalence is still higher in men than in including the Women’s Health Initiative study and