The 2018 AHA/ACC Guideline on the Management of Blood Cholesterol was a welcome update from the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults.¹ Our new guideline reinforces the importance of a heart-healthy lifestyle, the use of statins as the first line agent in primary and secondary cardiovascular prevention and the importance of risk stratification to identify those who benefit most from these measures. Also of note, our new guideline features a specific section on hypertriglyceridemia. This section is composed of one class I and three class IIa recommendations followed by a synopsis and supportive text to assist clinicians in recognising and treating patients with hypertriglyceridemia.

Identify and Address Secondary Factors

The class I recommendation first identifies a population 20 years of age or older who have moderate hypertriglyceridemia defined as fasting or nonfasting triglycerides (TG) 175-499 mg/dL (1.9-5.6 mmol/L) and advises searching for and treating secondary factors (see Table 1). The remaining three recommendations build on this.

Table 1: Secondary Factors

LIFESTYLE	Obesity	Metabolic syndrome
SECONDARY DISORDERS	Diabetes mellitus or Hypothyroidism	Chronic liver disease	Chronic kidney disease and/or nephrotic syndrome
MEDICATIONS	Hormone related: Oral estrogens Tamoxifen Raloxifene Retinoids Glucocorticoids	Immune related: Cyclosporine Tacrolimus Sirolimus Cyclophosphamide Interferon	Other: Beta blockers Thiazides Atypical antipsychotics Rosiglitazone Bile acid sequestrants L-asparaginase

Use of Statin Therapy in Moderate Hypertriglyceridemia

The second recommendation (class IIa) is targeted at adults age 40-75 with moderate or severe hypertriglyceridemia >500mg/dL (5.6mmol/L) with an ASCVD risk of 7.5% or higher for whom the above factors have been addressed. It identifies persistently elevated TG as a risk enhancer which favors initiation or intensification of statin therapy to reduce ASCVD risk.

Use of Statin Therapy in Severe Hypertriglyceridemia

The third recommendation (class IIa) endorses the initiation of statins in those with severe hypertriglyceridemia with ASCVD equal to or greater than 7.5% in concert with addressing secondary factors.

Other Therapies in Severe Hypertriglyceridemia

The fourth recommendation (class IIa) is directed towards those with severe hypertriglyceridemia and especially those with triglycerides ≥1,000 mg/dL (11.3mmol/L). It is more complex and addresses many of the factors traditionally discussed in the management of hypertriglyceridemia. Although most cases of severe hypertriglyceridemia have a genetic component, secondary conditions often contribute and addressing secondary factors is again recommended.

An understanding of the biochemical makeup of patients with hypertriglyceridemia is key to following the intricacies for managing moderate vs severe hypertriglyceridemia. The synopsis reviews this in the 2018 ACC/AHA guideline and is summarized in Table 2.

Table 2: The Categories of Hypertriglyceridemia, Lipoproteins Involved, Goals and Therapies

CATEGORY OF HYPERTRIGLYCERIDEMIA	ELEVATED LIPOPROTEIN(S)	GOAL	TREATMENT
MODERATE HTG - FASTING OR NONFASTING TRIGLYCERIDES 150-499 MG/DL	VLDL (atherogenic similar to LDL)	Reduce VLDL and ASCVD risk	-Address secondary factors -Statin
SEVERE HTG - FASTING TRIGLYCERIDES ≥500 MG/DL	Elevated VLDL and chylomicrons	Reduce ASCVD risk and risk of acute pancreatitis	-Address secondary factors -Statin and -Very low fat  diet -Avoid refined carbohydrates and alcohol -Omega-3 fatty acids -Fibrates

There are two categories of hypertriglyceridemia, moderate and severe. In the former, the excess TGs are carried in very low-density lipoprotein (VLDL) versus whereas in the latter they are carried in VLDL and chylomicrons. While VLDL is believed to be atherogenic, similar to LDL, elevated chylomicrons impart an increased risk of acute pancreatitis. This risk increases with the degree of elevation of TGs and those who have TGs in the range of 500-999 mg/dL are at risk of further significant fluctuations in TGs, placing them at especially high risk for acute pancreatitis.

If TGs remain elevated or are increasing after secondary factors are addressed, then clinicians are advised to further reduce TGs with a very low-fat diet, avoidance of refined carbohydrates and alcohol, consumption of omega-3 fatty acids and consideration of fibrate therapy if concern for acute pancreatitis. If a fibrate is necessary, then fenofibrate is recommended over gemfibrozil due to lower risk of myopathy.

The guidelines stress that although statins are known to reduce TGs, they alone cannot prevent acute hypertriglyceridemic pancreatitis in the setting of secondary causes. Rather fibrates or omega-3 fatty acids are the go-to pharmacological therapies. The ACC/AHA guidelines give passing mention to niacin as a TG lowering therapy, but do not explicitly recommend it. It is highlighted that statin therapy is not advised for pregnant women with hypertriglyceridemia due to unclear effects during pregnancy. It is advised that severe or life-threatening hypertriglyceridemia during pregnancy be managed in consultation with a lipid specialist.

2016 ESC/EAS Guideline

How do the 2018 guidelines compare with the current 2016 European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) guideline regarding hypertriglyceridemia?² While there is some variation in the details, the 2018 ACC/AHA and 2016 ESC/EAS guidelines are aligned in giving strong recommendations for lifestyle modification and selective use of pharmacotherapy.

There are modest differences in the TG cutpoints in the guidelines. The 2018 ACC/AHA classifies moderate hypertriglyceridemia as 150-499 mg/dL and severe hypertriglyceridemia as 500 mg/dL or more. The ESC/EAS guideline also classifies fasting TGs of <150 mg/dL (1.7 mmol/L) as desirable, noting that about one-third of individuals have levels 150 mg/dL or above. The ESC/EAS guideline classifies levels as more than ~880 mg/dL (~10 mmol/L) as requiring action to prevent acute pancreatitis, and advises that patients can develop pancreatitis even with TGs between ~440–880 mg/dL (~5-10 mmol/L).

A particularly useful element of the 2016 ESC/EAS guideline is a table which goes into more detail on the magnitude and level of evidence of various lifestyle interventions in reducing TG-rich lipoprotein levels (see Table 3).

Table 3: Adapted From ESC/EAS 2016 Guidelines

LIFESTYLE INTERVENTIONS TO REDUCE TG-RICH LIPOPROTEIN LEVELS	MAGNITUDE OF EFFECT	LEVEL OF EVIDENCE
REDUCE EXCESSIVE BODY WEIGHT	+++	A
REDUCE ALCOHOL INTAKE	+++	A
INCREASE HABITUAL PHYSICAL ACTIVITY	++	A
REDUCE TOTAL AMOUNT OF DIETARY CARBOHYDRATE	++	A
N-3 POLYUNSATURATED FAT	++	A
REDUCE INTAKE OF MONO- AND DISACCHARIDES	++	B
REPLACE SATURATED FAT WITH MONO- OR POLYUNSATURATED FAT	+	B

Similar to the ACC/AHA recommendation for a very low fat diet in severe hypertriglyceridemia, the ESC/EAS guideline discusses restriction of fat content to 10-15% of the diet. For pharmacotherapy in severe hypertriglyceridemia, the ESC/EAS guideline endorses fenofibrate, n-3 fatty acids (2-4 g/day), and niacin.

The Evolving Role for TG Lowering Therapies in ASCVD Risk Reduction

Looking beyond statin therapy, the role of pharmacotherapy for TG lowering to reduce ASCVD has been uncertain. The most action has occurred this past year with omega-3 fatty acid therapy. A meta-analysis of 78,000 patients published in JAMA Cardiology earlier this year showed no reduction in cardiovascular events with n-3 fatty acids compared with placebo.³ Consistent with this were the VITAL (Vitamin D and Omega-3 Trial) and ASCEND (A Study of Cardiovascular Events iN Diabetes) studies published earlier this year, both of which failed to demonstrate a benefit of lower dose omega-3 fatty acid therapy in primary prevention in a broad population and individuals with diabetes, respectively.^4,5 Both studies used 840mg of n-3 fatty acids, including 460mg of eicosapentaenoic acid (EPA) and 380mg of docosahexaenoic acid (DHA). In contrast, the REDUCE-IT (A Study of AMR101 to Evaluate Its Ability to Reduce Cardiovascular Events in High Risk Patients With Hypertriglyceridemia and on Statin) trial used purified EPA at a higher dose of 4 g/d, yielding a striking 25% relative risk reduction in ASCVD.⁶

Conclusion

The ACC/AHA 2018 guideline underscores the critical importance of assessing the hypertriglyceridemic patient for lifestyle factors, secondary disorders, and implicated medications. Pharmacological management in severe hypertriglyceridemia is centered on fenofibrate and omega-3 fatty acid therapy, with the goal of preventing pancreatitis. For ASCVD risk reduction, statins are advised as the cornerstone, with emerging evidence on omega-3 fatty acid therapy from the REDUCE-IT trial set to impact future guidelines.

References

1. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Assocaition Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2018. [Epub ahead of print]
2. Catapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart 2016;37:2999-3058.
3. Aung T, Halsey J, Kromhout D, et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: meta-analysis of 10 trials involving 77,917 individuals. JAMA Cardiol 2018;3:225-34.
4. Manson JE, Cook NR, Lee IM, et al. Marine n-3 fatty acids and prevention of cardiovacular disease and cancer. N Engl J Med 2019;380:23-32.
5. ASCEND Study Collaborative Group, Bowman L, Mafham M, et al. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med 2018;379:1540-50.
6. Bgatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.

Clinical Topics: Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Diet

Keywords: Dyslipidemias, Fibric Acids, Gemfibrozil, Eicosapentaenoic Acid, Fenofibrate, Niacin, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Docosahexaenoic Acids, Glucocorticoids, Asparaginase, Metabolic Syndrome, Antipsychotic Agents, Tacrolimus, Fatty Acids, Omega-3, Chylomicrons, Estrogens, Nephrotic Syndrome, Vitamin D, Dietary Carbohydrates, Diet, Fat-Restricted, Tamoxifen, Retinoids, Fatty Acids, Thiazides, Disaccharides, Cardiovascular Diseases, Risk Factors, Hypertriglyceridemia, Triglycerides, Thiazolidinediones, Lipoproteins, VLDL, Obesity, Body Weight, Life Style, Diabetes Mellitus, Atherosclerosis, Primary Prevention, Risk Reduction Behavior, Pancreatitis, Renal Insufficiency, Chronic, Cyclophosphamide, Muscular Diseases, Hypothyroidism, Liver Diseases, Sirolimus, Cholesterol, Cyclosporins, Bile Acids and Salts

< Back to Listings