Managing Hypertriglyceridemia

Introduction

Plasma triglyceride (TG) concentration reflects circulating triglyceride-rich lipoproteins and their metabolic remnants (predominantly chylomicrons, very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDLs) and to some extent low-density lipoprotein (LDL)). Mild to moderate hypertriglyceridemia (150-499 mg/dL) is common and the result of an increased burden of small effects from a number of common and rare genetic variants. Autosomal recessive monogenetic hypertriglyceridemia is rare, and results from large effect mutations in six different genes.

Hypertriglyceridemic gene expression is modified by environmental stimuli from the diet, excess adiposity, physical activity, and other factors.

On the basis of genetic data, hypertriglyceridemia can be classified into two states:

• Triglycerides 175-899 (~2 to ~10 mmol/L) usually results from a multigenetic disorder
• Triglycerides ≥900 mg/dL (>~10 mmol/L) usually results from a monogenetic disorder.

Because hypertriglyceridemia susceptibility alleles and environmental contributors cluster in families, screening and counseling for families is encouraged for those with severe hypertriglyceridemia (≥500 mg/dL). The genetic contributors are usually unknown.

The treatment approach is the same for almost all patients with hypertriglyceridemia. Lifestyle habits and secondary causes are the major drivers of hypertriglyceridemia and should be the primary focus of evaluation and treatment. Drug therapy is reasonable when TG levels remain ≥500 mg/dL despite efforts to improve lifestyle or control secondary causes.

Clinical Highlight I

• Triglycerides (TGs) are not a target of therapy for ASCVD risk reduction.
• Healthy lifestyle habits and weight loss should be the primary focus of therapy for reducing TG levels.
• Secondary contributors should be ruled out or treated.
• Maximize statin therapy to reduce ASCVD risk (as recommended in 2018 multi-society cholesterol guideline).
• Nonstatin therapy to further ASCVD risk may be considered for some high-risk patients.
• Treat TGs ≥1000 mg/dL since this potentially reduces the risk of pancreatitis.
• Lifestyle modification and control of secondary causes reduces TGs to <500 mg/dL in the majority of patients.
• Consider triglyceride-lowering drug therapy to reduce TGs to <500 mg/dL in some high-risk patients:
  • Baseline fasting TGs ≥1000 mg/dL
  • History of pancreatitis
  • Persistent TGs ≥500 mg/dL despite lifestyle efforts
  • Diabetes type 1 or 2
  • Clinical ASCVD
  • Untreated LDL-C ≥190 mg/dL or familial combined hyperlipidemia

Evaluation of Triglycerides ≥500 mg/dL

Patients with a TG level ≥500 mg/dL require further evaluation:

• Patients should fast at least 12 hours prior to obtaining the blood sample for TG measurement
• Rule out secondary causes of hypertriglyceridemia in all patients

Particular attention should be paid to detecting undiagnosed or poorly controlled diabetes or hypothyroidism. Other relatively common secondary causes include weight gain, excessive alcohol intake, drugs (retinoic acid, estrogens, glucocorticoids, protease inhibitors), third trimester pregnancy, chronic renal failure and nephrotic syndrome. Once secondary causes of hypertriglyceridemia are adequately treated, TG levels usually fall to <500 mg/dL.

Triglyceride Treatment Overview

Hypertriglyceridemia arises from abnormalities in one or more metabolic pathways exacerbated by lifestyle habits (high fat or high refined carbohydrate diet, excessive alcohol intake), excessive weight gain, or other secondary causes (often poorly controlled diabetes). Healthy lifestyle habits and weight loss should be the primary focus of therapy. Secondary contributors should be ruled out or treated.

Statins should be used to reduce ASCVD risk as recommended by the 2018 multi-society cholesterol guideline. Statins reduce TGs, and high intensity statins can reduce TGs by up to 30%, often obviating the need to consider a TG-lowering drug. No trials to date have evaluated whether TG-lowering drug therapy reduces cardiovascular events or pancreatitis in patients with TGs ≥500 mg/dL. Some observational data suggest individuals with a history of high TGs have lower risk of pancreatitis when subsequent TG levels are <500 mg/dL.

All recommendations to use drug therapy to lower TGs are based on expert opinion. When TGs are ≥1,000 mg/dL, a TG-lowering drug is usually started simultaneously with diet and lifestyle changes. Drug therapy to lower TGs is typically reserved for patients whose TGs remain ≥500 mg/dL despite lifestyle modification or who have a history of pancreatitis. However, selected patients with TG levels <500 mg/dL may also benefit from pharmacologic therapy.

Triglycerides and ASCVD Risk

Although individuals with TG levels ≥150 mg/dL are at increased cardiovascular risk, adjustment for low HDL-C levels and insulin resistance eliminates the majority of the cardiovascular risk associated with elevated TGs. To date, drug therapy to lower TGs per se has not been shown to reduce ASCVD risk (ACCORD, AIM-HIGH) or to lower risk more than expected from reductions in LDL-C or non–HDL-C levels. Mendelian randomization genetic studies have found that certain metabolic pathways that increase TG levels are associated with increased ASCVD risk. New drugs targeting these pathways are under development.

Triglycerides <500 mg/dL

The 2018 multi-society cholesterol guideline recommends healthy lifestyle habits for all patients regardless of TG levels. There are no recommendations to alter treatment based on TG levels when they are <500 mg/dL or to treat to specific TG levels. In patients with moderate hypertriglyceridemia (fasting or nonfasting TGs 175-499 mg/dL), lifestyle and secondary factors should be addressed (Class of Recommendation [COR] I).

Statins reduce the relative risk of ASCVD similarly across the range of TG levels ≤400 mg/dL (those with TGs >400 mg/dL were typically excluded from statin RCTs). Furthermore, there is no randomized trial evidence that TG-lowering per se from statin or nonstatin therapy reduces cardiovascular events. Therefore, statins are the recommended as first-line treatment for ASCVD risk reduction in patients with TGs <500 mg/dL. The 2021 ACC Expert Consensus Decision Pathway (ECDP) on ASCVD risk reduction in patients with persistent hypertriglyceridemia generally agrees with that approach, but adds that icosapent ethyl, a TG-lowering drug, may be considered in selected patients with TGs 150-499 mg/dL and LDL-C <70 mg/dL, after optimizing lifestyle changes and ruling out secondary causes. The 2021 ACC ECDP also suggests considering icosapent ethyl in patients with diabetes and TG levels 150-499 mg/dL who are 50 years of age or older and who have at least one ASCVD high-risk feature (age ≥55 [men] ≥65 [women], smoking, hypertension or on hypertensive medication, HDL-C ≤40 mg/dL [men] ≤50 mg/dL [women], hs-CRP >3.0 mg/L, renal dysfunction, retinopathy, albuminuria, or ankle-brachial index <0.9 without intermittent claudication).

If a patient with low HDL-C (<35-40 mg/dL) and high TGs (>200 mg/dL) is unable to tolerate a moderate- or high-intensity statin, an alternative treatment strategy that may be considered is the use of maximal statin therapy with fenofibrate. In completely statin-intolerant patients, either fenofibrate or gemfibrozil can be used. It appears most of the cardiovascular risk reduction benefit from fibrates occurred in this group with low HDL-C and high TGs in the fibrate cardiovascular outcomes trials (ACCORD, FIELD, BIP, Helsinki Heart Study and VA-HIT) (Figure 21-1). Patients with moderate hypertriglyceridemia (TGs 150-499 mg/dL) who also have elevated LDL-C (≥70 mg/dL and particularly ≥100 mg/dL) on maximized statin therapy can be considered for nonstatin therapy.

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Triglycerides ≥500 mg/dL

The 2018 multi-society cholesterol guideline made two recommendations for patients with severe hypertriglyceridemia (fasting TG levels ≥500 mg/dL):

• In adults 40-75 years of age with hypertriglyceridemia and an ASCVD risk of ≥7.5%, it is reasonable (COR IIa) to address secondary causes of hypertriglyceridemia and start statin therapy.
• In adult patients with hypertriglyceridemia (especially those with TG levels ≥1000 mg/dL), if TG levels remain elevated after addressing secondary causes, it is reasonable (COR IIa) to implement a very low-fat diet, counsel avoidance of refined carbohydrates and alcohol and counsel consumption of omega-3 fatty acids; if necessary to prevent acute pancreatitis, initiate fibrate therapy.

The 2021 ACC ECDP on hypertriglyceridemia generally agrees with the 2018 multi-society cholesterol guideline, suggesting an emphasis on a low-fat diet (and very low fat [10-15%] diet in selected cases) to lower TGs and considering fibrates (preferred) or omega-3 fatty acids (icosapent ethyl or omega-3 acid ethyl esters) to reduce the risk of pancreatitis.

Observational data suggest that patients with fasting TGs ≥500 mg/dL who are later observed to have TGs <500 mg/dL are less likely to develop pancreatitis. Nonetheless, pancreatitis is very uncommon (1%) in patients whose TGs remain >500 mg/dL over a 2- to 3-year follow-up period. No trials have been performed to evaluate the effect of lowering TGs to prevent pancreatitis.

• Triglycerides 500 to <1000 mg/dL. The treatment strategy in patients with TGs ≥500 to <1,000 mg/dL is to aggressively address lifestyle modification and avoid alcohol to achieve a TG level <500 mg/dL. Secondary contributors should be addressed. Statins should be used to reduce ASCVD risk if clinical ASCVD, untreated LDL-C ≥190 mg/dL, diabetes aged 40-75 or ≥7.5% 10-year ASCVD risk. If TGs persist at levels 500-999 mg/dL, drug therapy can be considered if the patient has other characteristics that may place them at higher risk of pancreatitis or cardiovascular disease.
• Triglycerides ≥1000 mg/dL or history of pancreatitis. Implement a very low-fat diet; otherwise, same lifestyle and ASCVD risk reduction advice as for TGs 500 to <1,000 mg/dL. Rule out secondary contributors. If TGs remain ≥1,000 mg/dL on recheck fasting for >8 hours, start triglyceride-lowering drug therapy (see below) for prevention of pancreatitis.

Lifestyle Modification to Reduce Triglycerides

A heart-healthy diet low in refined carbohydrates and saturated fat is recommended, along with regular aerobic activity. A Mediterranean dietary pattern is preferred. All patients with elevated TGs should lose 5% to 10% of body weight. Lifestyle modification is very effective for lowering TGs in almost all patients (Table 21-1) and should be considered the foundation of triglyceride-lowering therapy.

• Replace saturated and trans fats with monounsaturated and polyunsaturated oils. Avoid high saturated and trans fat intake and fried foods. Monounsaturated and polyunsaturated fats are acceptable up to 35% of daily calories for those with TGs 500-900 mg/dL. A <20% fat diet is recommended for those with TGs >900 mg/dL who are likely to have a monogenetic disorder. Trans fats were banned in the US food supply in 2018, but before then they were often found in deep-fried foods, baked goods and stick margarine.
• Avoid refined carbohydrates and processed foods. Avoid sugar, white flour, white rice and food items that contain them (bread, desserts, snacks). Avoid “clear” carbohydrates such as alcohol and the sugar and high fructose corn syrup used in soda as well as numerous other processed food products. Replace with whole grains and minimally processed carbohydrates, fruits and vegetables and low fat dairy and meat.
• Increase omega-3 fatty acids. Marine-derived omega-3 fatty acids lower TGs in a dose-dependent manner, with a 5% to 10% reduction in TGs for every 1 g of EPA/DHA. It is difficult to obtain more than 1-2 g of the TG-lowering marine omega-3 fatty acids EPA/DHA from food sources (Table 21-2). Plant-derived α-linolenic acid does not lower TGs but does occur in healthful foods such as walnuts, soybeans, flaxseed, and canola oil. It is reasonable to consume omega-3 fatty acid rich foods as part of a healthy dietary pattern.
• Avoid alcohol. Alcohol contains highly refined carbohydrate. Excessive alcohol intake should be avoided. Ask patients to entirely restrict alcohol for 1 month and recheck TGs. For patients who insist on continued alcohol intake, carefully monitor TG levels to establish if there is an acceptable level of intake that does not adversely affect the patient’s TG levels.
• Eat less and exercise more. Weight loss is a highly effective method of reducing TGs. Weight loss must be maintained through regular physical activity. Note that the muscles are the primary users of glucose and exercise increases insulin sensitivity and glucose uptake and lowers plasma glucose levels. Lower plasma glucose levels result in less fatty acid synthesis, and therefore less synthesis of TG-rich lipoproteins.

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Dietitian Referral

All patients with TGs remaining ≥500 mg/dL (and especially those with TGs ≥1000 mg/dL) should see a dietitian for counseling on a diet very low in fat (<15%) and refined carbohydrates, and obese patients should be counseled to lose weight.

Clinical Highlight II

• Provide concise lifestyle advice:
  • No white (or clear) carbohydrates
  • Eat food in nature’s package (avoid processed, refined, or deep-fat fried foods)
  • Eat less
  • Exercise more
• Refer to dietitian if triglycerides remain ≥500 mg/dL.

Drugs to Lower Triglycerides

Drug-related changes in HDL-C and TGs have not been associated with cardiovascular risk reduction. Based on the RCT evidence to date, it appears that the residual lipid abnormalities present in the inflammatory state of insulin resistance and obesity are likely to be markers, rather than causes, of increased cardiovascular risk.

No trials been conducted to determine if TG-lowering drug therapy reduces the risk of pancreatitis or cardiovascular events in patients with TGs ≥500 mg/dL.

Triglyceride-lowering effects of various drugs are provided in Table 21-3.

Statins should be used to reduce cardiovascular risk in hypertriglyceridemia patients as recommended in the 2018 multi-society cholesterol guideline. High-intensity statins can reduce TGs by 30%.

Fibrates are generally the first choice for triglyceride-lowering to prevent pancreatitis. Fibrates reduce TGs by 20% to 50%, with greater efficacy in severe hypertriglyceridemia. Fibrates reduce cardiovascular risk less than statins, appear to do so in relation to the magnitude of non–HDL-C rather than triglyceride-lowering, and have safety concerns when used in combination with statins.

High doses of omega-3 fish oil also effectively lower elevated TGs. Although omega-3 fatty acids have few adverse effects and can be used safely with high intensity statins, multiple capsules need to be taken to obtain 3.4 mg EPA/DHA daily. Niacin moderately lowers TGs but has multiple significant adverse effects that limit its use.

Niacin is probably of limited use in patients with diabetes or diabetes risk factors since it can markedly worsen hyperglycemia.

Ezetimibe has only modest triglyceride-lowering effects.

Bile acid sequestrants are absolutely contraindicated in severely hypertriglyceridemic patients since they can markedly exacerbate hypertriglyceridemia.

PCSK9 inhibitors and bempedoic acid have modest effects on TGs.

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Management of Suspected Pancreatitis

Patients with abdominal pain and TGs ≥1000 mg/dL should be evaluated for pancreatitis. Patients with suspected pancreatitis should be hospitalized. Oral caloric intake should cease and patients should receive supportive measures including fluid replacement without glucose, along with control of obvious precipitating factors such as uncontrolled diabetes. Fibrates, omega-3 fatty acids and statins and other nonstatins are less effective in the acute setting. Infusions of insulin in nondiabetic patients, heparin, plasma exchange and high-dose antioxidants also appear to be of little value.

Slowly reintroduce foods with small frequent meals, then over the longer term restrict fat to <20% of daily calories and avoid refined carbohydrates (including alcohol). Increase aerobic physical activity and encourage weight loss and maintenance as indicated.

Long-term monitoring to encourage maintenance of healthy lifestyle habits and adherence to TG-lowering drug therapy is essential.

The very rare patient with very severe hypertriglyceridemia and recurrent pancreatitis should be referred to a lipid specialist. They may benefit from lomitapide, which also lowers TGs in addition to LDL-C.