Is triglyceride therapy worth the effort?

WHAT HAPPENED TO THE ATP III TARGETS?

In 2002, the Third Adult Treatment Panel recommended that if triglyceride levels were higher than 200 mg/dL, non-HDL cholesterol should become a secondary target of therapy.²⁰ What happened to this recommendation?

The writing committee of the 2013 American College of Cardiology/American Heart Association cholesterol guidelines based its recommendations on clinical evidence available from randomized controlled trials.¹⁶ Unfortunately, neither LDL-C nor non-HDL-C targets were the primary or secondary variables of interest when the available trials were designed. Still, aggregate data over the past several decades, combined with our knowledge of the pathophysiology of both LDL-C and triglyceride-rich lipoproteins (ie, remnants), indicate that non-HDL-C levels predict the risk of cardiovascular disease.²¹

Moreover, a post hoc analysis of the PROVE IT-TIMI 22 trial demonstrated residual cardiovascular disease risk in hypertriglyceridemic patients after an acute coronary syndrome event even though the patients were currently on statin therapy at the time.²²

In addition, the ACCORD study also reported a reduction in cardiovascular disease risk in hypertriglyceridemic patients with low HDL-C assigned to triglyceride-lowering in addition to statin therapy.^17,19

Finally, data from two large US health care databases of more than 40,000 adults with triglyceride levels above 500 mg/dL at baseline found that patients who had triglyceride levels lower than 200 mg/dL at follow-up had lower rates of pancreatitis and coronary heart disease events.²³

DOES ADDING TO STATIN THERAPY HAVE LONG-TERM CLINICAL BENEFIT?

Two randomized clinical outcome trials are currently testing whether supplementing statin therapy in order to lower triglyceride levels is superior to statin therapy alone in reducing the risk of cardiovascular events in high-risk patients.

REDUCE-IT

REDUCE-IT²⁴ is studying whether AMR101 (Vascepa), a purified ethyl ester of eicosapentaenoic acid, reduces risk in patients with hypertriglyceridemia (with a baseline level of 200 to 500 mg/dL) who have cardiovascular disease or are at high risk for it. However, a number of factors in this trial will make it difficult to separate out the clinical benefit directly related to triglyceride-lowering. These factors include associated beneficial effects of the treatment on LDL-C composition, HDL-C remodeling, and remnant accumulation and clearance, as well as other potential benefits on cardiovascular disease risk independent of lipids and lipoproteins, such as inflammation.

Nevertheless, REDUCE-IT should provide valuable insight into whether this therapy may be clinically useful in these high-risk patients. Enrollment of 8,000 patients is nearing completion in this event-driven trial, with an anticipated median treatment and follow-up period of 4 years.²⁴

STRENGTH

The STRENGTH study will enroll 13,000 patients with hypertriglyceridemia (200–500 mg/dL) and low HDL-C to receive a fish-oil preparation or placebo. This large 5-year phase 3 outcomes study began enrollment in late 2014.²⁵

WHAT IS THE RISK OF PANCREATITIS FROM ELEVATED TRIGLYCERIDES?

The premise of screening for very high triglyceride levels (> 500 mg/dL) in the new cholesterol guidelines and superimposed on the 2011 American Heart Association scientific statement on triglycerides and cardiovascular disease is the concern that very high levels predict pancreatitis. The risk of pancreatitis increases as triglyceride levels exceed 1,000 mg/dL, with an approximate overall risk of 20%.²⁶

While there is no absolute proof that treating chylomicronemia reduces the risk of pancreatitis, ample data from case series show that strategies aimed at reducing plasma triglyceride concentrations are also effective in reducing the risk of pancreatitis.²⁷ Conversely, patients with previous triglyceride-induced pancreatitis unquestionably have recurrent episodes of pancreatitis when they develop severe chylomicronemia. The American Heart Association scientific statement provides a list of other factors, including metabolic conditions and medications, associated with increased risk of pancreatitis.¹

WHAT ARE THE RECOMMENDATIONS FOR VERY HIGH TRIGLYCERIDES?

Both the American College of Cardiology/American Heart Association cholesterol guidelines¹⁶ and the 2011 American Heart Association statement¹ reserve pharmacologic therapy for very high triglyceride levels, defined as 500 mg/dL or higher.

While lifestyle recommendations are still an important part of therapy (Table 1), genetically induced hypertriglyceridemia may not respond as well to diet, exercise, and fish oil. In addition to statin therapy, if there is concomitant cardiovascular disease or diabetes, primary triglyceride-lowering therapies include fibrates (which lower triglycerides 30% to 50%), niacin (20%–50%) and omega-3 fatty acids (10%–40%)¹ with eicosapentaenoic acid alone, docosahexaenoic acid alone, or the two in combination.

The focus of the American Heart Association statement was to intensify lifestyle therapies in patients with triglyceride levels between 200 and 500 mg/dL because weight loss, aerobic activity, and the addition of marine-derived polyunsaturated fatty acids can be very effective. The most important step is aimed at weight loss through combined caloric restriction and energy expenditure, increasing monounsaturated and polyunsaturated fat intake at the expense of less complex carbohydrates, and adding marine-derived omega-3 fatty acids. Intensive lifestyle therapy can reduce triglyceride levels by 30% to 50%, and by more in some cases.

Of note, without weight loss, a Mediterranean high-fat diet can aggravate hypertriglyceridemia, especially in patients with fasting triglyceride concentrations above 500 mg/dL. This is particularly true for patients with genetically induced states (eg, lipoprotein lipase deficiency) or other significant defects in chylomicron clearance because olive oil and nut oils serve as excellent substrates for chylomicron formation.