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Hypertriglyceridemia: Identifying Secondary Causes

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Screening for cardiovascular (CV) risk often includes a routine serum fasting lipid profile. However, with the focus on LDL cholesterol, triglyceride measurement is frequently overlooked. Yet this element of the lipid profile is particularly important, given its strong association with not only atherosclerotic coronary heart disease but also pancreatitis.

Hypertriglyceridemia is defined as a serum triglyceride level that exceeds 150 mg/dL. In the US, an estimated 25% of patients have hypertriglyceridemia.1 Of these, 33.1% have “borderline high” triglyceride levels (150 to 199 mg/dL), 17.8% have “high” levels (200 to 499 mg/dL), and 1.7% have “very high” levels (> 500 mg/dL).1,2

Most of the time, hypertriglyceridemia is caused (or at least exacerbated) by underlying etiology. The best way to identify and manage these secondary causes is through a systematic approach.

CONSIDER THE EVIDENCE

For mild to moderately elevated (borderline high) triglyceride levels, our reflex reaction may be to recommend a triglyceride-lowering medication, such as fenofibrate. But this may not be the best answer. Although there is increasing evidence of an independent association between elevated triglyceride levels and CV risk, it remains unclear whether targeting them specifically can reduce that risk.3

In well-designed, peer-reviewed clinical trials, statins have been shown to reduce CV risk in patients with known cardiovascular disease (CVD) and those at high risk for CVD, as well as in primary prevention. However, these trials also suggest that significant residual CV risk remains after statin therapy.4

Several trials have attempted to prove residual risk reduction following combination therapy including statins—with inconclusive results:

ACCORD: Fenofibrate showed no overall macrovascular benefit when added to a statin in patients with type 2 diabetes and a triglyceride level < 204 mg/dL.3,5

AIM-HIGH: There was a 25% reduction in triglyceride levels when niacin was added to a regimen of a statin +/- ezetimibe, with an aggressive LDL treatment target (40 to 80 mg/dL). But the study was stopped early due to the lack of expected reduction in CVD events.4,6

JELIS: A reduction in major CV events was seen with 1,800 mg/d of eicosapentaenoic acid (EPA) supplementation plus a low-dose statin, compared to statin monotherapy. However, there was minimal change in triglyceride levels, leading the researchers to hypothesize that multiple mechanisms—such as decreasing oxidative stress, platelet aggregation, plaque formation and stabilization—contributed to the outcome.4,7

Informed by the JELIS results, the much-anticipated REDUCE-IT trial is currently in progress to address the lingering question of whether combination therapy can reduce residual CV risk. In this trial, EPA omega-3 fatty acid is being added to the regimen of statin-treated patients with persistently elevated triglycerides. Results are expected in 2017 to 2018.8

Remember that a triglyceride level of 150 mg/dL is a parameter—it does not represent a therapeutic target. There is insufficient evidence that treating to this level improves CV risk beyond LDL target recommendations.7

The National Lipid Association Expert Panel’s consensus view is that non-HDL is a better primary target than triglycerides alone or LDL. Using non-HDL as a target for intervention also simplifies the management of patients with high triglycerides (200 to 499 mg/dL). The non-HDL goal is considered to be 30 mg/dL greater than the LDL target. For patients with diabetes and those with CVD, the individualized non-HDL targets are 130 mg/dL and 100 mg/dL, respectively.9

REVIEW THE MEDICATION LIST

Several commonly used medications, including ß-blockers and thiazide diuretics, can increase triglyceride levels.10 Other medications with exacerbating effects on triglycerides include corticosteroids, retrovirals, immunosuppressants, retinoids, and some antipsychotics.10 Bile acid sequestrants (eg, colesevelam) should be avoided in patients with elevated triglycerides (> 200 mg/dL).7

In women, oral estrogen (ie, menopausal hormone replacement and oral birth control) can greatly exacerbate triglyceride levels, making transdermal delivery a better option. Tamoxifen, the hormonal medication used for breast cancer prophylaxis, can also increase triglyceride levels.11

LOOK FOR UNDERLYING CONDITIONS

Among those to consider: Hypothyroidism is common and easily ruled out by a simple blood test. Nephrotic syndrome should be ruled out, particularly in patients with concomitant renal dysfunction and peripheral edema, by checking a random urine protein-to-creatinine ratio or 24-hour urine for protein. Other factors that should be explored because of their potential effect on lipid metabolism include obesity and excessive intake of sugary beverages (ie, soda, fruit juice) and alcohol.11

High triglyceride levels occurring with low HDL are characteristic of insulin resistance and concerning for metabolic syndrome and/or polycystic ovarian syndrome.3,12 Often, patients will have underlying prediabetes (fasting glucose ≥ 100 mg/dL or random glucose ≥ 140 mg/dL with an A1C > 5.7%13) or covert type 2 diabetes. Another underdiagnosed but very common condition, obstructive sleep apnea, can greatly affect insulin sensitivity and has been associated with lipid abnormalities and metabolic syndrome.14

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