Reaching hypertriglyceridemia goals

In the January issue of the journal Pintó et al.1 report the achievement of fasting triglyceride (TG) target values (≤2.2 mmol/L; 200 mg/dL) in patients (n = 929) attending lipid clinics of the Spanish Arteriosclerosis Society. Those who did not reach the TG goal (56% of the study population) had a poorer lifestyle (in terms of smoking, physical inactivity, weight gain and alcohol intake) than those who achieved adequate control. Independent predictors of treatment failure were the severity of hypertriglyceridemia, low high density lipoprotein cholesterol (HDL-C), as well as high non-HDL-C, alcohol consumption, and higher body mass index (BMI). Surprisingly, drug treatment had no predictive power.

The findings of Pintó et al.1 are of interest because their Spanish population was likely on a Mediterranean diet which has been reported to reduce TG levels2,3. However, despite the favorable ‘Mediterranean dietary background’, 56% of the participants failed to achieve their set TG target1. The beneficial effect of the Mediterranean diet extends to post-prandial hypertriglyceridemia, which may predict vascular risk4–6. Post-prandial TG levels were not assessed by Pintó et al.1, probably because standardized fat loading tests are time-consuming and more suited to smaller studies5,6.

Another variable associated with hypertriglyceridemia is an increase in the proportion of small dense low density lipoprotein (sdLDL)7, which is more atherogenic than buoyant LDL. However, sdLDL is another example of a potential vascular risk predictor where the methodology can be complex and costly as well as not clearly defined7. A similar situation is assessing the function, and not just the circulating levels, of high density lipoprotein (HDL)8. HDL function is likely to be adversely affected8 in the hypertriglyceridemic patient population studied by Pintó et al.1. Unfortunately, at present there is no easy, cheap, rapid, and widely acceptable method to reliably assess HDL function8.

Liver tests are not reported in the Pintó et al.1 study. This information may have been of interest because their patients are likely to have a high incidence of non-alcoholic fatty liver disease (NAFLD). Indeed, metabolic syndrome (MetS), increased BMI, hypertriglyceridemia, and insulin resistance are associated with NAFLD9–11. In turn, a multifactorial lifestyle approach together with statins and weight reduction can improve NAFLD (as assessed by liver tests and ultrasound)9–11. NAFLD is relevant because it is likely to be associated with an increased risk of vascular events, type 2 diabetes, and hepatic complications9–11.

It is likely that combination treatment is necessary to achieve both the LDL-cholesterol (LDL-C) goals as well as lower TG levels; 57.6% of patients were treated with lipid-lowering drugs in monotherapy at the final visit of the Pintó et al.1 study. Ezetimibe was not mentioned in detail by Pintó et al.1 as a treatment option for ‘add-on’ therapy. In our experience12, as baseline TG concentrations increase (tertiles: <139, 140–179, and ≥180 mg/dl; <1.57, 1.58–2.02, and ≥2.02 mmol/L), the fall in TG levels was 0.9, 16.1, and 30.3%, respectively, in patients taking simvastatin +ezetimibe. This finding is especially relevant because this study12 was carried out in Greece, another Mediterranean country. In another study also carried out in a Mediterranean country (Slovenia) the fall in TG levels with ‘add-on’ ezetimibe to statin therapy was proportional to baseline TG values13. Others also reported a greater fall (up to 25.9%) in TG levels after ‘add-on’ ezetimibe treatment to a statin in patients with raised baseline TG values14. These ezetimibe + statin combination findings are in line with the observations with statin monotherapy where the extent of the fall in LDL-C and higher baseline TG levels were associated with a greater statin-induced fall in TG levels15. There is also evidence that ezetimibe can influence post-prandial hypertriglyceridemia16–19. This effect may be related to improved glycemic response, decreased chylomicron production and apolipoprotein B48 levels, as well as a fall in remnant-like particles16–19. Ezetimibe even as monotherapy may turn out to be a TG-lowering option in patients who cannot tolerate other drugs used to treat dyslipidemias16–19. There is a need to clearly establish if ezetimibe can make a clinically-relevant contribution to lowering TG levels, since the current perception may be that it should be exclusively used to lower LDL-C levels.

Pintó et al.1 reported that MetS was more common (48.9 vs 61.9%; p < 0.001) in those who did not achieve the TG goals. They1 used the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) definition of MetS. A more ideal choice may have been to use the more recent Joint Interim definition of MetS, because it includes the definition of waist circumference based on ethnicity, and several learned societies were involved20. More specifically, defining waist circumference according to these more recent diagnostic criteria20 may be relevant because a Spanish population was studied. Furthermore, we reported considerable variations in the prevalence of MetS in a Greek (i.e., a Mediterranean) population, depending on which definitions were used21,22.

Pintó et al.1 concluded that a relatively high proportion of patients failed to reach their TG targets despite attending specialized lipid clinics. Based on our experience, we agree that there is a need to alter this situation. In addition to improving adherence with lifestyle measures1, other factors may contribute to poor control of hypertriglyceridemia. For example, treatment guidelines focus on achieving defined LDL-C levels23. The guidelines mention the risk of acute pancreatitis in patients with TG levels > 10 mmol/L (∼880 mg/dL) and that this risk increases even at TG values > 5 mmol/L (∼440 mg/dL)23. Whether the latter information is widely appreciated is not clear, but it certainly does not address lower TG levels. As for the link between hypertriglyceridemia and vascular risk, if the evidence was convincing, then target TG levels would be included in guidelines23,24. However, in the context of the Mediterranean diet it is of interest that fasting TG levels were predictive of subsequent vascular events in statin untreated patients in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study25. In this trial the statin (mainly atorvastatin)-induced decrease in TG levels was related to a significant reduction in vascular events. This benefit was more evident in patients with coronary heart disease + MetS. However, the value of this finding is limited because it was based on a post-hoc analysis25. Clearly, if it is proven that lowering TG levels below a threshold value results in a decrease in vascular events, then more aggressive treatment should become widely accepted. Whether such evidence becomes available will depend on if the intervention assessed exclusively influences TG levels. To our knowledge, such an agent is not currently available.

Other potential factors interfering with effective treatment of hypertriglyceridemia may include poor commercial ‘promotion’ or insufficient scientific/medical interest concerning this topic. If this assumption is correct, then this deficiency can be remedied by often including ‘hypertriglyceridemia’ in the programs of scientific/educational meetings. Clinicians may also be reluctant to prescribe several lipid lowering drugs concomitantly, especially when elevated TG levels occur with co-morbidities such as diabetes, alcoholism, NAFLD, chronic kidney disease, or if patients are seen as not capable of adhering to complex treatment regimens and regular follow-up visits which may be necessary to ensure safety. These co-morbidities are associated with polypharmacy as well as abnormal kidney and liver function, which can be interpreted as contraindications to adding more medication.

In view of the limited evidence regarding benefit from lowering TG levels that are not markedly raised it seems unreasonable to add medication to achieve a fall in modestly raised TG levels; however, the implementation of lifestyle measures should be strongly recommended and frequently re-enforced in such patients. This approach may avoid unnecessary adverse events and additional cost. However, it may be worth considering achieving LDL-C guideline targets using evidence-based drugs that simultaneously correct raised TG levels.

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Declaration of funding

This editorial was written independently; no company or institution supported the authors financially or by providing a professional writer.

Declaration of financial/other relationships

Some of the authors have given talks, attended conferences, and participated in trials and advisory boards sponsored by various pharmaceutical companies.