Amarin Corp Plc (AMRN)

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TGs: a direct and strong association between long-term mortality risk and triglycerides levels;

4.1 Serum Triglycerides and 10 years mortality
The contribution of triglycerides to CVD risk has been much debated in the past, with many important prospective studies observing an association between elevated triglycerides levels and CVD risk (in particular coronary risk) [18]-[20], but also risk for microangiopathy [21]; nevertheless, more recent studies gave different results, suggesting that this association might be weakened when adjustment for other risk factors was made [22]. The pathogenetic mechanism undergoing these findings remains uncertain, and could be mainly related to triglycerides induced endothelial dysfunction through oxidative stress. By Cox analysis (Model 1) we demonstrated a direct association between long-term mortality risk and triglycerides levels; the association was strong and significant even after multivariate adjustment for traditional CVD risk factors including BMI, HbA1c, LDL-C, and medication use. This independent association with long term all-cause mortality support the idea that serum triglycerides could play a role in type 2 diabetic patients mortality risk [23].

Treating residual risk by lowering triglycerides is still debated at present time [24]; infact, it is not clear whether or not a pharmacological intervention targeted to reducing triglycerides levels would contribute to a cardiovascular risk reduction [25]. Dedicated trials failed to find a significant reduction in CVD outcomes in a diabetic population treated with fenofibrates, [26] while meta-analyses conducted upon pre-specified subgroups have confirmed the clinical benefits of fibrates on major CVD events [27],[28]. A randomized clinical trail with statin therapy plus extended release niacin including over 3,000 patients (one-third with diabetes) with established cardiovascular disease, low levels of HDL cholesterol, and triglycerides levels of 150–400 mg/dL, was halted early due to lack of efficacy on the primary cardiovascular disease outcome, and a possible increase in ischemic stroke in those on combination therapy [29]. Hence, combination lipid-lowering therapy cannot be broadly recommended. However, ADA guidelines state that triglycerides concentrations below 150 mg/dL are desirable. According to this, in our population, the satisfaction of this “desirable” triglycerides level was associated with a lower 10 years total mortality. Thereby, we suggest that more attention should be given to cardiovascular risk management in type 2 diabetic patients with high triglycerides levels; specifically, a more strict management of the other modifiable risk factors (e.g. diet, physical exercise, blood pressure, LDL-C goal) could be indicated.

As a matter of fact, the second Cox analysis was modelled upon accomplishment of ADA criteria (Model 2), and confirmed the previous observation; among the criteria established for CVD prevention in patients with type 2 diabetes, only triglycerides desirable level criteria (<150 mg/dl) was significantly associated with a lower mortality risk in our population.

More interesting, diabetic patients belonging to the “partially satisfying criteria” group (reached triglycerides target for mean values, but failure in one or more follow-up visit) had a higher HR for mortality (HR: 2.02; 95% CI: 1.11-3.48) compared to the “satisfying criteria” reference group (always reached target); besides, their HR for total mortality was very similar to the “not satisfying criteria” group (HR: 1.83; 95%IC: 1.08-2.97). We are not sure about the nature of this finding in the “partially satisfying criteria” group, and there are at least two possible explanations: 1. the atherogenic process might be activated by hypertriglyceridemia, but might successively continue independently from the persistence of high fasting triglycerides; 2. in this group, unmeasured fluctuations of triglycerides levels might be present, and might be as atherogenic and dangerous as high fasting triglycerides levels, thus predisposing them to a similar increase in the risk [30].

http://www.cardiab.com/content/13/1/135