In this study, coadministration of P-OM3, 4 g/d, with atorvastatin, 10 to 40 mg/d, lowered non—HDL-C levels to a significantly greater extent than the same dose of atorvastatin alone in patients with elevated triglyceride and non—HDL-C levels. The effects of adding P-OM3 to either 10 or 20 mg/d of atorvastatin were comparable to that of doubling the atorvastatin dose in lowering non—HDL-C levels.
Combining P-OM3, 4 g/d, with atorvastatin also reduced median TC, triglyceride, and VLDL-C levels and increased HDL-C levels to a significantly greater extent than the same dose of atorvastatin alone. Lipoprotein parameters that were not significantly changed by the coadministration of P-OM3 and atorvastatin (vs atorvastatin alone) were LDL-C, apo A-I, and apo B levels.
In the COMBOS (COMBination of prescription Omega-3 with Simvastatin) study,12
addition of P-OM3 to ongoing simvastatin therapy slightly blunted the LDL-C—lowering effect (vs baseline) among those who continued to receive simvastatin monotherapy; however, the treatment effect was not statistically significant (P
=.052). In the current study, a different design was used in which P-OM3 was coadministered with atorvastatin at randomization, which significantly reduced the LDL-C level vs baseline in both groups (P-OM3 plus atorvastatin and atorvastatin alone). Although the magnitude of LDL-C lowering was numerically greater with atorvastatin alone, the difference was not statistically significant (P
=.24). This finding is consistent with results from a previous clinical trial with a similar (ie, coadministration) study design.16
From a safety and tolerability standpoint, the coadministration of P-OM3, 4 g/d, with atorvastatin was generally well tolerated. Although mild glucose elevations were observed in this trial, this finding is consistent with those from other randomized clinical trials involving omega-3 fatty acid administration.17,18
Otherwise, no unexpected tolerability or safety concerns were found in this study.
The triglyceride-lowering properties of omega-3 fatty acids are well known; however, the mechanisms through which this
effect is achieved are not completely understood.19
One potential mechanism involves increased degradation of fatty acids in the liver (through enhancing β-oxidation), which decreases the amount of substrate available for triglyceride synthesis and incorporation into VLDL particles.20
Omega-3 fatty acids may also lower triglyceride levels by enhancing triglyceride clearance from circulating VLDL particles through increased lipoprotein lipase activity.21
This may be mediated through a reduction in apo CIII, which inhibits lipoprotein lipase activity.22
Other proposed mechanisms to explain the triglyceride-lowering effects of omega-3 fatty acids include decreased activity of phosphatidic acid phosphatase/phosphohydrolase and diacylglycerol acyltransferase23
—2 key enzymes involved in triglyceride synthesis—and decreased lipogenesis through a reduction in enzymatic conversion of acetyl coenzyme A to fatty acids.24
However, not all evidence consistently supports these latter mechanisms.19
Non—HDL-C levels appear to be reduced because of decreased VLDL synthesis and secretion and through increased conversion to intermediate-density lipoprotein and low-density lipoprotein, which result from enhanced activity of lipoprotein lipase.19
The current study provides clinically relevant information for treating patients with elevated non—HDL-C levels and reflects the relative merits of coadministering another lipid-altering drug with a complementary mechanism of action to a statin vs simply doubling the statin dose. An advantage of increasing the statin dose is that statins are generally well tolerated and have been proven to reduce CHD events, as evidenced by numerous CHD outcomes trials. However, a potential disadvantage of increasing the statin dose is that statin-related adverse events typically occur at higher statin doses, particularly in older, chronically ill patients treated with multiple medications.25
The risk-to-benefit ratio associated with increasing the statin dose is an important consideration, given
that doubling the statin dose typically results in only a modest incremental reduction in LDL-C and non—HDL-C levels (approximately 6%).4,26
This consideration is substantiated by the current trial in which increasing the atorvastatin dosage from 10 to 20 mg/d resulted in further lowering of the median non—HDL-C level by 5.3% and by 7.3% when the atorvastatin dosage was increased from 20 to 40 mg/d. Finally, although increasing the statin dose may further reduce LDL-C levels (accounting for most of its non—HDL-C—lowering effects), it may have only a modest effect on other lipid parameters that potentially influence CHD risk, such as triglyceride, VLDL-C, and remnant-like particle cholesterol levels.6,27
Again, this is substantiated by the current study, which demonstrated that increasing the atorvastatin dosage from 10 to 20 mg/d resulted in further lowering of median triglyceride levels by only 3.8% and by only 4.1% when the atorvastatin dose was increased from 20 to 40 mg/d, whereas these same parameters were improved to a greater extent in the P-OM3 group.