COMBOS: Results of the combination of prescription omega-3 plus simvastatin trial

Patients with persistent fasting triglyceride levels >200 mg/dL after achieving their low density lipoprotein (LDL) cholesterol goal with statin therapy often present a challenge to clinicians. According to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) the next treatment goal is to lower non-high density lipoprotein (non-HDL) cholesterol, which sums the cholesterol carried by atherogenic lipoproteins. From a practical standpoint, this often means lowering triglycerides, because fasting triglycerides are carried by very low density lipoprotein (VLDL) particles, which carry cholesterol measured by non-HDL cholesterol measurements.¹

Omega-3 fatty acids significantly lower triglycerides, raise high density lipoprotein (HDL), and although not always consistent, may also lower non-HDL cholesterol and apoB.

The Combination of Prescription Omega-3 Plus Simvastatin (COMBOS) trial evaluated the common clinical presentation of statin-treated patients who, after achieving their LDL cholesterol treatment goal, have persistent triglyceride levels 200 mg/dL to 499 mg/dL.

COMBOS design

COMBOS assessed if therapeutic doses of omega-3 fatty acids added to stable statin therapy improved non-HDL cholesterol levels, triglyceride levels, and other lipid parameters.² COMBOS also evaluated the safety of adding prescription omega-3 fatty acids to stable statin therapy in hypertriglyceridemic patients whose LDL cholesterol was >10% of their NCEP ATP III treatment goals, and assessed the effects upon LDL particle size, LDL subclass pattern, and lipoprotein associated phospholipase A2 (LpPLA2).^2-4

COMBOS included 254 men and women aged 18 to 79 years with fasting triglyceride levels between 200 mg/dL and 499 mg/dL who were receiving stable statin therapy to control LDL cholesterol. All patients had LDL cholesterol levels less than 10% above their NECP ATP III goals when assessed 2 weeks and 1 week prior to randomization. All patients received 40 mg simvastatin daily for 8 weeks before randomization. They were then randomized to receive 4 g prescription omega-3 fatty acids, taken as two capsules twice a day or four capsules once a day, in addition to 40 mg simvastatin (n=122) or placebo plus 40 mg simvastatin daily (n=132) for 8 weeks.

Many in the COMBOS study were representative of a metabolic syndrome population, with mean blood glucose levels of 109.8 mg/dL in the group assigned to prescription omega-3 fatty acids and 106.9 mg/dL in the placebo group, with waist circumferences of 103.5 cm and 104.4 cm, respectively. Average weight was 91 kg in the treatment group and 92.9 kg in the placebo group.

Median baseline LDL cholesterol levels were 90.7 mg/dL in the prescription omega-3 fatty acid recipients and 88.2 mg/dL in the placebo recipients. At baseline, median triglyceride levels were 267.8 mg/dL in the active treatment group and 270.7 mg/dL in the placebo group; median HDL cholesterol levels were 46 mg/dL and 43.3 mg/dL, respectively; and median non-HDL cholesterol levels were 137 mg/dL and 141.3 mg/dL, respectively.

COMBOS results

The main outcome of this trial was the change in non-HDL cholesterol, which significantly decreased by 7.9% in the prescription omega-3 fatty acid subjects compared to a decrease of 1.5% found in those randomized in placebo (P<.001). Triglyceride levels were significantly decreased by 29.5% in the active treatment group compared with a decrease of 6.3% in the placebo group. VLDL cholesterol levels significantly decreased by 27.5% and 7.2% respectively, and HDL cholesterol levels significantly increased by 3.4% in the treated patients but decreased by 1.2% in the placebo patients. Median apoB levels significantly decreased. (P =.0232).

Median LDL cholesterol levels increased by 0.7% in the prescription omega-3 fatty acids group and declined by 2.8% in the placebo group, which was not of significant difference (P =.0522). Non-HDL cholesterol and triglyceride levels were predicted to decrease; but it was unknown whether the addition of prescription omega-3 fatty acids would cause a loss in the benefit of the statin on LDL cholesterol levels. These data do not suggest a clinically significant increase in LDL cholesterol levels when prescription omega-3 fatty acids are added to simvastatin.

Adverse experiences occurred in 41.8% of the prescription omega-3 fatty acid recipients and 47.7% of the placebo group. Nasopharyngitis, upper respiratory tract infection, diarrhea, dyspepsia, bronchitis, cystitis, alanine aminotransferase (ALT) increase, and gastroenteritis occurred in more than 1% of patients and with a greater incidence among those receiving prescription omega-3 fatty acids. No significant differences occurred between groups. Some patients experienced eructation, and the incidence was slightly increased in the prescription omega-3 fatty acids group.

Four patients assigned prescription omega-3 fatty acids experienced serious adverse experiences (Table). None were considered by the investigators to be due to the study drug.

COMBOS Safety Assessment
Table. COMBOS Safety Assessment

*Adverse experiences shown occurred in >1% of patients and at a greater rate in the P-OM3 plus simvastatin group.
†None of these serious adverse experiences were considered by the investigators to be related to the study treatment. In three subjects, the event resolved without changing the study regimen. In one event, study medication was discontinued and the experience was ongoing at the end of the study.
Adapted with permission from Davidson MH, Stein EA, Bays HE, et al. Clin Ther. 2007;29:1354-1367.

Tertiary assessment results

Further analysis demonstrated that patients achieving the lowest triglyceride levels also achieved the greatest increase in LDL particle size. Patients with end-of-treatment triglyceride levels of >250 mg/dL had a decrease in LDL particle size of 0.20 nm, those with triglyceride levels between 200 mg/dL and 249 mg/dL had a 0.15-nm increase in LDL particle size, patients achieving triglyceride levels of 150 mg/dL to 199 mg/dL showed a 0.40-nm increase in LDL particle size, and those achieving triglyceride levels <150 mg/dL had a 0.60-nm increase in LDL particle size.

When the LDL subclass pattern was analyzed, and baseline vs. end-of-treatment values compared, the proportion of patients expressing pattern A (representing a shift from small dense LDL to larger LDL) was increased with prescription omega-3 fatty acid therapy. Concomitantly, the proportion of patients who expressed pattern B, representing a shift from larger, and potentially less atherogenic LDL to small dense LDL, was decreased. These changes correlated with the reduction in triglyceride level.

Although no change in the levels of C-reactive protein was observed among COMBOS patients receiving prescription omega-3 fatty acids, a significant reduction occurred in the level of the inflammatory marker Lp-PLA₂. Patients treated with prescription omega-3 fatty acids had a significant 10.7% decrease in Lp-PLA₂ levels compared with a 1.4% decrease among placebo patients.⁴

Conclusion

Many patients with mixed dyslipidemia have persistent hypertriglyceridemia after statin monotherapy. Adding prescription omega-3 fatty acid therapy may improve not only triglycerides in these patients, but also improve secondary lipid treatment targets, such as non-HDL-C levels.

References

Third Report of the NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III). Circulation. 2002;106:3143-3421.
Davidson MH, Stein EA, Bays HE, et al. Efficacy and tolerability of adding prescription omega-3 fatty acids 4 g/d to simvastatin 40 mg/d in hypertriglyceridemic patients: an 8-week, randomized, double-blind, placebo-controlled study. Clin Ther. 2007;29:1354-1367.
Maki KC, et al. FASEB J. 2007;21:231-232. Abstract.
Shalwitz RA, et al. ATVB Abstract P328. Arterioscler Thromb Vasc Biol. 2007;27:e93.