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Triglyceride Levels, Alirocumab Treatment, and CV Outcomes After ACS
Quick Takes
- In patients with an ACS on maximal tolerated statin randomized to the PCSK9 inhibitor alirocumab vs. placebo, baseline triglyceride levels predicted MACE, even after adjustment for covariates associated with triglyceride levels and risk of MACE including diabetes and HDL-C.
- Among patients with baseline triglyceride levels ≥150 mg/dL, those with levels <150 mg/dL at month 4 had a lower adjusted risk of subsequent MACE than those whose levels remained ≥150 mg/dL.
- In the alirocumab group, despite the systematic reduction of triglyceride levels on treatment, the change in triglycerides from baseline to month 4 did not predict the subsequent risk of MACE.
- Whether triglyceride-rich lipoproteins are mediators or markers of risk, and hence whether they should be an independent target for treatment, remains a key unanswered question.
Study Questions:
Did baseline or on-treatment triglyceride concentration alter the clinical benefit of alirocumab in the ODYSSEY OUTCOMES trial?
Methods:
ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind controlled study compared alirocumab versus placebo in patients with a recent acute coronary syndrome (ACS) on maximum-tolerated high-intensity statin, a low-density lipoprotein cholesterol (LDL-C) level ≥70 mg/dL, a non–high-density lipoprotein cholesterol (non–HDL-C) level ≥100 mg/dL, and/or apolipoprotein B (apoB) level ≥80 mg/dL. Fasting triglycerides >400 mg/dL were exclusionary. Fasting lipids were obtained at randomization and at multiple time points. Patients were randomly assigned to subcutaneous alirocumab 75 mg or matching placebo every 2 weeks; dose of alirocumab was adjusted to target an LDL-C level of 25–50 mg/dL. The primary outcome of major adverse cardiovascular events (MACE) included death from coronary heart disease (CHD), nonfatal myocardial infarction (MI), fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization. The median duration of follow-up was 2.8 years. Primary outcome was assessed in the aggregate study population as well as in the alirocumab and placebo groups according to baseline triglyceride categories ≥150 versus <150 mg/dL and according to continuous baseline triglyceride concentration. Proportional hazard models were used to adjust for classic risk predictors including LDL-C and lipoprotein(a).
Results:
At randomization, mean and median triglyceride levels in both treatment groups were 150 mg/dL and 129 mg/dL, respectively. When baseline triglyceride levels were examined as a continuous variable, the adjusted risk of MACE was significantly higher by about 1% for every 10 mg/dL higher triglyceride level, with similar relationships observed in both treatment groups. The median absolute change in triglyceride levels between baseline and month 4 was −17.7 mg/dL in the alirocumab arm versus −0.9 mg/dL in the placebo arm (p < 0.0001). The reduction of LDL-C levels by alirocumab was similar among patients with an initial triglyceride level <150 mg/dL and ≥150 mg/dL. Compared with placebo, alirocumab reduced the risk of MACE consistently in both baseline triglyceride categories; however, the absolute reduction in the risk of MACE with alirocumab was greater in those with baseline triglycerides ≥150 versus <150 mg/dL.
After 4 months, the median (Q1:Q3) triglyceride levels were 108 and 127 mg/dL, while the LDL-C levels were 30 and 87 mg/dL in the alirocumab and placebo groups, respectively. Patients with month 4 triglycerides remaining at levels ≥150 mg/dL had a greater incidence of MACE than patients reaching triglyceride levels <150 mg/dL (10.3% vs. 7.5%; hazard ratio [HR], 1.302; 95% confidence interval [CI], 1.089–1.556) with adjustment for treatment group. Among patients who achieved LDL-C <55 mg/dL at month 4, those with triglycerides ≥150 mg/dL at month 4 had a significantly higher incidence of MACE after month 4 than those with month 4 triglycerides <150 mg/dL (9.0% vs. 6.4%; HR, 1.345; 95% CI, 1.010–1.791), adjusted for treatment group. There was a relatively linear relationship between the change from baseline triglyceride levels and the risk of MACE in the placebo group, but not in the alirocumab group. In the alirocumab group, despite the systematic reduction of triglyceride levels on treatment, a 10 mg/dL decrease in triglycerides from baseline to month 4 was not associated with the subsequent risk of MACE.
Conclusions:
Among patients with recent ACS on optimized statin therapy, baseline triglycerides are associated with cardiovascular (CV) risk. The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab reduced LDL-C, apoB, triglycerides, and CV risk versus placebo; however, the change in triglycerides with alirocumab did not contribute to its clinical benefit.
Perspective:
As lipids carried in VLDL remnant particles (atherogenic) with surface apoB, triglycerides have been thought to be a risk marker or risk factor for CHD in persons treated with statins, particularly in diabetes and the metabolic syndrome. Support as a risk factor includes genetic variants associated with low triglycerides as with low LDL-C are associated with similar lowering of CHD per unit difference in apoB (Ference BA, et al., JAMA 2019;322:1381-91). And in the PROVE IT-TIMI study comparing pravastatin to atorvastatin, reduction in triglycerides to <150 mg/dL was associated with a 1.6% reduction in CHD events for every 10 mg reduction in triglycerides.
However, clinical trials for reducing MACE by lowering triglycerides (niacin, fibrates, omega-3 fatty acids, and dietary supplement fish oil) like the PCSK9 inhibitor alirocumab did not result in clinical benefit when added to statin therapy despite moderate triglyceride lowering. This is in contrast to findings in the placebo-controlled REDUCE-IT trial in which there was a highly significant reduction in MACE using icosapent ethyl (pure EPA) where baseline triglycerides (range 135-499 mg/dL) on statins in diabetics and atherosclerotic CV disease were associated with higher risk, and the beneficial effect was not attributable to degree of triglyceride lowering. In contrast, the two large randomized clinical trials of the same dose of combination EPA+DHA and trial of the novel pemafibrate showed no CV benefit despite similar reduction in triglycerides. Findings suggest pure EPA has significant nonlipid effects and DHA may have negative effects on atherosclerosis. The water is still muddied.
Clinical Topics: Acute Coronary Syndromes, Diabetes and Cardiometabolic Disease, Dyslipidemia, Hypertriglyceridemia, Lipid Metabolism, Prevention
Keywords: Acute Coronary Syndrome, PCSK9 Inhibitors, Triglycerides
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