Fasting Triglycerides Predict CVD Risk in Statin-Treated Patients

May 29, 2015

DENVER, CO — In patients with ACS treated with statin therapy, elevated fasting triglyceride levels were significantly associated with an increased risk of cardiovascular events in the short- and long-term follow-up of two major clinical trials, according to the results of a new post hoc analysis [1].

Using data from the Myocardial Ischemia Reduction with Acute Cholesterol Lowering (MIRACL) study and the dal-OUTCOMES trial—two studies of ACS patients treated with statins to low LDL-cholesterol levels—the risk of cardiovascular events was significantly greater among those with higher baseline triglyceride levels.

In the MIRACL study, triglycerides were assessed at baseline before treatment was begun with high-dose atorvastatin. Patients with triglycerides in the highest tertile (>195 mg/dL) had a significant 50% increased relative risk of cardiovascular events over 16 weeks, compared with those with triglycerides in the lowest tertile (≤135 mg/dL).

In dal-OUTCOMES, the phase 3 trial that evaluated the cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib, 97% of patients were treated with statins at the time of baseline lipid measurements, and median baseline LDL cholesterol was 73 mg/dL. Over a median follow-up interval of 31 months, there was a significant gradient of cardiovascular risk across quintiles of baseline triglycerides. Patients with triglycerides in the highest quintile (>175 mg/dL) had a significant 61% increased relative risk of cardiovascular events compared with individuals in the lowest quintile of triglyceride levels (<80 mg/dL) after adjustment for multiple variables.

"Triglyceride-rich lipoproteins contain apolipoprotein B, and a relationship to atherosclerotic risk has been observed in prior studies. However, in dal-OUTCOMES that risk began to increase in the third quintile of triglycerides (103–130 mg/dL), levels that are generally considered to be normal, and continued to rise in the fourth and fifth quintiles, despite background statin therapy," lead investigator Dr Gregory Schwartz (VA Medical Center and University of Colorado School of Medicine, Denver) told heartwire from Medscape. "This suggests that approximately half of all statin-treated patients with ACS have residual risk that is associated with triglyceride-rich lipoproteins."

In an editorial[2] accompanying the study in the June 2, 2015 issue of the Journal of the American College of Cardiology, Drs Parag Joshi, Seth Martin, and Roger Blumenthal (Johns Hopkins School of Medicine, Baltimore, MD) say the findings support another post hoc analysis, this one from the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT)-TIMI 22 trial, which showed a reduction in recurrent events among ACS patients with lower on-treatment triglyceride levels. The editorialists also point to genetic studies, including a Danish analysis, showing that elevations in nonfasting triglycerides were associated with a significantly elevated risk of MI.

Short-Term and Long-Term Associations

The present analysis included 15,817 patients with ACS in dal-OUTCOMES randomly assigned to dalcetrapib on top of statin therapy and followed for 31 months. Dalcetrapib had no effect on cardiovascular outcomes, and there was no significant interaction of triglyceride levels and treatment assignment on those outcomes. In MIRACL, 1501 patients were treated with high-dose atorvastatin following an acute coronary event and followed for 16 weeks.

Like the long-term dal-OUTCOMES results, the researchers also observed a significantly increased risk of clinical events—defined as all-cause mortality, nonfatal MI, unstable angina, or cardiac arrest requiring resuscitation—among the MIRACL participants with elevated baseline triglyceride levels. In both studies, each 10-mg/dL increment in triglycerides was associated with a similar increase in adjusted relative cardiovascular risk: 1.4% in MIRACL and 1.8% in dal-OUTCOMES. In MIRACL, individuals with the highest baseline levels, those in the highest tertile with triglycerides >195 mg/dL, had a 50% increased risk of the composite primary end point compared with those in the lowest tertile (<135 mg/dL).

"We adjusted our relationships for multiple factors that are associated with triglycerides, such as diabetes, body-mass index, and HDL cholesterol, and yet saw no attenuation of the relationship between triglyceride concentration and risk," said Schwartz. "That doesn't prove a causal relationship between triglyceride-rich lipoproteins and residual risk, but it does, perhaps, make it more likely that this is a causal rather than an associative relationship. It's a hypothesis-generating analysis—the hypothesis being that if we were to reduce triglyceride-rich lipoproteins with the right pharmacologic intervention we would we see a consequent reduction in cardiovascular risk."

To heartwire , Schwartz added that non-HDL cholesterol remains the primary focus in clinical practice, with guidelines only recommending physicians specifically target triglycerides if they are moderately or severely elevated. Even then, the goal of such an intervention is to reduce the risk of pancreatitis rather than to lower the risk for cardiovascular outcomes. Non-HDL cholesterol incorporates cholesterol contained both in LDL and triglyceride-rich lipoproteins. The results of the present analysis would tend to support such a shifting focus, said Schwartz.

Regarding the clinical implications of the data, Schwartz said that despite the best contemporary management of patients with ACS, recurrence rates are still high. That said, clinical practice should adhere to the evidence available, and there simply isn't any yet to support lowering triglyceride levels to reduce residual cardiovascular risk. For the patient with moderately elevated triglycerides, say 150 mg/dL, lifestyle modification—diet, exercise, limiting alcohol intake, controlling existing diabetes, among other things—is first and foremost.

"If triglycerides are still elevated after lifestyle interventions, I might have a discussion with the patient regarding the adjunctive use of fish oil," said Schwartz. "That discussion would involve telling them the trials have been equivocal to this point in showing whether or not a reduction in triglycerides with conventional fish oil products, on top of the use of statins, reduces cardiovascular risk. Given the fact that these agents are relatively inexpensive, well tolerated, and safe, I'd give the patient the option, but I wouldn't necessarily do it in every case."

In their editorial, Joshi, Martin, and Blumenthal agree with the emphasis on lifestyle modification, especially given the populationwide rise in metabolic syndrome and the resulting increase in remnant lipoproteins. They note that modest weight loss can reduce triglyceride levels by approximately 20% and moderate to intense physical activity can reduce triglyceride levels by 20% to 30%.

There are several prescription omega-3 fatty acids currently approved for patients with triglyceride levels >500 mg/dL. The US Food and Drug Administration (FDA) turned down an expanded indication for one agent, Vascepa (Amarin), in October 2013, saying such an indication required cardiovascular-outcomes data to support it. That agent, a high eicosapentaenoic acid (EPA) omega-3 fatty acid, is currently being tested in the Reduction of Cardiovascular Events with EPA—Intervention Trial (REDUCE-IT) for its effect on cardiovascular outcomes in patients with moderately elevated triglycerides. Another major cardiovascular-outcomes trial, known as STRENGTH, is also ongoing. That study will randomize statin-treated patients with hypertriglyceridemia to placebo or a prescription-strength omega-3 fatty acid (Epanova, AstraZeneca) and follow them for 3 to 5 years.

Further behind fish oil in terms of study and development, another agent, an antisense oligonucleotide for apolipoprotein C3 (apoC3), is also being tested, said Schwartz. ApoC3 plays an important role in the clearance of triglyceride-rich lipoproteins, and its concentration is associated with triglyceride levels. One genetic analysis, previously reported by heartwire , showed that individuals with a rare mutation in the gene encoding apoC3 (APOC3) not only had lower plasma triglyceride levels but also a lower risk of developing coronary heart disease.

The dal-OUTCOMES trial was funded by Hoffmann-La Roche. The MIRACL trial was funded by Pfizer. Schwartz, through his institution, has received research grants from Anthera, Pfizer, Resverlogix, Roche, and Sanofi. Disclosures for the coauthors are listed in the article. Joshi and Martin have received support from the Pollin Cardiovascular Prevention Fellowship and National Institutes of Health training grants, respectively. Martin has also received support from the Marie-Josée and Henry R Kravis fellowship and is listed as a coinventor on a pending patent filed by Johns Hopkins University for an LDL-cholesterol estimation method. Blumenthal has reported that he has no relevant financial relationships.


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