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March 10, 2010

Eprotirome further reduces cholesterol levels in statin-treated patients

From theheart.org, by Michael O’Riordan

Baltimore, MD – Adding the investigational thyroid hormone analog eprotirome (Karo Bio) to statin therapy in patients with dyslipidemia results in substantially further reductions in LDL cholesterol and other lipid and lipoprotein levels, a new study shows [1]. The improvements in the atherogenic profile occurred without adversely affecting the heart or skeletal system, two common side effects of thyroid hormone analogs, report investigators.

“This study confirmed the expected efficacy of the thyroid mimetic compound to lower cholesterol and that its effects were in addition to those already experienced among patients taking a statin,” said lead investigator Dr Paul Ladenson (Johns Hopkins University School of Medicine, Baltimore, MD). “That’s pretty impressive, because we’re looking at another 30% reduction in LDL cholesterol in patients already taking lipid-lowering drugs. Also, this compound, somewhat unlike statins, has the ability to lower triglycerides, making it a potentially attractive agent for patients with mixed dyslipidemia.”

The results of the study are published in the March 11, 2010 issue of the New England Journal of Medicine.

Rapid heart rate and atrial dysrhythmias with past drugs

Speaking with heartwire, Ladenson said that it is well-known that thyroid hormone lowers cholesterol and that a normal feature of patients with an overactive thyroid gland is a low cholesterol concentration. There have been previous compounds investigated in the past, and while these analogs have been shown to lower cholesterol levels, concerns about side effects were a major issue.

“The limitations of those previous compounds have been the thyroid-toxic effects,” said Ladenson. “Eprotirome was identified in animal studies after screening a large number of candidate compounds and attempting to identify drugs that might target the liver without causing problems in other tissues, particularly in the two organs that are highly sensitive to thyroid hormone excess: the heart, such as rapid heart rate and atrial dysrhythmias, as well as myocardial hypertrophy, all known to occur with conventional thyroid organ excess; and the skeleton, because we know that even mild thyroid hormone increases can predispose to increased bone turnover and potential osteoporosis.”

In this 12-week study, the researchers wanted to determine whether eprotirome, which has minimal nonhepatic uptake, would provide incremental benefit in lowering levels of atherogenic lipoproteins without side effects. In this placebo-controlled, multicenter study, 137 patients treated with simvastatin (<40 mg) or atorvastatin (<20 mg) for at least three months were randomized to eprotirome 25 µg, 50 µg, or 100 µg.

The addition of eprotirome 25 µg to statin therapy further reduced total- and LDL-cholesterols 36 mg/dL and 32 mg/dL, respectively. Larger reductions were observed with the 50-µg and 100-µg doses, with the 100-µg dose reducing total- and LDL-cholesterol levels 57 mg/dL and 47 mg/dL, respectively. Triglyceride levels were reduced 29 mg/dL, 34 mg/dL, and 61 mg/dL, respectively, at the 25-, 50-, and 100-µg doses.

In addition to these reductions, non-HDL cholesterol, apolipoprotein B, and lipoprotein(a) levels were also significantly reduced in a dose-dependent manner.

Regarding side effects, the researchers report “no symptoms of clinical thyrotoxicosis or hyperthyroidism, no increased heart rate or dysrhythmias, no reductions in body weight, no pattern of serologic markers indicating accelerated bone turnover, and no thyrotropin suppression.”

“It accomplished these things, reducing LDL cholesterol and triglycerides, admittedly in a small and relatively short-term trial, without increasing heart rate, left ventricular wall thickness, or circulating markers of bone turnover, the things that we might be concerned about with this type of drug,” Ladenson told heartwire.

There were some increases in liver enzymes observed with eprotirome and statin therapy, similar to other lipid-lowering drugs, such as statins alone, fibrates, and niacin, but these were not sustained. Asked about the possible clinical role for this still-investigational compound, Ladenson suspects it could play a part in helping the roughly 25% of statin-treated patients he sees not currently at treatment goal.

“It’s often not so much that the statin didn’t work, but that at least a quarter of statin-treated patients have side effects that limit their use, usually myalgias like muscle pain or stiffness,” he said. “I do think there is a large unmet need in a few groups of patients, such as patients who don’t tolerate statins, patients who tolerate statins but aren’t able to get to goal, patients who have not only elevated LDL cholesterol but also high triglycerides, and finally, patients with elevations in lipoprotein(a).”


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