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Novel Thyroid Hormone Analogue Makes Statins More Effective
Just published is a study into a new drug which makes statins more effective — and it lowers the levels of thyroid hormones in the blood.
But wait a minute. Is it just me, or is there something cockeyed here?
The reason I ask is that, analogues of thyroxine have been used to lower blood cholesterol at least since the mid-1930s when dextrothyroxine was first studied. Right up to the 1970s Dr Broda Barnes and others showed that hypothyroidism — low levels of thyroid hormones — increased cholesterol levels. They suggested that, if a patient came to his doctor with high cholesterol, the first thing that should be checked was his thyroid levels. If thyroid hormone levels were low — and in these cases, they usual;ly were — then treatment with laevothyroxine (T4) or dessicated thyroid (T4 + T3) to raise thyroid hormones into the normal range was usually the most effective way to correct the patient's cholesterol.
Yet here we have a drug which lowers thyroid hormone levels being used to lower cholesterol. Does that stack up?
Why not forget statins and just go back to using thyroxine?
Well, of course, there is a good reason why this isn't contemplated: Statins are expensive (and good profit makers), while thyroxine is probably the cheapest drug on the market. It's even cheaper than aspirin. And who can make money out of that?
Here's a report of the new drug, which is called eprotirome:
An experimental agent that mimics thyroid hormone in the liver enhanced the lipid-lowering effect of statins in a randomized controlled trial.
The thyroid hormone analogue, eprotirome, reduced LDL cholesterol by up to 32% beyond statins alone, according to Bo Angelin, MD, PhD, of the Karolinska University Hospital in Stockholm, and colleagues.
This effect was greater than what would be expected from doubling the dose of statin, they reported in the March 11 issue of the New England Journal of Medicine.
Other thyroid hormone analogues developed over the past 30 years have failed because of hyperthyroid and cardiovascular side effects -- even those thought to be more selective for lipid metabolism.
In Angelin's 12-week study, though, eprotirome showed no adverse effects regarding the heart or bone. And although thyroxine levels dropped with the agent, serum thyrotropin and triiodothyronine remained unaffected.
When these results were initially reported at the American College of Cardiology meeting last year, Steven Nissen, MD, of the Cleveland Clinic, cautioned against over interpreting this short-term safety profile, given the long history of difficult development.
Thyroid hormones have been a draw for pharma developers because they modulate lipid metabolism primarily through increasing liver uptake of cholesterol.
In preclinical studies, eprotirome appeared to have "minimal uptake" outside the liver, with modestly lower binding affinity for the form found in the heart.
This study included 189 patients with elevated cholesterol levels of 116 mg/dL or higher while on a stable dose of simvastatin (Zocor) or atorvastatin (Lipitor). Investigators randomized them to placebo or eprotirome at a dose of 25, 50, or 100 µg daily for 12 weeks.
The effect appeared to be dose-related, with reductions from 138 to 144 mg/dL at baseline to the following (all P<0.001):
- 127 mg/dL with placebo, a 7% decline
- 113 mg/dL at the 25 µg dose of eprotirome, a 22% reduction
- 99 mg/dL at the 50 µg eprotirome dose, a 28% decrease
- 94 mg/dL with 100-µg eprotirome dosing, a 32% drop
Patients were also more likely to get their LDL level under 100 mg/dL with eprotirome (36%, 50%, and 57% at the three respective doses compared with 6% on placebo).
Among the findings for other lipid measures, the researchers reported:
- Reductions in apolipoprotein B levels of 20% to 30% with eprotirome versus 6% with placebo (all P<0.001 versus placebo)
- Serum triglycerides fell 16% to 33% compared with an increase of 5% with placebo (P<0.01 to P<0.001 versus placebo)
- Serum Lp(a) lipoprotein decreased 27% to 43% compared with 10% on placebo group (all P<0.001 versus placebo)
- Modest serum HDL cholesterol reductions of 2.5 to 3.3 mg/dL compared with 0.8 mg/dL increase on placebo (P<0.01 to P<0.001 versus placebo)
Lowered HDL cholesterol has been associated with cardiovascular risk, but it's unclear whether these treatment-induced changes would impact cardiovascular disease incidence, the researchers said.
But the effect on triglycerides was notable, they added.
"Particularly in view of its potent effect in lowering levels of apolipoprotein B, eprotirome may represent a useful treatment for combined hyperlipidemia, which is associated with a major cardiovascular risk with even relatively low triglyceride levels," they wrote in the NEJM.
They added, "Eprotirome might prove useful in combination with fibrates or nicotinic acid as well as in combination with statins."
Type and dose of statin didn't impact the results, Angelin's group reported.
Overall adverse events were similar between placebo and eprotirome groups.
Eprotirome was associated with mild, reversible increases in the liver enzyme alanine aminotransferase, as well as a dose-dependent increase in sex hormone-binding globulin (though without impact on sexual function or serum free testosterone or estradiol).
Thyroid function appeared largely unchanged as measured by serum thyrotropin, total triiodothyronine, or free triiodothyronine.
However, eprotirome yielded dose-dependent reductions of 22% to 34% in levels of serum total thyroxine and 12% to 21% in levels of free thyroxine. This effect was reversible and "within or at the lower limit of their respective reference ranges."
"Given the short duration of the present trial, careful monitoring for effects on the thyroid must be a component of longer and larger clinical trials of eprotirome in the future," Angelin and colleagues cautioned in the paper.
Reference
Ladenson PW, et al. se of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia.N Engl J Med 2010; 362: 906-16.
Last updated 12 March 2010
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