Use of the Thyroid Hormone Analogue Eprotirome in Statin-Treated Dyslipidemia

N Engl J Med. 2010 Mar 11;362(10):906-16.

Paul W. Ladenson, M.D., Jens D. Kristensen, M.D., Ph.D., E. Chester Ridgway, M.D., Anders G. Olsson, M.D., Ph.D.,

Bo Carlsson, M.Sc., Irwin Klein, M.D., John D. Baxter, M.D., and Bo Angelin, M.D., Ph.D.

Lipoproteins

• Central core hydrophobic lipid

• Hydrophilic coat of polar phospholipid, free cholesterol and apolipoprotein

• HDL

• LDL

• VLDL

• Chylomicrons

• VLDL and LDL transport cholesterol and triglycerides to the tissues• HDL absorbs cholesterol and returns it to LDL or VLDL• Atherosclerosis is strongly associated with a specific type of LDL -

Lipoprotein (a)• Statins reduce circulating LDL by inhibiting endogenous cholesterol

synthesis• Thyroid hormones increase excretion of LDL in bile acids and

activity of HDL

Treatment of dyslipidaemia

• Statins - primary prevention - significant reduction in the risk of all-cause mortality, fatal and non-fatal MI, stable angina, and a composite endpoint of coronary heart disease (CHD) death plus non-fatal MI

• Statins - secondary prevention - reduction in all-cause mortality, CVD mortality, coronary heart disease (CHD) mortality, fatal myocardial infarction (MI), and coronary revascularization

• Limited evidence for other lipid modifying drugs - bile acid sequestrants, ezetimibe, fibrates, nicotinic acid

Study design

• Randomised, placebo controlled• Double blind, double dummy (?)• 4 week dietary lead in• 12 weeks treatment Placebo or Eprotirome • Monitored 4 weeks after discontinuation• Primary efficacy (outcome) variable – change in

serum LDL• Secondary efficacy (outcome) variables –

levels/ratios of other lipids

Double Dummy

• A technique for retaining the blind when administering supplies in a clinical trial, when the two treatments cannot be made identical.

• Comparing surgery with medical treatment

• Group 1: Surgery then placebo

• Group 2: Sham surgery then medication

Study patients

• 18-65

• ≤ Simvastatin 40mg

• ≤ Atorvastatin 20mg

• LDL cholesterol ≥ 3.0 mmol/L

• Long list of exclusions

• 329 screened, 189 included, 5 no data, 184 included in efficacy analysis, 168 completed the trial.

Statistics

• Sample size aimed to detect mean decrease of LDL of 0.5 mmol/L

• Two sided type I error rate (α) of < 0.05 [p<0.05]• 172 patients for statistical power of 80%

[Type II error rate β = 0.2. Power = 1- β = 0.8]• Analysis based on absolute change in LDL

cholesterol levels between baseline and week 12

Statistics

• F test compares the variance (spread) of two groups, giving the F statistic

• The Jonckheere-Terpstra test used to measure dose related response. It tests for ordered differences among groups assumed to be arranged ordinally, and tests for differences among several independent samples

• Last-observation-carried-forward method allows inclusion of dropouts. It assumes that the patients improve gradually from the start of the study until the end, so that carrying forward an intermediate value is a conservative estimate of how well the person would have done had he or she remained in the study.

Results

Results

Discussion

• Addition of eprotirome to statin therapy resulted in substantial further reductions in levels of LDL, non HDL and Apolipoprotein B

• “Larger reductions that would be expected by doubling statin dose”

• Better reductions in triglycerides and Lp(a) than statin alone

• Small reduction in HDL adversely affect CV risk?

• No evidence that reduction in Lp(a) reduces CV risk despite being associated with atherosclerosis

• Unknown thyromimetic effects or effect of suppressing TSH

• 12 weeks insufficient time to assess possible adverse effects

• Mildly deranged LFTs

Possible problems• Drug company sponsored, all authors heavily sponsored. New drug,

so likely to be pressure to find positive results• Reasons for drop outs not given in main article• No statistical comparison of placebo to study groups• Long list of exclusions would imply largely patients on primary

prevention, who are treated differently to secondary prevention• Eprotirome added to moderate statin dose, not to patients on

maximum treatment. To be valuable, should be compared to current best treatment.

• Graphs plot main data points at top of CI for no obvious reason – is this to graphically exaggerate the results?

• No confidence intervals given for main results - standard deviations given instead

• Proof of reduction in LDL does not prove clinical benefit