A Randomized, Double-Blind Placebo-Controlled Study of 3,5-diiodothyropropionic Acid (DITPA) in Combination With Standard Therapy to Attain NCEP ATP III Goal for LDL Cholesterol in Hypercholesterolemic Patients

INTRODUCTION

BACKGROUND: In recent years, the need to achieve increasingly ambitious therapeutic goals for dyslipidemias has prompted the search for more potent pharmacological agents to lower circulating atherogenic lipoprotein concentrations and enhance reverse cholesterol transport (RCT). While mounting evidence supports the use of 3-hydroxy-3-methylglutaryl coenzyme reductase inhibitors (or statins) as the main stay of therapy for patients requiring lipid modification therapy, many patients remain under-treated or do not achieve the National Cholesterol Education Program (NCEP) recommended goals.1-5 Recognizing new and emerging data, NCEP III recently updated its guidelines to recognize the potential of a more aggressive low density lipoprotein (LDL) goal of <70 mg/dl in patients at high risk of cardiovascular events.3 The Treating to New Targets (TNT) study showed that even in patients with stable coronary artery disease, a goal that is lower than currently recommended, <80 mg/dl, may be desirable in further reducing and/or preventing recurrent cardiovascular events.6 More than 40% of all Americans have LDL levels of 130 mg/dl or higher, and 13 million Americans have coronary artery disease that may benefit from lipid modification therapy. In these individuals, to achieve the optimal LDL goal and to treat other associated lipid abnormalities, including low HDL cholesterol and/or high triglycerides, many patients will likely require combination therapy.3, 7-13 Among the novel therapeutic agents investigated have been selective thyroid hormone analogues. Such agents hold the promise of harnessing the cholesterol-lowering properties of the naturally occurring thyroid hormones, triiodothyronine (T3) and thyroxine (T4), but with greater receptor isoform and tissue specificity that should result in an improved safety profile.14, 15 Unlike statins, thyroid hormones and their analogues, in addition to cholesterol and LDL-lowering effects, may favorably lower lipoprotein (a) (Lp(a)) and triglyceride levels.15-22 Also, because of potential thyroid hormone-mediated genomic and non-genomic effects on the heart, certain populations, such as those with congestive heart failure, may derive dual benefits from use of such thyromimetic treatment.15, 22, 23 1.1.1 Effects of Thyroid Hormone on Lipid Metabolism Dyslipidemia has long been associated with disorders of thyroid metabolism (i.e., hypothyroidism) and to be potentially reversible by thyroid hormone therapy.17, 18, 21 Early autopsy series demonstrated more severe atherosclerosis in individuals with premorbid hypothyroidism.24, 25 In studies of how thyroid hormone status affected radiolabeled lipoprotein kinetics, LDL was found to be cleared less rapidly in hypothyroid animals and man.26 Subsequently, hepatic LDL receptor number27 and mRNA expression28 were shown to be lower in hypothyroid animals. More recently, characterization of the LDL receptor gene promoter has revealed the presence of functionally important T3 regulatory elements.29 In addition to lowering total and LDL cholesterol concentrations in treated hypothyroid patients, thyroid hormone therapy has been shown in some studies to have a favorable impact on particularly atherogenic lipoproteins, including Lp(a)30 and small dense and oxidizable LDL subfractions.31, 32 Finally, thyroid hormone replacement therapy has been shown to decrease apoB100 lipoprotein synthesis with a resulting decrease in Very Low Density Lipoprotein (VLDL) production and hepatic triglyceride production.33 There is now also considerable evidence that thyroid hormone receptor agonists can directly or indirectly affect reverse cholesterol transport, the process by which cholesterol is transported from peripheral cells, including cholesterol-laden endothelial cells in the initial stage of atherosclerosis, to the liver for conversion to bile acids. First, thyroid hormone affects the activity of apoA 1 lipoprotein,34 which plays several critical roles in RCT-generating HDL that transports cholesterol from peripheral tissues to the liver, as both the principal protein constituent of HDL and an activator of lecithin-cholesterol acyltransferase (LCAT), which esterifies cholesterol on the surface of pre-β-HDL. ApoA-I also stabilizes and increases the level of ATP-binding cassette A1 protein (ABCA1), which, in turn, promotes efflux of cholesterol and phospholipids to nascent HDL-particles. Thyroid hormone increases apoA-I gene expression in liver and intestine, in part through a 5' flanking thyroid hormone response element.35, 36 Thyroid hormone has also recently been shown to increased the scavenger class B type I receptor (SR-BI), another regulator of serum HDL concentrations and cholesterol flux, in livers of mice treated with either T3 or GC-1 (a thyroid hormone receptor modulator).37 Finally, thyroid hormones are also known to increase activity of cholesterol 7α-hydroxylase (CYP-7A1)38 which catalyzes the rate-limiting step in bile acid synthesis; in contrast, HMG-CoA reductase inhibitors have the opposite effect. This thyroid hormone-induced increase in CYP-7A1 would be expected to increase bile acid and cholesterol excretion, as has been observed in hyperthyroidism.39 1.1.2 Previous Clinical Research Previous studies have investigated the therapeutic potential of thyromimetic compounds in lipid modification and heart failure.14,15,40 Early clinical investigation focused on dextrothyroxine (D-T4), a D-isomer of thyroxine, which was thought to have similar actions, but produce less tachycardia and myocardial oxygen consumption.40, 41 Although DT4 was commonly used as a cholesterol lowering drug in the 1970s,42 it is no longer used in clinical practice. The therapeutic effects of DT4 were evaluated in the Coronary Drug Project (CDP).

The Coronary Drug Project was initiated in 1965, primarily to answer the prevailing question about the safety and efficacy of long term use of various cholesterol lowering agents in patients with coronary artery disease. The Coronary Drug Project was a randomized, double-blind, placebo-controlled study, conducted between 1966 and 1975. It was designed to evaluate the efficacy and safety of five lipid-modifying drugs in 8,341 men, with a history of prior myocardial infarction (MI). Niacin, clofibrate, dextrothyroxine, and two estrogen regimens were evaluated in the study along with a placebo arm.43, 44 DT4 was administered at 6.0 mg /day. The primary endpoint was overall mortality at 5 years. After a mean follow-up of 36 months, because of a nonsignificant trend toward higher mortality in the DT4 arm compared with placebo, the DT4 arm was discontinued.

As acknowledged by the original investigators, the observed DT4-placebo difference in overall mortality is not statistically significant as judged by the statistical methods utilized in this study.44 Nevertheless, given the mortality trend and the low probability of eventual benefits, a decision was made to discontinue the DT4 arm. In discontinuing the DT4 arm, the study leadership recognized that the findings of the CDP left open the possibility that dextrothyroxine may be efficacious for a limited group of carefully selected myocardial infarction (MI) patients and for persons free of clinical CHD. 44 The net effect of DT4 on serum lipids (the observed fall corrected for the concomitant rise for the placebo group) was a sustained significant fall from baseline levels. The decrease was approximately 12% in serum cholesterol levels and 15-20% in fasting serum triglyceride levels.44 Following the study, it was revealed that the DT4 dispensed in the study contained less than 0.5% of levothyroxine (approximately 30 µg of levothyroxine).44 Interestingly, it was later found that contamination of levothyroxine commercial preparations varied from lot to lot (from 0.5% to 2.3%).45 Also, this "DT4" formulation had other significant thyromimetic effects, leading to TSH suppression that may have become clinically relevant with prolonged use.47 Suboptimal dosing and thyrotoxic effects due to drug contamination may explain why more than 40% of the DT4 patients required a dose reduction.44 1.1.3 DITPA DITPA (3,5-diiodothyropropionic acid) is an analogue of naturally occurring thyroid hormone (T3) that has been specifically designed to improve cardiac performance with a lower potential for tachycardia.22, 40, 46 DITPA binds to the same thyroid hormone receptors α and β as T3 but with less affinity.41 In pre-clinical animal post-infarction models, DITPA improved calcium handling, promoted angiogenesis, and attenuated abnormal left ventricular remodeling.47-53 In a rat model of CHF, DITPA demonstrated increased cardiac output with increases in left ventricular dp/dt, comparable to effects seen with T4, but with significantly less tachycardia. In addition, there were increases in α-myosin heavy chain (MHC) RNA gene expression induced by DITPA treatment.41 When evaluated in combination with captopril, DITPA improved both cardiac output and dp/dt as well as increased the rate of LV relaxation when compared with captopril alone.54 In a rabbit post-infarction model, DITPA decreased left ventricular end diastolic pressure and increased positive and negative dp/dt without changes in heart rate or left ventricular systolic pressure.43 In the same model, use of DITPA prevented abnormal SERCA transport and abnormal contractile function associated with myocardial infarction.42, 44 Recently DITPA was also noted to improve endothelial function following myocardial infarction, an action mediated through nitric oxide.55 The objective of the present study is to evaluate the feasibility of DITPA, a thyroid hormone analogue, as a potential lipid modification agent.

KNOWN AND POTENTIAL TOXICITIES: Since DITPA is a thyroid hormone analogue with thyromimetic actions, safety and side effect profiles may be similar to those observed with thyroid hormones T3 and T4 preparations (e.g., liothyronine and levothyroxine). Although excess thyromimetic action is a theoretical side effect, it is also possible that tissue-specific hypothyroidism might result if the drug fails to have sufficient thyromimetic activity in a particular tissue. Due to pituitary effects of DITPA, a secondary lowering of TSH may result, which in turn may lead to decreased endogenous production of T4. The potential effects of such theoretical biochemical changes are unknown. Thus, DITPA safety will be diligently monitored throughout the study through multiple examinations, symptom scales, and laboratory evaluations.