study of tak-559 in treating subjects with type 2 diabetes mellitus

Conditions: Diabetes Mellitus

Summary: the purpose of this study was to determine the safety of tak-559, once daily (qd), in treating subjects receiving a stable dose of insulin to control type 2 diabetes mellitus.

insulin is a primary regulator of blood glucose concentrations. a subnormal response to circulating insulin levels at target tissues leads to a decrease in insulin-mediated glucose uptake. insulin resistance is associated with normal to high insulin levels and is often accompanied by dyslipidemia, a disruption in lipid metabolism resulting in increased triglycerides and low-density lipoprotein levels as well as decreased high-density lipoprotein levels in patients with type 2 diabetes mellitus. in the early stages of insulin resistance, a compensatory mechanism of increased insulin secretion by the pancreas maintains normal to near-normal glucose levels. once the pancreas fails to maintain the increased insulin output, overt type 2 diabetes mellitus occurs. insulin also plays an important role in the metabolism of fat and proteins and exerts its influence at the peroxisome proliferator-activated receptor level. peroxisome proliferator-activated receptor -alpha receptors are expressed predominantly in skeletal muscle, adipose tissue, heart, liver, kidney, gut, macrophages, and vascular tissue, and play a key role in energy storage, glucose homeostasis, and vascular biology. thus, as insulin activates peroxisome proliferator-activated receptor-alpha receptors, this results in the cellular uptake of glucose. peroxisome proliferator-activated receptor receptors are ligand-activated transcription elements that regulate gene expression necessary for metabolism. for this reason, peroxisome proliferator-activated receptors play a pivotal role in glucose homeostasis, adipocyte differentiation, and lipid storage. the genes predominantly targeted by transcription activity of activated peroxisome proliferator-activated receptor-alpha receptors are those that mediate fatty acid uptake, fatty acid oxidation, and lipoprotein metabolism. as such, peroxisome proliferator-activated receptor-alpha agonists have their greatest effect on lipid metabolism and vascular biology. tak-559 is a novel oxyiminoalkanoic acid under investigation for use as an oral agent in the treatment of patients with type 2 diabetes mellitus. tak-559 has partial peroxisome proliferator-activated receptor-alpha agonist activity, potent peroxisome proliferator-activated receptor-alpha activity, and modest peroxisome proliferator-activated receptor-gamma activity at high concentrations in nonclinical models. this study was designed to evaluate the safety of tak-559 in the treatment of patients with type 2 diabetes mellitus who were on a stable dose of insulin.

Eligibility criteria:
inclusion criteria: * had type 2 diabetes mellitus using american diabetes association diagnostic criteria, currently treated with insulin therapy. * required sponsor approval if older than 65 years. * had a screening glycosylated hemoglobin less than or equal to 8.0%. * had a screening fasting plasma glucose less than or equal to 200 mg/dl (11.1 mmol/l). * had a screening low density lipoprotein less than or equal to 160 mg/dl (4.1 mmol/l). * had a screening thyroid stimulating hormone level less than or equal to 5.5 μu/ml (5.5 μu/l) and greater than or equal to 0.35 μu/ml (0.35 μu/l). * was willing to continue dietary counseling during study and had dietary advice greater than or equal to 2.5 months prior to screening. * had a screening ejection fraction greater than or equal to 40% from echocardiogram. * had a screening blood pressure less than or equal to 140/95 mm hg. * was willing to perform daily self-monitoring blood glucose tests. * a female subject of childbearing potential who was sexually active agreed to use adequate contraception, and was neither pregnant nor lactating from screening throughout the duration of the study. * was in good health as determined by physician (via medical history and physical examination) other than having type 2 diabetes mellitus. * had clinical laboratory evaluations within normal reference range or deemed not clinically significant by the investigator or sponsor. * started insulin therapy at least 3 months prior to randomization. exclusion criteria: * had a hypersensitivity to peroxisome proliferator-activated receptor -alpha or gamma agonists, thiazolidinediones, or fibrates. * was diagnosed with type 1 diabetes mellitus or hemochromatosis, or had a history of ketoacidosis. * required greater than 2 hypertension medications to achieve adequate blood pressure control. * had a history of coronary angioplasty or bypass graft, or unstable angina pectoris within 1 year of screening. * had a history of myocardial infarction. * had a history of transient ischemic attack or documented cerebrovascular accident within 6 months of screening. * abdominal, thoracic, or vascular surgery within 6 months of screening warranting exclusion (investigator's opinion). * had a screening creatine phosphokinase value greater than 3 times the upper limit of normal. * had persistent unexplained microscopic or macroscopic hematuria or history of bladder cancer. * had a screening triglyceride level greater than 500 mg/dl (5.6 mmol/l). * experienced a change in allowed lipid-lowering medication (dose or drug) within 2 months of randomization. * experienced a change in blood pressure medication (dose or drug) within 1 month of randomization. * had systemic corticosteroids within 1 month of randomization. * had donated or received blood products within 3 months of randomization. * had a condition known to invalidate glycosylated hemoglobin. * had a history of drug abuse or alcohol abuse within 2 years. * had a significant cardiovascular disease, including new york heart association functional (cardiac) classification ii, iii or iv. * had a screening b-type natriuretic peptide greater than 100 pg/ml (100 ng/l). * had a history of left ventricular hypertrophy (women greater than 110 g/m2 and men greater than 134 g/m2). * had a clinically significant mitral insufficiency at screening. * had a clinically significant aortic stenosis at screening. * had a screening body mass index greater than 45. * had a history of cancer with no remission within 5 years of randomization, other than basal cell or stage 1 squamous cell carcinoma of the skin. * had an alanine transaminase or aspartate transaminase level greater than 3 times the upper limit of normal, active liver disease or jaundice at screening. * had a positive human immunodeficiency virus, hepatitis b surface antigen, or hepatitis b e antigen test at screening. * was required to take or intended to continue taking any disallowed medication, prescription medication, herbal treatment or over-the counter medication that may interfered with the evaluation of the study medication, including: * oral antidiabetic agents (including sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, peroxisome proliferator-activated receptor agonists and metformin) * fibrates * systemic corticosteroids * warfarin * rifampin * nicotinic acid * minoxidil * hydralazine * st. john's wort * was participating or had participated in an investigational study within the past 30 days. * had a serious disease or condition at screening or randomization that could affect life expectancy or made it difficult to manage/follow patient according to protocol.

Keywords: glucose metabolism disorder dysmetabolic syndrome type ii diabetes diabetes mellitus, lipoatrophic dyslipidemia drug therapy