safety and efficacy of tak-559 in combination with metformin in patients with type 2 diabetes mellitus.

Conditions: Diabetes Mellitus

Summary: the purpose of this study is to evaluate the safety and efficacy of tak-559, once daily (qd), taken in combination with metformin in treating subjects with 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 and glycemic control of tak-559 in patients with type 2 diabetes mellitus taking metformin for whom monotherapy with an oral anti-diabetic had been insufficient.

Eligibility criteria:
inclusion criteria: * diagnosed with type 2 diabetes mellitus, and on a stable dose of an oral antidiabetic monotherapy before screening a. * female patients of childbearing potential who were sexually active agreed to use adequate contraception, and could neither pregnant nor lactating from screening throughout the duration of the study. * had a glycosylated hemoglobin level greater than or equal to 8.0% and less than or equal to 10.0% at screening b. * had a fasting plasma glucose greater than or equal to 126 mg/dl (7.0 mmol/l) at screening b. * taking a stable dose of at least 1000 mg of metformin for at least 30 days before screening b. * had a stable or worsening self-monitoring blood glucose level while taking metformin. * had a low-density lipoprotein less than 160 mg/dl (4.1 mmol/l) at screening a. * had a body mass index was less than or equal to 45 kg/m2 at screening a. * was willing to be counseled by the investigator or designee to follow an individualized, weight-maintaining diet during the study period. * had evidence of insulin secretory capacity as demonstrated by a c-peptide concentration of greater than or equal to 1.5 ng/ml (0.50 nmol/l) at screening a, and if necessary, after a repeat at screening b. * was able to perform daily self-monitoring blood glucose tests throughout the study. * had a normal thyroid-stimulating hormone level of less than 5.5 μiu/ml (5.5 miu/l) and greater than or equal to 0.35 μiu/ml (0.35 miu/l) at screening a. * was in good health as determined by a physician (ie, via medical history and physical examination), other than a diagnosis of type 2 diabetes mellitus. * had fasting clinical laboratory results within the normal ranges for the testing laboratory, or if not, the results were deemed not clinically significant by the investigator before randomization. exclusion criteria: * diagnosed with type 1 diabetes mellitus, hemochromatosis, or had a history of ketoacidosis. * had any condition known to invalidate glycosylated hemoglobin results (eg, hemolytic states or hemoglobinopathies). * took any disallowed medication, prescription medication, herbal treatment or over-the counter medication that may have interfered with evaluation of the study medication, including: * insulin * oral antidiabetics including sulfonylureas and alpha-glucosidase inhibitors * systemic corticosteroids * warfarin * rifampin * st. john's wort. * thiazolidinediones * peroxisome proliferator-activated receptor agonists * nicotinic acid * fibrates * had a history of myocardial infarction, coronary angioplasty or bypass graft, unstable angina pectoris, transient ischemic attacks, clinically significant abnormal electrocardiogram, or documented cerebrovascular accident within 6 months before screening a. * had abdominal, thoracic, or vascular surgery within 6 months before screening a that in the investigator's opinion warranted exclusion from the study. * had a creatine phosphokinase value greater than 3 times the upper limit of normal at screening a. * had persistent unexplained microscopic or macroscopic hematuria or a history of bladder cancer. * had a triglyceride level greater than 500 mg/dl (5.6 mmol/l) at screening a. * received any alteration in allowed lipid lowering medication (dose or drug) within 2 months of randomization, if applicable. the patient remained on a stable dose throughout the study. if deemed necessary, the dose could have been lowered with prior approval from the sponsor. * donated and/or received any blood or blood products within 3 months before randomization. * had a history of drug abuse or a history of alcohol abuse within 2 years before randomization * had a systolic blood pressure greater than 140 mm hg or a diastolic blood pressure of greater than 95 mm hg at screening b. * had significant cardiovascular disease including but not limited to, new york heart association functional (cardiac) classification iii or iv. * had a history of cancer other than basal cell or stage 1 squamous cell carcinoma of the skin that had not been in remission within 5 years before randomization. * had an alanine aminotransferase or aspartate aminotransferase level greater than 3 times the upper limit of normal, active liver disease, or jaundice at screening a. * had a positive anti-hepatitis b surface antigen, or anti-hepatitis b e antigen test results at screening a. * was currently taking another investigational study medication or had taken an investigational study medication within 30 days before screening a. * had any other serious disease or condition at screening a or at randomization that might have affected life expectancy or made it difficult to successfully manage and follow the patient according to the protocol.

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