Hepatic safety signal identified.

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.

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.