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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
348
TAK-559 32 mg, tablets, orally, once daily and insulin stable dose injection for up to 54 weeks.
TAK-559 placebo-matching, tablets, orally, once daily and insulin stable dose injection for up to 54 weeks.
Incidence of Adverse events.
Time frame: All visits or at occurrence.
Clinical safety lab tests.
Time frame: Weeks 12, 24, and Final Visit.
12-lead electrocardiogram.
Time frame: Weeks: 24 and Final Visit.
Urinalysis.
Time frame: Weeks: 12, 24, 36, 48 and Final Visit.
Change from Baseline in Blood pressure and pulse.
Time frame: At all visits.
Change from Baseline in Body weight.
Time frame: At all visits.
Left ventricular mass index by body surface area measured by echocardiogram.
Time frame: Weeks: 24 and Final Visit.
Change from Baseline in total daily dose of insulin.
Time frame: At all visits.
Change from Baseline in triglycerides.
Time frame: Weeks: 24 and Final Visit.
Change from Baseline in cholesterol.
Time frame: Weeks 24 and Final Visit
Change from Baseline in total, high-density lipoproteins.
Time frame: Weeks: 24 and Final Visit.
Change from Baseline in low-density lipoproteins.
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Time frame: Weeks 24 and Final Visit
Change from Baseline in low-density lipoprotein fractionation.
Time frame: Weeks 24 and Final Visit
Change from Baseline in very low-density lipoprotein.
Time frame: Weeks 24 and Final Visit
Change from Baseline in free fatty acids.
Time frame: Weeks 24 and Final Visit
Change from Baseline in apolipoproteins (AI, B).
Time frame: Weeks 24 and Final Visit