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OBJECTIVE-To assess the efficacy and safety of MK-0941, a glucokinase activator (GKA), when added to stable-dose insulin glargine in patients with type 2 diabetes.
RESEARCH DESIGN AND METHODS-In this double-blind study, 587 patients taking stable-dose insulin glargine (±metformin ≥1,500 mg/day) were randomized (1:1:1:1:1) to MK-0941 10, 20, 30, or 40 mg or matching placebo t.i.d. before meals (a.c). This study included an initial 14-week, dose-ranging phase followed by a 40-week treatment phase during which patients were to be uptitrated as tolerated to 40 mg (or placebo) t.i.d. a.c. The primary efficacy end point was change from baseline in A1C at Week 14.
RESULTS-At Week 14, A1C and 2-h postmeal glucose (PMG) improved significantly versus placebo with all MK-0941 doses. Maximal placebo-adjusted least squares mean changes from baseline in A1C (baseline A1C 9.0%) and 2-h PMG were -0.8% and -37 mg/dL (-2 mmol/L), respectively. No significant effects on fasting plasma glucose were observed at any dose versus placebo. By 30 weeks, the initial glycemic responses noted at 14 weeks were not sustained. MK-0941 at one or more doses was associated with significant increases in the incidence of hypoglycemia, triglycerides, systolic blood pressure, and proportion of patients meeting criteria for predefined limits of change for increased diastolic blood pressure.
CONCLUSIONS-In patients receiving stable-dose insulin glargine, the GKA MK-0941 led to improvements in glycemic control that were not sustained. MK-0941 was associated with an increased incidence of hypoglycemia and elevations in triglycerides and blood pressure.
Diabetes Care 34:2560-2566, 2011
Glucokinase (GK) plays an integral role in glucose homeostasis and offers a potential therapeutic target for the treatment of type 2 diabetes (1). GK functions as a glucose sensor in pancreatic β-cells and as a mediator of hepatic glucose disposal. Increased or decreased GK activity, linked to specific genetic mutations, is associated with hypoglycemia and hyperglycemia, respectively (2). Glucokinase activators (GKAs) interact with the same region of the GK enzyme that is commonly affected by naturally occurring GK-activating mutations in humans (3). Treatment with different GKAs has been shown to increase insulin secretion, reduce hepatic glucose production, and improve glycemic excursion in normal and diabetic animals (4-6). In single- and multiple-dose studies, GKAs reduced fasting and postprandial glucose in patients with type 2 diabetes (7,8) and healthy adults...