Effects of MK-0941, a Novel Glucokinase Activator, on Glycemic Control in Insulin-Treated Patients With Type 2 Diabetes

Abstract

OBJECTIVETo 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 METHODSIn 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.RESULTSAt 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.CONCLUSIONSIn 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.

Chronic treatment with a glucokinase activator delays the onset of hyperglycaemia and preserves beta cell mass in the Zucker diabetic fatty rat

“…It is, however, currently uncertain whether long-term improvements in glycaemic control can be achieved with these agents. In the longest clinical trial of a GKA completed to date, antihyperglycaemic efficacy was not sustained beyond 14 weeks [17]. The mechanism underlying this loss of efficacy remains unclear.…”

“…GKAs have demonstrated prominent antihyperglycaemic activity in animal models [12][13][14][15] and in clinical trials [16,17]. It is, however, currently uncertain whether long-term improvements in glycaemic control can be achieved with these agents.…”

Glucokinase activation is beneficial or toxic to cultured rat pancreatic islets depending on the prevailing glucose concentration

“…However, given the metabolic heterogeneity of ␤-cells in rodent islets (37), the present study suggests that GKAs may be beneficial in poorly responsive ␤-cells while being simultaneously toxic to middle-and highly-responsive ␤-cells through a variety of mechanisms proposed to contribute to glucotoxicity (1). If such "glucotoxic-like" effects of long-term GKA treatment at intermediate glucose concentration were confirmed in human islets, it could contribute to the secondary failure of GKAs in T2D (22,31,47).…”

“…If GKAs undoubtedly trigger liver steatosis (4,6,34), their potential toxicity to ␤-cells remains unclear (4,35,38,43,44,46). Thus, although some GKAs proved beneficial to ␤-cell survival and GSIS under glucotoxic conditions and in islets from T2D patients (8,35,46), their secondary failure during long-term treatment (22,31,47) reopened the question of their toxicity to ␤-cells. This possible caveat of GKAs has been previously considered nonrelevant on the ground that ␤-cell stimulation is reduced following the GKA-mediated reduction in glycemia (12).…”

“…In ␤-cells, GK is the glucose sensor that controls the rate of glycolysis, hence insulin secretion, within the physiological range of glucose concentrations (28). Given the pivotal role of GK in glucose homeostasis, small-molecule GK activators (GKAs) were developed that augment GSIS and hepatic glucose utilization (17), thereby improving glucose homeostasis in rodent and human type 2 diabetes (T2D) (3,7,11,13,29,31,33,48). However, although some GKAs may improve ␤-cell survival and GSIS under glucotoxic conditions, the loss of GKA effectiveness during long-term treatment of T2D (22, 47) raises questions about their possible toxicity, e.g., through sustained ␤-cell stimulation.…”