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This study assessed the dose-dependent efficacy and safety of exenatide over 12 weeks in Japanese patients with type 2 diabetes suboptimally controlled despite therapeutic doses of sulfonylurea (SU), SU plus biguanide, or SU plus thiazolidinedione. Patients were randomly assigned to placebo (N = 40), 2.5 microg (N = 38), 5 microg (N = 37), or 10 microg (N = 38) exenatide administered subcutaneously twice daily (BID). Patients randomly assigned to 10 microg exenatide received 5 microg BID for the first 4 weeks, with the dose escalated to 10 microg BID for the final 8 weeks. Patients were 60.3 +/- 9.7 years old, with body mass index 25.3 +/- 4.3 kg/m(2) and hemoglobin A1c (HbA1c) 8.0 +/- 0.8%. Baseline-to-endpoint HbA1c changes (%) were +0.02 +/- 0.1 (placebo), -0.9 +/- 0.1 (2.5 microg), -1.2 +/- 0.1 (5 microg), and -1.4 +/- 0.1 (10 microg) (all p < 0.001 vs. placebo). Of patients with baseline HbA1c -7%, 5.1% (placebo), 50.0% (2.5 microg), 71.4% (5 microg), and 79.4% (10 microg) achieved HbA1c <7% at endpoint (p < 0.001, trend test). Baseline-to-endpoint fasting plasma glucose changes (mg/dL) were +6.0 +/- 4.8 (placebo), -18.6 +/- 5.7 (2.5 microg), -25.0 +/- 7.0 (5 microg), and -28.9 +/- 5.9 (10 microg) (all p < or = 0.001 vs. placebo). Treatment-emergent adverse events were mostly mild; dose-dependent increases in incidence were observed for hypoglycemia, nausea, anorexia, decreased appetite, and diarrhea (all p < or = 0.044, trend test). Over 12 weeks, exenatide dose-dependently improved glycemic control in Japanese patients with type 2 diabetes.

Objective: This 16-week study explored the safety of substituting exenatide for insulin in patients with type 2 diabetes using insulin in combination with oral antidiabetes agents., Research Design and Methods: Successful maintenance of glycemic control was predefined as an A1C increase of < 0.5%. A total of 49 patients (aged 53 +/- 8 years, with BMI 34 +/- 4 kg/m2, A1C 8.1 +/- 1.1%, and duration of diabetes 11 +/- 7 years) were randomized to either substitute exenatide for insulin or remain on their current insulin regimen. Patients who either completed > or = 8 weeks of study or discontinued because of loss of glycemic control were included in primary efficacy analysis., Results: A total of 62% (18 of 29) of the exenatide-treated patients maintained glycemic control compared with 81% (13 of 16) of the insulin-treated patients. Of the 11 exenatide-treated patients who did not maintain control, 5 discontinued before week 16 because of loss of glucose control. The overall safety profile was generally consistent with previous exenatide trials. The mean overall hypoglycemia rates were 1.72 and 0.97 events/patient-year for the exenatide and insulin reference groups, respectively., Conclusions: This pilot study suggests that it is feasible to sustain glycemic control when substituting exenatide for insulin. Although it is not possible to characterize clear predictors of outcome given the size and exploratory nature of the study, the data suggest that patients with longer disease duration, who are taking higher doses of insulin and have less endogenous beta-cell function, may experience deterioration in glucose control if exenatide is substituted for insulin therapy.

Objective: To compare the overall efficacy of combination therapies focused on fasting or postprandial blood glucose in patients with type 2 diabetes not adequately controlled with oral sulfonylurea agents alone., Research Design and Methods: A total of 135 patients were randomly assigned for 3 months to 1 of 3 combination regimens with glyburide (G) that addressed postprandial blood glucose with insulin lispro (L+G), premeal blood glucose with metformin (M+G), or fasting blood glucose (FBG) with bedtime NPH insulin (NPH+G)., Results: At end point, HbA1c was significantly lower with all therapies (P = 0.001) and was significantly lower for L+G (7.68+/-0.88%) compared with either NPH+G (8.51+/-1.38%, P = 0.003) or M+G (8.31+/-1.31%, P = 0.025). FBG at end point was significantly lower for NPH+G (8.49+/-2.36 mmol/l) compared with either L+G (10.57+/-1.97 mmol/l, P = 0.001) or M+G (9.69+/-2.89 mmol/l, P = 0.029). The mean 2-h postprandial glucose after a test meal was significantly lower for L+G (10.87+/-2.88 mmol/l) versus NPH+G (12.21+/-3.12 mmol/, P = 0.052) or versus M+G (12.72+/-3.26 mmol/l, P = 0.009). The overall rate of hypoglycemia (episodes per 30 days) was low and not statistically significant between groups (P = 0.156)., Conclusions: Adding a second antihyperglycemic agent, regardless of its timing of action, lowers HbA1c and glucose values. However, when insulin lispro was used to focus on postprandial blood glucose, there was a greater impact on overall metabolic control. These data support the importance of lowering postprandial blood glucose to optimize overall glycemic control and thus improve long-term outcomes.

To define whether rapid rate of fall in blood glucose stimulates counterregulatory hormonal responses in diabetic man, blood glucose in eight hyperglycemic diabetic subjects was rapidly lowered by intravenous insulin administration. Despite precipitous declines in blood glucose, plasma epinephrine and growth hormone remained virtually unchanged. In contrast, norepinephrine and cortisol increased significantly (P less than 0.025) in the face of hyperglycemia or euglycemia, while glucagon was suppressed (P less than 0.025). A transient modest fall in mean arterial pressure and a rise in pulse rate were noted. No correlation was observed between glucose disappearance rate or decrement in glucose concentration and the hormonal responses. After sham insulin administration, no change was observed in plasma epinephrine, norepinephrine, and cortisol levels. These findings suggest that rate of fall in blood glucose per se is not a primary signal for counterregulatory hormonal response. Cortisol but not growth hormone release during falling blood glucose in diabetic subjects can occur despite elevated blood glucose levels. The etiology of norepinephrine and cortisol change is unclear.

To investigate the adrenergic role in glucocounterregulatory mechanisms, single-blind randomised studies were performed in 7 normal males during severe insulin-induced hypoglycaemia with or without adrenergic blockade. Intravenous phentolamine administration (5 mg stat and 0.5 mg/min) did not interfere with the restoration of euglycaemia from hypoglycaemia. However, recovery of blood glucose in the presence of propranolol (3 mg/3 min and 0.8 mg/min) was retarded when compared with control studies (mean plasma glucose levels +/- SEM , 50 +/- 6 mg/dl versus 66 +/- 4 mg/dl at 120 min after insulin administration) despite appropriate glucagon, epinephrine, cortisol, and growth hormone responses. Plasma norepinephrine response was unaffected by propranolol but augmented threefold by phentolamine. Increases in plasma lactate, pyruvate and non-esterified fatty acids were blunted with propranolol while rebound non-esterified fatty acid was observed with phentolamine infusion. These data suggest that complete recovery of blood glucose from sever hypoglycaemia requires full sympathetic nervous system activity despite the integrity of other counterregulatory mechanisms.

The effect of insulin-induced hypoglycemia on plasma cyclic AMP levels was studied in normal volunteers, adrenalectomized, and sympathectomized subjects. Significant increases in plasma glucagon were observed in all groups. Normal subjects all had two- to threefold rises in plasma cAMP while no response was seen in any adrenalectomized or sympathectomized subject. These findings suggest that the mechanism for enhanced plasma cAMP release during insulin-induced hypoglycemia is catecholamine dependent. Glucagon does not contribute significantly to this response.