John H. Holcombe

Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years.

BACKGROUND Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes (T2DM), reduced hemoglobin A(1c) (A1C) and weight in clinical trials. The objective of this study was to evaluate the effects of > or = 3 years exenatide therapy on glycemic control, body weight, cardiometabolic markers, and safety. METHODS Patients from three placebo-controlled trials and their open-label extensions were enrolled into one open-ended, open-label clinical trial. Patients were randomized to twice daily (BID) placebo, 5 mug exenatide, or 10 mug exenatide for 30 weeks, followed by 5 mug exenatide BID for 4 weeks, then 10 mug exenatide BID for > or = 3 years of exenatide exposure. Patients continued metformin and/or sulfonylureas. RESULTS 217 patients (64% male, age 58 +/- 10 years, weight 99 +/- 18 kg, BMI 34 +/- 5 kg/m(2), A1C 8.2 +/- 1.0% [mean +/- SD]) completed 3 years of exenatide exposure. Reductions in A1C from baseline to week 12 (-1.1 +/- 0.1% [mean +/- SEM]) were sustained to 3 years (-1.0 +/- 0.1%; p < 0.0001), with 46% achieving A1C < or = 7%. Exenatide progressively reduced body weight from baseline (-5.3 +/- 0.4 kg at 3 years; p < 0.0001). Patients with elevated serum alanine aminotransferase (ALT) at baseline (n = 116) had reduced ALT (-10.4 +/- 1.5 IU/L; p < 0.0001) and 41% achieved normal ALT. Patients with elevated ALT at baseline tended to lose more weight than patients with normal ALT at baseline (-6.1 +/- 0.6 kg vs. -4.4 +/- 0.5 kg; p = 0.03), however weight change was minimally correlated with baseline ALT (r = -0.01) or ALT change (r = 0.31). Homeostasis Model Assessment B (HOMA-B), blood pressure, and aspartate aminotransferase (AST) all improved. A subset achieved 3.5 years of exenatide exposure and had serum lipids available for analysis (n = 151). Triglycerides decreased 12% (p = 0.0003), total cholesterol decreased 5% (p = 0.0007), LDL-C decreased 6% (p < 0.0001), and HDL-C increased 24% (p < 0.0001). Exenatide was generally well tolerated. The most frequent adverse event was mild-to-moderate nausea. The main limitation of this study is the open-label, uncontrolled nature of the study design which does not provide a placebo group for comparison. CONCLUSION Adjunctive exenatide treatment for > or = 3 years in T2DM patients resulted in sustained improvements in glycemic control, cardiovascular risk factors, and hepatic biomarkers, coupled with progressive weight reduction.

Effects of exenatide versus sitagliptin on postprandial glucose, insulin and glucagon secretion, gastric emptying, and caloric intake: a randomized, cross-over study.

ABSTRACT Background: This study evaluated the effects of exenatide, a GLP-1 receptor agonist, and sitagliptin, a DPP-4 inhibitor, on 2-h postprandial glucose (PPG), insulin and glucagon secretion, gastric emptying, and caloric intake in T2D patients. Methods: This double-blind, randomized cross-over, multi-center study was conducted in metformin-treated T2D patients: 54% female; BMI: 33 ± 5 kg/m2; HbA1c: 8.5 ± 1.2%; 2-h PPG: 245 ± 65 mg/dL. Patients received exenatide (5 µg BID for 1 week, then 10 µg BID for 1 week) or sitagliptin (100 mg QAM) for 2 weeks. After 2 weeks, patients crossed-over to the alternate therapy. Postprandial glycemic measures were assessed via standard meal test; caloric intake assessed by ad libitum dinner (subset of patients). Gastric emptying was assessed by acetaminophen absorption (Clinicaltrials.gov Registry Number: NCT00477581). Results: After 2 weeks of therapy, 2-h PPG was lower with exenatide versus sitagliptin: 133 ± 6 mg/dL versus 208 ± 6 mg/dL, p < 0.0001 (evaluable, N = 61). Switching from exenatide to sitagliptin increased 2-h PPG by +73 ± 11 mg/dL, while switching from sitagliptin to exenatide further reduced 2-h PPG by −76 ± 10 mg/dL. Postprandial glucose parameters (AUC, Cave, Cmax) were lower with exenatide than sitagliptin (p < 0.0001). Reduction in fasting glucose was similar with exenatide and sitagliptin (−15 ± 4 mg/dL vs. −19 ± 4 mg/dL, p = 0.3234). Compared to sitagliptin, exenatide improved the insulinogenic index of insulin secretion (ratio exenatide to sitagliptin: 1.50 ± 0.26, p = 0.0239), reduced postprandial glucagon (AUC ratio exenatide to sitagliptin: 0.88 ± 0.03, p = 0.0011), reduced postprandial triglycerides (AUC ratio exenatide to sitagliptin: 0.90 ± 0.04, p = 0.0118), and slowed gastric emptying (acetaminophen AUC ratio exenatide to sitagliptin: 0.56 ± 0.05, p < 0.0001). Exenatide reduced total caloric intake compared to sitagliptin (−134 ± 97 kcal vs. +130 ± 97 kcal, p = 0.0227, N = 25). Common adverse events with both treatments were mild to moderate in intensity and gastrointestinal in nature. Conclusions: Although this study was limited by a 2-week duration of exposure, these data demonstrate that, exenatide had: (i) a greater effect than sitagliptin to lower postprandial glucose and (ii) a more potent effect to increase insulin secretion and reduce postprandial glucagon secretion in T2D patients. In contrast to sitagliptin, exenatide slowed gastric emptying and reduced caloric intake. These key findings differentiate the therapeutic actions of the two incretin-based approaches, and may have meaningful clinical implications.

Effects of Exenatide and Lifestyle Modification on Body Weight and Glucose Tolerance in Obese Subjects With and Without Pre-Diabetes

OBJECTIVE To assess the effects of exenatide on body weight and glucose tolerance in nondiabetic obese subjects with normal or impaired glucose tolerance (IGT) or impaired fasting glucose (IFG). RESEARCH DESIGN AND METHODS Obese subjects (n = 152; age 46 ± 12 years, female 82%, weight 108.6 ± 23.0 kg, BMI 39.6 ± 7.0 kg/m2, IGT or IFG 25%) were randomized to receive exenatide (n = 73) or placebo (n = 79), along with lifestyle intervention, for 24 weeks. RESULTS Exenatide-treated subjects lost 5.1 ± 0.5 kg from baseline versus 1.6 ± 0.5 kg with placebo (exenatide − placebo, P < 0.001). Placebo-subtracted difference in percent weight reduction was −3.3 ± 0.5% (P < 0.001). Both groups reduced their daily calorie intake (exenatide, −449 cal; placebo, −387 cal). IGT or IFG normalized at end point in 77 and 56% of exenatide and placebo subjects, respectively. CONCLUSIONS Exenatide plus lifestyle modification decreased caloric intake and resulted in weight loss in nondiabetic obesity with improved glucose tolerance in subjects with IGT and IFG.

Exenatide elicits sustained glycaemic control and progressive reduction of body weight in patients with type 2 diabetes inadequately controlled by sulphonylureas with or without metformin

In two placebo‐controlled 30‐week trials, treatment with exenatide reduced HbA1c and body weight in patients with type 2 diabetes in the context of sulphonylurea (SU) or SU plus metformin (MET) as background treatment. This analysis examines the effects of 82 weeks of exenatide treatment for participants in these earlier 30‐week trials.

Comparison of Human Regular and Lispro Insulins After Interruption of Continuous Subcutaneous Insulin Infusion and in the Treatment of Acutely Decompensated IDDM

OBJECTIVE To compare the rapidity of metabolic decompensation after interruption of CSII between human regular and lispro insulin and to compare these two insulins in the correction of the hyperglycemia and ketosis of mildly decompensated IDDM. Lispro insulin may be especially useful for insulin pump therapy (continuous subcutaneous insulin infusion [CSII]). RESEARCH DESIGN AND METHODS A total of 18 patients with well-controlled IDDM (HbA1c 7.7 ± 1.1%, age 30 ± 11 years) were studied. All were being treated with CSII (nine with human regular and nine with lispro insulin). The study consisted of two phases: 1) an insulin interruption phase, in which the basal insulin infusion was stopped (at 0300) and plasma insulin, glucose, and β-O-hydroxybutyrate (β-OHB) were measured every 15–60 min for 6 h after interruption of the insulin infusion and 2) an insulin replacement phase, which involved measuring plasma insulin, glucose, and (β-OHB for 2 h after a single injection of either human regular or lispro insulin to correct the hyperglycemia and ketosis that developed during the first phase of the study. RESULTS After interruption of the basal insulin infusion during the insulin interruption phase, plasma insulin levels fell gradually in both groups to nadir values of 1.6 ± 0.8 and 2.0 ±1.2 μU/ml in the regular insulin- and insulin lispro-treated groups, respectively. Plasma glucose concentrations rose to 13.8 ±1.9 and 16.0 ±1.7 mmol/1 in the regular insulin- and insulin lispro-treated groups, respectively. No significant differences were seen between the therapy groups at any time in the insulin levels or in the concentrations of plasma glucose or (β-OHB. In the insulin replacement phase, insulin levels rose more rapidly in those treated with lispro insulin, reaching a greater peak value (e.g., at 60 min, plasma insulin 25 ± 3.4 vs. 15.6 ± 2.6 μUsol;ml, P < 0.05). In association with this, plasma glucose decreased to a lower nadir after lispro insulin (9.7 ± 0.4 vs. 13.7 ± 0.7 mmol/1, lispro- vs. regular-treated groups at 120 min after insulin administration, P <0.01). β-OHB levels decreased rapidly in both groups. CONCLUSIONS In patients treated with CSII, interruption of the basal insulin infusion in the middle of the night does not result in more rapid metabolic decompensation in patients treated with lispro compared with those treated with regular human insulin. Lispro insulin is effective in treating mild ketosis and hyperglycemia, and its rapid action may be advantageous in the “sick day” management at home of patients with IDDM.

Patient and physician satisfaction with the Humulin®/Humalog® Pen, a new 3.0-mL prefilled pen device for insulin delivery

OBJECTIVE This study assessed acceptability of a new 3.0-mL prefilled insulin pen device, the Humulin/Humalog Pen, as a method of delivering human insulin. Secondary objectives were to determine whether the pen device might facilitate initiation of insulin therapy in patients currently receiving oral antihyperglycemic agents and to monitor the safety of this pen device in clinical practice. BACKGROUND For both the patient and health care provider, significant negative perceptions of the use of insulin therapy persist, including patient inconvenience, social stigma from insulin injections, and insufficient time for the provider to train the patient. METHODS This 6-week, open-label, noncomparative study was conducted at 33 centers in the United States. Patients with type 1 or type 2 diabetes treated with insulin therapy or oral antihyperglycemic agents were enrolled in the study. Before the study, 62% (194 patients) had used a syringe and vial for insulin injection, 28% (87 patients) had used an insulin pen device, and 10% (30 patients) were insulin-naive. Prior therapy was unknown in 1% (4 patients). Patients used the Humulin/Humalog Pen for > or = 1 injection of insulin daily for 6 weeks. At the beginning and end of the study, patients completed a questionnaire designed to elicit their perceptions of the Humulin/Humalog Pen; physicians completed a questionnaire at the end of the study. Frequencies and percentages of all categoric responses were calculated and summarized. RESULTS A total of 315 patients (136 type 1, 179 type 2 diabetes) were enrolled. Of the 299 patients who completed questionnaires at the end of the study, 76% (226 patients) were somewhat or extremely satisfied with the pen, 78% (234 patients) probably or definitely would continue to use the pen, and 80% (239 patients) probably or definitely would recommend the pen to others. Of the 33 physicians who completed questionnaires at the end of the study, 97% (32) thought that the pen was better overall compared with a vial and syringe, 88% (29) thought that it took less time to teach patients to use the pen, and 73% (24) thought that it took less time to initiate insulin therapy with the pen. CONCLUSIONS The Humulin/Humalog Pen had an acceptable safety profile and was well accepted by patients and physicians.

A comparison of insulin lispro and buffered regular human insulin administered via continuous subcutaneous insulin infusion pump

This study compared glycemic control achieved with insulin lispro or buffered regular human insulin in patients with Type 1 diabetes treated with continuous subcutaneous insulin infusion (CSII) using an external insulin pump. In this 24-week multicenter, randomized, two-way crossover, open-label trial, 58 patients on CSII with adequate glycemic control received either insulin lispro or buffered regular human insulin for 12 weeks, followed by the alternate treatment for another 12 weeks. Efficacy and safety measures included hemoglobin A(1c) (HbA(1c)) at baseline and endpoint, home blood glucose monitoring, hypoglycemia, and frequency of pump catheter occlusion. Patients consumed a standard test meal on three occasions, with determinations of fasting, 1- and 2-h postprandial glucose values. Insulin lispro use was associated with a significantly lower HbA(1c) than was buffered regular human insulin (7.41+/-0.97 vs. 7.65+/-0.85 mmol/l; P=.004). Fasting serum glucose values before the test meal were similar between the two therapies. The 1-h (11.16+/-4.29 vs. 13.20+/-4.68 mmol/l; P=.012) and 2-h (9.64+/-4.10 vs. 12.53+/-4.64 mmol/l; P=.001) postprandial glucose concentrations were significantly lower during treatment with insulin lispro. No differences between treatments were observed in basal or bolus insulin doses, weight gain, or the incidence and rate of hypoglycemia, hyperglycemia, or pump occlusions. When used in external pumps, insulin lispro provides better glycemic control than buffered regular human insulin with a similar adverse event profile.

Comparison of insulin lispro with regular human insulin for the treatment of type 1 diabetes in adolescents

BACKGROUND Although insulin lispro (insulin LP) has been shown to improve postprandial blood glucose (BG) control and reduce hypoglycemic episodes in adult patients with type I diabetes, there appear to have been few clinical studies focusing on its use in adolescents. OBJECTIVE This study compared the effects of insulin LP with those of regular human insulin (insulin R) on postprandial BG control and hypoglycemia in adolescents with type diabetes. METHODS In this crossover, open-label study, adolescents between the ages of 9 and 18 years who had reached Tanner stage II puberty were randomized to receive either insulin LP immediately before meals or insulin R 30 to 45 minutes before meals, in addition to daily intermediate-acting insulin. After 4 months, patients were switched to the alternate treatment sequence. Eight-point BG profiles, hypoglycemia rate, and glycosylated hemoglobin (HbA1c) were measured at baseline and end point. RESULTS Four hundred eighty-one adolescents participated in the study at 53 investigative sites in 15 countries; 463 were randomized to treatment (228 insulin LP, 235 insulin R), and 457 completed the study. Insulin LP given before breakfast resulted in significantly lower mean (+/-SD) 2-hour postprandial BG levels compared with insulin R (9.7 +/- 4.0 mmol/L vs 10.6 +/- 4.3 mmol/L, respectively; P < 0.001). Insulin LP given before dinner resulted in significantly lower 2-hour postprandial BG levels compared with insulin R (8.6 +/- 3.5 mmol/L vs 9.3 +/- 3.7 mmol/L; P = 0.003). No differences were seen between treatments in 2-hour postprandial BG levels after the midday meal. Mean baseline HbA1c values were similar between sequence groups, and no between-group difference in HbA1c was observed at end point (insulin LP, 8.69% +/- 1.52%; insulin R, 8.70% +/- 1.65%). Treatment with insulin LP resulted in a significantly lower incidence of hypoglycemic episodes per patient per 30 days compared with insulin R (4.02 +/- 4.5 vs 4.37 +/- 4.5, respectively; P = 0.023) and significantly fewer hypoglycemic episodes between midnight and 6 AM (1.0 +/- 1.9 vs 1.7 +/- 2.6; P < 0.001). CONCLUSIONS In adolescents with type 1 diabetes, insulin LP significantly improved postprandial glycemic control and reduced episodes of nocturnal hypoglycemia compared with insulin R. Insulin LP was well tolerated and effective as part of an intensified insulin regimen in this study population.

Effect of exenatide on 24-hour blood glucose profile compared with placebo in patients with type 2 diabetes: a randomized, double-blind, two-arm, parallel-group, placebo-controlled, 2-week study.

OBJECTIVE The aim of this study was to examine the glucose-lowering effect of exenatide over 24 hours in patients with type 2 diabetes with inadequate glycemic control using metformin, with or without a thiazolidinedione (TZD). METHODS This randomized, double-blind, 2-arm, parallel-group, placebo-controlled, 2-week study was conducted in patients with type 2 diabetes with inadequate glycemic control, despite metformin with or without a TZD. Patients underwent a baseline and a week-2 (study end) 24-hour admission during which serial serum glucose measurements were taken. Preprandial and postprandial concentrations of triglycerides and free fatty acids were also measured. Meals provided for each patient were identical at the baseline and week-2 assessments. Following the baseline admission, patients were randomized to receive SC injections of either exenatide (5 microg BID for 1 week, then 10 microg BID for the next week) or placebo (volume equivalent) for 14 days. RESULTS A total of 30 patients (19 women [63%], 11 men [37%]; mean [SD] age, 52.6 [11.2] years; weight, 94.3 [23.0] kg; body mass index, 34.2 [6.1] kg/m(2); glycosylated hemoglobin value, 8.0% [0.9%]; diabetes duration, 8.7 [5.6] years; race, Hispanic 18 [60%], white 10 [33%], black 2 [7%]) were eligible. Seventeen patients (57%) were randomized to treatment with exenatide and 13 patients (43%) received placebo. Concurrent antidiabetic medications were metformin only (n = 19 [63%]) and metformin plus a TZD (n = 11 [37%]). All postbaseline values were least squares mean (SE). After 2 weeks (study end), the 24-hour time-average glucose values were 7.0 (0.2) and 8.8 (0.3) mmol/L for exenatide-treated and placebo-administered patients, respectively (P < 0.001). The glucose values for patients treated with exenatide were lower compared with those in patients who received placebo 2 hours after the morning meal (6.6 [0.4] vs 12.0 [0.5] mmol/L; P < 0.001), the midday meal (8.8 [0.5] vs 11.8 [0.6] mmol/L; P = 0.001), and the evening meal (6.8 [0.4] vs 11.3 [0.4] mmol/L; P < 0.001). The mean durations of patient exposure to glucose concentrations >7.8 and >11.1 mmol/L were significantly shorter for the exenatide group compared with the placebo group (>7.8 mmol/L: 6.8 [0.9] vs 14.1 [1.1] hours; >11.1 mmol/L: 1.0 [0.7] vs 4.7 [0.8] hours; both, P < 0.001). After 2 weeks, the postprandial triglyceride excursions after the morning and evening meals for patients treated with exenatide were significantly lower compared with those treated with placebo. There was no apparent effect on free fatty acid concentrations. CONCLUSIONS In these patients with type 2 diabetes, exenatide was associated with significantly reduced glucose concentrations at multiple time points during 24 hours, with the greatest effect seen on postprandial glucose concentrations. In addition, exenatide was associated with decreased overall hyperglycemic exposure and significantly decreased postprandial triglyceride excursions. These results are consistent with those seen in other studies that reported the effectiveness of exenatide in controlling hyperglycemia in patients with type 2 diabetes.

Prevalence of other diabetes-associated complications and comorbidities and its impact on health care charges among patients with diabetic neuropathy.

INTRODUCTION Diabetic neuropathy (DN) is a common complication associated with diabetes. This study assesses the prevalence of other diabetes-related complications or comorbidities among DN patients and its marginal contribution to health care charges. METHODS Using administrative claims database, we studied commercially insured patients below 65 years old with at least one claim of DN anytime from July 2004 through June 2005 (Year 1). Using propensity scoring, a 10:1 ratio of demographically matched controls with diabetes but no DN was constructed. Both DN patients and controls had 12 months of continuous enrollment in Year 1 and Year 2 (July 2005-June 2006). We compared the Year 1 prevalence of other diabetes-associated complications or comorbidities between DN patients and diabetic controls. Controlling for comorbidities, we used multivariate regressions to examine the incremental impact of DN or any other diabetes-related complication or comorbidity on Year 2 health care charges. RESULTS A higher percentage of DN patients had at least one other diabetes-related complication or comorbidity than diabetic controls. Individuals with DN had a higher prevalence of each individual other diabetes-related complication or comorbidity. Controlling for comorbidities, the presence of any other diabetes-related complication or comorbidity was statistically associated with higher outpatient pharmacy and total charges for both DN patients and controls. Total and outpatient pharmacy charges were also significantly higher for DN patients than for controls, among those with or without any other diabetes-related complications or comorbidities. CONCLUSIONS DN can occur in the absence of other diabetes-related complications or comorbidities. The presence of DN and any other diabetes-related complications or comorbidities significantly increases health care charges.