Effects of pramlintide in patients with type 2 diabetes mellitus: an analysis using daily insulin dose tertiles.

OBJECTIVE: The purpose of the analysis was to investigate if the efficacy and tolerability of 6 months of pramlintide therapy in patients with type 2 diabetes mellitus (T2DM) differed with increasing levels of concomitant insulin doses, using data from 3 previously described clinical trials. METHODS: In this post hoc analysis, data from 2 pooled, placebo-controlled pivotal trials and 1 clinical practice trial were evaluated by baseline insulin use tertile in patients with T2DM. RESULTS: In the pivotal trials, both glycated hemoglobin (A1C) and body weight decreased similarly across tertiles with pramlintide. A1C decreased slightly and body weight remained relatively unchanged across tertiles with placebo. Similarly, in the clinical practice trial, pramlintide was associated with decreases in A1C, body weight, and total daily insulin use across the tertiles. Overall, the most common adverse events were gastrointestinal in nature, and the rate of severe hypoglycemia was low. CONCLUSION: These results suggest that pramlintide therapy was associated with improved A1C and decreased body weight, with a low rate of severe hypoglycemia, among patients with T2DM, regardless of baseline insulin use.

Efficacy and tolerability of exenatide twice daily and exenatide once weekly in Asian versus White patients with type 2 diabetes mellitus: A pooled analysis.

AIMS: The efficacy and safety of exenatide twice daily (BID) and once weekly (QW) were assessed in Asian versus White patients with type 2 diabetes mellitus (T2DM). METHODS: This post-hoc pooled analysis evaluated patients receiving 10µg exenatide BID for 12-30 weeks or 2mg exenatide QW for 24-30 weeks in exenatide clinical development program trials. Race was self-identified. RESULTS: A total of 4625 patients were included (exenatide BID: Asian, n=787; White, n=2223; exenatide QW: Asian, n=511; White, n=1104). At study end, glycated hemoglobin (HbA1c), fasting glucose (FG), body weight, post-prandial glucose (PPG), and PPG excursions were significantly reduced (all P<0.0001 vs baseline). For exenatide BID, HbA1c reduction was greater in Asians (P<0.0001 vs Whites), whereas HbA1c reduction did not differ by race for exenatide QW. FG reduction did not differ by race for either exenatide formulation. Weight reduction was significantly greater in Whites (P<0.0001 vs Asians), regardless of exenatide formulation. PPG reduction was greater in Asians (P<0.0001 vs Whites) for exenatide BID but did not differ by race for exenatide QW. For exenatide BID, reductions in PPG excursions for all meals were significantly greater in Asians (P<0.0001 vs Whites), whereas only post-breakfast and post-lunch excursions were significantly greater in Asians for exenatide QW (P=0.0009 and P=0.0189 vs Whites, respectively). Common adverse events included nausea, headache, and diarrhea. CONCLUSIONS: Exenatide BID and QW improved glycemic control, including PPG, in Asian and White patients with T2DM. With exenatide BID, Asian patients exhibited significantly greater reductions in HbA1c and PPG than White patients. Both exenatide formulations were well tolerated in both groups.

Impact of Disease Duration on the Effects of Pramlintide in Type 1 Diabetes: A Post Hoc Analysis of Three Clinical Trials.

INTRODUCTION: Adjunctive mealtime use of the amylin analog pramlintide improves postprandial hyperglycemia in patients with type 1 diabetes. This post hoc analysis of three randomized trials evaluated whether disease duration affected responses to pramlintide. METHODS: Patients received mealtime pramlintide 30 or 60 µg (n = 714) or placebo (n = 537) as an adjunct to insulin and were stratified into tertiles by diabetes duration at baseline. Efficacy and safety end points were assessed at week 26 using analysis of covariance and logistic regression models. RESULTS: Disease durations for tertiles 1, 2, and 3 were 6.7, 16.5, and 29.9 years, respectively. In all tertiles, pramlintide resulted in greater reductions in glycated hemoglobin (HbA1c) and weight than placebo, with greater weight reductions and insulin sparing in tertiles 2 and 3. Insulin dose and weight increased in the placebo group in all tertiles. Baseline HbA1c was a predictor of HbA1c lowering in both treatment groups (P < 0.0001); higher daily insulin predicted a smaller percent increase in insulin dose for placebo (P = 0.01); and higher body weight predicted greater weight loss in both pramlintide- and placebo-treated patients (P < 0.05). Event rates for severe hypoglycemia were similar for pramlintide and placebo and increased with longer duration of diabetes for both groups. Nausea with pramlintide increased with longer disease duration. CONCLUSION: Mealtime pramlintide resulted in greater reductions in HbA1c than placebo, regardless of diabetes duration at baseline. Longer disease duration appeared to augment insulin sparing and weight loss with pramlintide, with a potential for increased incidence of hypoglycemia and nausea. FUNDING: The design and conduct of the study were supported by Amylin Pharmaceuticals, San Diego, CA, USA.

Anxiogenic effects during withdrawal from acute ethanol in adolescent and adult rats.

Elevated signs of anxiety are observed in adult rodents during withdrawal from chronic as well as acute ethanol exposure. To determine whether adolescents, in addition to their insensitivity to a number of acute ethanol effects, might likewise be hyposensitive to these anxiogenic manifestations of withdrawal from an acute ethanol challenge, the behavior of adolescent and adult male Sprague-Dawley rats was assessed in an elevated plus maze (EPM) 18 h following intraperitoneal challenge with 4 g/kg ethanol. Adult but not adolescent animals demonstrated evidence of anxiety in the plus maze during acute ethanol withdrawal. To ensure that this finding did not merely reflect age differences in ethanol clearance, clearance times at each age were determined, with additional adolescents tested at the same time postclearance as the adults were previously. Adolescents still failed to demonstrate anxiogenic signs of withdrawal. Suppression of activity during the withdrawal test, however, was evident in animals of both ages. A relative resistance to the anxiogenic effects associated with acute ethanol withdrawal during adolescence could serve as a permissive factor for development of binge drinking patterns among human adolescents.

Exenatide once weekly versus daily basal insulin as add-on treatment to metformin with or without a sulfonylurea: a retrospective pooled analysis in patients with poor glycemic control.

Basal insulin (b-INS) is typically the add-on treatment of choice for patients with poor glycemic control (ie, glycated hemoglobin [HbA1c] level ≥ 8.5%), but it is unclear whether b-INS is the best option. In this post hoc analysis, the efficacy and tolerability of exenatide once weekly (EQW) were compared with those of b-INS in patients with type 2 diabetes mellitus and a baseline HbA1c level 8.5% who were undergoing treatment with metformin ± a sulfonylurea. Data were pooled from two 26-week, randomized, controlled trials (EQW vs insulin glargine and EQW vs insulin detemir [EQW, N = 137; b-INS, N = 126]). Treatment with either EQW or b-INS for 26 weeks was associated with significant improvements in HbA1c level compared with baseline, although patients treated with EQW experienced a significantly greater decrease in HbA1c level than those treated with b-INS (least squares [LS] mean ± SE: -2.0% ± 0.08% vs -1.6% ± 0.08%; P = 0.0008). Treatment with EQW was associated with a weight loss of 2.4 kg ± 0.23 kg (LS mean ± SE), whereas treatment with b-INS was associated with a weight gain of 2.0 kg ± 0.24 kg (LS mean difference between groups, -4.4 kg ± 0.33; P < 0.0001). Patients in the EQW group were significantly more likely to achieve the composite endpoint of an HbA1c level < 7.0%, no weight gain, and no hypoglycemic events (defined as a blood glucose level < 54 mg/dL requiring self-treatment or assistance to resolve) than patients in the b-INS group (33.6% vs 3.2%; P < 0.0001). The exposure-adjusted hypoglycemic event rates were 0.08 and 0.37 events per patient-year in the EQW and b-INS groups, respectively. Gastrointestinal adverse events occurred at a higher rate in patients who underwent EQW treatment than those who were treated with b-INS. These results show that EQW treatment was associated with significantly greater improvement in HbA1c level compared with b-INS treatment among patients with poor glycemic control, with the added benefits of weight loss (vs weight gain with b-INS therapy) and a lower incidence of hypoglycemic events. These results suggest that EQW is an alternative treatment to b-INS for patients with type 2 diabetes mellitus and a baseline HbA1c level ≥ 8.5%.

Exenatide twice daily: analysis of effectiveness and safety data stratified by age, sex, race, duration of diabetes, and body mass index.

BACKGROUND: Exenatide, a glucagon-like peptide-1 receptor agonist, is used twice daily (BID) as monotherapy or adjunctive therapy for the improvement of glycemic control in patients with type 2 diabetes mellitus. The purpose of this pooled analysis was to evaluate the safety and efficacy of exenatide BID in patients stratified by various demographic characteristics. METHODS: This post hoc analysis included data from 16 randomized controlled trials in which patients with type 2 diabetes mellitus were treated with 10-µg exenatide BID. Each patient was classified into subgroups on the basis of his or her baseline values for age (< 65 or ≥ 65 years), sex (male or female), race (white, black, Asian, or Hispanic), duration of diabetes (< 10 years or ≥ 10 years), and body mass index (BMI; ≥ 20 to < 25, ≥ 25 to < 30, ≥ 30 to < 35, or ≥ 35 kg/m(2)). RESULTS: A total of 2067 patients were included. All groups experienced significant improvements in glycated hemoglobin, fasting plasma glucose levels (other than black patients, who had a relatively low baseline fasting plasma glucose level), and body weight from baseline to endpoint. Most groups had significant improvements in systolic blood pressure. All of the age, sex, and duration of diabetes groups experienced significant improvements in lipid levels (other than high-density lipoprotein cholesterol). Whites and Asians generally experienced significant improvements in lipid levels, whereas blacks and Hispanics did not. Significant improvements in lipid levels were generally seen across BMI groups. The most common adverse events overall were nausea (38.6%), hypoglycemia (28.4%), and vomiting (14.0%). Hypoglycemia was more common overall in patients who were taking a concomitant sulfonylurea than it was in patients who were not. CONCLUSION: In this pooled analysis, exenatide BID improved glycemic control and body weight, and had generally beneficial effects on blood pressure and lipid levels in patients regardless of baseline age, sex, race, duration of diabetes, or BMI. Gastrointestinal events were the most common adverse events. TRIAL REGISTRATION: www.ClinicalTrials.gov [NCT00039026, NCT00039013, NCT00082381, NCT00035984, NCT00082407, NCT00381342, NCT00360334, NCT00375492, NCT00603239, NCT00765817, NCT00577824, NCT00434954].

Exenatide once weekly for the treatment of type 2 diabetes mellitus: clinical results in subgroups of patients using different concomitant medications.

OBJECTIVE: In this pooled analysis, the efficacy and tolerability of exenatide once weekly (EQW) in patients categorized by baseline concomitant glucose-lowering therapy were evaluated. METHODS: This post hoc analysis included data from the intent-to-treat populations of 7 randomized controlled trials in which patients with type 2 diabetes mellitus were treated with EQW for 24 to 30 weeks. Patients were classified into subgroups on the basis of their baseline glucose-lowering therapy: diet and exercise only, metformin (MET) only, MET + sulfonylurea (SU), SU ± other (thiazolidinedione [TZD] only or MET + TZD), or TZD ± MET. Changes from baseline in key efficacy endpoints and tolerability were analyzed by baseline concomitant glucose-lowering therapy group. RESULTS: A total of 1719 patients were included. Treatment with EQW was associated with significant improvements from baseline in glycated hemoglobin levels, fasting glucose levels, and body weight in all of the groups. There were significant decreases from baseline for both systolic blood pressure and diastolic blood pressure in the MET and MET + SU groups, and a significant decrease in systolic blood pressure in the diet and exercise group. Lipid profiles generally improved in the diet and exercise, MET only, MET + SU, and TZD ± MET groups. Overall, the most frequent adverse events with EQW treatment, other than hypoglycemia, were nausea (14.7%), diarrhea (10.9%), and nasopharyngitis (7.2%). There was a higher incidence of hypoglycemia when EQW was added to regimens that included an SU. CONCLUSION: The addition of EQW for 24 to 30 weeks to regimens that included a wide variety of background glucose-lowering therapies was associated with significant improvements in glycemic control and weight loss. The tolerability profile of EQW appeared to be similar regardless of background therapy, except for a higher incidence of minor hypoglycemia when EQW was added to regimens that included an SU.

Use of concomitant glucose-lowering therapies and associated treatment results observed in clinical trials of twice-daily exenatide.

OBJECTIVE: To explore, by post hoc analyses of pooled data, the efficacy and safety of the use of exenatide twice daily (BID) in patients stratified by baseline glucose-lowering therapies. METHODS: Patients with type 2 diabetes from long-term randomized controlled trials who were treated with exenatide BID were classified into concomitant medication groups on the basis of background treatment (diet and exercise only, metformin only, sulfonylurea only, thiazolidinedione only, metformin + sulfonylurea, metformin + thiazolidinedione, or insulin with or without other oral antihyperglycemic medications). Seventeen studies were included in the analyses (N = 2,096). RESULTS: In these analyses of patients treated with exenatide BID for 12 to 30 weeks, there were significant decreases from baseline in hemoglobin A(1c) (A1C) and fasting glucose levels in all groups and significant decreases from baseline in body weight in all groups except the thiazolidinedione-only group. The decrease in A1C appeared to be greater in the insulin group than in the other groups, likely because the insulin dose was titrated whereas doses of concomitant antihyperglycemic medications were generally not titrated. Overall, changes in blood pressure and lipids were small. Across all groups, the most common adverse effects were gastrointestinal events. Hypoglycemia was more common in the sulfonylurea-only, metformin + sulfonylurea, and insulin groups than it was in the other concomitant medication groups. CONCLUSION: The use of exenatide BID across a wide range of background therapies was associated with reductions in A1C, fasting glucose, and body weight. Gastrointestinal adverse events were common.

Long-term cost-utility analysis of exenatide once weekly versus insulin glargine for the treatment of type 2 diabetes patients in the US.

OBJECTIVE: The purpose of this study was to estimate the long-term cost-utility of treating type 2 diabetes mellitus (T2DM) patients with exenatide once weekly (EQW) compared with insulin glargine (IG) from a US payer perspective. METHODS: A validated computer simulation model, the CORE Diabetes Model, was used to project lifetime clinical outcomes and direct medical costs. Direct medical costs included pharmacy costs and costs associated with the management of diabetes and its complications. The model was populated using patient characteristics (mean age: 57.9 years; mean diabetes duration: 7.9 years; mean HbA1(c): 8.3%; mean body mass index [BMI]: 32.3 kg/m(2)) and clinical data from a phase 3 clinical trial that compared EQW with IG in T2DM patients on a background of metformin alone or a combination of metformin and a sulphonylurea (DURATION-3). All EQW patients were assumed to have stayed on treatment for 3 years before switching to IG. Health outcomes and costs were discounted at 3% per year. Complication costs were derived from published sources. A range of sensitivity analyses was performed. RESULTS: Over a lifetime horizon, and compared with IG, EQW was associated with an incremental cost of $3914 (SD = 2923). EQW was projected to increase life expectancy by 0.135 (SD = 0.216) years and to improve quality-adjusted life expectancy by 0.246 (SD = 0.147) quality-adjusted life years (QALYs), generating an incremental cost-effectiveness ratio (ICER) of $15,936/QALY. Assuming a payer's willingness to pay threshold of $50,000/QALY, EQW is therefore cost-effective compared to IG. One-way and probabilistic sensitivity analyses confirmed EQW's cost-effective profile. LIMITATIONS: Short-term changes (26 weeks) in surrogate end-points (e.g., HbA1(c,) weight, complications) from one clinical trial were used to project long-term future effects on clinical outcomes. CONCLUSIONS: Treatment with EQW is projected to be cost-effective compared to treatment with IG.

Effect of stress on the voluntary intake of a sweetened ethanol solution in pair-housed adolescent and adult rats.

BACKGROUND: Data regarding the effects of stressors on ethanol intake are mixed. Previous experiments reporting greater voluntary intake of ethanol in adolescent than adult rats have examined intake in isolate-housed animals. Given that the stress of isolate housing may differ ontogenetically as well as confound interpretation of other stressor effects, the present study examined stressor/ethanol interactions among pair-housed adolescent and adult rats. METHODS: Sprague-Dawley male rats were implanted with identification tags that allowed individual monitoring of home cage intake of water and either a 10% (v/v) ethanol solution containing 0.1% (w/v) saccharin or saccharin alone over a 14-day access period. Animals were given zero, one, or eight daily 15-min footshock sessions, with shock-induced freezing and pre-, post-, and recovery corticosterone levels determined on the first and last footshock exposure days. After the access period, withdrawal was assessed with a plus maze, and tolerance to ethanol-induced loss of righting reflex was examined. RESULTS: Nonstressed adolescents drank considerably more sweetened ethanol than did adults, with chronic stress suppressing this adolescent consumption. Ethanol access in adolescents disrupted within-session adaptation to footshock in terms of freezing behavior, although no such disruption was evident at either age when indexed hormonally. Despite relatively high ethanol intakes (up to 6 g/kg/day in the adolescents), no evidence for withdrawal-associated anxiogenesis emerged. Evidence for tolerance was mixed and, to the extent that it was present, was metabolic in nature. CONCLUSIONS: Previous reports of heightened voluntary ethanol intake among adolescent rats are not a function of isolate stress but are evident in pair-housed animals. Adolescents were more sensitive to ethanol/stress interactions than were adults, with the elevated ethanol intake of pair-housed adolescents selectively disrupted by chronic stress, a stress-induced disruption not evident in adults. Likewise, ethanol disrupted behavioral adaptation to the footshock stressor among adolescents but not adults.

Factors influencing elevated ethanol consumption in adolescent relative to adult rats.

BACKGROUND: Many teenagers report frequent alcohol use during the adolescent period. Animal models may be an important tool for exploring factors that contribute to alcohol consumption during this critical period. METHODS: Using a 24-hour, free-access, two-bottle-choice procedure between water and a sweetened solution with or without ethanol in nondeprived rats, the present series of experiments examined the contribution of a variety of contextual and experimental variables (i.e., isolate-housing versus pair-housing, type of sipper tube, caloric value of solution, prior experimental perturbations) on alcohol consumption in both adolescent and adult Sprague-Dawley rats. RESULTS: Ethanol consumption was particularly magnified among adolescent rats using ball bearing-containing ball-point (BP) sipper tubes, with this exacerbated intake not due to caloric content of the ethanol solution. Isolation housing for 12 days did not alter ethanol consumption of adolescents relative to their socially housed counterparts while suppressing consumption of isolated adults. An examination of differences in the relative magnitude of adolescent ethanol consumption across experiments in this series revealed that ethanol intake among adolescents was elevated not only by the inclusion of BP sipper tubes but also by staggering the timing of isolate housing relative to the presentation of the novel ethanol solution. CONCLUSIONS: The results of this experimental series demonstrate that adolescent animals consume significantly more ethanol than adult animals under a variety of home cage continuous-access circumstances, with the relatively greater intake of adolescents further magnified by a number of test conditions. Subtle experimental details often thought to be innocuous can have a substantial impact on overall amount of voluntary ethanol consumption observed in both adolescent and adult animals.