Efficacy and safety of insulin lispro in geriatric patients with type 2 diabetes: a retrospective analysis of seven randomized controlled clinical trials.

BACKGROUND AND AIMS: Glycemic control in geriatric patients with type 2 diabetes (T2DM) remains clinically challenging. The objective of this study was to compare the safety and efficacy of insulin lispro in patients C65 years (geriatric) to those\65 years (non-geriatric), using a metaanalysis of randomized controlled clinical trials (RCT). METHODS: This is a retrospective analysis of predefined endpoints from an integrated database of seven RCTs of T2DM patients treated with insulin lispro. The primary efficacy measure tested the non-inferiority of insulin lispro (geriatric vs. non-geriatric; non-inferiority margin 0.4 %) in terms of hemoglobin A1c (HbA1c) change from baseline to Month 3 (N = 1,525), with change from baseline to Month 6 as a supportive analysis (N = 885). Changes in HbA1c from baseline were evaluated with an analysis of covariance model. Secondary measures included incidence and rate of hypoglycemia, and incidence of cardiovascular events. RESULTS: Mean change in HbA1c from baseline to Month 3 was similar for geriatric (-0.97 %) and non-geriatric patients (-1.05 %); least-square (LS) mean difference (95 % CI) was 0.02 % (-0.11, 0.15 %; p = 0.756). Similar results were observed in patients treated up to Month 6; LS mean difference (95 % CI) was 0.07 % (-0.12, 0.26 %; p = 0.490). Decrease in HbA1c from baseline to Months 3 and 6 was non-inferior in geriatric compared with non-geriatric patients. There were no significant differences in the incidence and the rate of hypoglycemia, incidence of cardiovascular events, or other serious adverse events including malignancy, post-baseline between the two cohorts. CONCLUSION: Key measures of efficacy and safety in geriatric patients with T2DM were not significantly different from non-geriatric patients when utilizing insulin lispro. Insulin lispro may be considered a safe and efficacious therapeutic option for the management of T2DM in geriatric patients.

Efficacy and safety of insulin lispro in obese patients with type 2 diabetes: a retrospective metaanalysis of 7 randomized controlled trials.

OBJECTIVE: To evaluate the efficacy and safety of insulin lispro in the treatment of patients with type 2 diabetes (T2DM) who had a body mass index (BMI) ≥30 kg/m2 (obese) compared with patients with BMIs <30 kg/m2 (nonobese). METHODS: A retrospective analysis of predefined end-points from 7 randomized clinical trials of T2DM patients treated with insulin lispro was performed. The primary efficacy measure was to assess the noninferiority of insulin lispro in obese patients versus nonobese patients as measured by the change in hemoglobin A1C (HbA1c) from baseline to Month 3 (n = 1,518), using a noninferiority margin of 0.4%. The secondary measures included overall hypoglycemia incidence and event rates and relative change in body weight. RESULTS: Mean changes in HbA1c from baseline (9.06% for obese and 8.92% for nonobese) to Month 3 were similar for obese patients (-1.03%) and nonobese (-1.02%), with a least squares (LS) mean difference (95% confidence interval [CI]) of -0.05% (-0.17%, 0.07%; P = .384). The overall incidence of hypoglycemia (53% vs. 63%; P<.001) and rate of hypoglycemia (0.93 vs. 1.76 events per 30 days; P<.001) was significantly lower in obese patients compared with nonobese patients. The 2 BMI cohorts did not demonstrate a significant difference in mean percent changes in body weights (LS mean difference = 0.4% [-0.2%, 0.9%]; P = .202). CONCLUSION: Obese patients with T2DM treated with insulin lispro were able to achieve the same level of glycemic control as their nonobese counterparts, with some evidence supporting a reduced risk of hypoglycemia.

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/m(2), 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.

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.

Comparing clinical and economic characteristics between commercially-insured patients with diabetic neuropathy and demographically-matched diabetic controls.

OBJECTIVE: To examine medical conditions associated with diabetic neuropathy (DN) and to identify drivers of healthcare charges and utilization using administrative claims. METHODS: The study examined commercially-insured under-age-65 individuals with 24 months continuous enrollment in a large US national health plan. DN patients were identified by having at least one claim with a DN diagnosis between July 2004 and June 2005. A demographically-matched control cohort of patients with diabetes but no DN (10: 1 ratio) was constructed using propensity scoring. Overall illness burden via a comprehensive disease classification, year 2 (July 2005 through June 2006) distribution of charges, and reasons for inpatient admissions and emergency room (ER) visits were compared between DN patients and diabetic controls. Multivariate regressions were used to assess the marginal contribution of DN to healthcare charges and utilization, and the most common reasons for ER and inpatient admissions, controlling for differences in overall illness burden. RESULTS: Both DN patients (n = 8655) and diabetic controls (n = 86 550) had a mean age of 51 years, and 46% were female. Compared with controls, DN patients had more comorbid medical conditions (9.7 vs. 6.8, p < 0.05) and higher total healthcare charges. Controlling for differences in overall illness burden, DN patients had significantly more hospital days (0.67), more ER (0.09), physician office (0.62), and outpatient hospital visits (2.87), and higher total healthcare charges ($5696) than controls (all p < 0.05), with majority of the difference in charges from inpatient service ($3975, p < 0.05). Patients with DN were also far more likely to be hospitalized (ketoacidosis, neurological manifestation, heart disease, skin infection) or have an ER encounter (amputation) for diabetes-related complications. Due to the use of a retrospective claims database, limitations of this analysis include a lack of formal diagnostic testing of patients, inability to measure factors such as disease duration and severity that are not captured in such databases, and the possible lack of generalization from this group of patients with diabetes to other populations. CONCLUSIONS: DN patients had significantly more comorbid medical conditions and higher healthcare charges and utilization than age- and sex-matched diabetic controls. Controlling for differences in overall illness burden, DN patients incurred more ER visits and inpatient admissions.

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

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/m(2); HbA(1c): 8.5 +/- 1.2%; 2-h PPG: 245 +/- 65 mg/dL. Patients received exenatide (5 microg BID for 1 week, then 10 microg 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, C(ave), C(max)) 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.

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.

Quantifying the effect of exenatide and insulin glargine on postprandial glucose excursions in patients with type 2 diabetes.

In this report, we quantify the effects of exenatide and glargine on the relative contributions of fasting and postprandial glucose (PPG) excursion to overall hyperglycemia based on self-monitored blood glucose. After 26 weeks of treatment, insulin glargine reduced fasting glucose to a greater extent than exenatide without significant effect on PPG excursion. The principal effect of exenatide on hyperglycemia was mitigating the rise in PPG with moderate improvement on fasting glucose. These findings may be limited by the fact that glucose measurements were collected through self-monitoring with six time points measured during the daytime, the meals were not standardized and the exact time for glucose measurements was unknown.

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.

Metabolic effects of two years of exenatide treatment on diabetes, obesity, and hepatic biomarkers in patients with type 2 diabetes: an interim analysis of data from the open-label, uncontrolled extension of three double-blind, placebo-controlled trials.

BACKGROUND: Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes mellitus (T2DM), reduced glycosylated hemoglobin (HbA(1c)) and weight in 30-week placebo-controlled trials. Some patients were followed up in open-label extensions to provide 'real-world' exenatide clinical experience. OBJECTIVE: The purpose of this study was to examine the metabolic effects of 2 years of exenatide treatment in patients with T2DM. METHODS: For this interim analysis, data were pooled from patients who completed 1 of three 30-week, multicenter, double-blind, placebo-controlled trials and their open-label extensions. In the initial trials, subjects were randomized to BID 5-microg exenatide, 10-microg exenatide, or placebo for 30 weeks. All subjects who enrolled in the extension phase then received 5-pg exenatide BID for 4 weeks, followed by open-label treatment with 10-pg exenatide BID. Subjects continued their existing metformin and/or sulfonylurea regimens. Analyses were conducted on data from all subjects who had the opportunity to achieve 2 years of exenatide exposure, irrespective of their treatment arm in the 30-week placebo-controlled trials. RESULTS: A total of 974 patients entered the open-label, extension phase of the trial. Two hundred eighty-three subjects (mean [SD] age, 57 [10] years; mean [SD] weight, 100[19] kg; sex, 63% male; mean [SD] body mass index, 34 [6] kg/m(2); mean [SD] HbA(1c), 8.3% [1.0%]) completed 2 years of exenatide treatment. Reductions in mean (SE) HbA(1c) from baseline to week 30 (-0.9% [0.1%]) were sustained through 2 years (-1.1% [0.1%]; P < 0.05 vs baseline), with 50% of the population achieving HbA(1c) < or = 7%. At week 30, exenatide was associated with a significant reduction in mean (SD) body weight from baseline (-2.1 [0.2] kg), with progressive reductions after 2 years (-4.7 [0.3] kg; P < 0.001 vs baseline). Patients with normal baseline alanine aminotransferase (ALT) (132/283 [47%]; normal: female < or =19 IU/L; male < or =30 IU/L) had no significant ALT change. However, patients with elevated ALT at baseline (151/283 [53%]) had a mean (SEM) reduction of ALT (-11 [1] IU/L from baseline 38 [1] IU/1; P < 0.05) and 39% achieved normal ALT by week 104. Patients with elevated ALT at baseline lost significantly more weight than patients with normal ALT at baseline (P = 0.04). However, weight change was minimally correlated with baseline ALT (r = -0.09) or ALT change (r = 0.31). Also, homeostasis model assessment of the beta-cell function (HOMA-B), blood pressure, and aspartate aminotransferase (AST) all improved. The most frequently reported adverse event was mild-to-moderate nausea. CONCLUSIONS: In these patients with T2DM, adjunctive exenatide treatment for 2 years was generally well tolerated and resulted in a sustained reduction of HbA(1c), progressive reduction in weight, and improvements in HOMA-B, blood pressure, and the hepatic injury biomarkers, AST and ALT.

A single-center, randomized, double-blind, three-way crossover study examining postchallenge glucose responses to human insulin 70/30 and insulin lispro fixed mixtures 75/25 and 50/50 in patients with type 2 diabetes mellitus.

OBJECTIVE: The aim of this study was to test the ability of human insulin 70/30, insulin lispro mixture 75/25 (75% neutral protamine lispro [NPL], 25% insulin lispro), and insulin lispro mixture 50/50 (50% NPL, 50% insulin lispro) to control postprandial glucose (PPG) concentrations in patients with type 2 diabetes mellitus (DM). METHODS: This single-center, randomized, double-blind, 3-way crossover study was conducted at the Diabetes and Glandular Disease Research Center, San Antonio, Texas. We measured serum glucose responses after a standardized breakfast test meal (500 kcal; 50% carbohydrate, 34% fat, 16% protein) in patients with type 2 DM receiving a single preprandial dose of human insulin 70/30, insulin lispro 75/25, or insulin lispro 50/50 by SC injection. All patients previously used insulin for at least 1 month prior to the study. The glucose responses were compared with those of healthy, untreated subjects administered the identical meal. RESULTS: A total of 33 patients were enrolled (23 with type 2 DM and 10 healthy controls). The baseline characteristics of the patients were as follows: sex ratio (M:F), 17:6; mean (SD) age, 61.3 (10.0) years; mean (SD) body weight, 98.5 (13.2) kg; mean (SD) body mass index, 33.0 (3.8) kg/m(2); mean (SD) glycosylated hemoglobin, 8.1% (1.6%); mean (SD) fasting serum glucose (FSG), 158.7 (27.6) mg/dL; and 56.5% white, 8.7% black, and 34.8% Hispanic. The mean (SD) doses (U/d) of the fixed-mixture preparations were similar: human insulin 70/30, 44.1 (18.2); insulin lispro 75/25, 44.1 (18.2); and insulin lispro 50/50, 43.8 (17.8). FSG levels obtained before the test meal were not significantly different between treatments. Compared with those in healthy subjects, incremental glucose AUC values for the 4 hours after the meal (AUCglucose 0-4) for patients with type 2 DM were 6.4-fold higher with human insulin 70/30, 4.6-fold higher with insulin lispro 75/25, and 3.0-fold higher with insulin lispro 50/50. Each insulin regimen produced AUC(glucose) 0-4 and 2-hour PPG values significantly different from all other regimens (all, P < 0.05). Mean (SD) 2-hour PPG values (mg/dL) were lower with mixtures containing insulin lispro than with human insulin 70/30 and decreased as the proportion of insulin lispro within the fixed mixtures increased: human insulin 70/30, 212.6 (47.0); insulin lispro 75/25, 198.0 (67.5); and insulin lispro 50/50, 158.8 (52.3). CONCLUSIONS: In this small study in patients with type 2 DM and healthy controls, preprandial administration of a fixed mixture containing rapid-acting or regular insulin and intermediate-acting components was associated with attenuation of the rise in PPG in patients with type 2 DM administered a test meal. Mixtures containing insulin lispro were associated with greater decreases in PPG concentrations compared with human insulin 70/30. Furthermore, greater amounts of rapid-acting insulin contained within the mixture were associated with better PPG control.

Management of Type 2 diabetes: the role of incretin mimetics.

Type 2 diabetes is characterised by insulin resistance and progressive beta-cell dysfunction (which leads to hyperglycaemia), the risk of progressive worsening of glycaemic control and an increased risk of both macrovascular and microvascular complications. Existing treatment strategies target deficient insulin secretion and insulin resistance, but do not generally address the underlying progressive beta-cell dysfunction that is common to Type 2 diabetes. Traditionally, Type 2 diabetes is first treated with medical nutrition therapy (reduced food intake and increased physical activity), followed by stepwise addition of oral antidiabetes therapies and, ultimately, exogenous insulin, as required. Unfortunately, these approaches have not been shown to delay the need for additional therapies, nor do they generally prevent or delay the inexorable decline in beta-cell function. Patients with Type 2 diabetes commonly experience deterioration in glycaemic control, and may have substantial weight gain due to the diabetes therapies that contribute to worsening obesity. In addition, insulin-providing therapies, such as sulfonylureas and exogenous insulin, carry the risk of hypoglycaemia, and cannot fully address the complex hormonal irregularities that characterise Type 2 diabetes, including the role of glucagon hypersecretion. New therapeutic approaches are being developed that couple durable glycaemic control with improved control of body weight. These approaches include development of the incretin mimetics, which are a novel class of agents that share several of the glucoregulatory effects of incretin hormones, such as glucagon-like hormone-1. Deficiency of glucagon-like hormone-1 secretion is known to be present in those with abnormal glucose tolerance. Agents that manipulate the physiological actions of incretin hormones, such as glucagon-like hormone-1, may significantly benefit patients with Type 2 diabetes.

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.

BACKGROUND: In two placebo-controlled 30-week trials, treatment with exenatide reduced HbA(1c) 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. METHODS: Data were pooled from the two pivotal trials of exenatide added to SU or SU plus MET. Both 30-week, placebo-controlled trials of 5 microg or 10 microg exenatide b.i.d. were followed by 52-week open-label, uncontrolled extension studies in which all participants received 10 microg exenatide b.i.d. and continued prior oral therapies. This interim analysis includes data for 222 patients who completed 82 weeks of exenatide treatment (61% M, age 57 +/- 10 y, weight 99 +/- 21 kg, BMI 34 +/- 6 kg/m(2), HbA(1c)8.4 +/- 1.0% [mean +/- SD]). RESULTS: Reduction in HbA(1c) from baseline to week 30 (-0.8 +/- 0.1% and -1.0 +/- 0.1% for 5 microg b.i.d. and 10 microg b.i.d., respectively [mean +/- SE]) was sustained up to week 82 (-1.0 +/- 0.1%). Of 207 patients with baseline HbA(1c) > 7%, 44% achieved HbA(1c) < or = 7% at week 82. Reduction of body weight from baseline to week 30 (-1.4 +/- 0.3 kg and -2.1 +/- 0.3 kg for 5 microg b.i.d. and 10 microg b.i.d., respectively) was progressive up to week 82 (-4.0 +/- 0.3 kg). The most frequent adverse events were nausea and hypoglycaemia, both generally mild to moderate in intensity. CONCLUSIONS: Exenatide added to maximally effective doses of SU or SU plus MET resulted in a sustained reduction in HbA(1c) and a progressive reduction in weight over 1 1/2 years.

Combined therapy with insulin lispro Mix 75/25 plus metformin or insulin glargine plus metformin: a 16-week, randomized, open-label, crossover study in patients with type 2 diabetes beginning insulin therapy.

OBJECTIVE: This study aimed to assess glycemic response to a mixture of 75% insulin lispro protamine suspension and 25% insulin lispro (Mix 75/25) BID plus metformin versus insulin glargine QD plus metformin in patients with type 2 diabetes mellitus (DM). METHODS: Adults new to insulin therapy were enrolled in a multicenter, randomized, prospective, open-label, crossover study with 16 weeks on each treatment. Variables included glycosylated hemoglobin (HbA(1c)), hypoglycemia rate, fasting blood glucose (FBG), 2-hour postprandial blood glucose (ppBG), and rise in blood glucose after meals. RESULTS: One hundred five patients (mean age, 55 years) were randomized. There was no difference in baseline mean values for either treatment sequence group for body mass index, duration of DM, or HbA(1c). Ninety-five patients completed the study and 67 were included in the efficacy analysis. Mix 75/25 was associated with lower mean (SD) HbA(1c) at end point (7.4% [1.1%] vs 7.8% [1.1%]; P = 0.002). More patients using Mix 75/25 achieved target HbA(1c) < or =7.0% (42% [30/71] vs 18% [13/71]; P < 0.001). With Mix 75/25, the mean (SD) 2-hour ppBG was similar after lunch but lower after breakfast (156.4 [43.6] vs 171.1 [44.9] mg/dL; P = 0.012) and dinner (164.8 [42.5] mg/dL vs 193.8 [51.0] mg/dL; P < 0.001), although FBG was higher (139.3 [36.6] mg/dL vs 123.9 [34.9] mg/dL; P < 0.001). Rise in ppBG was lower with Mix 75/25 after breakfast (16.9 [47.0] mg/dL vs 47.4 [34.8] mg/dL; P < 0.001) and dinner (14.2 [44.1] mg/dL vs 45.9 [41.3] mg/dL; P < 0.001). Gain in mean (SD) body weight was greater with Mix 75/25 than insulin glargine (2.3 [4.0] kg vs 1.6 [4.0] kg; P = 0.006). For all randomized patients, mean (SD) hypoglycemia rates were lower with insulin glargine (0.68 [1.38] vs 0.39 [1.24] episodes/patient per 30 days; P = 0.041), although nocturnal hypoglycemia was similar. CONCLUSION: In this study population, Mix 75/25 plus metformin was associated with lower HbA(1c) than insulin glargine plus metformin, smaller rise in ppBG after breakfast and dinner, and higher proportion of patients achieving HbA(1c) < or =7.0%, with a slight increase in overall (but not nocturnal) hypoglycemia.

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.