Plasma glucose and insulin response to two oral nutrition supplements in adults with type 2 diabetes mellitus.

OBJECTIVE: The purpose of this clinical trial was to compare the glucose usage of two oral nutritional supplement (ONS) products and to assess whether a diabetes-specific formulation provides improved glucose stabilization and management compared with a standard formula. RESEARCH DESIGN AND METHODS: A total of 12 subjects with type 2 diabetes (7 males and 5 females) completed a randomized, cross-over design trial. Each subject consumed isocaloric amounts of either the standard ONS or the diabetes-specific formula ONS on different dates, 1 week apart. Glucose and insulin measures were recorded at baseline, and 10, 20, 30, 60, 90, 120, 150, 180, 210 and 240 min after the beverage was consumed and then used to calculate area under the curve (AUC) for each subject. RESULTS: The mean glucose AUC was lower in the diabetes-specific ONS group than in the standard group (p<0.0001), but there was not a significant difference observed for mean insulin AUC (p=0.068). A sensitivity analysis of the mean insulin AUC measures was performed by removing a potential outlier from the analysis, and this resulted in a significant difference between the groups (p=0.012). First-phase insulin measures and an insulinogenic index calculated for the beverages showed no significant differences. CONCLUSIONS: On the basis of the results of this trial of 12 subjects, the diabetes-specific ONS appears to provide better glucose maintenance in persons with type 2 diabetes when compared to the standard formula ONS. TRIAL REGISTRATION NUMBER: NCT02612675.

A single-blind, placebo-controlled, dose-ranging trial of oral hepatic-directed vesicle insulin add-on to oral antidiabetic treatment in patients with type 2 diabetes mellitus.

The dose response of postprandial plasma glucose (PPG) to add-on, premeal oral hepatic-directed vesicle-insulin (HDV-I), an investigational lipid bio-nanoparticle hepatocyte-targeted insulin delivery system, was evaluated in a 3-test-meal/day model in type 2 diabetes patients. The single-blind, placebo-controlled, dose-escalating trial enrolled 6 patients with HbA(1c) 8.6 ± 2.0% (70.0 ± 21.9 mmol/mol) and on stable metformin therapy. Patients received oral HDV-I capsules daily 30 minutes before breakfast, lunch, and dinner as follows: placebo capsules, 0.05, 0.1, 0.2, and 0.4 U/kg on days 1, 2, 3, 4, and 5, respectively. Outcome measures were PPG and incremental PPG area under the concentration-time curve (AUC). All 4 doses of oral HDV-I statistically significantly lowered mean PPG (P ≤ .0110 each) and incremental PPG (P ≤ .0352 each) AUC compared to placebo. A linear dose response was not observed. The 0.05 U/kg dose was the minimum effective dose in the dosage range studied. Three adverse events unrelated to treatment were observed. Add-on oral HDV-I 0.05-0.4 U/kg significantly lowered PPG excursions and the dose response curve was flat. These results are consistent with the lack of a linear dose response between portal and systemic plasma insulin concentrations in previous animal and human studies. Oral HDV-I was safe and well tolerated.

Saxagliptin for the treatment of type 2 diabetes mellitus: focus on recent studies.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral antidiabetic drugs that improve glycemic control without causing weight gain or increasing hypoglycemic risk in patients with type 2 diabetes (T2DM). The efficacy and tolerability of saxagliptin, a once-daily DPP-4 inhibitor, administered as monotherapy, as add-on therapy to metformin, a sulfonylurea, or a thiazolidinedione, and as initial combination therapy with metformin, was demonstrated in pivotal 24-week clinical trials. Additional information about the clinical profile of saxagliptin was recently obtained from extension studies, head-to-head clinical trials, and post-hoc analyses. In extension studies, the efficacy and tolerability of add-on saxagliptin and initial saxagliptin-plus-metformin therapy were maintained for up to 102 weeks. Saxagliptin plus metformin was shown to be non-inferior to glipizide plus metformin in lowering glycated hemoglobin from base-line, with reduced body-weight and lower hypoglycemic risk. Post-hoc analyses indicate that the clinical benefits of saxagliptin extend across demographic subgroups and special populations. A meta-analysis found no evidence for increased cardiovascular risk in T2DM patients exposed to saxagliptin for > 1 year. On the basis of this clinical profile, saxagliptin is an attractive option for initial and add-on therapy for T2DM patients with inadequate glycemic control.

Safety, pharmacokinetic, and pharmacodynamic profiles of ipragliflozin (ASP1941), a novel and selective inhibitor of sodium-dependent glucose co-transporter 2, in patients with type 2 diabetes mellitus.

BACKGROUND: The sodium-dependent glucose co-transporter 2 (SGLT2) is a high-capacity, low-affinity transport system primarily expressed in the renal proximal tubules, where it plays an important role in the regulation of glucose levels. Inhibition of SGLT2 represents an innovative approach for plasma glucose control in type 2 diabetes mellitus (T2DM) by blocking glucose reabsorption and enhancing glucose loss in the urine. METHODS: This Phase 2, randomized, placebo-controlled study investigated the safety, tolerability, and pharmacokinetic and pharmacodynamic profiles of the novel oral SGLT2 inhibitor ipragliflozin (ASP1941) in T2DM patients. Sixty-one patients were randomized to placebo or ipragliflozin once daily at doses of 50, 100, 200, or 300 mg for 28 days. Patients were admitted to the clinic during the study and received a weight-maintenance diet. RESULTS: The incidence of treatment-emergent adverse events was similar for placebo and ipragliflozin groups. There were no deaths, and no patients discontinued ipragliflozin because of adverse events. Ipragliflozin was absorbed rapidly, taking approximately 1 h to reach the maximum concentration. The area under the concentration-time curve and maximum ipragliflozin concentration at steady state displayed dose linearity. All ipragliflozin doses significantly reduced glycosylated hemoglobin, fasting plasma glucose, and mean amplitude of glucose excursions compared with placebo. Significant dose-dependent increases in urinary glucose excretion were observed in all ipragliflozin groups. Mean weight decreased in the placebo and ipragliflozin groups, with greater reductions occurring in ipragliflozin-treated patients. CONCLUSION: Ipragliflozin was generally safe, well tolerated, and effective at blocking renal glucose reabsorption and decreasing plasma glucose levels in T2DM patients.

Humalog(®) KwikPen™: an insulin-injecting pen designed for ease of use.

Insulin pens offer significant benefits over vial and syringe injections for patients with diabetes who require insulin therapy. Insulin pens are more discreet, easier for patients to hold and inject, and provide better dosing accuracy than vial and syringe injections. The Humalog(®) KwikPen™ (prefilled insulin lispro [Humalog] pen, Eli Lilly and Company, Indianapolis, IN, USA) is a prefilled insulin pen highly rated by patients for ease of use in injections, and has been preferred by patients to both a comparable insulin pen and to vial and syringe injections in comparator studies. Together with an engineering study demonstrating smoother injections and reduced dosing error versus a comparator pen, recent evidence demonstrates the Humalog KwikPen device is an accurate, easy-to-use, patient-preferred insulin pen.

Insulin pharmacokinetics following dosing with Technosphere insulin in subjects with chronic obstructive pulmonary disease.

OBJECTIVES: Insulin exposure after inhalation has been reported to be altered significantly in subjects with chronic obstructive pulmonary disease (COPD). In this study, the rate and extent of insulin exposure was compared in healthy volunteers and subjects with COPD following administration of Technosphere * Insulin (TI), a dry powder insulin formulation for pulmonary delivery. METHODS: Insulin pharmacokinetics were evaluated in an open-label, single-dose, hyperinsulinemic-euglycemic glucose clamp study in 19 nondiabetic, nonsmoking healthy subjects (mean age [±SD] = 50.9 ± 14.1 years, body mass index = 29.1 ± 3.5 kg/m(2), forced expiratory volume in 1 second (FEV(1)) = 3.52 ± 1.02 L) and 17 nondiabetic subjects with mild-to-moderate COPD (mean age = 60.0 ± 9.0 years, body mass index = 28.5 ± 5 kg/m(2), FEV(1) = 2.56 ± 0.83 L). Subjects received a single 30-U dose of TI. Serial blood samples were obtained for insulin and C-peptide determination through 480 min after dosing. Insulin concentrations were adjusted for endogenous insulin by C-peptide correction; pharmacokinetic parameters were estimated using the corrected values. RESULTS: For the COPD and non-COPD groups, respectively, mean peak insulin (C(max)) was 34.7 µU/mL and 39.5 µU/mL (p = 0.29), median t(max) was 15 and 12 min (p = 0.24), and mean insulin exposure from time 0 to 240 min (AUC(0-240)) was 2037 µU/mL · min and 2279 µU/mL · min (p = 0.47). Cough was the most common respiratory adverse event observed. One instance of hypoglycemia was reported and was attributed to trial procedure. CONCLUSIONS: The rapid insulin absorption and the resulting insulin pharmacokinetic profile following TI inhalation were not significantly altered in the mild-to-moderate COPD population studied; however, long-term safety and efficacy of TI have not been established in patients with mild or moderate COPD. Longer-term experience is needed to fully characterize the effects of COPD on insulin PK following TI administration.

Hormonal and metabolic effects of morning or evening dosing of the dipeptidyl peptidase IV inhibitor vildagliptin in patients with type 2 diabetes.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Vildagliptin is an orally active, potent inhibitor of dipeptidyl peptidase IV and was developed for the treatment of type 2 diabetes. In clinical trials, once or twice daily dosing with vildagliptin (up to 100 mg day(-1)) has been shown to reduce endogenous glucose production and fasting plasma glucose in patients with type 2 diabetes. The comparative efficacy of vildagliptin under a morning vs. evening dosing regimen has not previously been determined. WHAT THIS STUDY ADDS: Once daily dosing with vildagliptin 100 mg for 28 days improved glycaemic control in patients with type 2 diabetes independent of whether vildagliptin was administered in the morning or evening. Morning or evening dosing with vildagliptin had similar effects on 24 h glycaemic control and plasma concentrations of the hormones insulin, glucagon and glucagon-like peptide 1. AIM: This randomized, double-blind, crossover study compared post-prandial hormonal and metabolic effects of vildagliptin, (an oral, potent, selective inhibitor of dipeptidyl peptidase IV [DPP-4]) administered morning or evening in patients with type 2 diabetes. METHODS: Forty-eight patients were randomized to once daily vildagliptin 100 mg administered before breakfast or before dinner for 28 days then crossed over to the other dosing regimen. Blood was sampled frequently after each dose at baseline (day -1) and on days 28 and 56 to assess pharmacodynamic parameters. RESULTS: Vildagliptin inhibited DPP-4 activity (>80% for 15.5 h post-dose), and increased active glucagon-like peptide-1 compared with placebo. Both regimens reduced total glucose exposure compared with placebo (area under the 0-24 h effect-time curve [AUE(0,24 h)]: morning -467 mg dl(-1) h, P= 0.014; evening -574 mg dl(-1) h, P= 0.003) with no difference between regimens (P= 0.430). Reductions in daytime glucose exposure (AUE(0,10.5 h)) were similar between regimens. Reduction in night-time exposure (AUE(10.5,24 h) was greater with evening than morning dosing (-336 vs.-218 mg dl(-1) h, P= 0.192). Only evening dosing significantly reduced fasting plasma glucose (-13 mg dl(-1), P= 0.032) compared with placebo. Insulin exposure was greater with evening dosing (evening 407 microU ml(-1) h; morning 354 microU ml(-1) h, P= 0.050). CONCLUSIONS: Both morning and evening dosing of once daily vildagliptin 100 mg significantly reduced post-prandial glucose in patients with type 2 diabetes; only evening dosing significantly decreased fasting plasma glucose. Although evening dosing with vildagliptin 100 mg tended to decrease night-time glucose exposure more than morning dosing, both regimens were equally effective in reducing 24 h mean glucose exposure (AUE(0,24 h)) in patients with type 2 diabetes.

Improved glycemic control with insulin glargine versus pioglitazone as add-on therapy to sulfonylurea or metformin in patients with uncontrolled type 2 diabetes mellitus.

OBJECTIVE: To compare glycemic control with add-on insulin glargine versus pioglitazone treatment in patients with type 2 diabetes. METHODS: This 48-week, multicenter, parallel-group, open-label study randomized 389 adults with poorly controlled type 2 diabetes (glycated hemoglobin A1c [A1C], 8.0% to 12.0%), despite > or =3 months of sulfonylurea or metformin monotherapy, to receive add-on therapy with insulin glargine or pioglitazone. Outcomes included A1C change from baseline to end point (primary), percentage of patients achieving A1C levels < or =7.0%, and changes from baseline in fasting plasma glucose, body mass index, weight, and serum lipids. The safety analysis included incidence of adverse events and rates of hypoglycemia. RESULTS: At end point, insulin glargine yielded a significantly greater reduction in A1C in comparison with pioglitazone (-2.48% versus -1.86%, respectively; 95% confidence interval, -0.93 to -0.31; P = .0001, 48-week modified intent-to-treat population). Insulin glargine also yielded significantly greater reductions in fasting plasma glucose at all time points (end point difference, -34.9 mg/dL; 95% confidence interval, -47.6 to -22.2; P<.0001). In comparison with pioglitazone, insulin glargine resulted in a lower overall incidence of possibly related treatment-emergent adverse events (12.0% versus 20.7%) and fewer study discontinuations (2.2% versus 9.1%), but a higher rate (per patient-year) of confirmed clinically relevant hypoglycemic episodes (blood glucose <70 mg/dL and all severe hypoglycemia) (4.97 versus 1.04; P<.0001) and severe hypoglycemia (0.07 versus 0.01; P = .0309). Weight and body mass index changes were similar between the 2 treatment groups. CONCLUSION: The addition of insulin glargine early in the diabetes treatment paradigm in patients for whom sulfonylurea or metformin monotherapy had failed resulted in significantly greater improvements in glycemic control in comparison with the addition of pioglitazone. Although severe hypoglycemia was more frequent in patients with insulin glargine therapy, hypoglycemic events occurred in <5% of patients in the insulin glargine treatment group.

The effect of colesevelam hydrochloride on insulin sensitivity and secretion in patients with type 2 diabetes: a pilot study.

BACKGROUND: This study evaluated the effect of colesevelam hydrochloride on insulin sensitivity, potential binding to glucose, and chronic effect(s) on fasting and postprandial glucose and insulin in patients with type 2 diabetes mellitus. METHODS: Patients meeting inclusion criteria were withdrawn from all antidiabetes agents for 2 weeks and randomized to colesevelam 3.75 grams/day (n = 17) or placebo (n = 18) for 8 weeks. Hyperinsulinemic-euglycemic clamp studies were performed at baseline (week -1) and weeks 2 and 8. A meal tolerance test was conducted at weeks -1, 0, 2, and 8. The meal tolerance test and study drug were coadministered at week 0 to assess the direct effect of colesevelam on glucose absorption. RESULTS: Insulin sensitivity as measured by the insulin clamp method did not change, but the Matsuda Index, a measure of whole-body insulin sensitivity calculated from postmeal tolerance test glucose and insulin levels, increased significantly within the colesevelam group from baseline to week 8 with last observation carried forward (P = 0.020). The postprandial area under the curve for glucose decreased with colesevelam versus placebo at weeks 2 and 8 with last observation carried forward (P = 0.012 and P = 0.061, respectively); the area under the curve for insulin did not decrease in concert with the decrease in area under the curve for glucose at week 2 (P = 0.585). Colesevelam had no effect on postmeal tolerance test glucose levels at week 0. CONCLUSIONS: These results suggest that colesevelam has no effect on peripheral insulin sensitivity or glucose absorption, but may improve glucose control by improving whole-body insulin sensitivity, although not by an acute effect on glucose absorption. CLINICAL TRIAL IDENTIFIER: NCT00361153.

Treatment of elderly patients with type 2 diabetes mellitus: a systematic review of the benefits and risks of dipeptidyl peptidase-4 inhibitors.

BACKGROUND: Achievement of glycemic control in elderly patients with type 2 diabetes mellitus (DM) is complicated by many factors. OBJECTIVE: The aim of this article was to systematically review evidence on the effectiveness of dipeptidyl peptidase-4 (DPP-4) inhibitors (ie, lowering of glycosylated hemoglobin [HbA(1c)]), the risk of hypoglycemia associated with these agents, and the effects of these agents on body weight in elderly patients with type 2 DM. METHODS: The PubMed and Biosis databases were searched for reports of clinical trials and meeting presentations (eg, abstracts, posters) published in English between January 1, 2000, and October 25, 2009, that included elderly patients with type 2 DM who were treated with sitagliptin, saxagliptin, vildagliptin, alogliptin, BI-1356, DSP-7238, or PF-734200. Pharmacokinetic and pharmacodynamic studies were excluded from the review, as were studies that did not specifically provide quantitative clinical data on glycemic parameters or specifically list patients aged ≥65 years. RESULTS: Eighty-five articles and 5 presentations were identified in the search; of those, 18 articles and 3 presentations were included in the review. These publications described studies of DPP-4 inhibitors administered as monotherapy or in combination with metformin, a thiazolidinedione, glimepiride, glibenclamide, or insulin. Quantitative data indicated that, in these elderly patients (generally defined as ≥65 years of age) with type 2 DM, DPP-4 inhibitors were associated with significant HbA(1c) reductions that ranged from ~0.7% (baseline HbA(1c) = 7.8%; P < 0.001) to 1.2% (baseline HbA(1c) = 8.3%; P < 0.05). Additional studies that did not quantify the number of elderly patients (as would a subanalysis), but did specify that elderly patients were included and that patient age did not influence the results, were incorporated in this review to support the quantitative results. No significant differences were noted in the HbA(1c)-lowering effects of these agents between elderly and younger patients. Less information about the incidence of hypoglycemia or weight gain in elderly patients was reported, but the available results suggested that the risk of hypoglycemia with DPP-4 inhibitors was not significantly different from that with placebo (sitagliptin 50 or 100 mg/d [0%] vs placebo [0%]; saxagliptin 5 mg/d [6.3%] vs placebo [8.0%]; vildagliptin 100 mg/d [2.32 events per patient-year] vs placebo [2.64 events per patient-year]; alogliptin 12.5 mg/d [8.0%] vs placebo [10.5%]) and that these agents were weight neutral (change, ≤0.9 kg). CONCLUSIONS: For elderly patients with type 2 DM, reductions in HbA(1c) after treatment with a DPP-4 inhibitor were not significantly different from those in younger patients. Use of DPP-4 inhibitors in these studies was associated with a low risk of hypoglycemia, and these agents were weight neutral.

Comparative device assessments: Humalog KwikPen compared with vial and syringe and FlexPen.

PURPOSE: The purpose of this study was to compare pen device-naïve patients' preferences for Humalog KwikPen (insulin lispro injection) (Eli Lilly and Company, Indianapolis, IN) to use of a vial and syringe and FlexPen(R) (insulin aspart injection) (Novo Nordisk A/S, Bagsvaerd, Denmark). METHODS: This open-label, randomized, crossover 1-day study tested the hypotheses that KwikPen was preferred to vial and syringe, and if this was found to be a significant preference, that KwikPen was preferred to FlexPen. Accuracy of doses prepared, ease of use via insulin device assessment battery, and preference via insulin device preference battery were administered following each pen evaluation, and a final preference question administered following the evaluation of both pens. Clinical measures were not included as subjects injected into an appliance to simulate the injection experience. Primary outcome variables were evaluated by Question 13 of the insulin device preference battery and the final preference question. RESULTS: Among 232 enrolled patients randomized to 1 of 4 sequences (n = 58), Humalog KwikPen was significantly preferred over vial and syringe and over FlexPen. After patients were asked to assess Humalog KwikPen or FlexPen versus V&S by choosing "strongly agreed" or "agreed" to the following attributes: easy to use, easy to hold in their hands when injecting, and easy to press the injection button, the results exhibited significant differences in patient responses. Humalog KwikPen was significantly more accurate and was preferred to vial and syringe in appearance, quality, discretion, convenience, public use, easy to learn, easy to use, reliability, dose confidence, following insulin regimen, overall satisfaction, and recommendation to others. CONCLUSIONS: Humalog KwikPen was significantly preferred over vial and syringe and FlexPen. When compared with vial and syringe, Humalog KwikPen and FlexPen were easier to use and operate, demonstrated superior accuracy of doses prepared, and preferred by pen-naïve users.

Safety profile and metabolic effects of 14 days of treatment with DIO-902: results of a phase IIa multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in patients with type 2 diabetes mellitus.

BACKGROUND: Elevated levels of cortisol have been implicated in the development of type 2 diabetes mellitus and the metabolic syndrome. Modulation of cortisol levels and activity may be useful in the treatment of type 2 diabetes and its comorbidities. OBJECTIVE: The purpose of this study was to evaluate the safety profile and pharmacodynamic effects of DIO-902 (2S,4R-ketoconazole), an inhibitor of cortisol synthesis. METHODS: Subjects with type 2 diabetes who were between the ages of 18 and 70 years and were drug naive or receiving metformin at a stable dose were randomized to receive one of the following once daily at bedtime for 14 days: ketoconazole 400 mg; DIO-902 200, 400, or 600 mg; or placebo. Tolerability was assessed based on adverse events reported by subjects and the results of physical examinations and standard hematology, chemistry, and urinalysis tests performed on days 8 and 15. Glycosylated hemoglobin (HbA1c) and levels of fructosamine, fasting glucose, lipoproteins, and C-reactive protein were measured at baseline and the end of treatment. The Jonckheere-Terpstra test was used to test for an ordinal dose-response trend between the DIO-902 doses and placebo. Morning (7:30 am) salivary cortisol levels were measured and overnight plasma cortisol levels were analyzed as a 12-hour AUC at baseline and the end of treatment. Adrenocorticotropic hormone (ACTH) levels were measured and an ACTH stimulation test was used to assess adrenal reserve at baseline and the end of treatment. RESULTS: The study enrolled 21 women (58.3%) and 15 (41.7%) men. Their mean (SD) age was 55.4 (8.5) years; mean HbA1c, 8.1% (1.3%); and mean duration of diabetes, 4.8 (3.7) years. White subjects were in the majority (86.1%), with black subjects constituting 11.1% of the population and those of other racial backgrounds constituting 2.8%; 47.2% of subjects were of Hispanic ethnicity. The proportions of subjects experiencing any adverse event were 62.5% in the ketoconazole group; 60.0%, 83.3%, and 100% in the DIO-902 200-, 400-, and 600-mg groups, respectively; and 50.0% in the placebo group. Gastrointestinal disorders were the most common adverse event, reported in 12.5% of the ketoconazole group, 35.0% of the combined DIO-902 treatment group, and 16.7% of the placebo group. Headache, the second most commonly reported adverse event, was reported in 12.5% of the ketoconazole group, 30.0% of the overall DIO-902 group, and none of the placebo group. DIO-902 treatment was not associated with any significant differences in measures of glycemic control relative to placebo or any significant decreases in mean morning salivary cortisol levels or mean overnight cortisol exposure. Dose-dependent reductions from baseline were seen in mean levels of low-density lipoprotein cholesterol (mean percent reductions: -11.39, -23.38, and -42.10 with DIO-902 200, 400, and 600 mg, respectively; P<0.001), as well as in total cholesterol (P<0.001) and high-density lipoprotein cholesterol (P=0.034). Mean levels of C-reactive protein were significantly reduced relative to placebo at all doses of DIO-902 (P=0.027); no reductions in either of these parameters were seen in the placebo group. CONCLUSION: In this small, short-term study in subjects with type 2 diabetes, DIO-902 was generally well tolerated, although it was associated with an increased incidence of gastrointestinal disorders and headache. Levels of low-density lipoprotein cholesterol were significantly decreased in subjects treated with DIO-902.

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.

Population exposure-response modeling of metformin in patients with type 2 diabetes mellitus.

The exposure-response properties of metformin were characterized in 12 subjects with type 2 diabetes mellitus. The time course of drug concentration and effects on fasting plasma glucose and lactic acid concentrations were used from a study in which subjects received 500 mg of metformin twice daily for 5 days followed by 850 mg twice daily for 5 days. Pharmacokinetic sampling included morning trough concentrations obtained on days 7 to 9 and rich sampling (15 time points) on day 10. Fasting plasma glucose and lactic acid concentrations were measured on days 0 to 10 and served as biomarkers of therapeutic effect and tolerability, respectively. A population pharmacokinetic/pharmacodynamic analysis was conducted using nonlinear mixed effects modeling. Metformin pharmacokinetics were described using a 1-compartment model with first-order absorption. Population mean estimates (relative standard error [RSE]) of clearance (CL/F) and volume of distribution were 79.0 L.h(-1) (6.8%) and 648 L (13.8%), respectively. Covariate analyses revealed that creatinine clearance (CL(CR)) significantly influenced metformin CL/F [CL/F = 79.0.(CL(CR)/80)(0.822)]. An indirect response model was applied to describe the antihyperglycemic effect of metformin. Population mean estimates (RSE) of baseline fasting plasma glucose and the drug concentration producing half-maximal effect were 241 mg.dL(-1) (4.6%) and 4.23 mg.L(-1) (31.0%). An empirical linear model was used to describe a slight progressive increase in fasting lactic acid during metformin treatment with an estimated slope coefficient (RSE) of 0.0005 mM.mL.ng(-1) (38.1%). Model evaluation by predictive check and nonparametric bootstrap analysis suggested that the proposed model is robust, and parameter values were estimated with good precision. Simulations suggested that the clinical utility of metformin was maintained over the dose range evaluated with respect to fasting plasma glucose and lactic acid response.

Effects of sulodexide in patients with type 2 diabetes and persistent albuminuria.

BACKGROUND: Urinary albumin excretion frequently persists in diabetic patients who are treated with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Sulodexide, a glycosaminoglycan mixture of 80% heparan sulfate and 20% dermatan sulfate, has been hypothesized to reduce persistent albuminuria. We have conducted a multi-center randomized double-blind pilot study in order to determine the effect of 6 months' therapy with sulodexide on urinary albumin excretion and to address logistical issues for a full-scale trial. METHODS: A total of 149 patients with type 2 diabetes and an albumin:creatinine ratio (ACR) between 20 and 300 mg/g were randomized with equal allocation to either placebo, 200 mg of sulodexide or 400 mg of sulodexide. The primary endpoint was the achievement, at 6 months, of either 3(1) return to normoalbuminuria (ACR < 20 mg/g with a decrease of at least 25%) or (2) a decrease in ACR of at least 50% from the baseline value. All patients used a maximum tolerated recommended FDA approved dose of an ACEI or ARB for at least 60 days and had stable blood pressure prior to randomization. RESULTS: The primary efficacy endpoint was achieved in 25.3% of the patients in the two sulodexide groups combined versus 15.4% of the placebo-treated patients (P = 0.26). The primary endpoint was achieved in 33.3% (P = 0.075 for the comparison to placebo) in the sulodexide 200 mg group and 18.4% (P = 0.781) in the sulodexide 400 mg group. (No consistent patterns of side effects were observed. CONCLUSION: Based on the experience gained in this pilot study, one full-scale trial is currently being conducted to evaluate the effects of sulodexide on change in ACR in patients with persistent microalbuminuria, and a longer-term trial is underway to evaluate the effects of sulodexide on long-term renal disease progression in patients with overt proteinuria.

United States patient preference and usability for the new disposable insulin device Solostar versus other disposable pens.

The uptake of insulin pen use has been slow in the United States, despite their advantages over the vial/ syringe. We present results of a United States subset of 150 patients with type 1/type 2 diabetes, who were enrolled in an open-label study, that assessed usability, pen features, and patient preferences for four prefilled insulin pens: SoloSTAR, FlexPen, Lilly disposable pen, and a prototype, Pen X. Overall, the SoloSTAR and FlexPen were more user-friendly; 95 and 88% of patients, respectively, completed the steps correctly (without safety/attach-needle step-deemed independent of device) versus the Lilly disposable pen (60%) and Pen X (61%; all p < 0.05). The SoloSTAR was rated highest most frequently for pen feature comparisons. Results suggest that the SoloSTAR and FlexPen could potentially facilitate insulin use in the United States.

Accuracy of the 5-day FreeStyle Navigator Continuous Glucose Monitoring System: comparison with frequent laboratory reference measurements.

OBJECTIVE: The purpose of this study was to compare the accuracy of measurements of glucose in interstitial fluid made with the FreeStyle Navigator Continuous Glucose Monitoring System with Yellow Springs Instrument laboratory reference measurements of venous blood glucose. RESEARCH DESIGN AND METHODS: Fifty-eight subjects with type 1 diabetes, aged 18-64 years, were enrolled in a multicenter, prospective, single-arm study. Each subject wore two sensors simultaneously, which were calibrated with capillary fingerstick measurements at 10, 12, 24, and 72 h after insertion. Measurements from the FreeStyle Navigator system were collected at 1-min intervals and compared with venous measurements taken once every 15 min for 50 h over the 5-day period of sensor wear in an in-patient clinical research center. Periods of high rates of change of glucose were induced by insulin and glucose challenges. RESULTS: Comparison of the FreeStyle Navigator measurements with the laboratory reference method (n = 20,362) gave mean and median absolute relative differences (ARDs) of 12.8 and 9.3%, respectively. The percentage in the clinically accurate Clarke error grid A zone was 81.7% and that in the in the benign error B zone was 16.7%. During low rates of change (< +/-1 mg x dl(-1) x min(-1)), the percentage in the A zone was higher (84.9%) and the mean and median ARDs were lower (11.7 and 8.5%, respectively). CONCLUSIONS: Measurements with the FreeStyle Navigator system were found to be consistent and accurate compared with venous measurements made using a laboratory reference method over 5 days of sensor wear (82.5% in the A zone on day 1 and 80.9% on day 5).

Results of the glucose-lowering effect of WelChol study (GLOWS): a randomized, double-blind, placebo-controlled pilot study evaluating the effect of colesevelam hydrochloride on glycemic control in subjects with type 2 diabetes.

OBJECTIVE: This study evaluated the glycosylated hemoglobin (HbA(1c)-lowering effect of colesevelam hydrochloride, a bile acid sequestrant, in subjects with type 2 diabetes that was inadequately controlled by existing antihyperglycemic therapy. METHODS: After a 4-week placebo run-in period, subjects with type 2 diabetes and an HbA(1c) value of 7.0% to 10.0% were randomized to receive colesevelam 3.75 g/d or matching placebo for 12 weeks. Subjects' previous oral anti hyperglycemic medication (sulfonylurea and/or metformin) was continued throughout the study. Fasting blood samples were obtained at weeks -5, -1, 0, 1, 4, 8, and 12. The primary efficacy end point was the change in HbA(1c) from baseline to week 12. Secondary end points included changes in fructosamine levels, fasting plasma glucose levels, postprandial glucose level, and meal glucose response (ie, difference between preprandial and postprandial levels), and percent changes in lipid parameters from baseline to week 12. RESULTS: The 65 randomized subjects (31 colesevelam, 34 placebo) had a mean age of 56.2 years and a mean body mass index of 32.4 kg/m(2); 55.4% were male and 53.8% were white. The difference in least squares (LS) mean (SE) change in HbA(1c) between the colesevelam group and the placebo group was -0.5% (0.18) (P = 0.007). In subjects with a baseline HbAIc > or = 8.0%, the difference in LS mean change in HbA(1c) was -1.0% (0.27) (P = 0.002). Relative to placebo, colesevelam treatment was associated with reductions in levels of fructosamine (-29.0 [10.9] pmol/L; P = 0.011) and postprandial glucose (-31.5 [13.6] mg/dL; P = 0.026). The mean percent change in low-density lipoprotein cholesterol was -9.6% in the colesevelam group, compared with 2.1% in the placebo group (treatment difference, -11.7% [4.2]; P = 0.007); the respective mean percent changes in total cholesterol were -4.0% and 3.4% (treatment difference, -7.3% [3.0]; P = 0.019). Colesevelam also was associated with significant decreases in the percent change in apolipoprotein B (P = 0.003) and low-density lipoprotein particle concentration (P = 0.037). The incidence of treatment-emergent adverse events (TEAEs) was similar in both groups, although treatment-related adverse events were more frequent in the colesevelam group than in the placebo group (29.0% vs 8.8%, respectively). The most frequent TEAEs in the colesevelam group were gastrointestinal disorders (22.6%), primarily constipation (19.4%), compared with an 8.8% incidence of gastrointestinal disorders (0% constipation) in the placebo group. There were no significant changes in body weight or the occurrence of hypoglycemia between treatment groups. CONCLUSIONS: In these subjects with type 2 diabetes, 12 weeks of colesevelam treatment were associated with significant reductions in HbA(1c) and in fructosamine and postprandial glucose levels compared with placebo. The 2 groups had a similar adverse-event profile, with the exception of an increased incidence of constipation in the colesevelam group. These results suggest that colesevelam may improve both lipid control and glycemic control in patients with type 2 diabetes receiving oral antihyperglycemic medications.

Dextromethorphan and quinidine in adult patients with uncontrolled painful diabetic peripheral neuropathy: a 29-day, multicenter, open-label, dose-escalation study.

BACKGROUND: Pain associated with diabetic peripheral neuropathy (DPN) has a substantial negative impact on patients' quality of life. OBJECTIVES: The primary objective of this study was to evaluate the tolerability of capsules containing dextromethorphan (DM) and quinidine (Q) in patients with painful DPN. A secondary objective was to perform a preliminary assessment of the efficacy of DM/Q in this patient population. METHODS: This was a multicenter, open-label, dose-escalation study. Eligible patients were aged between 18 and 80 years, had a confirmed diagnosis of diabetes with acceptable glycemic control, had been receiving established diabetic therapy for at least 3 months, and had a clinical diagnosis of distal symmetric sensory neuropathy with daily DPN-associated pain for the previous 3 months. On study entry, patient-rated diabetic pain had to be moderate or greater. Patients who met the inclusion criteria underwent a 2-week washout period during which all analgesics were discontinued, followed by 29 days of treatment with capsules containing DM 30 mg and Q 30 mg (DM30/Q30), beginning with 1 capsule/d and escalating at approximately 1-week intervals, as tolerated, to a maximum dose of 4 capsules/d (DM120/Q120). Tolerability was assessed based on adverse events and changes in clinical and laboratory parameters and nerve conduction velocity. Preliminary efficacy assessments included changes from baseline in scores on the pain intensity rating scale (PIRS), pain relief rating scale (PRRS), peripheral neuropathy quality-of-life instrument, and patients' diary assessments of sleep, present pain intensity, pain, and activity. RESULTS: The study included 36 men and women (mean age, 58 years; mean body mass index, 32.8 kg/m(2)). Of the 33 subjects who completed the study, 23 (69.7%) did so at the highest permitted dose (DM120/Q120). The most commonly reported adverse events (occurring in > or =5% of subjects) were nausea (27.8%), dizziness (25.0%), and headache (25.0%). Three patients experienced 5 serious adverse events, only 1 of which was considered possibly related to study drug. The most commonly occurring laboratory abnormalities (involving glycosylated hemoglobin, serum glucose, triglycerides, and cholesterol) were considered typical of a population with diabetes. Improvements from baseline in scores on the PIRS, PRRS, and other exploratory efficacy measures were noted (P < 0.001). CONCLUSIONS: The results of this open-label study indicated that the combination of DMIQ (dose range, DM30/Q30-DM120/Q120) was well tolerated in patients with pain associated with DPN. Based on the preliminary efficacy results, a randomized, controlled, double-blind trial is warranted to assess the tolerability and efficacy of this combination in patients with DPN.

Diabetes and dyslipidaemia.

The risk of developing cardiovascular disease (CVD) is higher and the prognosis poorer for diabetic than for non-diabetic individuals. Diabetic dyslipidaemia is characterized by hypertriglyceridaemia, low levels of high-density lipoprotein cholesterol (HDL-C) and the presence of small, dense low-density lipoprotein (LDL) particles. Increased physical activity and weight loss are the first steps in managing diabetic dyslipidaemia. A secondary goal is to achieve non-HDL-C targets with cholesterol-lowering therapy. Improved glycaemic control, the first priority in managing hypertriglyceridaemia, can also aid in lowering levels of LDL-C. Lipid-lowering therapy should be initiated if lifestyle changes and glycaemic control fail to reduce LDL-C levels to <100 mg/dl (5.5 mmol/l), regardless of the status of CVD, coronary heart disease or peripheral vascular disease, and to reduce triglyceride levels of > or =150 mg/dl (8.3 mmol/l). Many diabetic patients may need oral hypoglycaemic agents or insulin to achieve adequate glycaemic control. Intensive insulin therapy can provide tight glycaemic control and reduce elevated triglyceride levels.