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Sergliflozin, the active entity of sergliflozin etabonate, is a selective inhibitor of sodium-dependent glucose cotransporter 2 (SGLT2). The pharmacokinetics and pharmacodynamics of sergliflozin were evaluated following single oral dose administration of sergliflozin etabonate (5-500 mg) in healthy volunteers (n = 22) and patients with type 2 diabetes mellitus (n = 8). The prodrug was rapidly and extensively converted to sergliflozin; the latter displayed linear kinetics, reached maximum plasma concentrations at approximately 30 to 45 minutes postdose (t(max)), and had a plasma elimination half-life (t(1/2)) of ~0.5 to 1 hour. Both prodrug and active entity showed low glomerular filtration and/or extensive renal tubular reabsorption, with <0.5% of the administered dose being recovered in the urine. In both populations, sergliflozin etabonate produced a dose-related glucosuria under fasting conditions and following glucose loading but did not appreciably affect urinary electrolyte excretion or fluid balance. The magnitude and duration of the glucosuric effect closely paralleled plasma sergliflozin concentrations. Sergliflozin did not significantly affect fasting plasma glucose levels but produced transient attenuation of the plasma glucose AUC following glucose challenge. Single doses of sergliflozin etabonate 5 to 500 mg were well tolerated, and there were no clinically significant adverse laboratory findings. [ABSTRACT FROM AUTHOR]

Abstract Background: The complications of diabetes may be minimized by adequate glycemic control, which is aided by self-monitoring of blood glucose (SMBG) levels. A new SMBG system, TRUE2go (Home Diagnostics, Inc., Fort Lauderdale, FL), does not require calibration of test strips, thereby eliminating the potential source of error in blood glucose determination associated with mis-calibration. This study tested the performance of the TRUE2go system. The very small size and attachment of the meter to a vial of test strips make the TRUE2go system unique. Methods: The studies were carried out with adult patients with type 1 or 2 diabetes, using procedures for testing accuracy as specified in International Organization for Standardization (ISO) 15197:2003. The evaluation included patients' compliance with the TRUE2go system's written instructions, ease of understanding the supplied instructions, and ease of use of the system. Results: The study demonstrated the accuracy and precision of the TRUE2go system, with 100% of glucose test results falling within ISO-recommended limits for glucose concentrations ranging from 24 mg/dL to 549 mg/dL. There was agreement between data obtained with TRUE2go when used by healthcare professionals and by lay users on capillary blood from both fingertip and a forearm sticks. Lay users' understanding of and compliance with TRUE2go system instructions were excellent, as was their satisfaction with the system. Conclusions: The TRUE2go system is accurate and convenient to use, and its instructions are easily understood by lay users. TRUE2go features that contribute to convenience, and therefore could improve compliance with monitoring regimens, include its small size, attachment to the vial of strips, easy-to-read display, automatic calibration for test strips, and suitability for fingertip as well as forearm testing. [ABSTRACT FROM AUTHOR]

BACKGROUND: Coronary heart disease is the major cause of mortality in individuals with diabetes mellitus (DM). Given the increasingly aggressive low-density lipoprotein cholesterol (LDL-C) goals for patients with DM set by the National Cholesterol Education Program Adult Treatment Panel III and the American Diabetes Association, many patients remain above target. Treatment with thiazolidinediones (TZDs) improves glycemic control but does not lower (and may raise) LDL-C concentrations. OBJECTIVE: This study assessed the lipid-modifying efficacy and tolerability of adding the hydroxymethylglutaryl coenzyme A-reductase inhibitor simvastatin to existing TZD therapy in patients with type 2 DM. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. Patients with type 2 DM who were taking a stable dose of pioglitazone or rosiglitazone and had a glycosylated hemoglobin (HbA1c) value < or =9.0% and an LDL-C concentration > 100 mg/dL were randomized to receive simvastatin 40 mg (the recommended initial dose for patients with DM) or placebo for 24 weeks. The primary end point was the effect of treatment on LDL-C concentrations. Other lipid, lipoprotein, and safety measures were also assessed. RESULTS: Two hundred fifty-three patients (127 [50.2%] men, 126 [49.8%] women; mean age, 56 years) were randomized to treatment (123 simvastatin, 130 placebo). At the end of the study, mean LDL-C concentrations were reduced 34.)% from baseline (from 134.3 to 89.5 mg/dL) in the simvastatin group and were unchanged in the placebo group (P<0.001). Simvastatin produced significant reductions in concentrations of total cholesterol, triglycerides (TG), non-high-density lipoprotein cholesterol, and apolipoprotein (apo) B compared with placebo (all, P<0.001 ) and significant increases in concentrations of high-density lipoprotein cholesterol (HDL-C) ( P=0.002 ) and apo A-I ( P=0.006 ). In patients who had not attained target concentrations of LDL-C (<100 mg/dL), TG (<150 mg/dL), or HDL-C (>45 mg/dL) at baseline, significantly more simvastatin recipients had achieved these goals at the end of the study compared with placebo recipients (LDL-C: 67.3% vs 5.2%, respectively, P<0.001; HDL-C: 95.3% vs 83.6%, P<0.05; TG: 40.8% vs 11.0%, P<0.001 ). Simvastatin was well tolerated, and no clinically meaningful differences in the incidence of serious adverse events, treatment-related adverse events, or discontinuations due to adverse events were observed between groups. There were no significant between-group differences in glycemic control (HbA1c) or concentrations of fasting insulin, creatine phosphokinase, or hepatic transaminases. CONCLUSION: Simvastatin was an effective and generally well tolerated treatment for hyperlipidemia when used in combination with TZD therapy in this population of patients with type 2 DM. [ABSTRACT FROM AUTHOR]

Objective: To examine the efficacy and safety of the tubeless Omnipod 5 automated insulin delivery (AID) system compared with pump therapy with a continuous glucose monitor (CGM) in adults with type 1 diabetes with suboptimal glycemic outcomes., Research Design and Methods: In this 13-week multicenter, parallel-group, randomized controlled trial performed in the U.S. and France, adults aged 18-70 years with type 1 diabetes and HbA1c 7-11% (53-97 mmol/mol) were randomly assigned (2:1) to intervention (tubeless AID) or control (pump therapy with CGM) following a 2-week standard therapy period. The primary outcome was a treatment group comparison of time in range (TIR) (70-180 mg/dL) during the trial period., Results: A total of 194 participants were randomized, with 132 assigned to the intervention and 62 to the control. TIR during the trial was 4.2h/day higher in the intervention compared with the control group (mean difference 17.5% [95% CI 14.0%, 21.1%]; P < 0.0001). The intervention group had a greater reduction in HbA1c from baseline compared with the control group (mean ± SD -1.24 ± 0.75% [-13.6 ± 8.2 mmol/mol] vs. -0.68 ± 0.93% [-7.4 ± 10.2 mmol/mol], respectively; P < 0.0001), accompanied by a significantly lower time <70 mg/dL (1.18 ± 0.86% vs. 1.75 ± 1.68%; P = 0.005) and >180 mg/dL (37.6 ± 11.4% vs. 54.5 ± 15.4%; P < 0.0001). All primary and secondary outcomes were met. No instances of diabetes-related ketoacidosis or severe hypoglycemia occurred in the intervention group., Conclusions: Use of the tubeless AID system led to improved glycemic outcomes compared with pump therapy with CGM among adults with type 1 diabetes, underscoring the clinical benefit of AID and bolstering recommendations to establish AID systems as preferred therapy for this population., (© 2024 by the American Diabetes Association.)

Background: During MiniMed™ advanced hybrid closed-loop (AHCL) use by adolescents and adults in the pivotal trial, glycated hemoglobin (A1C) was significantly reduced, time spent in range (TIR) was significantly increased, and there were no episodes of severe hypoglycemia or diabetic ketoacidosis (DKA). The present study investigated the same primary safety and effectiveness endpoints during AHCL use by a younger cohort with type 1 diabetes (T1D). Methods: An intention-to-treat population ( N  = 160, aged 7-17 years) with T1D was enrolled in a single-arm study at 13 investigational centers. There was a run-in period (∼25 days) using HCL or sensor-augmented pump with/without predictive low-glucose management, followed by a 3-month study period with AHCL activated at two glucose targets (GTs; 100 and 120 mg/dL) for ∼45 days each. The mean ± standard deviation values of A1C, TIR, mean sensor glucose (SG), coefficient of variation (CV) of SG, time at SG ranges, and insulin delivered between run-in and study were analyzed (Wilcoxon signed-rank test or t -test). Results: Compared with baseline, AHCL use was associated with reduced A1C from 7.9 ± 0.9% ( N  = 160) to 7.4 ± 0.7% ( N  = 136) ( P  < 0.001) and overall TIR increased from the run-in 59.4 ± 11.8% to 70.3 ± 6.5% by end of study ( P  < 0.001), without change in CV, time spent below range (TBR) <70 mg/dL, or TBR <54 mg/dL. Relative to longer active insulin time (AIT) settings ( N  = 52), an AIT of 2 h ( N  = 19) with the 100 mg/dL GT increased mean TIR to 73.4%, reduced TBR <70 mg/dL from 3.5% to 2.2%, and reduced time spent above range (TAR) >180 mg/dL from 28.7% to 24.4%. During AHCL use, there was no severe hypoglycemia or DKA. Conclusions: In children and adolescents with T1D, MiniMed AHCL system use was safe, A1C was lower, and TIR was increased. The lowest GT and shortest AIT were associated with the highest TIR and lowest TBR and TAR, all of which met consensus-recommended glycemic targets. ClinicalTrials.gov ID: NCT03959423.

Background: Safety and significant improvement in overall glycated hemoglobin (A1C) and percentage of time spent in (TIR), below (TBR), and above (TAR) glucose range were demonstrated in the pivotal trial of adolescents and adults using the MiniMed™ advanced hybrid closed-loop (AHCL) system with the adjunctive, calibration-required Guardian™ Sensor 3. The present study evaluated early outcomes of continued access study (CAS) participants who transitioned from the pivotal trial investigational system to the approved MiniMed™ 780G system with the non-adjunctive, calibration-free Guardian™ 4 Sensor (MM780G+G4S). Study data were presented alongside those of real-world MM780G+G4S users from Europe, the Middle East, and Africa. Methods: The CAS participants ( N  = 109, aged 7-17 years and N  = 67, aged >17 years) used the MM780G+G4S for 3 months and data of real-world MM780G+G4S system users ( N  = 10,204 aged ≤15 years and N  = 26,099 aged >15 years) were uploaded from September 22, 2021 to December 02, 2022. At least 10 days of real-world continuous glucose monitoring (CGM) data were required for analyses. Glycemic metrics, delivered insulin and system use/interactions underwent descriptive analyses. Results: Time in AHCL and CGM use were >90% for all groups. AHCL exits averaged 0.1/day and there were few blood glucose measurements (BGMs) (0.8/day-1.0/day). Adults in both cohorts met most consensus recommendations for glycemic targets. Pediatric groups met recommendations for %TIR and %TBR, although not those for mean glucose variability and %TAR, possibly due to low use of recommended glucose target (100 mg/dL) and active insulin time (2 h) settings (28.4% in the CAS cohort and 9.4% in the real-world cohort). The CAS pediatric and adult A1C were 7.2% ± 0.7% and 6.8% ± 0.7%, respectively, and there were no serious adverse events. Conclusions: Early clinical use of the MM780G+G4S was safe and involved minimal BGMs and AHCL exits. Consistent with real-world pediatric and adult use, outcomes were associated with achievement of recommended glycemic targets. Clinical Trial Registration number: NCT03959423.

Introduction: This trial assessed safety and effectiveness of an advanced hybrid closed-loop (AHCL) system with automated basal (Auto Basal) and automated bolus correction (Auto Correction) in adolescents and adults with type 1 diabetes (T1D). Materials and Methods: This multicenter single-arm study involved an intent-to-treat population of 157 individuals (39 adolescents aged 14-21 years and 118 adults aged ≥22-75 years) with T1D. Study participants used the MiniMed™ AHCL system during a baseline run-in period in which sensor-augmented pump +/- predictive low glucose management or Auto Basal was enabled for ∼14 days. Thereafter, Auto Basal and Auto Correction were enabled for a study phase (∼90 days), with glucose target set to 100 or 120 mg/dL for ∼45 days, followed by the other target for ∼45 days. Study endpoints included safety events and change in mean A1C, time in range (TIR, 70-180 mg/dL) and time below range (TBR, <70 mg/dL). Run-in and study phase values were compared using Wilcoxon signed-rank test or paired t -test. Results: Overall group time spent in closed loop averaged 94.9% ± 5.4% and involved only 1.2 ± 0.8 exits per week. Compared with run-in, AHCL reduced A1C from 7.5% ± 0.8% to 7.0% ± 0.5% (<0.001, Wilcoxon signed-rank test, n  = 155), TIR increased from 68.8% ± 10.5% to 74.5% ± 6.9% (<0.001, Wilcoxon signed-rank test), and TBR reduced from 3.3% ± 2.9% to 2.3% ± 1.7% (<0.001, Wilcoxon signed-rank test). Similar benefits to glycemia were observed for each age group and were more pronounced for the nighttime (12 AM-6 AM). The 100 mg/dL target increased TIR to 75.4% ( n  = 155), which was further optimized at a lower active insulin time (AIT) setting (i.e., 2 h), without increasing TBR. There were no severe hypoglycemic or diabetic ketoacidosis events during the study phase. Conclusions: These findings show that the MiniMed AHCL system is safe and allows for achievement of recommended glycemic targets in adolescents and adults with T1D. Adjustments in target and AIT settings may further optimize glycemia and improve user experience. Clinical Trial Registration number: NCT03959423.

Objective: To evaluate the single-dose pharmacokinetics (PK), pharmacodynamics (PD), and safety of sitagliptin in pediatric patients with type 2 diabetes mellitus (T2DM)., Study Design: This was a randomized, placebo-controlled, double-blind evaluation of sitagliptin in 35 patients 10 to 17 years old with T2DM at 7 clinical research sites. The safety, tolerability, PK, and PD (dipeptidyl peptidase-4 [DPP-4] inhibition and aspects of glucose metabolism) of single doses of 50, 100, and 200 mg were assessed. Appropriate transformations on the PK parameters were used and back-transformed summary statistics are reported., Results: Adverse experiences were reported by eight study participants; all were of mild intensity except one (intravenous site pain of moderate intensity). PK characteristics in the young patients were comparable to reference adult data, with geometric mean ratios (youths/adults) for AUC 0-∞ , C max , and C 24hr of 0.82, 1.04, and 0.74, respectively. Single doses of 50, 100, and 200 mg sitagliptin inhibited 67.2%, 73.8%, and 81.2% of plasma DPP-4 activity over 24 hours, respectively. Least squares (LS) mean glucose concentrations 2 hours after an oral glucose tolerance test or a meal tolerance test decreased in study participants treated with sitagliptin, compared to placebo, while active LS mean glucagon-like peptide 1 concentrations increased significantly at all sitagliptin doses in both tests., Conclusions: Single doses of sitagliptin as high as 200 mg were generally well tolerated in 10- to 17-year-old male and female study participants with T2DM, and a daily sitagliptin dose of 100 mg is appropriate for evaluation in Phase III safety and efficacy studies in pediatric patients with T2DM. (ClinicalTrials.gov: NCT00730275)., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A phase 3, 26-week, open-label, titrate-to-target study (n=418) assessed the safety of azilsartan medoxomil (AZL-M) alone and with chlorthalidone (CLD), followed by a 6-week, double-blind, placebo-controlled reversal phase with change in clinic diastolic blood pressure (DBP) as the primary endpoint. Target blood pressure (BP) was <140/90 mm Hg (<130/80 mm Hg with diabetes/chronic kidney disease). AZL-M was initiated at 40 mg once a day (QD), force-titrated to 80 mg at week 4. CLD 25 mg QD could be added (weeks 8-22), if required, to reach target, followed by additional antihypertensives from week 12. At the end of the open-label phase, mean change in systolic BP (SBP)/DBP from baseline was -23/-16 mm Hg. The most common adverse events, irrespective of treatment, were dizziness (8.9%) and headache (7.2%). Serious AEs were reported in eight patients (1.9%). Consecutive creatinine elevations ≥50% with values exceeding the upper limit of normal (ULN) were reported in nine (2.2%) patients. All returned to below the 50% threshold; most also returned to below the ULN after drug discontinuation. Mean DBP was maintained through the reversal phase in patients receiving AZL-M, but increased with placebo (difference: -7.8 mm Hg, 95% confidence interval, -9.8 to -5.8; P<.001). AZL-M alone or with CLD showed good long-term safety and stable BP improvements in a titrate-to-target approach. BP improvements caused by AZL-M therapy were safely reversible upon AZL-M withdrawal., (© 2015 Wiley Periodicals, Inc.)

A length-dependent neuropathy with pain in the feet is a common complication of diabetes (painful diabetic neuropathy). It was hypothesized that pain may arise from sensitized-hyperactive cutaneous nociceptors, and that this abnormal signaling may be reduced by topical administration of the α(2)-adrenergic agonist, clonidine, to the painful area. This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. Nociceptor function was measured by determining the painfulness of 0.1% topical capsaicin applied to the pretibial area of each subject for 30minutes during screening. Subjects were then randomized to receive 0.1% topical clonidine gel (n=89) or placebo gel (n=90) applied 3 times a day to their feet for 12weeks. The difference in foot pain at week 12 in relation to baseline, rated on a 0-10 numerical pain rating scale (NPRS), was compared between groups. Baseline NPRS was imputed for missing data for subjects who terminated the study early. The subjects treated with clonidine showed a trend toward decreased foot pain compared to the placebo-treated group (the primary endpoint; P=0.07). In subjects who felt any level of pain to capsaicin, clonidine was superior to placebo (P<0.05). In subjects with a capsaicin pain rating ⩾2 (0-10, NPRS), the mean decrease in foot pain was 2.6 for active compared to 1.4 for placebo (P=0.01). Topical clonidine gel significantly reduces the level of foot pain in painful diabetic neuropathy subjects with functional (and possibly sensitized) nociceptors in the affected skin as revealed by testing with topical capsaicin. Screening for cutaneous nociceptor function may help distinguish candidates for topical therapy for neuropathic pain., (Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Aim: To evaluate the dose-response relationship of the recombinant glucagon-like peptide-1 (7-36) amide (rGLP-1) administered by continuous subcutaneous infusion (CSCI) in subjects with type 2 diabetes, with respect to reductions in fasting, postprandial and 11-h serum glucose profiles., Methods: In a double-blind, parallel, placebo-controlled trial, 47 patients were randomized to placebo or rGLP-1 (1.25, 2.5, 5.0 or 8.5 pmol/kg/min) by CSCI for 7 days. On day 1 (pretreatment) and on day 8, patients underwent monitoring of fasting, postprandial, and 11-h profiles of glucose and hormones., Results: Fasting serum glucose decreased by 76.2, 53.9, 37.0 and 22.7 mg/dl for the 8.5, 5.0, 2.5 and 1.25 pmol/kg/min rGLP-1 groups, respectively, compared to a decrease of 1.1 mg/dl for placebo (p = 0.0002, 0.005, 0.064 and 0.27, respectively). Mean 11-h serum glucose area under the curve decreased by 36.3, 23.3, 16.9 and 10.0% for 8.5, 5.0, 2.5 and 1.25 pmol/kg/min rGLP-1, respectively, compared to no change for placebo (p = 0.0001, 0.0019, 0.012 and 0.14, respectively). Mean fasting C-peptide increased dose dependently with rGLP-1 (p = 0.0023 for the highest dose) and decreased with placebo. There were no serious safety concerns and no instances of hypoglycaemia., Conclusions: rGLP-1 produced continuous improvements in glycaemic control across a broad dose range of up to 8.5 pmol/kg/min., (© 2011 Blackwell Publishing Ltd.)

Background: We assessed the efficacy, safety, and patient-reported outcomes (PROs) of insulin pump therapy in patients with type 2 diabetes mellitus (T2DM) who were suboptimally controlled with a multiple daily injection (MDI) regimen., Methods: In this subanalysis of a 16-week multicenter study, 21 insulin-pump-naïve patients [age 57 ± 13 years, hemoglobin A1c (A1C) 8.4 ± 1.0%, body weight 98 ± 20 kg, total daily insulin dose 99 ± 65 U, mean ± standard deviation] treated at baseline with MDI therapy with or without oral antidiabetic agents discontinued all diabetes medications except metformin and initiated insulin pump therapy. Insulin was titrated to achieve the best possible glycemic control with the simplest possible dosing regimen. Outcome measures included A1C, fasting and postprandial glucose, body weight, incidence of hypoglycemia, and PROs., Results: Glycemic control improved significantly after 16 weeks: A1C 7.3 ± 1.0% (-1.1 ± 1.2%, p < .001), fasting glucose 133 ± 33 mg/dl (-32 ± 74 mg/dl, p < .005), and postprandial glucose 153 ± 35 mg/dl (-38 ± 46 mg/dl, p < .001). At week 16, the mean daily basal, bolus, and total insulin doses were 66 ± 36, 56 ± 40, and 122 ± 72 U (1.2 U/kg), respectively, and 90% of patients were treated with two or fewer daily basal rates. Body weight increased by 2.8 ± 2.6 kg (p < .001). Mild hypoglycemia was experienced by 81% of patients at least once during the course of the study with no episodes of severe hypoglycemia. There were significant improvements in PRO measures., Conclusions: Insulin pump therapy using a relatively simple dosing regimen safely improved glucose control and PROs in patients with T2DM who were unable to achieve glycemic targets with MDI therapy. Controlled trials are needed to further assess the clinical benefits and cost-effectiveness of insulin pumps in this patient population., (© 2011 Diabetes Technology Society.)

Background: This study assessed insulin dose and dosing patterns required to optimize glycemic control with an insulin pump in patients with type 2 diabetes., Methods: In this 16-week, open-label, multicenter, pilot study, 56 insulin pump-naive patients treated at baseline with two or more oral antidiabetes agents (OADs), basal insulin with or without OADs, or basal-bolus insulin with or without OADs discontinued all diabetes medications except metformin and initiated insulin pump therapy. Insulin doses were adjusted to optimize glycemic control with the simplest possible insulin regimen. Outcomes included total daily insulin dose, daily basal and bolus insulin doses, number of daily basal rates, hemoglobin A1C, fasting and postprandial glucose, patient-reported outcomes and rate of hypoglycemia., Results: After 16 weeks of pump therapy, the mean +/- SD total daily insulin dose was 95 +/- 59 U. The percentage of the total daily insulin dose used as basal and as bolus delivery was 55% and 45%, respectively. Eighty-eight percent of patients were treated with two or fewer daily basal rates. Mean A1C was lowered by 1.2 +/- 1.2% (P < 0.001), and there was no severe hypoglycemia. Mean change in body weight was +1.9 +/- 3.3 kg (P < 0.001). Overall treatment preference improved with pump therapy compared to baseline., Conclusions: Insulin pump therapy using a simple dosing regimen significantly improved glycemic control in patients with type 2 diabetes. Patients experienced limited weight gain, there was no severe hypoglycemia, and overall treatment preference improved significantly.

Aim: To evaluate the efficacy and safety of taranabant in overweight and obese patients with type 2 diabetes mellitus (T2DM)., Methods: This was a multicenter, double-blind, randomized, placebo-controlled study in overweight and obese patients with T2DM (ages > or = 18 and < or = 75 years) with a BMI > or = 27 kg/m(2) and < or = 43 kg/m(2) and HbA1c > or =7.0 and < or = 10.0%, who were either not on an antihyperglycaemic agent or on a stable dose of metformin (> or = 1500 mg/day). After a 2-week placebo run-in, patients were randomized to placebo (N = 156) or taranabant 0.5-mg (N = 155), 1-mg (N = 157), or 2-mg (N = 155) once daily for 52 weeks. Primary efficacy endpoints were changes from baseline in body weight (BW) and HbA1c at Week 36, with results at Week 52 being key secondary endpoints., Results: In the all-patients-treated population, using a last-observation-carried-forward analysis, reductions in BW were -2.5, -3.7, -4.5 and -5.1 kg at Week 36 and -2.4, -4.0, -4.6 and -5.3 kg at Week 52 in the placebo, 0.5-, 1- and 2-mg groups, respectively (all doses significant vs. placebo at both time points). The proportion of patients who lost > or = 5 and > or = 10% of their baseline BW was significantly greater in the 1- and 2-mg groups vs. placebo at Week 36 and all taranabant groups vs. placebo at Week 52. Reductions in HbA1c were -0.40, -0.47, -0.68 and -0.71% at Week 36 and -0.30, -0.43, -0.65 and -0.64% at Week 52, in the placebo, 0.5-, 1- and 2-mg groups, respectively (1- and 2-mg doses significant vs. placebo at both time points). After 52 weeks, the incidences of adverse experiences classified in the gastrointestinal (diarrhoea, nausea, vomiting), nervous system-related (dizziness, sensory-related), and psychiatric (irritability, depression-related) organ systems were numerically higher or statistically significantly higher in all taranabant groups compared with the placebo group., Conclusions: After 36 and 52 weeks, treatment with taranabant at the 1- and 2-mg doses led to clinically significant weight loss and improvement in glycaemic parameters in overweight and obese patients with T2DM that was associated with dose-related increases in adverse experiences. Based on these data and data from other Phase III clinical studies, it was determined that the overall safety and efficacy profile of taranabant did not support further development for the treatment of obesity.

Background and Objectives: Long-term (>1 year) safety and efficacy studies of combination lipid therapy are lacking. This year 2 study evaluated fenofibric acid 135 mg in combination with moderate-dose statin (rosuvastatin 20 mg, simvastatin 40 mg or atorvastatin 40 mg) in patients with mixed dyslipidaemia., Methods: This was a phase 3, open-label, year 2 extension study in patients who had completed one of three double-blind, 12-week, controlled studies and the subsequent open-label, year 1 extension study. Patients in this study had mixed dyslipidaemia (high-density lipoprotein cholesterol [HDL-C] <40 mg/dL [<1.02 mmol/L] for men or <50 mg/dL [<1.28 mmol/L] for women, triglycerides [TG] > or =150 mg/dL [> or =1.69 mmol/L], and low-density lipoprotein cholesterol [LDL-C] > or =130 mg/dL [> or =3.37 mmol/L]) at the start of the controlled study, and had completed the year 1 extension study. Treatment was once-daily oral coadministration of fenofibric acid 135 mg and moderate-dose statin (rosuvastatin 20 mg, simvastatin 40 mg or atorvastatin 40 mg), and was identical to the treatment received in the year 1 study. The year 2 population safety data were summarized for the entire duration of fenofibric acid + statin therapy. Efficacy data were summarized by combination therapy group, as well as pooled across combination therapies, and summarized across the controlled and open-label studies., Results: Of the 310 patients enrolled into the year 2 study, 287 (93%) completed therapy. The mean cumulative exposure to combination therapy was 743 days across the studies. Adverse event rates were similar for all three combination therapy groups. No deaths or treatment-related serious adverse events occurred. The incidence of discontinuation due to adverse events was 2.9% overall. Rhabdomyolysis was not reported in any group. Overall, fenofibric acid + moderate-dose statin for > or =2 years resulted in sustained improvements in HDL-C (+17.4%), TG (-46.4%) and LDL-C (-40.4%)., Conclusions: This long-term study demonstrated that fenofibric acid + moderate-dose statin was generally well tolerated with no new or unexpected safety concerns, and resulted in comprehensive and sustained lipid improvements in patients with mixed dyslipidaemia.

Aim: To evaluate the efficacy and safety of alogliptin, a potent and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor, in combination with glyburide in patients with type 2 diabetes inadequately controlled by sulphonylurea monotherapy., Methods: After a 2-week screening period, adult patients 18-80 years of age entered a 4-week run-in/stabilization period in which they were switched from their own sulphonylurea medication to an equivalent dose of glyburide (open label) plus placebo (single blind). After the run-in period, patients were randomly assigned to double-blind treatment with alogliptin 12.5 mg (n = 203), alogliptin 25 mg (n = 198), or placebo (n = 99) for 26 weeks. The primary end-point was change from baseline to week 26 in glycosylated haemoglobin (HbA1c). Secondary end-points included clinical response rates and changes in fasting plasma glucose, beta-cell function (fasting proinsulin, insulin, proinsulin/insulin ratio, and C-peptide, and homeostasis model assessment beta-cell function), body weight, and safety end-points [adverse events (AEs), clinical laboratory tests, vital signs and electrocardiographic readings]., Results: The study population had a mean age of 57 years and a mean disease duration of 8 years; it was well balanced for gender (52% women) and was mainly white (71%). The mean baseline HbA1c was approximately 8.1% in each group. Significantly greater least squares (LS) mean reductions in HbA1c were seen at week 26 with alogliptin 12.5 mg (-0.38%) and 25 mg (-0.52%) vs. placebo (+0.01%; p < 0.001), and more patients in the alogliptin 25-mg group had HbA1c levels < or =7.0% at week 26 (34.8%, p = 0.002) vs. placebo (18.2%). Proportionately more patients in the alogliptin 12.5 mg (47.3%) and 25 mg (50.5%) groups had an HbA1c reduction > or =0.5% from baseline compared with patients in the placebo group (26.3%; p < 0.001). Minor improvements in individual markers of beta-cell function were seen with alogliptin, but no significant treatment group differences were noted relative to placebo. Minor LS mean changes in body weight were noted across groups (placebo, -0.20 kg; alogliptin 12.5 mg, +0.60 kg; alogliptin 25 mg, +0.68 kg). AEs were reported for 63-64% of patients receiving alogliptin and 54% of patients receiving placebo. Few AEs were treatment limiting (2.0-2.5% across groups), and serious AEs (2.0-5.6%) were infrequent, similar across groups, and generally considered not related to treatment. The incidences of hypoglycaemia for placebo, alogliptin 12.5 mg and alogliptin 25 mg groups were 11.1, 15.8 and 9.6% respectively., Conclusions: In patients with type 2 diabetes inadequately controlled by glyburide monotherapy, the addition of alogliptin resulted in clinically significant reductions in HbA1c without increased incidence of hypoglycaemia.

Objective: To examine the efficacy and safety of once-daily oral sitagliptin as monotherapy in patients with type 2 diabetes., Research Design and Methods: In a randomized, double-blind, placebo-controlled study, 741 patients (baseline HbA(1c) [A1C] 8.0%) were randomized to sitagliptin 100 or 200 mg or placebo for 24 weeks., Results: Sitagliptin 100 and 200 mg produced significant (P < 0.001) placebo-subtracted reductions in A1C (-0.79 and -0.94%, respectively) and fasting plasma glucose (-1.0 mmol/l [-17.1 mg/dl] and -1.2 mmol/l [-21.3 mg/dl], respectively). Patients with baseline A1C >or=9% had greater reductions in placebo-subtracted A1C with sitagliptin 100 and 200 mg (-1.52 and -1.50%, respectively) than those with baseline A1C <8% (-0.57 and -0.65%) or >or=8 to <9.0% (-0.80 and -1.13%, respectively). In a meal tolerance test, sitagliptin 100 and 200 mg significantly decreased 2-h postprandial glucose (PPG) (placebo-subtracted PPG -2.6 mmol/l [-46.7 mg/dl] and -3.0 mmol/l [-54.1 mg/dl], respectively). Results for the above key efficacy parameters were not significantly different between sitagliptin doses. Homeostasis model assessment of beta-cell function and proinsulin-to-insulin ratio improved with sitagliptin. The incidence of hypoglycemia was similar, and overall gastrointestinal adverse experiences were slightly higher with sitagliptin. No meaningful body weight changes from baseline were observed with sitagliptin 100 (-0.2 kg) or 200 mg (-0.1 kg). The body weight change with placebo (-1.1 kg) was significantly (P < 0.01) different from that observed with sitagliptin., Conclusions: In this 24-week study, once-daily sitagliptin monotherapy improved glycemic control in the fasting and postprandial states, improved measures of beta-cell function, and was well tolerated in patients with type 2 diabetes.

Context: In response to a meal, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are released and modulate glycemic control. Normally these incretins are rapidly degraded by dipeptidyl peptidase-4 (DPP-4). DPP-4 inhibitors are a novel class of oral antihyperglycemic agents in development for the treatment of type 2 diabetes. The degree of DPP-4 inhibition and the level of active incretin augmentation required for glucose lowering efficacy after an oral glucose tolerance test (OGTT) were evaluated., Objective: The objective of the study was to examine the pharmacodynamics, pharmacokinetics, and tolerability of sitagliptin., Design: This was a randomized, double-blind, placebo-controlled, three-period, single-dose crossover study., Setting: The study was conducted at six investigational sites., Patients: The study population consisted of 58 patients with type 2 diabetes who were not on antihyperglycemic agents., Interventions: Interventions included sitagliptin 25 mg, sitagliptin 200 mg, or placebo., Main Outcome Measures: Measurements included plasma DPP-4 activity; post-OGTT glucose excursion; active and total incretin GIP levels; insulin, C-peptide, and glucagon concentrations; and sitagliptin pharmacokinetics., Results: Sitagliptin dose-dependently inhibited plasma DPP-4 activity over 24 h, enhanced active GLP-1 and GIP levels, increased insulin/C-peptide, decreased glucagon, and reduced glycemic excursion after OGTTs administered at 2 and 24 h after single oral 25- or 200-mg doses of sitagliptin. Sitagliptin was generally well tolerated, with no hypoglycemic events., Conclusions: In this study in patients with type 2 diabetes, near maximal glucose-lowering efficacy of sitagliptin after single oral doses was associated with inhibition of plasma DPP-4 activity of 80% or greater, corresponding to a plasma sitagliptin concentration of 100 nm or greater, and an augmentation of active GLP-1 and GIP levels of 2-fold or higher after an OGTT.

The aim of this study was to evaluate changes in lipid profiles in patients with type 2 diabetes after treatment conversion from rosiglitazone to pioglitazone while maintaining stable statin and other lipid-altering therapies. A total of 305 patients were enrolled in this open-label study. Patients had been taking stable dosages of rosiglitazone and statins for > 90 days. At baseline, patients discontinued rosiglitazone and started pioglitazone 30 mg/day, but continued statins and other lipid-altering therapies. The primary end point was change from baseline in fasting triglyceride levels. At 17 weeks after treatment conversion, patients had significant reductions in triglycerides (-15.2%), total cholesterol (-9.0%), and low-density lipoprotein (LDL) particle concentration (-189 nmol/L), and increases in LDL cholesterol (+2.2%), high-density lipoprotein (HDL) cholesterol (+1.8%), and LDL particle diameter (+0.23 nm). In conclusion, after treatment conversion from rosiglitazone to pioglitazone while maintaining stable statin therapy, patients with type 2 diabetes had marked improvements in lipid profiles along with stable glycaemic control.

NBI-6024 is an altered peptide ligand (APL) corresponding to the 9-23 amino acid region of the insulin B chain (B(9-23)), an epitope recognized by inflammatory interferon-gamma-producing T helper (Th)1 lymphocytes in type 1 diabetic patients. Immunomodulatory effects of NBI-6024 administration in recent-onset diabetic patients in a phase I clinical trial (NBI-6024-0003) were measured in peripheral blood mononuclear cells using the enzyme-linked immunosorbent spot assay. Analysis of the mean magnitude of cytokine responses to B(9-23) and NBI-6024 for each cohort showed significant increases in interleukin-5 responses (a Th2 regulatory phenotype) in cohorts that received APL relative to those receiving placebo. A responder analysis showed that Th1 responses to B(9-23) and NBI-6024 were observed almost exclusively in the placebo-treated diabetic population but not in nondiabetic control subjects and that APL administration (five biweekly subcutaneous injections) significantly and dose-dependently reduced the percentage of patients with these Th1 responses. The results of this phase I clinical study strongly suggest that NBI-6024 treatment shifted the Th1 pathogenic responses in recent-onset type 1 diabetic patients to a protective Th2 regulatory phenotype. The significance of these findings on the clinical outcome of disease is currently under investigation in a phase II multidose study.

Objective: The primary objective of the study was to compare the percentage of men with mean serum total T (C(ave(0-24))) within normal range during the 24-h pharmacokinetic (PK) sampling period on Days 14 and 15., Methods: Treatment with a new testosterone (T) buccal system, (Striant), 30 mg twice daily was compared to a transdermal gel delivery system, (T-gel) [AndroGel 5 g containing 1% (50 mg) T] daily for 14 days in T-deficient men. Safety parameters included laboratory assessments and collection of adverse events. Patients were otherwise healthy T-deficient men with total T

This study compared the efficacy and tolerability of eplerenone and enalapril in 499 patients with stage 1 or 2 hypertension who were randomized to receive eplerenone or enalapril for 6 months in a 3-step titration-to-effect study. After 6 months, patients whose diastolic blood pressure (BP) was <90 mm Hg had their dosages down-titrated were followed for an additional 6 months. Diastolic BP was the primary end point. Eplerenone was as effective as enalapril in reducing both systolic BP (eplerenone, -14.5 mm Hg; enalapril, -12.7 mm Hg; p = 0.199) and diastolic BP (eplerenone, -11.2 mm Hg; enalapril, -11.3 mm Hg; p = 0.910) at 6 months. BP reductions at 12 months were also similar between groups (-16.5/-13.3 mm Hg for eplerenone, -14.8/-14.1 mm Hg for enalapril; p = 0.251 and 0.331, respectively). Withdrawal rates for adverse events (eplerenone 7.9%, enalapril 9.3% at 6 months) and treatment failures (eplerenone 23.3%, enalapril 22.8% at 6 months) were also equivalent. Approximately 2/3 of each group had normal BP with monotherapy treatment at 6 months. BP response was independent of renin levels in the eplerenone group, but not in the enalapril group. Both agents reduced albuminuria in patients who had an elevated value at baseline, with significantly greater improvement in patients treated with eplerenone versus enalapril (-61.5% vs -25.7%; p = 0.01). Both agents were similarly well tolerated, and there was no increased incidence of any sexual adverse events in the eplerenone group. Patients taking enalapril had a higher rate of cough. Both agents increased serum potassium levels, but <1% in each group reported adverse events from hyperkalemia. Eplerenone was as effective as enalapril as monotherapy in patients with stage 1 or 2 hypertension, was more effective in reducing albuminuria, and was well tolerated for 12 months.

Objective: An acid-induced-viscosity (I-V) complex containing alginate, citrate, and insoluble calcium was incorporated into a glucose-based beverage. We hypothesized that the acid I-V beverage would become viscous in the stomach (due to the solubilization of calcium and its interaction with alginate and citrate) and would blunt glycemia., Methods: Thirty subjects were used in a double-masked, placebo-controlled crossover study evaluating the acid I-V complex. The placebo was a glucose-based beverage that had a similar total dietary fiber level and initial viscosity (Control). After a 12-h overnight fast, serum glucose and insulin were monitored over a 3-h postprandial period., Results: The postprandial mean peak incremental change from baseline in serum glucose tended (P < 0.06) to be lower for the acid I-V product. The net incremental area under the curve (AUC) for serum glucose was reduced 75% (P < 0.01) by the acid I-V product, which was due mainly to an increased undershoot. The mean peak incremental change from baseline in serum insulin was higher (P < 0.05) for the acid I-V product. Net incremental AUC for serum insulin did not differ (P > 0.20) between products., Conclusions: Results of this study suggested that the acid I-V complex may attenuate the postprandial glycemic response to a glucose challenge in healthy subjects.

Several controlled clinical trials have shown that zinc gluconate glycine lozenges can reduce symptom severity and duration of symptoms in patients with the common cold. Over-the-counter zinc lozenges are used commonly by the general population, including people with diabetes. The purpose of this study was to assess the effects of sugar-free Cold-Eeze (The Quigley Corp., Doylestown, PA), a commonly used zinc preparation, on glucose control in patients maintained on stable antidiabetic therapy. Forty-eight patients with either type 1 (n = 3) or type 2 (n = 45) diabetes were randomized in a 3:1 ratio to receive either zinc lozenges (four to six lozenges/day for 10 days) or matching placebo. The primary endpoint was change in serum fructosamine concentration. Secondary endpoints included daily home glucose and fasting blood glucose monitoring (baseline, days 10 and 21). The mean age for all patients was 54 years (range, 25 to 76), with slightly more women (60%). The treatment groups did not differ with respect to age, sex, body mass index, duration of diabetes, baseline hemoglobin A1C level, or fasting plasma glucose level. The patients treated with placebo (n = 13) and zinc (n = 34) had similar fructosamine levels (mean +/- SD) at baseline (318 +/- 90 versus 297 +/- 86 micromol/l, respectively). After 10 days of dosing, both groups showed modest reductions in serum fructosamine (-7 +/- 42 and -9 +/- 90 micromol/l). These changes were not statistically significant. In conclusion, these findings suggest that sugar-free zinc lozenges can be administered safely to patients with diabetes without deleterious effects on glycemic control.

Purpose: To evaluate the efficacy and tolerability of pioglitazone in combination with a sulfonylurea in the treatment of type 2 diabetes mellitus., Subjects and Methods: This 16-week, double-blind study included patients on a stable regimen of a sulfonylurea for > or = 30 days and with a glycosylated hemoglobin (HbA1C) level > or = 8.0%. Patients were randomly assigned to receive once daily pioglitazone 15 mg (n = 184), pioglitazone 30 mg (n = 189), or placebo plus sulfonylurea (n = 187)., Results: Patients receiving pioglitazone + sulfonylurea had significant (P < 0.05) decreases from baseline in HbA1C and fasting plasma glucose levels compared with patients treated with placebo + sulfonylurea. As compared with placebo, HbA1C decreased by 0.9% (95% confidence interval [CI]: 0.06% to 1.2%) with pioglitazone 15 mg and 1.3% (CI: 1% to 1.6%) with 30 mg pioglitazone; fasting plasma glucose levels decreased by 39 mg/dL (95% CI: 27 to 52 mg/dL) with pioglitazone 15 mg and by 58 mg/dL (95% CI: 46-70 mg/dL) with 30 mg pioglitazone. Both pioglitazone + sulfonylurea groups had significant (P < 0.05) mean percent decreases in triglyceride levels (17%, 95% CI: 6% to 27% for 15 mg; 26%, 95% CI: 16% to 36% for 30 mg) and increases in high-density lipoprotein cholesterol levels (6%, 95% CI: 1% to 11% for 15 mg; 13%, CI: 8% to 18% for 30 mg) compared with placebo + sulfonylurea. There were small but statistically significant mean percent increases in low-density lipoprotein cholesterol levels in all groups. Pioglitazone was well tolerated, and the rates of adverse events were similar in all groups., Conclusion: In patients with type 2 diabetes, pioglitazone plus sulfonylurea significantly improves HbA1C and fasting plasma glucose levels with beneficial effects on serum triglyceride and HDL-cholesterol levels.

This open-label, randomized, placebo lead-in, three-treatment crossover study in 19 hypogonadal men (27-82 years of age) evaluated dose proportionality of serum testosterone concentrations with application of one or two investigational transdermal testosterone systems for application to the arm or torso. Testosterone in vivo kinetics profiles were determined using DeMonS, a recently developed numerical deconvolution method that estimates drug absorption at different time intervals and/or drug disposition model parameters. After application of the investigational transdermal systems, the mean serum testosterone, dihydrotestosterone, estradiol, and free testosterone concentrations were elevated to normal levels. Treatment allowed approximation of the normal circadian pattern of endogenous testosterone secretion, and the increase in serum testosterone concentrations was proportional to the surface area of systems applied. The investigational transdermal system provided effective testosterone replacement therapy as judged by pharmacokinetic parameters.

Data from studies in diabetic rodents and evidence from clinical situations of severe resistance to insulin suggest that insulin-like growth factor I (IGF-I) is able to at least partly overcome insulin resistance. To assess the efficacy of recombinant human IGF-I in subjects with the most common form of insulin resistance, e.g., obese, type II diabetic patients, we administered recombinant human IGF-I (rhIGF) in doses of 120 and 160 micrograms/kg twice daily for 4-52 days to seven such individuals who had been treated previously with high doses of insulin (> 0.7 U.kg-1 x day-1). Four patients exhibited comparable or enhanced, whereas three had diminished, blood glucose control on rhIGF-I relative to that while on twice daily NPH insulin during the six-week control period. The occurrence of adverse effects in all patients compelled us to discontinue rhIGF-I administration before completing the 8-week treatment period. These adverse effects included edema primarily on the face and hands, mild weight gain, occasional dyspnea, bilateral jaw tenderness, arthralgias and myalgias, fatigue, tachycardia, flushing, orthostatic hypotension, and local burning at the injection site. We conclude that the frequency and severity of side effects associated with administering high-dose subcutaneous rhIGF-I to obese insulin-resistant diabetic patients make it an unacceptable therapeutic agent for these patients despite its ability to produce reasonable blood glucose control in approximately 50% of them.

The effect of glipizide alone and glipizide preceded by a short course of insulin therapy (10 weeks) was studied in 69 patients with non-insulin-dependent diabetes mellitus (NIDDM) in a 10-month study. The patients were obese, had poor glycemic control, and, in all patients, first-generation sulfonylurea therapy had failed. The majority were Mexican-Americans, an ethnic population with a high incidence of NIDDM and insulin resistance. Plasma glucose levels were monitored using the eight-point [Saarstedt] series. In the group receiving glipizide alone, mean fasting plasma glucose levels decreased from 255.9 mg/dl at baseline to 228.7 mg/dl at the end of the study; two-hour postprandial glucose levels decreased from 280.1 to 260.5 mg/dl; glycosylated hemoglobin decreased from 9.1 to 7.4 percent; and post-Sustacal C-peptide levels increased from 0.7 to 1.0 pmol/ml. In the group receiving insulin/glipizide, mean fasting plasma glucose levels decreased from 241.1 mg/dl at baseline to 217.0 mg/dl; two-hour postprandial glucose levels increased from 267.2 to 279.0 mg/dl; glycosylated hemoglobin decreased from 9.1 to 7.5 percent; and post-Sustacal C-peptide levels increased from 0.6 to 1.0 pmol/ml. At the end of 10 weeks, insulin administration was associated with a more rapid decrease in the levels of fasting plasma glucose, two-hour postprandial glucose, and glycosylated hemoglobin, but there was no significant difference between the two therapies by the end of the study. Both regimens had a positive influence on reducing the total cholesterol/high-density lipoprotein ratio. More patients in the group receiving insulin/glipizide withdrew from the study, which may have been due to difficulties associated with insulin administration. In conclusion, there does not appear to be a prolonged effect of insulin treatment on the post-receptor defect. Some patients in whom first-generation oral agents fail may not have to be given permanent insulin therapy, especially those with fasting plasma glucose levels of less than 200 mg/dl. There was no overall difference between these treatments with respect to glycemic control or lipoprotein profiles. In the interests of simplifying both therapy and monitoring, enhancing patient compliance, and achieving cost reductions, therapy with glipizide alone ultimately may be sufficient for cases in which immediate control is unnecessary (for example, patients with asymptomatic hyperglycemia, and in the absence of hyperlipidemia and vascular disease).