Dose response of subcutaneous GLP-1 infusion in patients with type 2 diabetes.

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.

A one-year study to assess the safety and efficacy of the CB1R inverse agonist taranabant in overweight and obese patients with type 2 diabetes.

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.

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes inadequately controlled by glyburide monotherapy.

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.

Immunomodulation in type 1 diabetes by NBI-6024, an altered peptide ligand of the insulin B epitope.

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.

Short-term pharmacokinetic comparison of a novel testosterone buccal system and a testosterone gel in testosterone deficient men.

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

Sugar-free zinc gluconate glycine lozenges (Cold-Eeze) do not adversely affect glucose control in patients with type 1 or type 2 diabetes mellitus.

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.

Pioglitazone hydrochloride in combination with sulfonylurea therapy improves glycemic control in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study.

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.

Testosterone pharmacokinetics after application of an investigational transdermal system in hypogonadal men.

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.

Adverse effects of recombinant human insulin-like growth factor I in obese insulin-resistant type II diabetic patients.

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.

Effects of short-term insulin therapy upon therapeutic response to glipizide.

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).