Vildagliptin: a novel DPP-4 inhibitor with pancreatic islet enhancement activity for treatment of patients with type 2 diabetes.

Type 2 diabetes is now one of the most challenging health-care problems, and novel treatment strategies are required. The pancreatic islet dysfunction of type 2 diabetes involves problems with both insulin and glucagon since appropriate levels of both hormones are required for maintenance of glucose homeostasis. Enhancement of pancreatic function by incretins such as glucagon-like peptide (GLP)-1 is a new therapeutic approach. These incretins are inactivated by the enzyme dipeptidyl peptidase (DPP)-4. Vildagliptin is a potent, orally active, highly selective DPP-4 inhibitor that enhances the antidiabetic actions of the incretins. Pharmacokinetic studies showed that it is absorbed rapidly but has a sufficiently long period of action to require only once-daily dosing. Three phase II studies of vildagliptin use for 12 weeks in patients with type 2 diabetes have been reported. When vildagliptin was used either as monotherapy or combined with metformin, the treatment versus placebo resulted in significant reductions in hemoglobin (Hb)A(1c). The HbA(1c) was maintained during extended treatment over one year in the study of combination use with metformin. The studies indicated that the greater glycemic control appears to reflect an improvement in islet function. The improvement in glycemic control with vildagliptin was not associated with any body weight gain. Vildagliptin did not cause any clinically relevant changes in safety and was well tolerated. Therefore, further studies are being carried out on vildagliptin to assess long-term efficacy and safety in patients with type 2 diabetes.

An individualized GH dose regimen for long-term GH treatment in Japanese patients with adult GH deficiency.

OBJECTIVES: To investigate the effects of growth hormone (GH) treatment, using a dose-adjustment regimen based on serum insulin-like growth factor (IGF)-I concentrations, in adult Japanese hypopituitary patients with GH deficiency. STUDY DESIGN: Japanese patients who had initially been administered GH (n = 31) or placebo (n = 28) in a 24-week double-blind study received individualized GH treatment in an open-label study for 48 weeks. Body composition from dual-energy X-ray absorptiometry (DXA) and serum IGF-I, IGF-binding protein 3 (IGFBP-3) and lipid levels were determined centrally. RESULTS: Significant increases in lean body mass (4.5%) and decreases in fat mass (-10.5%) were observed in the group that received individualized GH doses in the present open-label study following placebo in the double-blind study. This was comparable with the changes observed in these parameters (4.7 and -9.2%, respectively) with fixed-dose GH treatment in the double-blind study; this latter group maintained these improvements throughout the open-label study. Individualized dose adjustment allowed for more moderate dose increases than the fixed-dose titration method. Individualized dosing also resulted in a lower mean dose for adult-onset compared with childhood-onset GH-deficient patients (0.032+/-0.019 versus 0.061+/-0.023 mg/kg per week for patients treated with GH for 48 weeks in the open-label study following placebo in the double-blind study). Dosing patterns in the two groups were paralleled by the changes in IGF-I and IGFBP-3. The incidence of oedema and cases with high IGF-I level were less frequent under the IGF-I controlled regimen compared with those during the fixed-dose titration method. CONCLUSION: Individualized GH administration based on IGF-I levels was safe and effective. This regimen demonstrated differences in dose requirements between adult- and childhood-onset patients. An individualized dose regimen is recommended in adult Japanese GH-deficient patients.

Adult GH deficiency in Japanese patients: effects of GH treatment in a randomised, placebo-controlled trial.

OBJECTIVE: To evaluate the influence of factors intrinsic to the Japanese population on consequences of growth hormone deficiency (GHD) and effects of GH treatment in adult Japanese hypopituitary patients with GHD. STUDY DESIGN: A 24-week, randomised, placebo-controlled, double-blind study in 64 patients in Japan, with GHD onset during adulthood (AO; n=27) or childhood (CO; n=37). Body composition measured by dual-energy X-ray absorptiometry (DXA) was evaluated centrally. Serum IGF-I, IGF binding protein-3 (IGFBP-3) and lipid levels were determined centrally. RESULTS: In contrast to Caucasian patients, there were no significant differences before treatment between AO and CO patients for body mass index (BMI), lean body mass (LBM) and fat mass (FM). Baseline BMI was >/=25 kg/m(2) for 32.8% of patients. For all patients combined, a significant increase in LBM and decrease in FM (P<0.001 for each) was seen with GH treatment. Serum IGF-I and IGFBP-3 were significantly lower at baseline in CO compared with AO patients, similar to Caucasian patients, and were increased in both onsets following GH treatment. Serum total and low-density lipoprotein (LDL)-cholesterol concentrations did not differ between AO and CO patients at baseline and were elevated compared with normal ranges. GH-induced decreases were significant compared with placebo for both total (P=0.036) and LDL-cholesterol (P=0.040). Glycosylated haemoglobin was increased with GH compared with placebo treatment (P=0.016) but remained within the upper limit of normal for all patients at endpoint. CONCLUSIONS: Adult Japanese hypopituitary patients with GHD demonstrated obesity relative to healthy Japanese subjects but the clinical presentation differed from that of Caucasian patients. GH treatment improved body composition and serum cholesterol profiles of adult Japanese hypopituitary patients with GHD.

A comparison of the effects of thiazolidinediones and metformin on metabolic control in patients with type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus is a condition characterized by impaired insulin secretion and resistance to insulin-mediated glucose uptake and utilization. A number of oral antidiabetic medication are available for its treatment, including metformin and the thiazolidinediones (TZDs). The TZDs have been shown to improve insulin resistance, and it has been suggested that metformin has similar effects. Although both types of agents improve glycemic control, their mechanisms of action and effects on metabolic processes differ. OBJECTIVE: The goal of this review was to compare the effects of TZDs and metformin on metabolic control in patients with type 2 diabetes. METHODS: A search of MEDLINE to March 2004 using the terms metformin and biguanides, and thiazolidinediones and glitazones was conducted to identify preclinical and clinical studies focusing on the mechanisms of action and comparative effects of TZDs and metformin. Also searched were published abstracts from recent major diabetes and endocrinology conferences. RESULTS: In the studies reviewed, both TZDs and metformin demonstrated the ability to improve glycemic control, although long-term monotherapy with TZDs appeared to be more effective than metformin. There continues to be debate about whether metformin is more effective than TZDs in terms of inhibition of hepatic glucose production. However, various studies have found TZDs to be more effective in promoting an increase in whole-body insulin sensitivity. With respect to lipid metabolism, patients who received TZDs had a greater reduction in concentrations of both plasma triglycerides and free fatty acids. Metformin was more effective in promoting weight loss in patients with type 2 diabetes, although TZDs may decrease visceral fat levels. Treatment with either metformin or TZDs was associated with a reduction in the risk of cardiovascular disease, although the mechanisms by which they accomplished this seem to differ. CONCLUSIONS: The evidence suggests that the predominant effect of metformin is inhibition of hepatic glucose production, whereas the primary effects of TZDs is reduction of insulin resistance and promotion of peripheral glucose uptake. TZDs appear to have more positive effects on other metabolic processes and to be associated with greater improvements in cardiovascular risk factors compared with metformin.

Effects of rapid-acting insulin analogs on overall glycemic control in type 1 and type 2 diabetes mellitus.

The altered pharmacokinetics of new rapid-acting insulin analogs make them very effective in controlling blood glucose peaks after meals. However, simple replacement of regular human insulin by rapid-acting analogs may not be sufficiently effective for overall daily glycemic control. Both basal and bolus insulins need to be addressed with overall changes in insulin regimens for long-term reductions of glycated hemoglobin (HbA(1c)) levels. Clinical studies in patients with type 1 diabetes have shown that better control of postprandial peaks together with optimal use of basal insulin, in multiple injection regimens or with continuous subcutaneous insulin infusion, resulted in improved HbA(1c) levels of 0.3-0.4% in comparison with regular human insulin. In patients with type 2 diabetes the combination therapy of insulin lispro with an oral agent improved metabolic control in the range of 1.5-2.5%. Such decreases in HbA(1c) should lead to a reduction in risk of complications with both type 1 and type 2 diabetes. The better overall metabolic control with rapid-acting insulin analogs was not accompanied by any increased risk for hypoglycemia.

Body composition, IGF-I and IGFBP-3 concentrations as outcome measures in severely GH-deficient (GHD) patients after childhood GH treatment: a comparison with adult onset GHD patients.

If GH therapy of children with GH deficiency (GHD) has been adequate, body composition should be comparable to that of patients who have undergone normal childhood development and become hypopituitary thereafter. To assess this, body composition was determined in 92 patients with childhood onset (CO) GHD, aged 18-30 yr, who had been treated to final height with GH for 8.98 +/- 4.30 yr and had stopped treatment 1.57 +/- 1.20 yr previously, but who remained GHD (assessed by a GH stimulation test and IGF-I values). These were compared with 35 age-matched GH-naïve hypopituitary patients with adult onset (AO) GHD. Lean body mass, fat mass, and total bone mineral content were assessed by dual energy x-ray absorptiometry and corrected for actual height. CO patients were shorter (CO height, -1.18 +/- 1.16 SD score; AO height, -0.38 +/- 1.12 SD score; P < 0.001) and had lower body mass index (CO, 23.19 +/- 5.76 kg/m(2); AO, 28.9 +/- 6.27 kg/m(2); P < 0.001) than the AO group. Although there were gender differences, within genders CO patients had lower lean body mass, fat mass, and bone mineral content (P < 0.001 in all cases) compared with AO patients. Standard deviation scores for IGF-I (CO female, -9.2 +/- 3.1; AO female, -5.2 +/- 2.6; CO male, -6.4 +/- 2.7; AO male, -3.5 +/- 2.3; P < 0.001 within each gender) and IGFBP-3 (CO female, -3.5 +/- 2.5; AO female, -1.7 +/- 1.5; CO male, -2.8 +/- 2.0; AO male, -1.1 +/- 1.6; P < 0.001 within each gender) were significantly lower in the CO group. These results suggest that patients with CO GHD who were treated to final height suffer a significant maturational deficit despite GH replacement during childhood.

Short-term safety and efficacy of human GH replacement therapy in 595 adults with GH deficiency: a comparison of two dosage algorithms.

The aim of GH replacement therapy in GH-deficient adults is to optimize response with minimum incidence of adverse reactions, but optimal therapy regimens are still to be established. This two-arm parallel study examined effects of two GH dose algorithms in adults with GH deficiency of adult or childhood onset. Patients on low dose (LD; n = 302) received GH at 3 microg/kg per day for 3 months increasing to 6 microg/kg per day for 3 months, and those on conventional dose (CD; n = 293) started on 6 microg/kg per day for 3 months increasing to 12 microg/kg per day for 3 months. The proportion of patients completing therapy was greater for the LD group than the CD group for the first 3 months (93.0% vs. 88.1%; P = 0.037) and overall for the 6 months (90.7% vs. 84.0%; P = 0.013). Both dose groups showed significant increases in lean body mass and decreases in fat mass for all time points. Percent increase in lean body mass was less with LD than CD over the first 3 months (2.43 +/- 4.33 vs. 3.58 +/- 4.69%; P = 0.006) but not overall for the 6-month period (4.38% +/- 5.34% vs. 5.21% +/- 5.99%; P = 0.141). Percent decrease in fat mass was less with LD than CD for the first 3 months (-2.81% +/- 7.81% vs. -5.53% +/- 8.64%; P < 0.001) and overall for the 6-month period (-6.35% +/- 9.42% vs. -9.45% +/- 12.07%; P = 0.006). IGF-I SD score increased less with LD than CD for 0 to 3 and 0 to 6 months, although for IGF-binding protein-3 SD score, there was no significant difference between doses at any time. Arthralgia was the only adverse event that occurred significantly less frequently with LD than with CD. Calculated changes based on gender and onset indicated greater changes in males than females for body composition, but there was little difference in GH-related adverse events between males and females. The lower starting dose with dose titration appeared more favorable, but differences in response between genders and onset of GH deficiency need to be taken into account when setting an individual dose regimen.

Acceptability of a reusable insulin pen, HumaPen Ergo, by patients with type 1 and type 2 diabetes.

A reusable insulin pen (HumaPen Ergo) was tested for patient acceptability and safety in two multinational studies involving a total of 230 patients with either type 1 (27%) or type 2 (73%) diabetes. Prior to the studies, all patients used other insulin injection pen models. During the 5-7-week studies, the acceptability of HumaPen Ergo was assessed with a questionnaire which was issued to all patients. The HumaPen Ergo was considered easy/very easy with respect to learning to use (97%), reading dose numbers (95%) and correcting dose mistakes (97%), and 62% considered it easy/very easy to hold during use. HumaPen Ergo features considered easier/much easier compared to the previously used model of pen were ease of correcting dose (Study 1/Study 2: 89%/93%), ease of reading the dose number (77%/61 %) and ease of changing cartridge (54%/68%). At the end of the studies the majority of patients (60%/69%) said that they would continue to use HumaPen Ergo and would recommend it to other patients, even though they had expressed satisfaction with the pen that they had used previously. Health-care professionals evaluated HumaPen Ergo according to the same criteria as the patients and said that they would recommend the HumaPen Ergo owing to ease of dialling back without wasting insulin (80%) and reading dose numbers (74%). The HumaPen Ergo was well accepted by both patients and health-care professionals and provides an important tool to combat the trauma and inconvenience associated with insulin self-injection.

Confirmation of severe GH deficiency after final height in patients diagnosed as GH deficient during childhood.

OBJECTIVE: Human GH treatment of patients with childhood-onset (CO) growth hormone deficiency (GHD) ceases when they reach final height; this provides an opportunity to retest GH status in all patients before determining whether GH therapy will be required in adult life. At present, the diagnostic approach to these patients is not fully standardized. This study aimed to characterize a large group of previously GH-treated CO GHD patients and establish their GH status. PATIENTS AND METHODS: The multinational study included 167 patients diagnosed as GH deficient and treated with hGH to final height during childhood. Mean age was 19.2 years and mean height standard deviation score (SDS) was -1.08. Peak serum GH concentrations were determined in standard GH stimulation tests. IGF-I and IGFBP-3 concentrations were determined at a central laboratory and converted to SDS values by reference to a normal population. RESULTS: Using only a peak GH value of less than 3 microg/l (1 mg = 3 U) in stimulation tests as the cut-off, 133 (79.6%) patients would be classed as GH deficient. Using only an IGF-I value less than -2 SDS as the cut-off, 134 (80.2%) patients would be classed as GH deficient. However, by using both criteria there were 120 (71.9%) patients who were definitely severely GH deficient (group 1) and 20 (12.0%) who were not GH deficient (group 2), leaving 14 (8.4%) classed as GH deficient from IGF-I SDS only (group 3) and 13 (7.8%) classed as GH deficient from stimulation test only (group 4). There was no difference between the groups in height SDS or body mass index (BMI), but the GH-deficient patients tended to have been diagnosed at a younger age (group 1, 8.2 +/- 3.9; group 2, 10.0 +/- 4.0; P = 0.052). For patients classed as GH deficient compared with those not GH deficient, the percentage of males was lower (group 1, 64.2%; group 2, 90.0%; P = 0.022) and the percentage with multiple pituitary hormone deficiencies was higher (group 1, 81.7%; group 2, 20.0%; P < 0 .001), with the other two groups being intermediate in each case. Only the group classed as GH deficient by both criteria had a mean IGFBP-3 less than -2 SDS and both IGF-I SDS and IGFBP-3 SDS increased steadily across the four groups. CONCLUSIONS: A high percentage (71.9%) of these childhood-onset GH-deficient patients were still GH deficient in adult life and are likely to require further hGH treatment. While 12.0% could be classed as definitely no longer GH deficient, there are some patients who are intermediate (16.2%) and may be classed as GH deficient by one criterion but not the other. When GH stimulation test results and IGF-I concentration are discordant, the IGFBP-3 level does not establish diagnosis and the hGH treatment requirement of such patients remains a dilemma.

Human growth hormone replacement in adult hypopituitary patients: long-term effects on body composition and lipid status--3-year results from the HypoCCS Database.

The Hypopituitary Control and Complications Study is an international surveillance study evaluating efficacy and safety of GH therapy of adult GH-deficient patients in clinical practice. The present report examined baseline data from 1,123 adult onset (AO) and 362 childhood onset (CO) patients, as well as efficacy in 242 patients who had completed 3 yr of GH treatment. At study entry, mean height, body mass index, waist to hip ratio, and lean body mass were significantly (P < 0.001 for each) lower in CO compared with AO patients. After 3 yr on GH, lean body mass was significantly increased in AO males and females and CO males but not CO females, whereas fat mass was significantly decreased in AO males only. Serum total cholesterol was decreased in females (-0.32 +/- 1.00 mmol/liter; P = 0.045) and males (-0.36 +/- 0.96 mmol/liter; P = 0.004). High-density lipoprotein (HDL) cholesterol was increased for females (0.10 +/- 0.26 mmol/liter; P = 0.026) and males (0.10 +/- 0.34 mmol/liter; P = 0.022). The low-density lipoprotein/HDL ratio was decreased in AO males (-0.93 +/- 2.00; P = 0.003), AO females (-0.65 +/- 0.74; P < 0.001), and CO females (-0.69 +/- 0.76; P = 0.038), but the decrease in CO males was not significant (-0.84 +/- 2.85; P = 0.273). In AO patients, lean body mass increase from baseline was greatest in the those younger than 40 yr old, less but still significant in the middle group (40-60 yr) and unchanged in older (>60 yr) patients; conversely, decreases in the low-density lipoprotein/HDL ratio were small and not significant in the younger patients but greater and significant in the middle and older age groups. During the 3-yr treatment, 114 (7.7%) patients discontinued, including 9 (0.6%) for tumor recurrences, 9 (0.6%) for neoplasia, and 9 (0.6%) for side effects. Therefore, these observational data showed significant long-term efficacy of adult GH replacement therapy on body composition and lipid profiles and indicate that age is an important predictor of response.