Efficacy and safety of generic exenatide injection in Chinese patients with type 2 diabetes: a multicenter, randomized, controlled, non-inferiority trial.

AIMS: This study aimed to compare the efficacy and safety of generic exenatide with branded exenatide Byetta® in Chinese patients with type 2 diabetes mellitus (T2DM) inadequately controlled on monotherapy or combination therapy of metformin and insulin secretagogues. METHODS: A multicenter, randomized, controlled, non-inferiority trial was performed. A total of 240 patients with T2DM and glycated hemoglobin (HbA1c) ≥ 7% (53 mmol/mol) to ≤ 9.0% (75 mmol/mol) on monotherapy or combination therapy of metformin and insulin secretagogues for at least 3 months were randomized into generic exenatide or branded exenatide groups with a 1:1 ratio for 16 weeks of treatment. The primary endpoint was the change in HbA1c levels from baseline at week 16, with a non-inferiority margin of - 0.35% (- 3.83 mmol/mol) (lower bound of one-sided 95% confidence interval (CI) > - 0.35% (- 3.83 mmol/mol)). Secondary endpoints included the proportion of participants achieving HbA1c < 7% (53 mmol/mol), the changes in fasting plasma glucose (FPG), 2-h postprandial glucose (2hPG) following a standard meal, 7-point self-monitoring blood glucose (SMBG) profiles, body weight change from baseline at week 16 and the change in HbA1c levels from baseline at week 8. Safety issues were also evaluated. RESULTS: After 16 weeks of treatment, HbA1c levels decreased significantly from baseline in the two groups, with a reduction of - 1.10% ± 1.31% (- 12.0 mmol/mol ± 14.3 mmol/mol) in the generic exenatide group and - 1.08% ± 1.11% (- 11.8 mmol/mol ± 12.1 mmol/mol) in the branded exenatide group (both P < 0.001). The least-squares mean difference of HbA1c reduction between the two groups was - 0.03% (- 0.33 mmol/mol), with a lower one-sided 95% CI limit of - 0.27% (- 2.95 mmol/mol), which was higher than the prespecified non-inferiority margin of - 0.35% (- 3.83 mmol/mol). Moreover, there were no significant differences in the proportion of participants achieving HbA1c < 7% (53 mmol/mol) and the changes in FPG, 2hPG, 7-point SMBG profiles and body weight at week 16 and the change in HbA1c levels from baseline at week 8 (all P > 0.05) between the two groups. The incidence of adverse events, including the incidence of hypoglycemia (18.3% and 17.5%, respectively), was similar for the generic and branded exenatide groups (P > 0.05). CONCLUSIONS: In patients with T2DM inadequately controlled on monotherapy or combination therapy of metformin and insulin secretagogues, add-on treatment with generic exenatide demonstrated non-inferiority to branded exenatide in terms of improvements in HbA1c after 16 weeks of treatment. Furthermore, the two drugs were also similar for other efficacy endpoints and safety profile. Trial registration Chinese Clinical Trial Registry: ChiCTR-IPR-15006558, Date registered May 27, 2015.

Acid Hydrolyzed Silk Peptide Consumption Improves Anti-Diabetic Symptoms by Potentiating Insulin Secretion and Preventing Gut Microbiome Dysbiosis in Non-Obese Type 2 Diabetic Animals.

: Silk fibroin hydrolysates have been reported to reduce hyperglycemia, but the mechanism has not been determined in Asian type 2 diabetes (T2DM). We hypothesized that the consumption of acid hydrolyzed silk peptides (SPs) alleviates hyperglycemia by improving insulin sensitivity and subsequently normalizing glucose-stimulated insulin secretion in T2DM. We investigated this hypothesis in a partial pancreatectomized (Px) rat model. Px rats was assigned randomly to the following six groups and fed assigned diet for 8 weeks: the Px-CON (0.5 g/kg/day dextrin), the SP-L (0.05 g/kg/day), the SP-M (0.1 g/kg/day), the SP-H (0.5 g/kg/day), the positive-CON (30 mg/kg/day metformin), or the normal-CON (sham-operated rats; 0.5 g/kg/day dextrin). SPs contained high levels of glycine, alanine, and serine. We found SPs dose-dependently increased food efficiency and body weight gain in Px rats. Animals in the Px-control group rats exhibited lower glucose metabolism, as evidenced by impaired glucose-stimulated insulin secretion coupled with impaired insulin sensitivity, and reduced bone mineral density (BMD) and lean body mass (LBM), compared to normal-CON. SPs and metformin similarly partially protected against Px-induced BMD loss in the lumbar spine and femur. Px-induced decreases in LBM were dose-dependently prevented by SPs, and muscle forces in the SP-M and SP-H groups were maintained at the normal-CON level. Glucose tolerance was dose-dependently improved by SPs as determined by oral glucose tolerance and oral maltose tolerance tests, and glucose tolerances were similar in the SP-H and positive-CON groups. Insulin tolerance, an index of insulin sensitivity, was dose-dependently enhanced by SPs, and the SP-H group exhibited better insulin tolerance than the positive-CON group as determined by intraperitoneal insulin sensitivity testing. Insulin secretory capacity assessed using a hyperglycemic clamp improved in the following order: Px-control

Mechanisms, Evaluation, and Management of Chronic Constipation.

With a worldwide prevalence of 15%, chronic constipation is one of the most frequent gastrointestinal diagnoses made in ambulatory medicine clinics, and is a common source cause for referrals to gastroenterologists and colorectal surgeons in the United States. Symptoms vary among patients; straining, incomplete evacuation, and a sense of anorectal blockage are just as important as decreased stool frequency. Chronic constipation is either a primary disorder (such as normal transit, slow transit, or defecatory disorders) or a secondary one (due to medications or, in rare cases, anatomic alterations). Colonic sensorimotor disturbances and pelvic floor dysfunction (such as defecatory disorders) are the most widely recognized pathogenic mechanisms. Guided by efficacy and cost, management of constipation should begin with dietary fiber supplementation and stimulant and/or osmotic laxatives, as appropriate, followed, if necessary, by intestinal secretagogues and/or prokinetic agents. Peripherally acting µ-opiate antagonists are another option for opioid-induced constipation. Anorectal tests to evaluate for defecatory disorders should be performed in patients who do not respond to over-the-counter agents. Colonic transit, followed if necessary with assessment of colonic motility with manometry and/or a barostat, can identify colonic dysmotility. Defecatory disorders often respond to biofeedback therapy. For specific patients, slow-transit constipation may necessitate a colectomy. No studies have compared inexpensive laxatives with newer drugs with different mechanisms. We review the mechanisms, evaluation, and management of chronic constipation. We discuss the importance of meticulous analyses of patient history and physical examination, advantages and disadvantages of diagnostic testing, guidance for individualized treatment, and management of medically refractory patients.

Use of non-insulin diabetes medicines after insulin initiation: A retrospective cohort study.

BACKGROUND: Clinical guidelines recommend that metformin be continued after insulin is initiated among patients with type 2 diabetes, yet little is known regarding how often metformin or other non-insulin diabetes medications are continued in this setting. METHODS: We conducted a retrospective cohort study to characterize rates and use patterns of six classes of non-insulin diabetes medications: biguanides (metformin), sulfonylureas, thiazolidinediones (TZDs), glucagon-like peptide 1 receptor agonists (GLP1 receptor agonists), dipeptidyl peptidase 4 inhibitors (DPP4 inhibitors), and sodium-glucose co-transporter inhibitors (SGLT2 inhibitors), among patients with type 2 diabetes initiating insulin. We used the 2010-2015 MarketScan Commercial Claims and Encounters data examining 72,971 patients with type 2 diabetes aged 18-65 years old who initiated insulin and had filled a prescription for a non-insulin diabetes medication in the 90 days prior to insulin initiation. Our primary outcome was the proportion of patients refilling the various non-insulin diabetes medications during the first 90 days after insulin initiation. We also used time-to-event analysis to characterize the time to discontinuation of specific medication classes. RESULTS: Metformin was the most common non-insulin medication used prior to insulin initiation (N = 53,017, 72.7%), followed by sulfonylureas (N = 25,439, 34.9%) and DPP4 inhibitors (N = 8,540, 11.7%). More than four out of five patients (N = 65,902, 84.7%) refilled prescriptions for any non-insulin diabetes medications within 90 days after insulin initiation. Within that period, metformin remained the most common medication with the highest continuation rate of 84.6%, followed by SGLT2 inhibitors (81.9%) and TZDs (79.3%). Sulfonylureas were the least likely medications to be continued (73.6% continuation) though they remained the second most common medication class used after insulin initiation. The median time to discontinuation varied by therapeutic class from the longest time to discontinuation of 26.4 months among metformin users to the shortest (3.0 months) among SGLT2 inhibitor users. CONCLUSION: While metformin was commonly continued among commercially insured adults starting insulin, rates of continuation of other non-insulin diabetes medications were also high. Further studies are needed to determine the comparative effectiveness and safety of continuing insulin secretagogues and newer diabetes medications after insulin initiation.

Growth Hormone Secretagogue (A233) Improves Growth and Changes the Tissue Fatty Acid Profile in Juvenile Tilapia (Oreochromis niloticus).

Growth hormone (GH) release is a process that is well regulated by several factors, including GH secretagogues. GH can mediate the regulation of the fatty acid level and composition. The aim of this study was to determine the effect of a synthetic GH secretagogue peptide (A233) on the growth and fatty acid composition in tilapia (Oreochromis niloticus). To address this objective, we administrated a diet supplemented with A233 to juvenile tilapia for 60 days. The group fed with a diet supplemented with 600 µg of A233 per kg of feed increased in weight (4.81 ± 0.09 g) and specific growth rate (2.49 ± 0.03%/day) compared to the control diet group (3.63 ± 0.08 g, 2.07 ± 0.04%/day; respectively) (p < 0.001). In the muscle, the total lipids for the control diet group were higher than that in the group fed with 600 µg of A233 per kg feed; however, no differences were detected in the liver. In both tissues, the patterns of fatty acid composition and content were generally similar, with some exceptions. Tilapia fed with 600 µg of A233 per kg of feed showed, in liver and muscle, a significantly higher composition and content of n-3 polyunsaturated fatty acids (such as 20:5n-3, 22:5n-3, 22:6n-3) and n-3/n-6 PUFA than animals fed with the control diet. To our knowledge, this is the first report on the the effects of natural or synthetic GH secretagogues (GHS) on fatty acid composition, implying an increase in the nutritional quality of the tilapia.

A Prospective, Randomized Trial of Two Mucin Secretogogues for the Treatment of Dry Eye Syndrome in Office Workers.

The purpose of the study was to compare the two mucin secretogogues, diquafosol (DQS) and rebamipide (RBM), for the treatment of dry eye syndrome (DES) in office workers. Dry eye patients using computers for >4 h/day were randomly assigned treatment with either DQS or RBM. Main outcomes measures included changes in tear film break-up time (TBUT) and subjective symptoms assessed by the Dry Eye-Related Quality of Life Score (DEQS). The subjects had scheduled examinations at 0 and 4 weeks, and the examinations at 2 and 8 weeks were optional. Changes in keratoconjunctival fluorescein score and a patient satisfaction questionnaire were also recorded. Both groups showed significant improvements in the DEQS scores at 2, 4, and 8 weeks following the initiation of the study. Both groups showed significant increases in the TBUT at 2 and 4 weeks. No significant difference was found between the DQS and RBM groups at any time periods. Patients reported more comfort with the use of DQS compared with the use of RBM. No local or systemic side effects were noted. The results of the present study indicated that both DQS and RBM were effective for the treatment of DES in office workers.

Growth hormone secretagogues hexarelin and JMV2894 protect skeletal muscle from mitochondrial damages in a rat model of cisplatin-induced cachexia.

Chemotherapy can cause cachexia, which consists of weight loss associated with muscle atrophy. The exact mechanisms underlying this skeletal muscle toxicity are largely unknown and co-therapies to attenuate chemotherapy-induced side effects are lacking. By using a rat model of cisplatin-induced cachexia, we here characterized the mitochondrial homeostasis in tibialis anterior cachectic muscle and evaluated the potential beneficial effects of the growth hormone secretagogues (GHS) hexarelin and JMV2894 in this setting. We found that cisplatin treatment caused a decrease in mitochondrial biogenesis (PGC-1α, NRF-1, TFAM, mtDNA, ND1), mitochondrial mass (Porin and Citrate synthase activity) and fusion index (MFN2, Drp1), together with changes in the expression of autophagy-related genes (AKT/FoxO pathway, Atg1, Beclin1, LC3AII, p62) and enhanced ROS production (PRX III, MnSOD). Importantly, JMV2894 and hexarelin are capable to antagonize this chemotherapy-induced mitochondrial dysfunction. Thus, our findings reveal a key-role played by mitochondria in the mechanism responsible for GHS beneficial effects in skeletal muscle, strongly indicating that targeting mitochondrial dysfunction might be a promising area of research in developing therapeutic strategies to prevent or limit muscle wasting in cachexia.