The efficacy and safety of tofacitinib, peficitinib, solcitinib, baricitinib, abrocitinib and deucravacitinib in plaque psoriasis - A network meta-analysis.

Janus kinase (JAK) inhibitors are novel treatment approaches for psoriasis. However, there is no direct comparison of JAK inhibitors in plaque psoriasis. In order to compare the efficacy and safety of JAK inhibitors in psoriasis, we conducted a network meta-analysis using eligible randomized clinical trials (RCTs). The efficacy of JAK inhibitors was evaluated using a 75% improvement in Psoriasis Area and Severity Index (PASI75) from baseline, and the proportion of patients achieving the Physician's Global Assessment (PGA) response. The incidence of treatment-related adverse events (AEs) was also assessed. A total of eight RCTs with tofacitinib, peficitinib, solcitinib, baricitinib, abrocitinib and deucravacitinib were included. A total of 3612 participants who were diagnosed with moderate-to-severe plaque psoriasis were analysed. Overall, JAK inhibitors showed superior PASI75 response over placebo at both 8 and 12 weeks. Among all included JAK inhibitors, tofacitinib 15 mg twice a day (BID) had the highest probability of achieving PASI75 at both 8 and 12 weeks (SUCRA = 0.938 and 0.937, separately), followed by tofacitinib 10 mg BID (SUCRA = 0.905 and 0.908, separately) and deucravacitinib 12 mg once daily (QD) (SUCRA = 0.874 and 0.837, separately). A similar finding was observed for PGA response. Safety assessment showed that all JAK inhibitors had non-inferior safety compared with placebo, except for deucravacitinib 6 mg BID and 12 mg QD. Tofacitinib 2 mg BID was the first-ranked drug for safety profile followed by deucravacitinib 3 mg QD, and tofacitinib 5 mg BID. When comprehensively evaluated the efficacy and safety, tofacitinib (2 mg, 5 mg, 10 mg, 15 mg BID) was superior to other included JAK inhibitors with satisfying PASI75 and PGA response, as well as relatively low incidence of AEs. Our study confirmed that JAK inhibitors had promising treatment efficacy for moderate-to-severe plaque psoriasis. Tofacitinib showed superior efficacy and safety over peficitinib, solcitinib, baricitinib, abrocitinib and deucravacitinib.

Comparative Safety of Dipeptidyl Peptidase-4 Inhibitors and Sudden Cardiac Arrest and Ventricular Arrhythmia: Population-Based Cohort Studies.

In vivo studies suggest that arrhythmia risk may be greater with less selective dipeptidyl peptidase-4 inhibitors, but evidence from population-based studies is missing. We aimed to compare saxagliptin, sitagliptin, and linagliptin with regard to risk of sudden cardiac arrest (SCA)/ventricular arrhythmia (VA). We conducted high-dimensional propensity score (hdPS) matched, new-user cohort studies. We analyzed Medicaid and Optum Clinformatics separately. We identified new users of saxagliptin, sitagliptin (both databases), and linagliptin (Optum only). We defined SCA/VA outcomes using emergency department and inpatient diagnoses. We identified and then controlled for confounders via a data-adaptive, hdPS approach. We generated marginal hazard ratios (HRs) via Cox proportional hazards regression using a robust variance estimator while adjusting for calendar year. We identified the following matched comparisons: saxagliptin vs. sitagliptin (23,895 vs. 96,972) in Medicaid, saxagliptin vs. sitagliptin (48,388 vs. 117,383) in Optum, and linagliptin vs. sitagliptin (36,820 vs. 78,701) in Optum. In Medicaid, use of saxagliptin (vs. sitagliptin) was associated with an increased rate of SCA/VA (adjusted HR (aHR), 2.01, 95% confidence interval (CI) 1.24-3.25). However, in Optum data, this finding was not present (aHR, 0.79, 95% CI 0.41-1.51). Further, we found no association between linagliptin (vs. sitagliptin) and SCA/VA (aHR, 0.65, 95% CI 0.36-1.17). We found discordant results regarding the association between SCA/VA with saxagliptin compared with sitagliptin in two independent datasets. It remains unclear whether these findings are due to heterogeneity of treatment effect in the different populations, chance, or unmeasured confounding.

Comparison of the Efficacy, Tolerability and Side Effect Profile of Vildagliptin-Metformin with Metformin-GlibenclamideMamong Nigerian.

BACKGROUND: The use of fixed dose combination oral antidiabetic drugs (OADs) in the therapeutic management of type 2 diabetes mellitus (DM) patients is becoming popular among clinicians. Reduced pill burden with fixed combination OADs is generally perceived to improve adherence and efficacy. The aim of this study was to compare the efficacy, tolerability and side effects (SEs) profile of vildagliptin-metformin (VM) combination with metformin-glibenclamide (MG) combination in type 2 DM patients at the Aminu Kano Teaching Hospital (AKTH). METHODS: A descriptive prospective open-labeled comparative out-patient study of type 2 DM patients spanning over three months with 60 Patients assigned to two treatment groups - VM (Group 1) and MG (Group 2) of 30 patients each. Parameters measured at baseline, 6 weeks and 12 weeks of study included demographic and anthropometric data; fasting plasma glucose (FPG) level; 2-hour post-prandial (2-hrPPG) glucose; liver function tests (LFTs); Electrolyte, Urea and Creatinine (EUCr); and fasting plasma lipids. Glycated haemoglobin (HbA1c) was measured at baseline and at 12 weeks of the study. A p-value of <0.05 was considered to be significant. RESULTS: There was improvement in FPG, 2hr PPG, HbA1c in all subjects in both groups at the end of the study (6.44±0.79mmol/ l, 8.80±1.16mmol/l and 7.22±1.20% respectively in group 1(VM); and 6.40±0.83mmol/l, 9.29±1.39 and 7.25±0.96% respectively for group 2(MG). There was a significant improvement in body mass index (BMI) of subjects in group 1 (30.02±4.16 at baseline, 29.71±4.12 at study end) compared to those in group 2 (31.98±6.32 at baseline, 32.62±6.30 at study end), p=0.04. At the end of the study, the efficacy of VM (HbA1C-7.22±1.20%) was comparable to that of MG (HbA1c-7.25±0.96), P=0.92. The tolerability of MG (attrition rate 6.7%) was better than that of VM (attrition rate 13%), although this difference was not statistically significant P=0.16. The subjects on VM experienced more gastrointestinal (GIT) side effects compared to those on MG. The major SEs experienced by those on MG were hypoglycaemia and weight gain. VM was less tolerated and had more GIT side effects than MG. CONCLUSION: The use of single pill combination oral antidiabetic medications is associated with improved efficacy.

CONTEXTE: L'utilisation d'associations fixes d'antidiabétiques oraux (ADO) dans la prise en charge thérapeutique des patients atteints de diabète sucré (DM) de type 2 est en train de devenir populaire parmi les cliniciens. La réduction du fardeau de la pilule avec des ADO à combinaison fixe est généralement perçue comme améliorant l'observance et l'efficacité. Le but de cette étude était de comparer l'efficacité, la tolérabilité et le profil d'effets secondaires (ES) de l'association vildagliptine - metformine (VM) avec l'association metformine - glibenclamide (MG) chez des patients atteints de DM de type 2 à l'hôpital universitaire Aminu Kano (AKTH). MÉTHODES: Une étude descriptive prospective ouverte comparative ambulatoire de patients atteints de diabète de type 2 s'étalant sur trois mois avec 60 patients répartis en deux groupes de traitement - VM (groupe 1) et MG (groupe 2) de 30 patients chacun. Les paramètres mesurés au départ, 6 semaines et 12 semaines d'étude comprenaient des données démographiques et anthropométriques ; taux de glucose plasmatique à jeun (FPG); Glycémie post-prandiale 2 heures (2-hrPPG) ; tests de la fonction hépatique (LFT); électrolyte, urée et créatinine (EUCr); et les lipides plasmatiques à jeun. L'hémoglobine glyquée (HbA1c) a été mesurée au départ et à 12 semaines de l'étude. Une valeur p < 0,05 a été considérée comme significative. RÉSULTATS: Il y avait une amélioration de la FPG, 2h PPG, HbA1c chez tous les sujets dans les deux groupes à la fin de l'étude (6,44 ± 0,79 mmol/l, 8,80 ± 1,16 mmol/l et 7,22 ± 1,20 % respectivement dans le groupe 1 (VM) et 6,40 ± 0,83 mmol/l, 9,29 ± 1,39 et 7,25 ± 0,96 % respectivement pour le groupe 2 (MG). Il y avait une amélioration significative de l'indice de masse corporelle (IMC) des sujets du groupe 1 (30,02 ± 4,16 au départ, 29,71 ± 4,12 à la fin de l'étude) par rapport à ceux du groupe 2 (31,98 ± 6,32 à l'inclusion, 32,62 ± 6,30 à la fin de l'étude), p = 0,04. À la fin de l'étude, l'efficacité de la VM (HbA1C-7,22 ± 1,20 %) était comparable à celle de MG (HbA1c-7,25 ± 0,96), P= 0,92. La tolérance de MG (taux d'attrition 6,7 %) était meilleure que celle de VM (taux d'attrition 13 %), bien que cette différence n'ait pas été statistiquement significative P= 0,16. Les sujets sous VM ont présenté plus d'effets secondaires gastro-intestinaux (GIT) que ceux sous MG. Les principaux effets secondaires ressentis par ceux sous MG étaient l'hypoglycémie et la prise de poids. La VM était moins tolérée et avait plus d'effets secondaires GIT que MG. CONCLUSION: L'utilisation de médicaments antidiabétiques oraux combinés à une seule pilule est associée à une efficacité améliorée. Mots clés: Diabète, Efficacité, Metformine-Glibenclamide, Tolérabilité, Vildagliptine-Metformine.

Cardiovascular events and all-cause mortality in patients with type 2 diabetes treated with dipeptidyl peptidase-4 inhibitors: An extensive meta-analysis of randomized controlled trials.

AIMS: Meta-analyses of randomized trials on Dipeptidyl Peptidase-4 inhibitors (DPP4i) reported discordant results on major cardiovascular events (MACE), mortality, and heart failure. Aim of this meta-analysis of randomized trials is the assessment of the cardiovascular safety of DPP4i. DATA SYNTHESIS: A Medline, Embase, Cochrane database search for sitagliptin, vildagliptin, omarigliptin, saxagliptin, alogliptin, trelagliptin, anagliptin, linagliptin, gemigliptin, evogliptin, and teneligliptin was performed up to up January 1st, 2020. All trials with a duration ≥24 weeks and comparing the effects of DPP4i with placebo or active drugs were collected. Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all outcomes defined above. A total of 182 eligible trials were identified. DPP-4i were not associated with an increased risk of MACE (MH-OR 0.99 [0.93, 1.04]), all-cause mortality (MH-OR 0.99 [0.93, 1.06]), and heart failure (MH-OR 1.05 [0.96, 1.15]) with no significant differences across individual molecules, except for saxagliptin, which was associated with an increased risk of heart failure. CONCLUSIONS: As a class, DPP4i are not associated with any increase or reduction of MACE, all-cause mortality, and heart failure. Saxagliptin seems to be associated with an increased risk of hospitalization for heart failure.

Acute and long-term effects of saxagliptin on a set of cardiovascular targets measured at fasting and post-prandially in obese patients with impaired glucose tolerance: A placebo-controlled study.

BACKGROUND AND AIMS: Studies of dipeptidyl peptidase inhibitors (DPP4is) report heterogeneous effects on cardiovascular targets in type 2 diabetes. This study aimed to investigate, in patients with impaired glucose tolerance (IGT), whether saxagliptin, a DPP4i, had beneficial cardiovascular effects at fasting and during the post-prandial state. METHODS AND RESULTS: In this randomized, placebo-controlled, double-blind, single-center pilot exploratory study, we included obese individuals with IGT. Twenty-four individuals (BMI 36.8 ± 4.8 kg/m2) were randomized to receive for 12 weeks either saxagliptin 5 mg a day or placebo. They were explored before and after a standardized breakfast for biological markers; microcirculatory blood flow at baseline and after transcutaneous administration of acetylcholine (Periflux System 5000® PERIMED); post-occlusive digital reactive hyperhemia (Endopat2000®); pulse wave velocity, augmentation index, central pulse pressure and subendocardial viability ratio (Sphygmocor®); cardiac hemodynamic parameters and cardiovascular autonomic nervous system activity (Task force monitor®). The results of all the investigations were similar after breakfast in the two groups at Visit 1 (acute post-prandial effects, after the first tablet) and Visit 2 (long-term post-prandial effects), and at fasting at Visit 1 and 2 (long-term effects, after 12 weeks of treatment). Only at Visit 2 the decrease in cardiac vagal activity occurring after breakfast was more sustained in the saxagliptin group than in the placebo group (interaction between treatment and time effect: p = 0.016). CONCLUSION: In obese patients with IGT, the effects of saxagliptin on the large set of cardiovascular parameters measured are neutral, except for a more marked post-prandial depression of vagal activity. CLINICAL TRIAL REGISTRATION NUMBER: NCT01521312.

Acute and long-term effects of saxagliptin on post-prandial glycemic response in obese patients with impaired glucose tolerance.

BACKGROUND AND AIMS: Dipeptidyl-peptidase inhibitors might be useful in type 2 diabetes prevention. ACCES (ACute and Chronic Effects of Saxagliptin) was a randomized, placebo-controlled, double-blind, controlled phase 2, pilot study aiming to examine in obese patients with impaired glucose tolerance (IGT) the acute effects and the effects after 12 weeks of treatment by saxagliptin on glucose levels at fasting and postprandially after a standard breakfast, and on glucose tolerance. METHODS AND RESULTS: We included 24 obese patients with IGT. Patients were randomized to receive saxagliptin 5 mg or placebo in the morning. The treatment was taken on Visit 1 before breakfast, then continued for 12 weeks. Biochemical measurements were performed before, one, two and three hours after a standard breakfast including 75 g of carbohydrates, during Visit 1 and Visit 2 (12 weeks). Glucose variability (GV) was evaluated at Visit 1 from 24-h continuous glucose monitoring including the breakfast. A second OGTT was performed at Visit 3 (3-5 days after Visit 2). Compared with placebo-treated patients, saxagliptin-treated patients had lower 1 h and 2 h post-meal plasma glucose levels at Visit 1 and similar changes at Visit 2 (p < 0.01 to p < 0.004), with lower GV indexes after breakfast at Visit 1. At Visit 3, all patients but one in saxagliptin group and only 4 patients in placebo group turned to normal glucose tolerance. Lower glucose response to breakfast at Visit 1 was predictive of recovery of glucose tolerance. CONCLUSION: Saxagliptin has metabolically beneficial effects in glucose-intolerant obese patients by significantly lowering postprandial blood glucose levels. CLINICAL TRIAL REGISTRATION NUMBER: NCT01521312: https://clinicaltrials.gov/ct2/show/NCT01521312.

The Bioequivalence of Two Peficitinib Formulations, and the Effect of Food on the Pharmacokinetics of Peficitinib: Two-Way Crossover Studies of a Single Dose of 150 mg Peficitinib in Healthy Volunteers.

The marketed tablet formulation of peficitinib differs from the tablet used during the clinical trials. The bioequivalence of the marketed formulation and developmental tablet, and the food effect on the marketed formulation, were analyzed in 2 Japanese open-label, randomized, 2-way crossover studies in healthy male volunteers. Volunteers received a single oral dose of the marketed 150-mg peficitinib tablet under fasted conditions (bioequivalence), and under fed or fasted conditions (food effect). Bioequivalence was compared with the developmental 150-mg tablet. Samples for pharmacokinetic analysis were collected before dose and ≤72 hours after dose. Safety assessments included adverse events, vital signs, and laboratory variables. In total, 40 and 18 subjects were randomized to the bioequivalence and food effect studies, respectively. The 2 peficitinib formulations were bioequivalent (90% confidence intervals of the geometric mean ratios for Cmax and AUCt of peficitinib were within predefined limits of 0.8 to 1.25). The AUClast and the Cmax of the marketed tablet were 36.8% and 56.4% higher, respectively, under fed versus fasted conditions. Peficitinib was well tolerated. The marketed 150-mg tablet formulation of peficitinib was bioequivalent to the developmental 150-mg formulation, with no discernible safety differences. Bioavailability increased under fed conditions with the marketed tablet formulation.

A pooled safety analysis of peficitinib (ASP015K) in Asian patients with rheumatoid arthritis treated over a median of 2 years.

OBJECTIVE: To evaluate the safety of peficitinib for the treatment of rheumatoid arthritis (RA) in Asian patients. METHODS: Safety data from one Phase 2b, two Phase 3, and one open-label long-term extension study [data cut-off 31 May 2018] were pooled into Phase 3 studies (peficitinib 100 and 150 mg/day, and placebo) and Phase 2/3 studies (all peficitinib-treated patients). Incidence rates per 100 patient-years (PY) of adverse events (AEs) of special interest were calculated. RESULTS: Overall, 1052 patients received peficitinib for 2336.3 PY of exposure (median 2.1 years); four deaths occurred, including one death after the studies. AE incidence was similar across peficitinib 100 and 150 mg/day groups (Phase 3 studies). Respective peficitinib and placebo incidence rates (95% confidence interval) per 100 PY were 2.9 (1.9, 4.6) and 0.0 for serious infections, 5.7 (4.2, 7.9) and 2.3 (0.6, 9.4) for herpes zoster-related disease, and 0.6 (0.2, 1.6) and 1.2 (0.2, 8.3) for malignancies (excluding non-melanoma skin cancer) (Phase 3 studies), and 0.1 (0.0, 0.3) for venous thromboembolism in all peficitinib-treated patients (Phase 2/3 studies). CONCLUSION: Peficitinib was well tolerated in Asian patients with RA over a median of 2 years, with no observed dose or temporal dependency for AEs with prolonged administration.

Efficacy and safety of saxagliptin for the treatment of type 2 diabetes mellitus.

INTRODUCTION: Saxagliptin, a member of the dipeptidyl peptidase-4 inhibitor (DPP-4i) class of drugs, was approved by the FDA for the treatment of type 2 diabetes (T2D) in 2009, and has been in clinical use for more than a decade. Since the drug was first launched, much real-world evidence has also been accumulated. The efficacy and safety of saxagliptin, especially its cardiovascular safety, are of particular interest. AREAS COVERED: This review provides an overview of the safety and efficacy of saxagliptin based on observational studies, pharmacovigilance, and meta-analyses. In addition, with the findings of recent cardiovascular outcome trials (CVOTs), the authors discuss, herein, the efficacious use of saxagliptin. EXPERT OPINION: Saxagliptin exhibits a moderate glucose-lowering effect and is well tolerated by patients with T2D. SAVOR-TIMI 53, a CVOT of saxagliptin, reported neutral effects of saxagliptin in respect of the cardiovascular outcomes, but did raise a concern about the risk of heart failure. Conversely, recent CVOTs on sodium-glucose co-transporter-2 inhibitors (SGLT2i) have shown a favorably reduced risk of heart failure with these drugs. Also, DPP-4is decrease the serum glucagon level, whereas the SGLT2is increase it. Given the characteristics of the two classes of drugs, combined therapy with the two might be a promising option.

Glucose-lowering agents for treating pre-existing and new-onset diabetes in kidney transplant recipients.

BACKGROUND: Kidney transplantation is the preferred management for patients with end-stage kidney disease (ESKD). However, it is often complicated by worsening or new-onset diabetes. The safety and efficacy of glucose-lowering agents after kidney transplantation is largely unknown. This is an update of a review first published in 2017. OBJECTIVES: To evaluate the efficacy and safety of glucose-lowering agents for treating pre-existing and new onset diabetes in people who have undergone kidney transplantation. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 16 January 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: All randomised controlled trials (RCTs), quasi-RCTs and cross-over studies examining head-to-head comparisons of active regimens of glucose-lowering therapy or active regimen compared with placebo/standard care in patients who have received a kidney transplant and have diabetes were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Four authors independently assessed study eligibility and quality and performed data extraction. Continuous outcomes were expressed as post-treatment mean differences (MD) or standardised mean difference (SMD). Adverse events were expressed as post-treatment absolute risk differences (RD). Dichotomous clinical outcomes were presented as risk ratios (RR) with 95% confidence intervals (CI). MAIN RESULTS: Ten studies (21 records, 603 randomised participants) were included - three additional studies (five records) since our last review. Four studies compared more intensive versus less intensive insulin therapy; two studies compared dipeptidyl peptidase-4 (DPP-4) inhibitors to placebo; one study compared DPP-4 inhibitors to insulin glargine; one study compared sodium glucose co-transporter 2 (SGLT2) inhibitors to placebo; and two studies compared glitazones and insulin to insulin therapy alone. The majority of studies had an unclear to a high risk of bias. There were no studies examining the effects of biguanides, glinides, GLP-1 agonists, or sulphonylureas. Compared to less intensive insulin therapy, it is unclear if more intensive insulin therapy has an effect on transplant or graft survival (4 studies, 301 participants: RR 1.12, 95% CI 0.32 to 3.94; I2 = 49%; very low certainty evidence), delayed graft function (2 studies, 153 participants: RR 0.63, 0.42 to 0.93; I2 = 0%; very low certainty evidence), HbA1c (1 study, 16 participants; very low certainty evidence), fasting blood glucose (1 study, 24 participants; very low certainty evidence), kidney function markers (1 study, 26 participants; very low certainty evidence), death (any cause) (3 studies, 208 participants" RR 0.68, 0.29 to 1.58; I2 = 0%; very low certainty evidence), hypoglycaemia (4 studies, 301 participants; very low certainty evidence) and medication discontinuation due to adverse effects (1 study, 60 participants; very low certainty evidence). Compared to placebo, it is unclear whether DPP-4 inhibitors have an effect on hypoglycaemia and medication discontinuation (2 studies, 51 participants; very low certainty evidence). However, DPP-4 inhibitors may reduce HbA1c and fasting blood glucose but not kidney function markers (1 study, 32 participants; low certainty evidence). Compared to insulin glargine, it is unclear if DPP-4 inhibitors have an effect on HbA1c, fasting blood glucose, hypoglycaemia or discontinuation due to adverse events (1 study, 45 participants; very low certainty evidence). Compared to placebo, SGLT2 inhibitors probably do not affect kidney graft survival (1 study, 44 participants; moderate certainty evidence), but may reduce HbA1c without affecting fasting blood glucose and eGFR long-term (1 study, 44 participants, low certainty evidence). SGLT2 inhibitors probably do not increase hypoglycaemia, and probably have little or no effect on medication discontinuation due to adverse events. However, all participants discontinuing SGLT2 inhibitors had urinary tract infections (1 study, 44 participants, moderate certainty evidence). Compared to insulin therapy alone, it is unclear if glitazones added to insulin have an effect on HbA1c or kidney function markers (1 study, 62 participants; very low certainty evidence). However, glitazones may make little or no difference to fasting blood glucose (2 studies, 120 participants; low certainty evidence), and medication discontinuation due to adverse events (1 study, 62 participants; low certainty evidence). No studies of DPP-4 inhibitors, or glitazones reported effects on transplant or graft survival, delayed graft function or death (any cause). AUTHORS' CONCLUSIONS: The efficacy and safety of glucose-lowering agents in the treatment of pre-existing and new-onset diabetes in kidney transplant recipients is questionable. Evidence from existing studies examining the effect of intensive insulin therapy, DPP-4 inhibitors, SGLT inhibitors and glitazones is mostly of low to very low certainty. Appropriately blinded, larger, and higher quality RCTs are needed to evaluate and compare the safety and efficacy of contemporary glucose-lowering agents in the kidney transplant population.

Efficacy and safety of peficitinib in rheumatoid arthritis.

Peficitinib is a Janus kinase (JAK) inhibitor, newly developed and approved in Japan. In contrast to other JAK inhibitors, it is a unique pan-JAK inhibitor, demonstrating inhibition of all JAKs. In patients with rheumatoid arthritis with an inadequate response to previous disease-modifying anti-rheumatic drugs, the efficacy of peficitinib (100 mg and 150 mg) has been confirmed with a comparison to placebo in Phase 2b and 3 trials conducted in Asia. Reportedly, peficitinib was well tolerated for 52 weeks during the trial duration, as well as for the next few years in a subsequent, ongoing long-term extension study. Safety signals, especially, the increased risk of herpes zoster was comparable with other JAK inhibitors.

[Efficacy of Saxagliptin for Blood Glucose Control in Hemodialysis Patients with Diabetes].

Studies on the drug saxagliptin (marketed in Japan since 2013) suggest favorable efficacy in hemodialysis patients, but included small sample sizes. Noting that some hemodialysis patients at our medical institution had been switched to saxagliptin 2.5 mg from treatment with other dipeptidyl peptidase-4 inhibitors, we decided to evaluate the effects of switching to saxagliptin on blood glucose control in these patients. The study included 11 patients. Before switching drugs, six of the patients used teneligliptin 20 mg and five used linagliptin 5 mg. Mean glycated albumin (GA) from before to 4 months after switching tended to increase in the previous users of teneligliptin 20 mg (18.4±3.0% to 19.5±2.7%) and tended to decrease in the previous users of linagliptin 5 mg (18.8±3.3% to 17.7±1.4%). Lack of a substantial change in GA when the previous users of teneligliptin 20 mg and linagliptin 5 mg were switched to saxagliptin 2.5 mg indicates that these three agents might have comparable antihyperglycemic profiles when used in patients on hemodialysis. Future research following from this pilot study must evaluate the risk of cardiac failure and incidences of adverse events in a larger population, to investigate the long-term efficacy and safety of switching to saxagliptin.

Clinical Parameters, Fuel Oxidation, and Glucose Kinetics in Patients With Type 2 Diabetes Treated With Dapagliflozin Plus Saxagliptin.

OBJECTIVE: To examine the mechanisms responsible for improved glycemia with combined sodium-glucose cotransporter 2 inhibitor (SGLT2i) plus dipeptidyl peptidase 4 inhibitor therapy in type 2 diabetes. RESEARCH DESIGN AND METHODS: Fifty-six patients (HbA1c 8.9 ± 0.2% [74 ± 2 mmol/mol]) were randomized to dapagliflozin (DAPA) 10 mg, DAPA/saxagliptin (SAXA) 10/5 mg, or placebo (PCB) for 16 weeks. Basal endogenous glucose production (EGP) (3-3H-glucose), urinary glucose excretion, glucose/lipid oxidation, HbA1c, and substrate/hormone levels were determined before treatment (Pre-Tx) and after treatment (Post-Tx). RESULTS: At week 16, HbA1c decrease was greater (P < 0.05) in DAPA/SAXA (-2.0 ± 0.3%) vs. DAPA (-1.4 ± 0.2%) and greater than PCB (0.2 ± 0.2%). Day 1 of drug administration, EGP (∼2.40 mg/kg/min) decreased by -0.44 ± 0.09 mg/kg/min in PCB (P < 0.05) but only by -0.21 ± 0.02 mg/kg/min in DAPA and DAPA/SAXA (P < 0.05 vs. PCB). At week 16, EGP increased to 2.67 ± 0.09 mg/kg/min (DAPA) and 2.61 ± 0.08 mg/kg/min (DAPA/SAXA), despite reductions in fasting plasma glucose by 47 and 77 mg/dL, respectively, and no changes in PCB. Baseline plasma free fatty acids rose by 40 µmol/L with DAPA but declined by -110 with PCB and -90 µmol/L with DAPA/SAXA (P < 0.05, Pre-Tx vs. Post-Tx). In DAPA, carbohydrate oxidation rates decreased from 1.1 ± 0.1 to 0.7 ± 0.1 mg/kg/min, whereas lipid oxidation rates increased from 0.6 ± 0.1 to 0.8 ± 0.1 mg/kg/min (P < 0.01). In DAPA/SAXA, the shift in carbohydrate (1.1 ± 0.1 to 0.9 ± 0.1 mg/kg/min) and lipid (0.6 ± 0.1 to 0.7 ± 0.1 mg/kg/min) oxidation was attenuated (P < 0.05). CONCLUSIONS: The addition of SAXA to DAPA resulted in superior glycemic control compared with DAPA monotherapy partly because of increased glucose utilization and oxidation. Although the decrease in insulin/glucagon ratio was prevented by SAXA, EGP paradoxical elevation persisted, indicating that other factors mediate EGP changes in response to SGLT2i-induced glucosuria.

Platensimycin-Encapsulated Liposomes or Micelles as Biosafe Nanoantibiotics Exhibited Strong Antibacterial Activities against Methicillin-Resistant Staphylococcus aureus Infection in Mice.

Platensimycin (PTM) is a promising natural product drug lead against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), while the clinical development was hampered by problems related to its poor solubility and pharmacokinetic properties. In this study, we used liposomes and micelles as carriers of PTM to prepare PTM nanoformulations for the treatment of MRSA infection in mice. PTM-loaded nanoparticles could effectively reduce residual bacteria in the MRSA-infected macrophage cell model, comparing to free PTM. More importantly, in vivo studies showed that encapsulation of PTM by liposomes or micelles effectively improved the pharmacokinetic properties of PTM in Sprague-Dawley rats and the survival rate of MRSA-infected C57BL/6J mice. Our study has thus suggested that the clinically used nanocarriers, such as liposome and micelle, might also be useful to improve the efficacy of other natural product drug leads to accelerate their in vivo evaluation and preclinical development.

Comparison of the efficacy and safety of tofacitinib and peficitinib in patients with active rheumatoid arthritis: A Bayesian network meta-analysis of randomized controlled trials.

OBJECTIVES: The relative efficacy and safety of tofacitinib and peficitinib were assessed in patients with rheumatoid arthritis (RA) with an inadequate response to disease-modifying antirheumatic drugs (DMARDs). METHOD: We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of tofacitinib and peficitinib in combination with DMARDs in patients with an inadequate response to DMARDs. RESULTS: Nine RCTs, including 3836 patients, met the inclusion criteria. Fifteen pairwise comparisons were performed, including six direct comparisons of seven interventions. Tofacitinib 10 mg+methotrexate (MTX) and peficitinib 150 mg+MTX were among the most effective treatments for patients with active RA with an inadequate DMARD response. The efficacy of tofacitinib 10 mg+MTX, peficitinib 150 mg+MTX or tofacitinib 5 mg+MTX tended to be higher than that of adalimumab+MTX. The ranking probability based on the surface under the cumulative ranking curve indicated that tofacitinib 10 mg+MTX had the greatest probability of being the best treatment to achieve the American College of Rheumatology 20 response rate, followed by peficitinib 150 mg+MTX, tofacitinib 5 mg+MTX, adalimumab+MTX, peficitinib 100 mg+MTX, and placebo+MTX. No significant differences were observed in the incidence of serious adverse events after treatment with tofacitinib+MTX, peficitinib+MTX, adalimumab+MTX, or placebo+MTX. CONCLUSIONS: In patients with RA with an inadequate response to DMARDs, tofacitinib 10 mg+MTX and peficitinib 150 mg+MTX were the most efficacious interventions and were not associated with a significant risk of serious adverse events.

A drug-drug interaction study to evaluate the impact of peficitinib on OCT1- and MATE1-mediated transport of metformin in healthy volunteers.

PURPOSE: Peficitinib is an oral pan-Janus kinase inhibitor for the treatment of rheumatoid arthritis. Co-administration of peficitinib with metformin, a type 2 diabetes therapy, can occur in clinical practice. Hepatic and renal uptake of metformin is mediated by organic cation transporter 1 (OCT1) and OCT2, respectively, and its renal excretion by multidrug and toxin extrusion 1 (MATE1) and MATE2-K. This study investigated the effect of peficitinib on metformin pharmacokinetics in vitro and in healthy volunteers. METHODS: Inhibitory effects of peficitinib and its metabolite H2 on metformin uptake into human OCT1/2- and MATE1/2-K-expressing cells were assessed in vitro. In an open-label, drug-drug interaction study, 24 healthy volunteers received a single dose of metformin 750 mg on Days 1 and 10, and a single dose of peficitinib 150 mg on Days 3 and 5-11. Blood and urine samples were collected pre-dose on Days 1 and 10, and at intervals ≤ 48 h post-dose. Metformin concentration was determined by liquid chromatography-tandem mass spectrometry and its pharmacokinetic parameters calculated. RESULTS: Peficitinib, but not H2, inhibited metformin uptake into OCT1- and MATE1/2-K-expressing cells. Repeated-dose administration of peficitinib reduced metformin area under the concentration-time curve from 0 h extrapolated to infinity (AUCinf) by 17.4%, maximum plasma concentration (Cmax) by 17.0%, and renal clearance (CLR) by 12.9%. Co-administration of peficitinib with metformin was generally well tolerated. CONCLUSION: Slight changes in AUCinf, Cmax and CLR of metformin were observed when co-administered with peficitinib; however, these changes were considered not clinically relevant.

Liver Enzyme Elevations in Plasmodium falciparum Volunteer Infection Studies: Findings and Recommendations.

Malaria volunteer infection studies (VISs) accelerate new drug and vaccine development. In the induced blood-stage malaria (IBSM) model, volunteers are inoculated with erythrocytes infected with Plasmodium falciparum. Observations of elevated liver enzymes in the IBSM model with new chemical entities (NCEs) promoted an analysis of available data. Data were reviewed from eight IBSM studies of seven different NCEs, plus two studies with the registered antimalarial piperaquine conducted between June 2013 and January 2017 at QIMR Berghofer, Brisbane, Australia. Alanine aminotransferase (ALT) was elevated (> 2.5 times the upper limit of normal [×ULN]) in 20/114 (17.5%) participants. Of these, 8.9% (10/114) had moderate increases (> 2.5-5 × ULN), noted in seven studies of six different NCEs ± piperaquine or piperaquine alone, and 8.9% (10/114) had severe elevations (> 5 × ULN), occurring in six studies of six different NCEs ± piperaquine. Aspartate aminotransferase (AST) was elevated (> 2.5 × ULN) in 11.4% (13/114) of participants, across six of the 10 studies. Bilirubin was > 2 × ULN in one participant. Published data from other VIS models, using sporozoite inoculation by systemic administration or mosquito feeding, also showed moderate/severe liver enzyme elevations. In conclusion, liver enzyme elevations in IBSM studies are most likely multifactorial and could be caused by the model conditions, that is, malaria infection/parasite density and/or effective parasite clearance, or by participant-specific risk factors, acetaminophen administration, or direct hepatotoxicity of the test drug. We make recommendations that may mitigate the risk of liver enzyme elevations in future VISs and propose measures to assist their interpretation, should they occur.