Combination treatment with ipragliflozin and metformin: a randomized, double-blind, placebo-controlled study in patients with type 2 diabetes mellitus

BackgroundIpragliflozin (ASP1941) is a selective sodium glucose cotransporter 2 inhibitor in clinical development for the treatment of patients with type 2 diabetes mellitus (T2DM).ObjectivesThe primary objective was to evaluate the safety profile and tolerability of ipragliflozin as a glucose-lowering agent in combination with stable metformin therapy in patients with T2DM. A secondary objective was to evaluate the effect of ipragliflozin on the pharmacokinetic (PK) properties of metformin.MethodsThirty-six patients with T2DM stable on metformin therapy (850, 1000, or 1500 mg bid) were randomized in a double-blind manner to receive ipragliflozin (300 mg qd; n = 18) or matching placebo (n = 18) for 14 days. Safety profiles, including monitoring of hypoglycemic events, treatment-emergent adverse events (TEAEs), laboratory measurements, and vital signs were assessed throughout the study. The PK properties of metformin and ipragliflozin were determined in plasma. The geometric mean ratio and its 90% CI for the maximum plasma concentration and AUC_0–10 were calculated for metformin + ipragliflozin (day 14) versus metformin alone (day ?1). Pharmacodynamic properties were assessed by measurement of urinary glucose excretion over 24 hours (UGE_0–24).ResultsAll the TEAEs, except 1, were mild. Fifteen TEAEs were observed in the ipragliflozin group (7 of 18 patients [38.9%]), and 19 TEAEs were observed in the placebo group in (8 of 18 patients [44.4%]). Treatment-related TEAEs were reported by 3 of 18 patients (16.7%) receiving metformin + ipragliflozin and by 5 of 18 patients (27.8%) receiving metformin + placebo. No hypoglycemic events (blood glucose level <54 mg/L [to convert to millimoles per liter, multiply by 0.0555]) were observed. The geometric mean ratios for C_max and AUC_0–10 of metformin + ipragliflozin versus metformin alone were 1.11 (90% CI, 1.03–1.19) and 1.18 (90% CI, 1.08–1.28), respectively. After ipragliflozin treatment, UGE_0–24 on day 14 (74.9 g) was significantly higher than that in the placebo group (3.6 g) and at baseline (3.3 g).ConclusionsCombination treatment for 14 days with ipragliflozin and metformin was well tolerated in patients withT2DM without hypoglycemia. The addition of ipragliflozin (300 mg qd) to metformin therapy did not result in a clinically relevant change in the PK properties of metformin. ClinicalTrials.gov identifier: NCT01302145.     

Pharmacokinetic and Pharmacodynamic Characteristics of Single-dose Canakinumab in Patients With Type 2 Diabetes Mellitus

PurposeInterleukin (IL)-1β, an inflammatory molecule, contributes to the development of atherothrombosis and worsening of islet β-cell function. Canakinumab, a human monoclonal antibody, targets IL-1β–dependent inflammation and reduces the vascular inflammatory biomarker, high-sensitivity C-reactive protein (hsCRP), and other inflammatory cardiovascular biomarkers. Here, we aimed to assess the pharmacokinetic (PK) and pharmacodynamic characteristics, including the effect on hsCRP, of canakinumab in patients with type 2 diabetes mellitus (T2DM) after a 2-hour single-dose intravenous infusion.MethodsThis multicenter, randomized, double-blind, placebo-controlled, dose-escalation study was conducted in patients with T2DM (diagnosed ≥6 months before screening) on a stable daily dose of metformin. Patients were randomly assigned to receive a single intravenous dose of canakinumab 0.03, 0.1, 0.3, 1.5, or 10 mg/kg or placebo. The study was initially designed with 1 small cohort (15 patients, 0.3 mg/kg) on a stable dose of metformin ≥500 mg/d for an initial tolerability evaluation; all other patients were on a stable dose of ≥850 mg/d of metformin. The PK profile was assessed at 0 and 2 hours and at days 2, 14, 28, 56, 84, and 168. Changes in hsCRP and hemoglobin (Hb) A_1c levels were assessed at weeks 4, 8, 12, and 24.FindingsOf the 231 enrolled patients, 222 completed the study. Median hsCRP values at screening ranged from 1.8 to 3.2 mg/L, and the median daily dose of metformin ranged from 1000 to 2000 mg. Exposure to canakinumab was dose proportional. The mean half-life ranged from 17 to 26 days, and mean systemic clearance ranged from 0.094 to 0.128 mL/h/kg. Dose-related reductions in hsCRP were significantly greater with canakinumab compared with those with placebo at week 4 (−0.2 mg/L, −0.5 mg/L, −1.5 mg/L, and −1.7 mg/L with the 0.1-, 0.3-, 1.5-, and 10-mg/kg doses, respectively; all, P < 0.05). Significant reductions in hsCRP were maintained up to week 12 with the 2 highest doses of canakinumab (−0.8 mg/L with 1.5 mg/kg and −1.3 mg/L with 10 mg/kg; both, P < 0.05). A placebo-adjusted decrease in HbA1c of 0.31% at week 12 was reported with canakinumab 10 mg/kg (P = 0.038), and a reduction of 0.23% at week 4 was found with canakinumab 1.5 mg/kg (P = 0.011).ImplicationsThe findings from this study suggest that IL-1β blockade after single-dose administration of canakinumab at 1.5 and 10 mg/kg provided sustained suppression of hsCRP levels for 12 weeks in patients with T2DM. ClinicalTrials.gov identifier: NCT00900146.     

2型糖尿病患者骨骼肌厚度和弹性变化及其影响因素

目的 观察2型糖尿病患者骨骼肌厚度和弹性变化及其影响因素。方法 前瞻性招募62例2型糖尿病患者（T2DM组）及60名健康成年人（HC组）,以剪切波弹性成像（SWE）技术检测其放松及收缩状态下腹直肌和腓肠肌最大杨氏模量（E_max）,比较组间2种状态下骨骼肌厚度及弹性模量,并采用多重线性回归分析影响腹直肌和腓肠肌弹性模量的因素。结果 组间放松及收缩状态下腹直肌和腓肠肌厚度差异均无统计学意义（P均>0.05）;T2DM组放松及收缩状态下腹直肌及腓肠肌E_max均低于HC组（P均<0.05）。多重线性回归分析显示,T2DM组放松及收缩状态下腹直肌及腓肠肌弹性模量均随病程、空腹血糖（FBG）及糖化血红蛋白（HbA1c）而呈线性降低（P均<0.05）。结论 2型糖尿病患者骨骼肌弹性模量降低,且随病程、FBG及HbA1c而呈线性下降。     

Pharmacokinetics and Tolerability of Budesonide/Glycopyrronium/Formoterol Fumarate Dihydrate and Glycopyrronium/Formoterol Fumarate Dihydrate Metered Dose Inhalers in Healthy Chinese Adults: A Randomized,Double-blind,Parallel-group Study

PurposeThe objective of this study was to assess pharmacokinetic (PK) and safety profiles of 2 fixed-dose combinations in development for the treatment of chronic obstructive pulmonary disease (COPD): budesonide/glycopyrronium/formoterol fumarate dihydrate metered-dose inhaler (BGF MDI; triple combination) and glycopyrronium/formoterol fumarate dihydrate (GFF MDI; dual combination). The PK and safety profiles of BGF MDI and GFF MDI were assessed for the first time in healthy Chinese adults after single and repeated (7-day) dosing.MethodsThis Phase I, randomized, double-blind, parallel-group study was conducted at a single site in Shanghai, China. Male or female Chinese subjects, 18–45 years of age and in good general health, were randomized 1:1:1 to receive BGF MDI 320/14.4/10 μg, BGF MDI 160/14.4/10 μg, or GFF MDI 14.4/10 μg. PK parameters were assessed after a single dose (day 1) and at steady state (day 8), and included AUC_0–12, C_max, and T_max. Tolerability was assessed using physical examination findings, adverse events reporting, 12-lead ECG, vital signs, and clinical laboratory values.FindingsNinety-six subjects (mean age, 25.6 years; 83.3% male) were randomized and received treatment. All randomized subjects were included in the safety and PK populations. After single and repeated dosing, budesonide AUC_0–12 and C_max were increased dose proportionally from BGF MDI 160/14.4/10 μg to BGF MDI 320/14.4/10 μg, respectively (single dose: AUC_0–12, 811.8 vs 1748 h · pg/mL; C_max, 224.3 vs 459.3 pg/mL; repeated dosing: AUC_0–12, 1250 vs 2510 h · pg/mL; C_max, 315.4 vs 626.4 pg/mL). After single and repeated dosing, glycopyrronium AUC_0–12 and C_max were similar across all treatments (single dose: AUC_0–12, 27.20–29.40 h · pg/mL; C_max, 4.884–5.674 pg/mL; repeated dosing: AUC_0–12, 69.49–77.08 h · pg/mL; C_max, 11.30–13.12 pg/mL) and formoterol (single dose: AUC_0–12, 46.49–53.58 h · pg/mL; C_max 9.651–10.62 pg/mL; repeated dosing: AUC_0–12, 81.94–85.32 h · pg/mL; C_max, 16.13–17.71 pg/mL), suggesting that the addition of budesonide did not appreciably alter the PK properties of GFF MDI. All treatment-emergent adverse events were mild in severity and rates were similar across groups (range, 50.0%–56.3%). There were no new or unexpected findings on tolerability.ImplicationsOverall, all treatments were well tolerated and PK parameters were generally comparable to those previously reported in Western and Japanese healthy subjects, suggesting that the doses of BGF MDI and GFF MDI in development globally for COPD are also appropriate for Chinese patients with COPD. ClinicalTrials.gov identifier: NCT03075267.     

Population pharmacokinetics and pharmacodynamics of sitafloxacin in patients with community-acquired respiratory tract infections

An optimal dosage regimen of sitafloxacin was considered based on a pharmacokinetics and pharmacodynamics (PK–PD) analysis in patients with community-acquired respiratory tract infections (RTI). A population pharmacokinetic analysis of sitafloxacin was conducted using clinical data of five clinical pharmacology studies and one clinical PK–PD study in patients with RTIs. The pharmacokinetic parameters in individual patients were estimated by the Bayesian method to examine any correlation between pharmacokinetics and bacteriological efficacy. Efficacy data were obtained from the clinical PK–PD study, in which 50 or 100 mg sitafloxacin was administered twice daily for 7 days. In addition, an efficacy was simulated for a hypothetical dose regimen of 100 mg once daily. The fAUC_0–24h/MIC and the fC _max/MIC of sitafloxacin at a dose of 50 mg twice daily were 117.5 ± 78.0 and 7.3 ± 4.7 (mean ± SD), respectively. As a result of the univariate logistic regression analysis, the larger the value of fAUC_0–24h/MIC or fC _max/MIC becomes, the higher the bacteriological efficacies. The eradication rates for fAUC_0–24h/MIC ≥ 30 and for fC _max/MIC ≥ 2 were 96.4 % and 96.3 %, respectively. The PK–PD target values of sitafloxacin for the treatment of mild to moderate RTIs were considered to be fAUC_0–24h/MIC ≥ 30 and fC _max/MIC ≥ 2. The PK–PD parameters at the regimen of 50 or 100 mg twice daily in patients with RTIs reached the target values. Furthermore, a 100 mg once-daily regimen was expected to show similar efficacy based on the PK–PD simulations.     

二维剪切波弹性成像评价2型糖尿病患者跟骨下脂肪垫改变

目的 观察二维剪切波弹性成像（2D-SWE）评价2型糖尿病（T2DM）患者跟骨下脂肪垫硬度改变的价值。方法 将104例T2DM患者根据病程分为长病程组（n=54）和短病程组（n=50）,另纳入38名健康志愿者作为对照组。采用2D-SWE技术测量受试者跟骨下脂肪垫弹性模量（E_hp）及其大腔室弹性模量（E_macro）、微腔室弹性模量（E_micro）,比较组内左、右足各参数差异及组间双足参数差异。采用Pearson相关性分析评价E_hp与实验室指标的相关性;以多元线性逐步回归分析影响E_hp的独立因素。结果 各组内左、右足各弹性参数差异均无统计学意义（P均>0.05）。长、短病程组E_hp、E_macro及E_micro均高于对照组（P均<0.05）;长病程组各参数均高于短病程组（P均<0.05）。E_hp与空腹血糖（FBG）、糖化血红蛋白（HbA1c）均呈正相关（r=0.516、0.403,P均<0.001）,与高密度脂蛋白胆固醇（HDL-C）呈负相关（r=－0.521,P<0.001）。FBG、HbA1c及HDL-C均为影响E_hp的独立因素（P均<0.05）。结论 利用2D-SWE技术能够准确、客观地评价T2DM患者跟骨下脂肪垫异常改变。     

The role of lycopene for the amelioration of glycaemic status and peripheral antioxidant capacity among the Type II diabetes mellitus patients: a case–control study

BackgroundThe use of lycopene as a complementary medicine for Type II diabetes mellitus (T2DM) is limited and controversial. This study evaluated the effect of lycopene intake on the changes of glycaemic status and antioxidant capacity among the T2DM patients.Patients and methodsThis case–control study involved the participation of 87 patients and 122 healthy individuals. Lycopene intake was assessed by using a food frequency questionnaire. The peripheral antioxidant capacity among the T2DM patients was evaluated. Glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) were measured as indications of glycaemic status.ResultsPeripheral antioxidant capacity was significantly lower in the T2DM group. Direct positive correlations were found between the lycopene intake and peripheral antioxidant level among the T2DM patients. Contrarily, HbA1c and FPG levels decreased significantly with the higher lycopene intake.ConclusionsT2DM patients with a higher lycopene intake showed a greater peripheral antioxidant capacity and better glycaemic control. Lycopene may act to ameliorate oxidative stress and improve the pathophysiology of T2DM.     

Pharmacokinetic and Pharmacodynamic Interactions Between Henagliflozin,a Novel Selective SGLT-2 Inhibitor,and Warfarin in Healthy Chinese Subjects

PurposeWhile controlling blood glucose, patients with diabetes and abnormal coagulation should be treated with positive anticoagulation because the hypercoagulable state of their blood is the primary cause of macroangiopathy. The goal of this study was to evaluate the pharmacokinetic and pharmacodynamic (PK/PD) interactions between henagliflozin, a novel selective sodium-glucose cotransporter 2 inhibitor, and warfarin in healthy subjects.MethodsThis single-center, open-label, single-arm clinical study was conducted in 16 healthy male Chinese subjects. According to the study protocol, the PK properties of henagliflozin 10 mg/d and warfarin 5 mg/d were collected and tabulated in accordance with sampling time. All study drugs were given with once-daily administration. Subjects were monitored for adverse reactions and their severity, outcomes, and relationship to study drug. This influences of warfarin on the PK properties of henagliflozin (C_max,ss and AUC_τ,ss), the effects of henagliflozin on the PK properties of warfarin (C_max, AUC_0–t, and AUC_0–∞), and the influences of henagliflozin on the PD properties of warfarin (PT_max, PT_AUC, INR_max, and INR_AUC) were evaluated.FindingsThe geometric mean ratios (GMRs; 90% CIs) of henagliflozin C_max,ss and AUC_τ,ss were 101.75% (96.11%–107.72%) and 102.21% (100.04%–104.42%), respectively. The GMRs (90% CIs) of S- and R-warfarin C_max, AUC_0–t, and AUC_0–∞ were as follows: C_max, 114.31% (106.30%–122.91%) and 115.09% (109.46%–121.01%), respectively; AUC_0–t, 120.15% (116.71%–123.69%) and 119.01% (116.32%–121.76%); and AUC_0–∞, 120.81% (117.17%–124.58%) and 121.94% (118.90%–125.05%). The GMRs (90% CIs) of warfarin PT_max and PT_AUC were 92.73% (91.25%–94.22%) and 97.42% (96.61%–98.24%). The GMRs (90% CIs) of warfarin INR_max and INR_AUC were 92.66% (91.17%–94.17%) and 97.36% (96.52%–98.21%). A total of 32 cases of mild adverse events were reported, and were recovered/resolved. There were no serious adverse events reported.ImplicationsNo significant clinically relevant effects on the PK/PD properties of henagliflozin or warfarin were found with coadministration of the two drugs in these healthy male Chinese subjects. Based on these findings, it is expected that henagliflozin and warfarin can be used in combination without dose adjustment. Chinadrugtrials.org.cn identifier: CTR20190240.     

Pharmacokinetics of duloxetine hydrochloride enteric-coated tablets in healthy Chinese volunteers: A randomized,open-label,single- and multiple-dose study

Background: Duloxetine hydrochloride is a balanced selective serotonin and norepinephrine reuptake inhibitor. Despite being widely used for the treatment of major depressive disorder in China, little information is available on the pharmacokinetic (PK) properties of duloxetine in Chinese subjects.Objectives: This study was designed to determine the concentration of duloxetine in human plasma and to compare the PK properties of duloxetine after administration of single and multiple doses of duloxetine in healthy Chinese volunteers.Methods: A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determining the concentration of duloxetine in human plasma was developed and applied to this single-center, open-label, single- and multiple-dose PK study. Subjects were randomized to receive a single dose of 30, 60, or 90 mg of duloxetine. Those who received the 30-mg dose continued on to the multiple-dose phase and received 30 mg twice daily for 7 days. In the single-dose phase, sequential blood samples were collected from 0 to 60 hours after drug administration. In the multiple-dose phase, samples were obtained before drug administration on days 4, 5, 6, and 7 to determine the Cssmin of duloxetine; on day 7, samples were collected from 0 to 60 hours after drug administration. The PK parameters that were calculated included C_max, T_max, t_1/2, AUC_0?t AUC_0?∞, CL, V_d, C_ssmax, C_ssmin, C_ssav, AUC_ss, AUC_ss(0?t), and C_max:C_min ratio. All values were expressed as mean (SD). Tolerability was assessed throughout the study.Results: The LC-MS/MS method was developed and validated. The standard calibration curve was linear in the concentration range from 0.89 to 106.8 ng/mL; the correlation coefficient was >0.995. The methodo-logic recovery and extraction recovery ranged from 87.22% to 113.75% and 72.81% to 89.96%, respectively. Both the intraday and interday relative SDs were <11%. Thirty Chinese subjects (3 groups of 10 subjects [5 men, 5 women] each) were enrolled in the single-dose phase of the PK study. The mean (SD) age of the subjects was 23.2 (1.8) years (range, 21–25 years); their mean (SD) weight was 61.0 (7.7) kg (range, 52–80 kg) and height was 169.0 (7.1) cm (range, 155–180 cm). The main PK parameters for duloxetine after administration of a single oral dose of 30, 60, and 90 mg were as follows: C_max = 22.46 (15.15), 44.40 (17.18), and 60.78 (27.84) ng/mL, respectively; AUC_0–60 = 328.64 (203.64), 696.04 (337.82), and 1219.33 (598.29) ng/mL · h^?1; AUC_0?∞) = 359.68 (201.01), 733.82 (343.40), and 1280.51 (644.81) ng/mL · h^?1; T_max = 6.83 (1.99), 6.10 (1.29), and 6.60 (1.58) hours; t1/2 = 12.95 (3.64), 12.81 (2.31), and 11.66 (2.06) hours; CL = 107.90 (53.05), 98.41 (41.98), and 109.58 (52.74) L/hour; and V_d = 2518.88 (1707.71), 1879.74 (999.09), and 1858.47 (1203.69) L. The 10 subjects who received the 30-mg dose in the single-dose phase continued on to the multiple-dose phase and received 30 mg of duloxetine twice daily for 7 days. Mean (SD) values for the main PK parameters for duloxetine after administration of multiple doses were as follows: C_ssmax = 47.33 (16.95) ng/mL; C_ssmm = 27.92 (9.46) ng/mL; AUC_ss(0?t) = 407.25 (125.94) ng/mL · h^?1; C_ssav = 33.94 (13.00) ng/mL; T_max = 6.36 (0.92) hours; t_1/2 = 11.19 (1.98) hours; CL = 83.12 (28.75) L/hour; and V_d = 1359.01 (590.06) L.Conclusions: In these healthy Chinese subjects, AUC and Cmax increased proportionally with the dose, whereas t_1/2 was independent of the dose. Linear PK properties were found at doses of 30 to 90 mg. No statistically significant differences were observed between the PK parameters for the subjects in the multiple-dose phase (t_1/2, CL, V_d) and those for subjects in the single-dose phase. The AUC and C_max were greater after administration of multiple doses than after administration of a single dose, suggesting du-loxetine accumulation with multiple-dose administration of 30 mg.     

Efficacy and Safety of Linagliptin in Subjects With Long-standing Type 2 Diabetes Mellitus (>10 Years): Evidence From Pooled Data of Randomized,Double-blind,Placebo-controlled,Phase III Trials

PurposeLong duration of type 2 diabetes mellitus (T2DM) is associated with progressive β-cell loss and may pose a challenge to maintenance of good glycemic control. This study aimed to assess the efficacy and safety of the dipeptidyl peptidase-4 inhibitor linagliptin in an understudied population of patients with long-standing T2DM.MethodsData from 202 individuals with T2DM for >10 years were pooled from 2 randomized, placebo-controlled, Phase III trials. Participants received either linagliptin 5 mg once daily (n = 122) or placebo (n = 80) for 24 weeks as an add-on to their current glucose-lowering therapy.FindingsLong-standing T2DM was associated with older age (mean [SD], 69.1 [10.0] years) and a high prevalence of diabetes-related complications (78% with diabetic kidney disease and 83% with macrovascular disease). The mean baseline glycosylated hemoglobin (HbA_1c) level was 8.22% (1.08%), and mean baseline fasting plasma glucose level was 161.8 (49.2) mg/dL. Linagliptin significantly improved glycemic control after 24 weeks, with a placebo-adjusted mean change in HbA_1c from baseline of −0.66% (95% CI, −0.95 to −0.38; P < 0.0001). This change was accompanied by a significant reduction in fasting plasma glucose, with a placebo-adjusted mean change from baseline of −15.5 mg/dL (95% CI, −29.6 to −1.3; P = 0.0323) at week 24. Overall, linagliptin was well tolerated, with drug-related adverse events in 21.3% and 16.3% of the linagliptin and placebo groups, respectively. Investigator-reported hypoglycemia occurred more often with linagliptin (25.4%) compared with placebo (12.5%). However, no severe hypoglycemic events were reported with linagliptin. Moreover, in patients not receiving concomitant sulfonylureas, the incidence of hypoglycemia with linagliptin (12.5%) was similar to that with placebo (12.2%). Patients’ mean weight remained unchanged in both groups.ImplicationsThis pooled analysis found that linagliptin was well tolerated and significantly improved hyperglycemia in a clinically challenging population of patients with long-standing T2DM (>10 years). Although T2DM is commonly associated with diminished β-cell function, the extent of glucose lowering was similar to that in linagliptin trials, which largely included patients in earlier stages of the disease. Thus, this observation supports the hypothesis that regulation of glucagon release from pancreatic α cells may be of particular relevance for improving hyperglycemia in patients with long-term T2DM (NCT01194830 and NCT01084005).     

Celecoxib-tramadol co-crystal: A Randomized 4-Way Crossover Comparative Bioavailability Study

PurposeCelecoxib-tramadol co-crystal (CTC) is a first-in-class co-crystal of celecoxib and racemic tramadol. This Phase 1 bioavailability study compared single-dose pharmacokinetic (PK) parameters of CTC with those of the individual reference products from the United States, immediate-release celecoxib and tramadol, taken alone and simultaneously to determine their systemic exposure.MethodsThis was a single-center, randomized, single-dose, open-label, 4-period, 4-sequence, crossover study conducted in healthy subjects between October and December 2016. Study treatments included 200-mg CTC (equivalent to 112-mg celecoxib and 88-mg tramadol; Treatment-1); 100-mg tramadol (Treatment-2); 100-mg celecoxib (Treatment-3); and 100-mg celecoxib plus 100-mg tramadol (Treatment-4). The PK parameters of interest were C_max, AUC_0–T, and AUC_0–∞, which were also calculated normalized to the dose. T_max was only considered as supportive. The statistical analysis was based on a parametric analysis of variance model of the PK parameters; the two-sided 90% CI of the ratio of geometric mean values for the C_max, AUC_0–T, and AUC_0–∞ was based on ln-transformed data, and T_max was rank-transformed.FindingsThirty-six subjects aged 18 to 55 years (21 male subjects, 15 female subjects; mean age, 35 years) participated in the study. Celecoxib from CTC presented a lower C_max, reduced AUCs, and a faster T_max. The interference in celecoxib absorption when celecoxib and tramadol are administered together was minimized with the CTC. For Treatment-1, -3, and -4, celecoxib PK parameters were 259, 318, and 165 ng/mL (C_max), respectively; 1930, 2348, and 1929 ng • h/mL (AUC_0–T); and 1.5, 3.0, and 2.5 hours (T_max). Tramadol and its active metabolite O-desmethyl tramadol from CTC presented lower C_max and AUCs as well as a longer T_max. Tramadol/O-desmethyl tramadol PK parameters for Treatment-1, -2, and -4 were 214/55, 305/78, and 312/78 ng/mL for C_max; 2507/846, 2709/965, and 2888/1010 ng • h/mL for AUC_0–T; and 3.0/4.0, 2.0/2.5, and 1.9/2.5 hours for T_max. Reported adverse events (none unexpected) occurred more frequently with Treatment-2 and Treatment-4.ImplicationsThe aim of this study was to compare the PK profile of the US-marketed tramadol and celecoxib products with CTC to determine their systemic exposure and to validate the dosing regimen for a subsequent pivotal factorial Phase 3study. PK parameters of each active component in CTC were favorably modified by co-crystallization and did not result in higher systemic exposure compared with US-marketed celecoxib, tramadol, and their concomitant administration. © 2021 Elsevier HS Journals, Inc.     

Pharmacokinetic and Pharmacodynamic Properties of Single- and Multiple-Dose of Dapagliflozin,a Selective Inhibitor of SGLT2, in Healthy Chinese Subjects

Background

Dapagliflozin, a selective, orally active, renal sodium glucose cotransporter 2 (SGLT2) 2 inhibitor, is under investigation as a treatment of type 2 diabetes mellitus (T2DM). Dapagliflozin reduces hyperglycemia by inhibiting renal glucose reabsorption and dose-dependently increasing urinary glucose excretion, independent of insulin secretion or action.

Objectives

These studies assessed the single- and multiple-dose pharmacokinetic and pharmaco dynamic properties of dapagliflozin and its major inactive metabolite, dapagliflozin 3-O-glucuronide (D3OG), in healthy subjects residing in China.

Methods

In 2 identically designed, open-label, single- and multiple-dose studies (n = 14 for both studies), healthy Chinese subjects were administered oral dapagliflozin 5 or 10 mg. In both studies, subjects received a single dose on day 1 (single-dose administration period) followed by 6 once-daily doses on days 5 to 10 (multiple-dose administration period). Pharmacokinetic parameters (plasma and urinary dapagliflozin and D3OG), pharmacodynamic response (urinary glucose excretion), and tolerability were assessed.

Results

Fourteen subjects completed the dapagliflozin 5-mg study, and 13 completed the dapagliflozin 10-mg study. Baseline characteristics were balanced across the two studies: 9 versus 10 men; mean age, 27.1 versus 28.9 years; mean weight, 62.8 versus 62.2 kg; and mean body mass index, 23.0 versus 22.2 kg/m² in the dapagliflozin 5- and 10-mg studies, respectively. In both doses, dapagliflozin was rapidly absorbed (T_max, ≤1.5 h), accumulation (defined as the geometric mean ratio of AUC_τ at day 10 to AUC_τ at day 1) after multiple dosing was minimal (<1.13 fold), and elimination half-life was 10 to 12 h. D3OG showed a slightly longer median T_max (≤2 h) but a similar plasma concentration–time profile and half-life compared with dapagliflozin. The majority of D3OG (up to 69.7% of the dapagliflozin dose) was excreted in urine, while ≤1.9% of dapagliflozin was excreted unchanged in urine. Over a 24-hour period and at steady state (day 10), urinary glucose excretion values were 28.1 and 41.1 g with dapagliflozin 5 and 10 mg, respectively. Dapagliflozin was generally well tolerated; one dapagliflozin 10 mg–treated subject discontinued the study because of a serious adverse event (bronchitis) considered by the investigator as unrelated to dapagliflozin dosing.

Conclusions

Pharmacokinetic and pharmacodynamic characteristics following single- and multiple-dose dapagliflozin 5 and 10 mg oral administration in healthy Chinese subjects were as predicted from previous studies and were similar to findings observed in non-Chinese healthy subjects. Dapagliflozin dosing was well tolerated. The clinically recommended dapagliflozin dose of 10 mg once daily is expected to be appropriate in patients of Chinese ethnicity; results from an efficacy and tolerability study in Chinese patients with T2DM are awaited.     

Clinical applications of virosomes in cancer immunotherapy

ABSTRACT

Introduction: Early short-term insulin treatment (STIT), defined as insulin administration shortly after diabetes diagnosis for only a brief period of time, is an alternative concept, aiming to entirely revise the perspective of type 2 diabetes (T2DM) management.

Areas covered: The present review intends to summarize what is already known regarding early STIT in T2DM and highlight questions and dilemmas from the clinician’s point of view, with a discourse on future research agenda.

Expert opinion: STIT has the potential to modify the natural history of T2DM, resulting in improved drug-free remission rates by favorably affecting the underlying pathophysiology of the disease. Existing data in the field manifest significant weaknesses, mainly being the small number of trials and patients included, the lack of control groups in most studies and the wide heterogeneity between study designs and explored outcomes, which limit definitive conclusions. Therefore, before such a therapeutic strategy is incorporated into daily practice, important issues require further clarification by future trials. These issues include the optimal time point for the intervention, the ideal insulin type, the identification of patients being most likely to benefit, the STIT effects on cardiovascular and other clinical outcomes and the cost-effectiveness evaluation of this therapeutic strategy.

Abbreviations: T2DM: Type 2 Diabetes Mellitus; HbA_1C: Hemoglobin A_1c; OHA: Oral Hypoglycemic Agents; STIT: Short-term Insulin Treatment; CSII: Continuous Subcutaneous Insulin Infusion; MDI: Multiple Daily Injections; PPG: Postprandial Plasma Glucose; FPG: Fasting Plasma Glucose; HOMA-b: Homeostasis Model Assessment of beta-cell function; TDD: Total Daily Insulin Dose; DI: Disposition Index; HOMA-IR: Homeostasis Model Assessment of Insulin Resistance; ROS: Reactive Oxygen Species; TNF: Tumor Necrosis Factor; GLP-1: Glucagon-like peptide-1; GIP: Glucose-dependent Insulinotropic Polypeptide; BMI: Body Mass Index; CV: Cardiovascular; DR: Diabetic Retinopathy; SU: Sulfonylurea; IGI: Insulinogenic Index     

Hypoglycemic Potential of Current and Emerging Pharmacotherapies in Type 2 Diabetes Mellitus

Abstract

Intensive glycemic control can reduce the risk of microvascular complications in patients with type 2 diabetes mellitus (T2DM). However, hypoglycemia induced by diabetes medications is recognized as a major limiting factor in the attainment of glycemic goals. Mild hypoglycemia is relatively common in patients with T2DM, and the prevalence of severe hypoglycemia increases with insulin treatment and can approach the prevalence seen in patients with type 1 diabetes. Mild hypoglycemia and the fear of hypoglycemia can have a substantial impact on the physical, mental, social, and economic well–being of patients with T2DM. Severe hypoglycemia is more serious and may be associated with an increased risk of dementia, cardiovascular events, and death. Insulin and insulin secretagogue therapies (eg, sulfonylureas and meglitinides) are the major causes of hypoglycemia in patients with T2DM. Other diabetes drugs, such as metformin, when used as monotherapy, have a low risk of hypoglycemia. Emerging experimental therapies, such as activators of the free fatty acid receptor 1, G protein–coupled receptor 119 agonists, glucokinase activators, inhibitors of 11β-hydroxysteroid dehydrogenase type 1, and sodium–glucose co–transporter 2 inhibitors, some of which have mechanisms of action consistent with a potential low risk of hypoglycemia, may help patients with T2DM achieve improved glycemic control.     

高尿酸血症与2型糖尿病合并血管并发症的相关性研究

目的探讨高尿酸血症和合并2型糖尿病患者血管并发症的相关危险因素。方法选取体检健康者97例纳入对照组,单纯2型糖尿病组103例和2型糖尿病合并高尿酸血症组78例。比较3组受试者空腹血糖(FPG)、糖化血红蛋白(HbA1c)、总胆固醇(TC)、三酰甘油(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、载脂蛋白(Apo)A1、ApoB、肌酐(Cr)、尿酸(UA),同时留取晨尿检测尿微量清蛋白(UMA)及体质量指数(BMI),并研究高尿酸血症和糖尿病相关并发症的相关性。结果单纯2型糖尿病组FPG、TG、Cr、UMA、HbA1c水平均高于对照组(P0.05);2型糖尿病合并高尿酸血症组BMI、FPG、TG、TC、LDL-L、UMA、Cr、HbA1c均高于对照组(P0.05);2型糖尿病合并高尿酸血症组BMI、TG、Cr、UMA、HbA1c均高于单纯2型糖尿病组(P0.05)。2型糖尿病合并高尿酸血症组患者的糖尿病肾病、下肢动脉斑块发病率明显高于单纯2型糖尿病组,差异有统计学意义(P0.05)。结论 2型糖尿病合并高尿酸血症组患者比单纯2型糖尿病患者更易发生血脂异常,2型糖尿病合并高尿酸血症组患者糖尿病肾病、下肢动脉斑块发病率也明显高于单纯2型糖尿病患者。     

Dulaglutide Shows Sustained Reduction in Glycosylated Hemoglobin Values: 2-Year US Real-world Study Results

PurposeDue to the chronic and progressive nature of type 2 diabetes mellitus (T2DM), it is important to understand the long-term outcomes associated with antihyperglycemic medications. There are currently few long-term studies evaluating the real-world effectiveness of dulaglutide, a glucagon-like peptide-1 receptor agonist. The primary objective of this retrospective observational study was to evaluate glycemic control over a 24-month follow-up period among dulaglutide initiators with continuous treatment. The study used US claims data from the HealthCore Integrated Research Database between May 2014 and May 2019.MethodsPatients were included if they were ≥18 years old with T2DM and had ≥1 pharmacy claim for dulaglutide during the index period between November 2014 and May 2017 (with index date = set as the earliest dulaglutide fill during index period), continuous enrollment in the 6 months' preindex and 24 months' postindex, ≥1 claim for dulaglutide or ≥60 days’ supply in every quarter during the 24-month follow-up period, and ≥1 glycosylated hemoglobin (HbA_1c) result at both baseline and 24 months.FindingsAt baseline, 872 patients (47.5% female) had a mean (SD) age of 54.5 (8.2) years and an HbA_1c value of 8.68% (1.8%) (71.36 [19.7] mmol/mol). More than two thirds were being treated for dyslipidemia, hypertension, or cardiovascular disease. A significant HbA_1c reduction was observed from baseline to 24 months (−1.3% [–14.2 mmol/mol]; P < 0.0001) for dulaglutide initiators with continuous treatment. A significant reduction in HbA_1c level was also observed for all prespecified subgroups (age, index dulaglutide dose [0.75 mg or 1.5 mg], insulin use, sodium-glucose co-transporter 2 inhibitor use, and dipeptidyl peptidase-4 inhibitor use; all, P < 0.0001). Forty-three percent of patients achieved an HbA_1c value < 7% (53 mmol/mol), and 73% achieved an HbA_1c value < 8% (64 mmol/mol) at 24 months. Most (520 [59.6%]) patients were initiated on dulaglutide 0.75 mg. Of these patients, 70% increased to dulaglutide 1.5 mg during follow-up. The mean time to first dose change was 242 (196) days for 0.75 mg–1.5 mg and 225 (160) days for 1.5 mg–0.75 mg. Antihyperglycemic medication use preindex/postindex included: insulin, 28%/35%; dipeptidyl peptidase-4 inhibitors, 37%/20%; and sodium-glucose co-transporter 2 inhibitors, 29%/44%.ImplicationsIn this real-world study among dulaglutide initiators with continuous treatment, a clinically significant reduction in HbA_1c value was seen at the 3-month assessment and persisted for up to 24 months. These data support the use of dulaglutide as an effective long-term treatment for T2DM in clinical practice.     

Association between serum Sestrin2 level and diabetic peripheral neuropathy in type 2 diabetic patients

BACKGROUNDDiabetic peripheral neuropathy (DPN) is a chronic and serious microvascular complication of diabetes linked to redox imbalance. Sestrin2, a novel inducible stress protein, participates in glucose metabolic regulation and redox homeostasis. However, the association between serum Sestrin2 and DPN is unknown.AIMTo explore the association between serum Sestrin2 and DPN in patients with type 2 diabetes mellitus (T2DM).METHODSA total of 96 T2DM patients and 39 healthy volunteers, matched by age and sex, participated in this cross-sectional study. Clinical features and metabolic indices were identified. Serum Sestrin2 was measured by ELISA. The association between Sestrin2 and DPN was studied. Correlation and logistic regression analyses were used to evaluate the associations of different metabolic indices with Sestrin2 and DPN.RESULTSThe 96 patients with T2DM were divided into DPN (n = 47) and patients without DPN (n = 49). Serum Sestrin2 was significantly lower in healthy volunteers than in all T2DM patients combined [9.10 (5.41-13.53) ng/mL vs 12.75 (7.44-23.80) ng/mL, P < 0.01]. T2DM patients without DPN also had significantly higher levels of Sestrin2 than healthy volunteers [14.58 (7.93-26.62) ng/mL vs 9.10 (5.41-13.53) ng/mL, P < 0.01]. However, T2DM patients with DPN had lower circulating Sestrin2 levels compared to T2DM patients without DPN [9.86 (6.72-21.71) ng/mL vs 14.58 (7.93-26.62) ng/mL, respectively, P < 0.01]. Bivariate correlation analysis revealed that serum Sestrin2 was positively correlated with body mass index (r = 0.672, P = 0.000), hemoglobin A1c (HbA1c) (r = 0.292, P = 0.000), serum creatinine (r = 0.206, P = 0.016), triglycerides (r = 0.731, P = 0.000), and fasting glucose (r = 0.202, P = 0.040), and negatively associated with estimated glomerular filtration rate (r = -0.230, P = 0.007). After adjustment for sex, age, HbA1c, and diabetes duration, multiple regression analysis revealed that Sestrin2 was independently correlated with body mass index and triglyceride levels (P = 0.000). Logistic regression analyses indicated that Sestrin2, diabetes duration, and high-density lipoprotein were strongly associated with DPN (odds ratio = 0.855, 1.411, and 0.041, respectively).CONCLUSIONOur results show Sestrin2 is decreased in T2DM patients with DNP. As lower Sestrin2 is independently associated with DPN, Sestrin2 may contribute to progression of DPN in T2DM patients.     

新诊断2型糖尿病患者血清miR-126、VEGF水平与胰岛素抵抗的相关性分析

目的分析新诊断2型糖尿病(T2DM)患者血清微小核糖核酸-126(miR-126)、血管内皮生长因子(VEGF)水平与胰岛素抵抗的相关性。方法选取该院2018年2月至2019年4月收治的T2DM患者86例设为观察组,另选取同期体检健康者86例设为对照组。检测两组空腹血清miR-126、VEGF、总胆固醇(TC)、三酰甘油(TG)、空腹血糖(FPG)、糖化血红蛋白(HbA1c)、空腹血胰岛素(FIns)水平,计算体质量指数(BMI)、胰岛β细胞功能指数(HOMA-β)、胰岛素抵抗指数(HOMA-IR)、胰岛素敏感指数(ISI)。分析新诊断T2DM患者miR-126、VEGF水平与胰岛素抵抗的相关性。结果两组性别、年龄比较,差异无统计学意义(P>0.05);两组BMI、血清TC、TG、FPG、HbA1c、FIns水平及HOMA-IR、HOMA-β、ISI比较,差异有统计学意义(P<0.05);观察组血清VEGF水平[(523.48±145.36)ng/L]明显高于对照组[(295.45±94.46)ng/L],血清miR-126水平明显[(0.08±0.01)ng/μL]低于对照组[(0.18±0.02)ng/μL],差异有统计学意义(P<0.05);Pearson相关分析发现:VEGF与BMI、TC、TG、FPG、HbA1c、FIns、HOMA-IR呈正相关,与HOMA-β、ISI呈负相关(P<0.05);miR-126与BMI、TC、TG、FPG、HbA1c、FIns、HOMA-IR呈负相关,与HOMA-β、ISI呈正相关(P<0.05);经多因素逐步回归分析得出:影响血清VEGF表达的因素为ISI,影响血清miR-126水平表达的因素为ISI、HbA1c(P<0.05)。结论新诊断T2DM患者VEGF水平升高、miR-126水平降低,二者可能参与了胰岛素抵抗及T2DM的发生、发展。     

Pharmacokinetics of Efavirenz 600 mg Once Daily During Pregnancy and Post Partum in Ghanaian Women Living With HIV

PurposeThe updated World Health Organization guidelines recommend efavirenz (EFV) 400 mg as the preferred alternate first-line antiretroviral therapy to dolutegravir, with EFV 600 mg recommended only in special situations. We examined the pharmacokinetic (PK) properties of EFV 600 mg/d during pregnancy and post partum to inform EFV dosing decisions in pregnant women.MethodsGhanaian pregnant women with HIV infection initiating tenofovir disoproxil fumarate 300 mg/lamivudine 300 mg/EFV 600 mg fixed-dose combination tablet once daily were enrolled. Efavirenz concentrations were measured at 4 weeks of antiretroviral therapy initiation during pregnancy and 6 weeks post partum using validated LC-MS/MS assays. Efavirenz PK parameters were calculated using noncompartmental analysis, and within-group parameters between the 2 periods were compared.FindingsOf 25 enrolled women, 19 completed PK sampling during pregnancy and post partum. The C_max, C_min, AUC_0–24h, and CL/F for EFV during pregnancy were similar to values at 6 weeks post partum. The pregnancy/postpartum geometric mean ratios for EFV C_max, C_min, AUC_0–24, and CL/F were 1.10 (95% CI, 0.93–1.31), 0.88 (95% CI, 0.67–1.17), 0.84 (95% CI, 0.71–0.98), and 1.20 (95% CI, 1.02–1.40), respectively. Viral load suppression (HIV RNA <200 copies/mL) was achieved in 16 of 17 participants (94%) by the time of delivery. There was 1 maternal-to-child transmission.ImplicationsWe found that the PK parameters of EFV 600 mg once daily during pregnancy were similar to those in the postpartum period. Our findings suggest that EFV dose adjustment during pregnancy is not necessary in our study population.     

Insulin Glargine U100 Improved Glycemic Control and Reduced Nocturnal Hypoglycemia in Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease Stages 3 and 4

PurposeGlycemic control in patients with chronic kidney disease (CKD) is particularly hard to achieve because of a slower insulin degradation by the kidney. It might modify the long-acting insulin analogue pharmacokinetics, increasing its time–action and the risk of hypoglycemia. However, because this insulin has no peak action, it might be a more tolerable approach to patients with CKD. This hypothesis remains to be tested, because no study has thus far examined the efficacy and safety profile of long-acting basal analogues in patients with significant loss of renal function. The purpose of this study was to compare the glycemic response to treatment with glargine U100 or neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes mellitus (T2DM) and CKD stages 3 and 4.MethodsThirty-four patients were randomly assigned to glargine U100 or NPH insulin after a 2-way crossover open-label design. The primary end point was the difference in glycosylated hemoglobin (HbA_1c) and in the number of hypoglycemic events between weeks 1 and 24, whereas secondary end points included changes in glycemic patterns, weight and body mass index, and total daily dose of insulin. HbA_1c was determined by ion-exchange HPLC, and hypoglycemia was defined as glucose concentration of 54 mg/dL (3.0 mmol/L) detected by self-monitoring of plasma glucose or continuous glucose monitoring.FindingsAfter 24 weeks, mean HbA_1c decreased on glargine U100 treatment (−0.91%; P < 0.001), but this benefit was not observed for NPH (0.23%; P = 0.93). Moreover, incidence of nocturnal hypoglycemia was 3 times lower with glargine than with NPH insulin (P = 0.047).ImplicationsOur results found that insulin glargine U100 could be effective, once it improved glycemic control, reducing HbA_1c with fewer nocturnal hypoglycemia episodes compared with NPH insulin in this population. These clinical benefits justify the use of basal insulin analogues, despite their high cost to treat patients with T2DM and CKD stages 3 and 4. Clinical Trials identifier: NCT02451917.