Empagliflozin as adjunct to insulin in Japanese participants with type 1 diabetes: Results of a 4‐week,double‐blind,randomized, placebo‐controlled phase 2 trial

Aims

This phase 2, double‐blind, randomized, placebo‐controlled trial ( ClinicalTrials.gov NCT02702011) with 4 sites in Japan investigated the pharmacodynamics (PD), pharmacokinetics (PK) and safety profile of empagliflozin in Japanese participants with type 1 diabetes mellitus (T1DM) as adjunctive therapy to insulin.

Materials and methods

Participants using multiple daily injections of insulin for ≥12 months, with HbA1c of 7.5%‐10.0%, entered a 2‐week, open‐label, placebo run‐in period, followed by a 4‐week, double‐blind period during which participants were randomized 1:1:1:1 to receive empagliflozin 2.5 mg (n = 13), empagliflozin 10 mg (n = 12), empagliflozin 25 mg (n = 12) or placebo (n = 11). The primary objective was to assess the effect of empagliflozin vs placebo on urinary glucose excretion (UGE) after 7 days of treatment.

Results

PD: Empagliflozin resulted in a dose‐dependent significant increase in 24‐hour UGE compared with placebo (UGE placebo‐corrected mean [95% confidence interval] change from baseline: 2.5 mg, 65.10 [43.29, 86.90] g/24 h; 10 mg, 81.19 [58.80, 103.58] g/24 h; 25 mg, 98.11 [75.91, 120.31] g/24 h). After 4 weeks of treatment, UGE increase was associated with improved glycaemic control, reduced body weight and decreased insulin needs. Empagliflozin treatment also resulted in dose‐dependent increases in serum ketone bodies and free fatty acids. PK: Plasma empagliflozin levels increased in a dose‐dependent manner and peaked at 1.5 hours. In this short study, empagliflozin was well tolerated, with no increase in rate of hypoglycaemia and no diabetic ketoacidosis events reported.

Conclusions

Based on this short‐duration phase 2 study, the PK/PD profile of empagliflozin in Japanese participants with T1DM is comparable to that of non‐Japanese participants.     

Oral apremilast in the treatment of active psoriatic arthritis: Results of a multicenter,randomized, double‐blind,placebo‐controlled study

Objective

To evaluate the efficacy and safety of apremilast, a novel, orally available small molecule that specifically targets phosphodiesterase 4, in the treatment of active psoriatic arthritis (PsA).

Methods

This phase II, multicenter, randomized, double‐blind, placebo‐controlled study included the following: a 12‐week treatment phase, with patients receiving placebo, apremilast 20 mg twice per day, or apremilast 40 mg once per day; a 12‐week treatment‐extension phase, with patients in the placebo group re‐randomized to receive apremilast; and a 4‐week observational phase after treatment cessation. The primary end point was the proportion of patients achieving the American College of Rheumatology criteria for 20% improvement (ACR20) at week 12. Safety assessments included adverse events (AEs), physical examinations, vital signs, laboratory parameters, and electrocardiograms.

Results

Of the 204 patients with PsA who were randomized to a treatment group, 165 completed the treatment phase. At the end of the treatment phase (week 12), 43.5% of patients receiving apremilast 20 mg twice per day (P < 0.001) and 35.8% of those receiving 40 mg once per day (P = 0.002) achieved an ACR20 response, compared with 11.8% of those receiving placebo. At the end of the treatment‐extension phase (week 24), >40% of patients in each group (patients receiving apremilast 20 mg twice per day, patients receiving apremilast 40 mg once per day, and patients in the placebo group re‐randomized to receive apremilast) achieved the ACR20 level of improvement. Most patients in the treatment phase (84.3%) and treatment‐extension phase (68.3%) reported ≥1 AE. Diarrhea, headache, nausea, fatigue, and nasopharyngitis were reported most frequently; most events were mild or moderate. No clinically relevant laboratory or electrocardiographic abnormalities were reported.

Conclusion

Treatment with apremilast at a dosage of 20 mg twice per day or 40 mg once per day demonstrated efficacy in comparison with placebo and was generally well tolerated in patients with active PsA. The balance of efficacy, tolerability, and safety supports further study of apremilast in PsA.

     

Canagliflozin improves glycaemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin

Aim: Canagliflozin is a sodium‐glucose co‐transporter 2 (SGLT2) inhibitor that is being investigated for the treatment of type 2 diabetes mellitus (T2DM). Methods: This was a randomized, double‐blind, placebo‐controlled, parallel‐group, 28‐day study conducted at two sites, in 29 subjects with T2DM not optimally controlled on insulin and up to one oral antihyperglycaemic agent. Subjects were treated with canagliflozin 100 mg QD or 300 mg twice daily (BID) or placebo. Safety, tolerability, pharmacokinetic characteristics and pharmacodynamic effects of canagliflozin were examined. Glucose malabsorption following a 75‐g oral glucose challenge was also examined. Results: Canagliflozin pharmacokinetics were dose‐dependent, and the elimination half‐life ranged from 12 to 15 h. After 28 days, the renal threshold for glucose excretion was reduced; urinary glucose excretion was increased; and A1C, fasting plasma glucose and body weight decreased in subjects administered canagliflozin (A1C reductions: 0.19% with placebo, 0.73% with 100 mg QD, 0.92% with 300 mg BID; body weight changes: 0.03 kg increase with placebo, 0.73 kg reduction with 100 mg QD, 1.19 kg reduction with 300 mg BID). Glucose malabsorption was not observed with canagliflozin treatment. There were no deaths, serious adverse events or severe hypoglycaemic episodes. The incidence of adverse events was similar across groups. There were no clinically meaningful changes in routine laboratory safety tests, vital signs or electrocardiograms. Conclusion: In subjects receiving insulin and oral antihyperglycaemic therapy, canagliflozin was well tolerated without evidence for glucose malabsorption, had pharmacokinetic characteristics consistent with once‐daily dosing, and improved glycaemic control.     

Remogliflozin etabonate, a selective inhibitor of the sodium-dependent transporter 2 reduces serum glucose in type 2 diabetes mellitus patients

Aims: Remogliflozin etabonate (RE) is the pro‐drug of remogliflozin (R), a selective inhibitor of renal sodium‐dependent glucose transporter 2 (SGLT2) that improves glucose control via enhanced urinary glucose excretion (UGE). This study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of repeated doses of RE in subjects with type 2 diabetes mellitus (T2DM). Methods: In a double‐blinded, randomized, placebo‐controlled trial, subjects who were drug‐naïve or had metformin discontinued received RE [100 mg BID (n = 9), 1000 mg QD (n = 9), 1000 mg BID (n = 9)], or placebo (n = 8) for 12 days. Safety parameters were assessed, including urine studies to evaluate renal function. Plasma concentrations of RE and metabolites were measured with the first dose and at steady state. RE effects on glucose levels were assessed with fasting glucose concentrations, frequently sampled 24‐h glucose profiles and oral glucose tolerance tests. Results: No significant laboratory abnormalities or safety events were reported; the most frequent adverse events were headache and flatulence. Plasma exposure to RE and R were proportional to administered dose with negligible accumulation. Mean 24‐h UGE increased in RE treatment groups. Compared with the placebo group, 24‐h mean (95% CI) changes in plasma glucose were ?1.2 (?2.2 to ?0.3) (100 mg BID), ?0.8 (?1.7 to 0.2) (1000 mg QD) and ?1.7 (?2.7 to ?0.8) mmol/l (1000 mg BID). Conclusions: Administration of RE for 12 days is well‐tolerated and results in clinically meaningful improvements in plasma glucose, accompanied by changes in body weight and blood pressure in subjects with T2DM.     

LY2189265, a long‐acting glucagon‐like peptide‐1 analogue,showed a dose‐dependent effect on insulin secretion in healthy subjects

Aim: To assess the safety, tolerability, pharmacokinetics, pharmacodynamics and potential immunogenicity of single, escalating subcutaneous injections of a once‐weekly glucagon‐like peptide‐1 analogue in healthy subjects. Methods: This phase 1, three‐period, crossover, double‐blind, placebo‐controlled study investigated single, escalating subcutaneous doses of LY2189265 (LY) ranging from 0.1 to 12 mg; approximately six subjects were randomized to each dose. Parameters of safety, including adverse events, were assessed. The pharmacokinetic profile was assessed over 14 days. Pharmacodynamic parameters (glucose and insulin concentrations) were measured following a step‐glucose infusion (day 3) and as part of an oral glucose tolerance test (OGTT) (day 5). Results: LY was generally well tolerated with some increase in gastrointestinal symptoms with escalating doses. There were small dose‐dependent increases in pulse rate with doses ≥1.0 mg and diastolic blood pressure with doses ≥3.0 mg. The half‐life of LY was approximately 90 h, with C_max occurring between 24 and 48 h in most subjects. Evidence of increase in glucose‐dependent insulin secretion and suppression of serum glucose excursions were observed during an OGTT at all doses compared to placebo; no episodes of hypoglycaemia occurred. No subjects developed antibodies to LY2189265. Conclusions: LY showed an acceptable safety profile and exhibited the expected glucagon‐like peptide‐1 pharmacological effects on glucose suppression and insulin secretion with a half‐life that supports once‐weekly dosing.     

Efficacy and safety of alirocumab in insulin‐treated individuals with type 1 or type 2 diabetes and high cardiovascular risk: The ODYSSEY DM‐INSULIN randomized trial

Aims

To investigate the efficacy and safety of alirocumab in participants with type 2 (T2D) or type 1 diabetes (T1D) treated with insulin who have elevated LDL cholesterol levels despite maximally tolerated statin therapy.

Methods

Participants at high cardiovascular risk with T2D (n = 441) or T1D (n = 76) and LDL cholesterol levels ≥1.8 mmol/L (≥70 mg/dL) were randomized 2:1 to alirocumab:placebo administered subcutaneously every 2 weeks, for 24 weeks' double‐blind treatment. Alirocumab‐treated participants received 75 mg every 2 weeks, with blinded dose increase to 150 mg every 2 weeks at week 12 if week 8 LDL cholesterol levels were ≥1.8 mmol/L. Primary endpoints were percentage change in calculated LDL cholesterol from baseline to week 24, and safety assessments.

Results

Alirocumab reduced LDL cholesterol from baseline to week 24 by a mean ± standard error of 49.0% ± 2.7% and 47.8% ± 6.5% vs placebo (both P < .0001) in participants with T2D and T1D, respectively. Significant reductions were observed in non‐HDL cholesterol (P < .0001), apolipoprotein B (P < .0001) and lipoprotein (a) (P ≤ .0039). At week 24, 76.4% and 70.2% of the alirocumab group achieved LDL cholesterol <1.8 mmol/L in the T2D and T1D populations (P < .0001), respectively. Glycated haemoglobin and fasting plasma glucose levels remained stable for the study duration. Treatment‐emergent adverse events were observed in 64.5% of alirocumab‐ vs 64.1% of placebo‐treated individuals (overall population).

Conclusions

Alirocumab produced significant LDL cholesterol reductions in participants with insulin‐treated diabetes regardless of diabetes type, and was generally well tolerated. Concomitant administration of alirocumab and insulin did not raise any safety concerns (NCT02585778).     

Safety,Tolerability, and Efficacy of Azilsartan Medoxomil With or Without Chlorthalidone During and After 8 Months of Treatment for Hypertension

A phase 3, 26‐week, open‐label, titrate‐to‐target study (n=418) assessed the safety of azilsartan medoxomil (AZL‐M) alone and with chlorthalidone (CLD), followed by a 6‐week, double‐blind, placebo‐controlled reversal phase with change in clinic diastolic blood pressure (DBP) as the primary endpoint. Target blood pressure (BP) was <140/90 mm Hg (<130/80 mm Hg with diabetes/chronic kidney disease). AZL‐M was initiated at 40 mg once a day (QD), force‐titrated to 80 mg at week 4. CLD 25 mg QD could be added (weeks 8–22), if required, to reach target, followed by additional antihypertensives from week 12. At the end of the open‐label phase, mean change in systolic BP (SBP)/DBP from baseline was ?23/?16 mm Hg. The most common adverse events, irrespective of treatment, were dizziness (8.9%) and headache (7.2%). Serious AEs were reported in eight patients (1.9%). Consecutive creatinine elevations ≥50% with values exceeding the upper limit of normal (ULN) were reported in nine (2.2%) patients. All returned to below the 50% threshold; most also returned to below the ULN after drug discontinuation. Mean DBP was maintained through the reversal phase in patients receiving AZL‐M, but increased with placebo (difference: ?7.8 mm Hg, 95% confidence interval, ?9.8 to ?5.8; P<.001). AZL‐M alone or with CLD showed good long‐term safety and stable BP improvements in a titrate‐to‐target approach. BP improvements caused by AZL‐M therapy were safely reversible upon AZL‐M withdrawal.     

Endurance testing for evaluation of antianginal therapy with amlodipine, a calcium channel blocking agent

The utility of using an endurance test as well as a maximal exercise test to assess the effect of amlodipine, a dihydropyridine calcium antagonist, was evaluated in 16 patients with angina pectoris. Amlodipine, 10 mg/day, was compared with placebo in a double blind crossover study. After a 2 week single blind placebo period, patients entered a double blind crossover phase alternating between 4 weeks of placebo and 4 weeks of amlodipine. The two 4 week periods were separated by a 1 week single blind placebo washout period. The efficacy of drug therapy was assessed by frequency of angina, nitroglycerin consumption, peak oxygen consumption during a maximal treadmill exercise test and endurance time during a separate exercise test performed at 70% of the peak work capacity determined before randomization. There was a reduction in angina frequency during the double blind placebo and amlodipine studies (single blind placebo 14 +/- 2 episodes/2 weeks, double blind placebo 7 +/- 2 episodes/2 weeks [p less than 0.005], amlodipine 6 +/- 3 episodes/2 weeks, [p less than 0.005]), whereas nitroglycerin consumption was reduced with amlodipine (single blind placebo 12 +/- 4 tablets/2 weeks, double blind placebo 8 +/- 3 tablets/2 weeks, amlodipine 5 +/- 3 tablets/2 weeks [p less than 0.01]). Amlodipine produced a significant increase in peak oxygen consumption (single blind placebo 18.7 +/- 1.1 ml/kg per min, double blind placebo 18.2 +/- 1.8 ml/kg per min, amlodipine 20.4 +/- 1.6 ml/kg per min [p less than 0.05]) and endurance time (single blind placebo 15.2 +/- 1.5 min, double blind placebo 15.8 +/- 2.1 min, amlodipine 20.2 +/- 2.5 min [p less than 0.005]).(ABSTRACT TRUNCATED AT 250 WORDS)     

Long‐term safety profile of belimumab plus standard therapy in patients with systemic lupus erythematosus

Objective

To evaluate the safety profile of long‐term belimumab therapy combined with standard therapy for systemic lupus erythematosus (SLE) in patients with active disease.

Methods

Patients who were randomized to receive intravenous placebo or belimumab 1, 4, or 10 mg/kg, plus standard therapy, and completed the initial 52‐week double‐blind treatment period were then allowed to enter a 24‐week open‐label extension phase. During the extension period, patients in the belimumab group either received the same dose or were switched to 10 mg/kg and patients in the placebo group were switched to belimumab 10 mg/kg. Patients who achieved a satisfactory response during the 24‐week extension period were allowed to participate in the long‐term continuation study of monthly belimumab 10 mg/kg. Adverse events (AEs) and abnormal laboratory results were analyzed per 100 patient‐years in 1‐year intervals.

Results

Of the 364 patients who completed the 52‐week double‐blind treatment period, 345 entered the 24‐week extension, and 296 continued treatment with belimumab in the long‐term continuation study. Safety data through 4 years of belimumab exposure (1,165 cumulative patient‐years) are reported. Incidence rates of AEs, severe/serious AEs, infusion reactions, infections, malignancies, grades 3/4 laboratory abnormalities, and discontinuations due to AEs were stable or declined during 4‐year belimumab exposure. The most common AEs included arthralgia, upper respiratory tract infection, headache, fatigue, and nausea. Serious infusion reactions were rare: only 1 occurred during the 4‐year followup period. Rates of serious infection decreased from 5.9/100 patient‐years to 3.4/100 patient‐years, and no specific type of infection predominated.

Conclusion

Belimumab added to standard therapy was generally well‐tolerated over the 4‐year treatment period in patients with SLE, which suggests that belimumab can be administered long term with an acceptable safety profile.

     

Dutogliptin,a selective DPP4 inhibitor,improves glycaemic control in patients with type 2 diabetes: a 12‐week,double‐blind,randomized, placebo‐controlled,multicentre trial

Aim: To determine efficacy and tolerability of dutogliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor, in patients with type 2 diabetes mellitus. Methods: This was a 12‐week, multicentre, randomized, double‐blind, placebo‐controlled trial in 423 patients with type 2 diabetes with suboptimal metabolic control. Following a 2‐week single‐blind placebo run‐in, patients aged 18–75 years with a body mass index of 25–48 kg/m² and baseline HbA1c of 7.3–11.0% were randomized 2:2:1 to receive once‐daily oral therapy with either dutogliptin (400 or 200 mg) or placebo on a background medication of either metformin alone, a thiazolidinedione (TZD) alone or a combination of metformin plus a TZD. Results: Average HbA1c at baseline was 8.4%. Administration of dutogliptin 400 and 200 mg for 12 weeks decreased HbA1c by ?0.52% (p < 0.001) and ?0.35% (p = 0.006), respectively (placebo‐corrected values), with absolute changes in HbA1c for the 400 mg, 200 mg and placebo groups of ?0.82, ?0.64 and ?0.3%, respectively. The proportion of patients achieving an HbA1c < 7% was 27, 21 and 12% at dutogliptin doses of 400 and 200 mg or placebo, respectively (p = 0.008 for comparison of 400 mg vs. placebo). Fasting plasma glucose (FPG) levels were significantly reduced in both active treatment groups compared to placebo: the placebo‐corrected difference was ?1.00 mmol/l (p < 0.001) for the 400 mg group and ?0.88 mmol/l (p = 0.003) for the 200 mg group. Dutogliptin caused significantly greater reductions in postprandial glucose AUC _0–2h in both the 400 and 200 mg groups (placebo corrected values ?2.58 mmol/l/h, p < 0.001 and ?1.63 mmol/l/h, p = 0.032, respectively). In general, patients tolerated the study drug well. There were minor, not clinically meaningful differences in adverse events (AEs) between dutogliptin‐treated patients and placebo controls, and 60% of all reported AEs were mild. Vital signs and body weight were stable, and routine safety laboratory parameters did not change compared with placebo. Trough ex vivo DPP4 inhibition at the end of the 12‐week treatment period was 80 and 70%, at the 400 and 200 mg doses of dutogliptin, respectively. Conclusions: Dutogliptin treatment for 12 weeks improved glycaemic control in patients with type 2 diabetes who were on a background medication of metformin, a TZD or metformin plus a TZD. Tolerability was favourable for both doses tested. The 400 mg dose of dutogliptin resulted in larger changes of HbA1c and FPG and more subjects reached an HbA1c target of < 7% than the 200 mg dose.     

Bopindolol for the treatment of chronic stable angina pectoris--a clinical study of the relationship between dose and effect

Following a 4-week placebo period, 19 patients (12 male, average age 62.3 years) with chronic stable angina pectoris and a positive exercise test were treated with the beta-adrenoceptor antagonists bopindolol at increasing doses of 0.5, 1 and 2 mg, each being given once daily for 4 weeks. For the final 4 weeks of the study, active treatment was replaced by placebo. Maximum tolerated exercise (bicycle ergometry, performed 24 h after drug administration) increased dose-dependently from 519 +/- 59 s (baseline) to 758 +/- 95 s with 2 mg (p less than 0.001) and fell again to 508 +/- 48 s (placebo). The frequency of anginal attacks also fell dose-dependently from an average of 5.4 per week (baseline) to 0.5 with 2 mg (p less than 0.001) and rose again to 5.1 per week when active treatment was stopped.     

Pharmacokinetic and pharmacodynamic properties of taspoglutide,a once‐weekly,human GLP‐1 analogue,after single‐dose administration in patients with Type 2 diabetes

Aims The study objectives were to evaluate the pharmacokinetic and pharmacodynamic properties, as well as safety and tolerability, of single doses of taspoglutide, a human glucagon‐like peptide‐1 (GLP‐1) analogue. Methods In a double‐blind, placebo‐controlled study, 48 patients with Type 2 diabetes [mean age 56 ± 7 years; mean body mass index (BMI) 30.4 ± 3.0 kg/m²] inadequately controlled with metformin (≤ 2 g/day) were enrolled in three sequential cohorts; 12 patients in each cohort were randomized to a single subcutaneous injection of taspoglutide (1, 8 or 30 mg) and four received placebo. Results Plasma concentrations peaked within 24 h after injection and were sustained for ≥ 14 days with all doses. In comparison with placebo, the 8‐ and 30‐mg doses of taspoglutide significantly reduced glycaemic parameters, including 24‐h blood glucose and 5‐h postprandial glucose areas under the curve (AUCs), for up to 14 days with the 30‐mg dose (P < 0.001). The most common adverse events, primarily gastrointestinal in nature, were dose‐dependent and transient. Conclusions A single dose of taspoglutide significantly improved glycaemic parameters in Type 2 diabetes patients for up to 14 days. The formulation was well tolerated and appears suitable for weekly administration.     

阿德福韦治疗乙型肝炎e抗原阳性慢性乙型肝炎3年的临床研究

目的评价阿德福韦酯（ADV）10 mg／d治疗HBeAg阳性的慢性乙型肝炎患者52、104、156周末的临床疗效和安全性。方法第一阶段：为随机、双盲、安慰剂对照研究,患者按3：1的比例随机接受ADV 10 mg（36例）或安慰剂（12例）治疗,每日1次,持续12周。第二阶段：患者均接受开放的ADV 10mg治疗,每日1次,持续28周。第三阶段：完成40周的治疗后,最初接受ADV治疗的患者重新按2：1的比例随机分入ADV组（24例）或安慰剂组（12例）接受相应的治疗,持续12周。即分为A、B、C 3组,A组：12例,前12周为安慰剂治疗,后40周为ADV治疗;B组：24例,52周均为ADV治疗;C组：12例,前40周为ADV治疗,后12周为安慰剂治疗。第四阶段：所有仍在研究中的患者继续接受开放的ADV 10 mg治疗共208周（4年）。结果（1）治疗12周后,HBV DNA水平降低,安慰剂组为-0．2 log10拷贝／ml,ADV组为-3．7 log10拷贝／ml,差异有统计学意义（t=8．0,P〈0．01）。（2）治疗12周后,ALT复常率,安慰剂组为0（0／11）,ADV组为10／36（27．8％）,差异有统计学意义（χ^2=3．9,P〈0．05）。（3）治疗40周后,3个治疗组ALT复常率相似。在B组,ALT复常率呈累积性增加。而在C组,ALT复常率显著降低。（4）治疗40周后,3个治疗组HBV DNA水平对数值降低中位数相似。40周后继续12周ADV治疗可以保持HBV DNA水平持续降低至52周。而在C组,HBV DNA水平降低被显著逆转。（5）治疗40周后,3个治疗组HBV DNA转阴率相似。在C组,52周时HBV DNA转阴率显著降低。（6）对于B组,HBeAg消失患者在52周时为12．5％（3／24）。两因素（血清HBeAg转阴,血清抗-HBe转阳）和三因素（血清HBeAg转阴,血清抗-HBe转阳且HBV DNA水平下降到≤10^5拷贝／ml）血清转换比率均为8．3％（2／24）。（7）治疗104周末及156周末,HBV DNA被持续抑制,104周HBV DNA水平对数值降低中位数为-4．2 log10拷贝／ml,156周为-4．3 log10拷贝／ml。HBV DNA阴转率均为31．0％,ALT复常率分别为46．3％、85．4％,HBeAg阴转率分别为23．8％、31．0％,HBeAg血清转换率均为23．8％。（8）研究期间各治疗组肌酐及血磷值平均水平与基线相比无变化,无数据表明肾脏安全性问题。结论ADV 10 mg／d治疗HBeAg阳性慢性乙型肝炎,可明显抑制HBV DNA的复制,使ALT复常,促进HBeAg的血清学转换,使用安全且耐受性良好。     

Empagliflozin as add‐on to linagliptin in a fixed‐dose combination in Japanese patients with type 2 diabetes: Glycaemic efficacy and safety profile in a 52‐week,randomized, placebo‐controlled trial

Aims

This double‐blind, randomized, placebo‐controlled trial ( ClinicalTrials.gov NCT02453555) evaluated the efficacy and safety of empagliflozin (Empa) 10 or 25 mg as add‐on to linagliptin (Lina) 5 mg (fixed‐dose combination, Empa/Lina 10/5 or 25/5) in insufficiently controlled Japanese type 2 diabetes patients.

Methods

The trial (40 sites; May 2015‐March 2017) involved screening 433 adults (≥20 years) who were treatment‐naive or were using one oral antidiabetic drug for ≥12 weeks, which was discontinued at enrolment. Patients with HbA1c 7.5%‐10.0% after ≥16 weeks of using Lina (pre‐enrolment or during a 16‐week, open‐label period) and 2 weeks of using placebo (Plc) for Empa/Lina 10/5, plus Lina, were randomized (2:1) to once‐daily Empa/Lina 10/5 (n = 182) or Plc/Lina 10/5 (n = 93) for 24 weeks. Patients with HbA1c ≥ 7.0% at Week 24 received Empa/Lina up‐titrated to 25/5 (n = 126) or the corresponding placebo (n = 80), per randomization, from Week 28; 172 Empa/Lina and 84 Plc/Lina patients completed 52 weeks.

Results

Change from baseline in HbA1c was greater (P < .0001) with Empa/Lina than with Plc/Lina at Week 24 (primary outcome, ?0.93% vs 0.21%; adjusted mean difference, ?1.14%) and Week 52 (?1.16% vs 0.06%; adjusted mean difference, ?1.22%). More patients with HbA1c < 7.0% and greater decreases in fasting plasma glucose, body weight and systolic blood pressure were seen in the Empa/Lina group than in the Plc/Lina group. Empa/Lina was well tolerated. The adverse events that were more frequent with Empa/Lina were known empagliflozin‐associated events (eg, increased urination, increased blood ketones). There were no adjudication‐confirmed diabetic ketoacidosis events or lower limb amputations.

Conclusions

These results support the notion that empagliflozin‐linagliptin in fixed‐dose combination is a therapeutic option for Japanese patients with type 2 diabetes.     

A randomized-controlled trial to investigate the effects of rivoglitazone, a novel PPAR gamma agonist on glucose-lipid control in type 2 diabetes

Aim: To examine the efficacy, safety and tolerability of rivoglitazone, a novel thiazolidinedione (TZD), and explore its effects on glucose and lipid control compared to placebo and pioglitazone in Chinese type 2 diabetic patients who are treatment naÏve or treated with a single oral blood glucose‐lowering drug. Methods: This was a double‐blind, randomized, placebo‐ and active‐controlled study. A total of 287 Chinese type 2 diabetic patients with suboptimal glycaemic control (defined as HbA1c ≥6.5 to <10% and fasting plasma glucose ≥7 to ≤15 mmol/l) were enrolled. One hundred and seventy‐four eligible patients were randomized into one of the five treatment arms for 12 weeks: placebo, pioglitazone 30 mg daily, rivoglitazone of dose 0.5, 1.0 or 1.5 mg daily. In a full set analysis, we used analysis of covariance to compare the primary endpoint defined as change in HbA1c from baseline to week 12/last observation carried forward in the rivoglitazone group at each dose level with the placebo group. Results: Changes in HbA1c were ?0.11% in the 0.5‐mg group; ?0.22% in the 1‐mg group and ?0.17% in the 1.5‐mg rivoglitazone group; ?0.06% in the 30‐mg pioglitazone group and 0.61% in the placebo group. Compared to placebo, changes were significant in all active treatment groups (all p < 0.05). Increase in high‐density lipoprotein cholesterol and decrease in triglyceride were observed in the rivoglitazone 1 and 1.5 mg groups, respectively, compared to placebo from baseline to week 12 (p < 0.05). Drug‐related oedema was reported in eight patients (7.7%) in all rivoglitazone groups compared to six patients (16.2%) in the pioglitazone group and one patient (3.0%) in the placebo group. Conclusions: Rivoglitazone is an efficacious, safe and well‐tolerated TZD which improved glycaemic control in Chinese type 2 diabetic patients up to 3 months.     

Effects of liraglutide on cardiovascular risk factors in patients with type 1 diabetes

We investigated the short‐term effect of adding liraglutide 1.8 mg once daily to insulin treatment on cardiovascular risk factors in patients with type 1 diabetes. In total, 100 overweight (BMI ≥25 kg/m²) adult patients (age ≥18 years) with type 1 diabetes and HbA1c ≥ 8% (64 mmol/mol) were randomized to liraglutide 1.8 mg or placebo added to insulin treatment in a 24‐week double‐blinded, placebo‐controlled trial. At baseline and after 24 weeks of treatment, 24‐hour blood pressure and heart rate, pulse pressure, pulse wave velocity and carotid intima‐media thickness were evaluated. Compared with placebo, liraglutide increased 24‐hour heart rate by 4.6 beats per minute (BPM); P = .0015, daytime heart rate by 3.7; P = .0240 and night‐time heart rate by 7.5 BPM; P < .001 after 24 weeks. Diastolic nocturnal blood pressure increased by 4 mm Hg; P = .0362 in the liraglutide group compared with placebo. In conclusion, in patients with long‐standing type 1 diabetes, liraglutide as add‐on to insulin increased heart rate and did not improve other cardiovascular risk factors after 24 weeks of treatment.     

Improved glycaemic control with minimal hypoglycaemia and no weight change with the once‐daily human glucagon‐like peptide‐1 analogue liraglutide as add‐on to sulphonylurea in Japanese patients with type 2 diabetes

Aim: Sulphonylureas (SUs) are often used as first‐line treatments for type 2 diabetes in Japan, hence it is important to study new antidiabetic drugs in combination with SUs in Japanese patients. Methods: The efficacy and safety of the once‐daily human glucagon‐like peptide‐1 (GLP‐1) analogue liraglutide were compared in 264 Japanese subjects [mean body mass index (BMI) 24.9 kg/m²; mean glycated haemoglobin (HBA1c) 8.4%] randomized and exposed to receive liraglutide 0.6 mg/day (n = 88), 0.9 mg/day (n = 88) or placebo (n = 88) each added to SU monotherapy (glibenclamide, glicazide or glimeprimide) in a 24‐week, double‐blind, parallel‐group trial. Results: The mean change in HBA1c from baseline to week 24 (LOCF) was ?1.56 (s.d. 0.84) and ?1.46 (s.d. 0.95) with liraglutide 0.9 and 0.6 mg respectively, and ?0.40 (s.d. 0.93) with placebo. HBA1c decreased in the placebo group from 8.45 to 8.06%, while liraglutide reduced HBA1c from 8.60 to 7.14%, and from 8.23 to 6.67% at the 0.6 and 0.9 mg doses respectively. Mean HBA1c at week 24 of the two liraglutide groups were significantly lower than the placebo group (p < 0.0001 for both). More subjects reached HBA1c < 7.0% with liraglutide (0.6 mg: 46.5%; 0.9 mg: 71.3%) vs. placebo (14.8%). Fasting plasma glucose (FPG) levels were significantly improved with liraglutide (difference ?1.47 mmol/l and ?1.80 mmol/l with 0.6 and 0.9 mg vs. placebo; p < 0.0001). Overall safety was similar between treatments: no major hypoglycaemic episodes were reported, while 84/77/38 minor hypoglycaemic episodes occurred in the 0.6 mg/0.9 mg and placebo treatment groups (all in combination with SU), reflecting lower ambient glucose levels. No relevant change in mean body weight occurred in subjects receiving liraglutide (0.6 mg: 0.06 kg; 0.9 mg: ?0.37 kg), while mean body weight decreased in subjects receiving placebo (?1.12 kg). Conclusions: The addition of liraglutide to SU treatment for 24 weeks dose‐dependently improved glycaemic control vs. SU monotherapy, without causing major hypoglycaemia or weight gain or loss.     

Treatment of rheumatoid arthritis with anakinra,a recombinant human interleukin‐1 receptor antagonist,in combination with methotrexate: Results of a twenty‐four–week,multicenter, randomized,double‐blind,placebo‐controlled trial

Objective

To evaluate the efficacy and safety of anakinra in combination with methotrexate (MTX) in patients with active rheumatoid arthritis (RA).

Methods

Patients with moderate‐to‐severe active RA who were receiving MTX for 6 consecutive months, with stable doses for ≥3 months (those with disease duration of >6 months but <12 years) were randomized into 6 groups: placebo or 0.04, 0.1, 0.4, 1.0, or 2.0 mg/kg of anakinra administered in a single, daily, subcutaneous injection. The primary efficacy end point was the proportion of subjects who met the American College of Rheumatology 20% improvement criteria (attained an ACR20 response) at week 12.

Results

A total of 419 patients were randomized in the study. Patient demographics and disease status were similar in the 6 treatment groups. The ACR20 responses at week 12 in the 5 active treatment plus MTX groups demonstrated a statistically significant (P = 0.001) dose‐response relationship compared with the ACR20 response in the placebo plus MTX group. The ACR20 response rate in the anakinra 1.0‐mg/kg (46%; P = 0.001) and 2.0‐mg/kg (38%; P = 0.007) dose groups was significantly greater than that in the placebo group (19%). The ACR20 responses at 24 weeks were consistent with those at 12 weeks. Similar improvements in anakinra‐treated subjects were noted in individual ACR components, erythrocyte sedimentation rate, onset of ACR20 response, sustainability of ACR20 response, and magnitude of ACR response. Anakinra was safe and well tolerated. Injection site reaction was the most frequently noted adverse event, and this led to premature study withdrawal in 7% (1.0‐mg/kg group) to 10% (2.0‐mg/kg group) of patients receiving higher doses.

Conclusion

In patients with persistently active RA, the combination of anakinra and MTX was safe and well tolerated and provided significantly greater clinical benefit than MTX alone.

     

MQX‐503, a novel formulation of nitroglycerin,improves the severity of Raynaud's phenomenon: A randomized,controlled trial

Objective

Raynaud's phenomenon (RP) affects 3–9% of the general population and >90% of patients with systemic sclerosis. Nitrates are often prescribed for the treatment of RP, but currently available formulations are limited by side effects, particularly headaches, dizziness, and skin irritation. The purpose of this study was to evaluate the tolerability and efficacy of a novel formulation of topical nitroglycerin, MQX‐503, in the treatment of RP in an ambulatory setting.

Methods

We conducted a multicenter, randomized, placebo‐controlled study with a 2‐week single‐blind run‐in period to determine baseline severity, followed by a 4‐week double‐blind treatment phase. Two hundred nineteen adult patients with a clinical diagnosis of primary or secondary RP received 0.9% MQX‐503 gel or matching placebo during the treatment period. Gel was applied immediately before or within 5 minutes of the beginning of an episode of RP (maximum of 4 applications daily). End points included the change in the mean Raynaud's Condition Score (RCS; scale 0–10), the frequency and duration of episodes, and subjective assessments at the target week (the week during the treatment phase that most closely matched the run‐in period in terms of ambient temperature) compared with baseline.

Results

The mean (%) change in the RCS at the target week compared with baseline was significantly greater in the MQX‐503 group (0.48 [14.3%]) than that in the placebo group (0.04 [1.3%]; P = 0.04). Changes in the frequency and duration of RP episodes and subjective assessments were not statistically different between the groups. MQX‐503 had a side effect profile similar to that of placebo.

Conclusion

MQX‐503 is well tolerated and more effective than placebo for the treatment of RP.