Pharmacokinetic Interaction of the Direct Renin Inhibitor Aliskiren with Furosemide and Extended‐Release Isosorbide‐5‐Mononitrate in Healthy Subjects

This study investigated the pharmacokinetics, safety, and tolerability of aliskiren administered alone or in combination with either the loop diuretic furosemide or an oral extended‐release formulation of isosorbide‐5‐mononitrate (ISMN). In separate studies, 22 healthy subjects (ages 18–45 years) received either ISMN 40 mg or furosemide 20 mg once‐daily for 3 days followed by a 3‐day washout. Subjects then received aliskiren 300 mg once‐daily for 7 days followed by combination therapy for 3 days. Pharmacokinetic assessments were taken at regular intervals over 24 h after dosing on the last day of each treatment period. At steady state, aliskiren AUC_τ was decreased by 7% (geometric mean ratio [90% CI], 0.93 [0.84, 1.04]), and C_max by 20% (0.80 [0.65, 0.97]) with furosemide coadministration compared with aliskiren administration alone. Aliskiren coadministration reduced furosemide AUC_τ by 28% (0.72 [0.64, 0.81]) and C_max by 49% (0.51 [0.39, 0.66]) compared with furosemide alone. Coadministration of aliskiren and ISMN was associated with only minor changes in the pharmacokinetic parameters of aliskiren (AUC_τ 1.03 [0.90, 1.18]; C_max 0.94 [0.69, 1.29]) and ISMN (AUC_τ 0.88 [0.71, 1.10]; C_max 0.94 [0.79, 1.13]). Headache and dizziness were the most common adverse events in both studies; dizziness and BP values below normal (SBP <90 and/or DBP <50 mmHg) were more frequent with aliskiren and ISMN coadministration than with either agent alone. Coadministration of aliskiren and ISMN had no clinically relevant effect on either aliskiren or ISMN pharmacokinetics. In conclusion, coadministration of aliskiren and furosemide reduced furosemide exposure and had a minor effect on aliskiren pharmacokinetics. The clinical significance of reduced systemic exposure to furosemide during coadministration of aliskiren is uncertain.     

Direct renin inhibition in addition to or as an alternative to angiotensin converting enzyme inhibition in patients with chronic systolic heart failure: rationale and design of the Aliskiren Trial to Minimize OutcomeS in Patients with HEart failuRE (ATMOSPHERE) study

AIMS: The renin-angiotensin-aldosterone system (RAAS) represents a key therapeutic target in heart failure (HF) management. However, conventional agents that block this system induce a reflex increase in plasma renin activity (PRA), which may lead to RAAS 'escape'. Direct renin inhibitors (DRIs) have been developed that decrease PRA and thus may provide a greater RAAS blockade. Aliskiren is the first orally active DRI. Plasma levels of B-type natriuretic peptide (BNP) have been observed to be reduced with aliskiren compared with placebo. The aim of the Aliskiren Trial of Minimizing OutcomeS for Patients with HEart failuRE (ATMOSPHERE) study is to evaluate the effect of both aliskiren and enalapril monotherapy and aliskiren/enalapril combination therapy on cardiovascular death and HF hospitalization in patients with chronic systolic HF, NYHA functional class II-IV symptoms, and elevated plasma levels of BNP. Methods Patients tolerant to at least 10 mg or equivalent of enalapril will undergo an open-label run-in period where they receive enalapril then aliskiren. Approximately 7000 patients tolerating this run-in period will then be randomized 1:1:1 to aliskiren monotherapy, enalapril monotherapy, or the combination. The primary endpoints of ATMOSPHERE are (i) whether the aliskiren/enalapril combination is superior to enalapril monotherapy in delaying time to first occurrence of cardiovascular death or HF hospitalization and (ii) whether aliskiren monotherapy is superior or at least non-inferior to enalapril monotherapy on this endpoint. Perspective The ATMOSPHERE study will definitively determine the role of a DRI strategy additional to or as an alternative to conventional RAAS blockade in patients with chronic systolic HF.     

Efficacy and Safety of an Oral Fixed Low-Dose Perindopril 2 mg/Indapamide 0.625 mg Combination: A Randomized,Double-Blind,Placebo-Controlled Study in Elderly Patients with Mild to Moderate Hypertension

The efficacy and safety of 12 weeks treatment with an oral fixed low-dose perindopril 2 mg + indapamide 0.625 mg (Per/Ind) combination in elderly and very elderly patients (65-85 years) with mild to moderate systolic and diastolic     

Efficacy and safety of vildagliptin and voglibose in Japanese patients with type 2 diabetes: a 12‐week,randomized, double‐blind,active‐controlled study

Aim: To confirm the efficacy of vildagliptin in patients with type 2 diabetes (T2D) by testing the hypothesis that glycosylated haemoglobin (HbA1c) reduction with vildagliptin is superior to that with voglibose after 12 weeks of treatment. Methods: In this 12‐week, randomized, double‐blind, active‐controlled, parallel‐group study, the efficacy and safety of vildagliptin (50 mg bid, n = 188) was compared with that of voglibose (0.2 mg tid, n = 192) in patients with T2D who were inadequately controlled with diet and exercise. Results: The characteristics of two groups were well matched at baseline. The mean age, body mass index (BMI) and HbA1c were 59.1 years, 24.9 kg/m² and 7.6%, respectively. At baseline, fasting plasma glucose (FPG) and 2‐h postprandial glucose (PPG) were 9.01 mmol/l (162.2 mg/dl) and 13.57 mmol/l (244.3 mg/dl), respectively. The adjusted mean change in HbA1c from baseline to endpoint was ?0.95 ± 0.04% in the vildagliptin‐treated patients and ?0.38 ± 0.04% in those receiving voglibose (between‐group change = 0.57 ± 0.06%, 95% confidence interval (CI) (?0.68 to ?0.46%), p < 0.001), showing that vildagliptin was superior to voglibose. Endpoint HbA1c ≤ 6.5% was achieved in 51% vildagliptin‐treated patients compared with 24% patients who were on voglibose (p < 0.001). Vildagliptin also exhibited significantly (p < 0.001) greater reduction compared with voglibose in both FPG [1.34 vs. 0.43 mmol/l (24.1 vs. 7.8 mg/dl)] and 2‐h PPG [2.86 vs. 1.1 mmol/l (51.5 vs. 19.8 mg/dl)]. Overall adverse events (AEs) were lower in the vildagliptin‐treated patients compared with that in the voglibose‐treated patients (61.2 vs. 71.4%), with no incidence of hypoglycaemia and serious adverse events with vildagliptin. Gastrointestinal AEs were significantly lower with vildagliptin compared with that of the voglibose (18.6 vs. 32.8%; p = 0.002). Conclusions: Vildagliptin (50 mg bid) showed superior efficacy and better tolerability compared with voglibose in Japanese patients with T2D.     

Efficacy and safety of teneligliptin added to canagliflozin monotherapy in Japanese patients with type 2 diabetes mellitus: A multicentre,randomized, double‐blind,placebo‐controlled,parallel‐group comparative study

Dipeptidyl peptidase‐4 (DPP‐4) inhibitors and sodium glucose co‐transporter 2 (SGLT2) inhibitors are frequently used in combination for the treatment of type 2 diabetes mellitus (T2DM). We examined the efficacy and safety of teneligliptin (a DPP‐4 inhibitor) added to canagliflozin (an SGLT2 inhibitor) monotherapy in Japanese patients with poorly controlled T2DM as part of the development of a fixed‐dose combination of teneligliptin and canagliflozin. Japanese patients treated with canagliflozin (100 mg) for ≥12 weeks were randomized to receive add‐on teneligliptin (20 mg; C + T group) or placebo (C + P group) for 24 weeks. The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline to Week 24. The between‐group differences in reductions from baseline to Week 24 were significantly greater in the C + T group for HbA1c (?0.94%; P < .001). The incidence of adverse events was similar in both groups (55.8% and 49.4% in the C + T and C + P groups, respectively). No episodes of hypoglycaemia were reported. Teneligliptin added to ongoing canagliflozin monotherapy improved glycaemic control and was well tolerated in Japanese patients with inadequately controlled T2DM.     

Efficacy and safety of teneligliptin,a novel dipeptidyl peptidase‐4 inhibitor,in Korean patients with type 2 diabetes mellitus: a 24‐week multicentre,randomized, double‐blind,placebo‐controlled phase III trial

We assessed the 24‐week efficacy and safety of teneligliptin, a novel dipeptidyl peptidase‐4 inhibitor, in Korean patients with type 2 diabetes mellitus (T2DM) that was inadequately controlled with diet and exercise. The present study was designed as a multicentre, randomized, double‐blind, placebo‐controlled, parallel‐group, phase III study. Patients (n = 142) were randomized 2 : 1 into two different treatment groups as follows: 99 received teneligliptin (20 mg) and 43 received placebo. The primary endpoint was change in glycated haemoglobin (HbA1c) level from baseline to week 24. Teneligliptin significantly reduced the HbA1c level from baseline compared with placebo after 24 weeks. At week 24, the differences between changes in HbA1c and fasting plasma glucose (FBG) in the teneligliptin and placebo groups were ?0.94% [least‐squares (LS) mean ?1.22, ?0.65] and ?1.21 mmol/l (?1.72, ?0.70), respectively (all p < 0.001). The incidence of hypoglycaemia and adverse events were not significantly different between the two groups. This phase III, randomized, placebo‐controlled study provides evidence of the safety and efficacy of 24 weeks of treatment with teneligliptin as a monotherapy in Korean patients with T2DM.     

The association of calcium channel blockers with β‐cell function in type 2 diabetic patients: A cross‐sectional study

Type 2 diabetes mellitus (T2DM) patients are often accompanied with hypertension. However, the association of antihypertensive drugs with β‐cell function has not been well studied. To investigate this question, the authors performed a cross‐sectional study involving 882 hypertensive T2DM patients. To assess β‐cell function, patients were given 75g glucose orally and C‐peptide levels before and 1, 2, and 3 hours after glucose intake were measured. Homa‐β was computed by Homeostasis Model Assessment model to evaluate β‐cell function using fasting C‐peptide and glucose levels in the plasma. Multivariable‐adjusted analysis was performed to evaluate the association of antihypertensive drugs with C‐peptide levels, HbA1c, and Homa‐β. Among 882 hypertensive patients, 547 (62.0%) received antihypertensive treatment. Multivariate‐adjusted analysis demonstrated that use of calcium channel blockers (CCBs) was negatively associated with HbA1c levels (CCBs: 0.95 [95% CI: 0.92‐0.98], P = 0.002). Our data further illustrated that the C‐peptide levels before and 1, 2, and 3 hours of OGTT were 1.10‐, 1.18‐, 1.19‐, and 1.15‐fold increase in T2DM patients taking CCBs (P = 0.084 for fasting C‐peptide levels; P ≤ 0.024 for C‐peptide levels at 1, 2, and 3 hours after OGTT) in comparison with non‐CCB users. Nevertheless, usage of any other antihypertensive drugs did neither associated with HbA1c nor associated with C‐peptide levels (P ≥ 0.11). In conclusion, CCB treatment was negatively associated with HbA1c levels but positively associated with β‐cell function in hypertensive T2DM patients, implying that CCBs could be considered to treat hypertensive T2DM patients with reduced β‐cell function.     

Efficacy and safety of sitagliptin monotherapy compared with voglibose in Japanese patients with type 2 diabetes: a randomized,double‐blind trial

Objective: To compare the efficacy and safety of sitagliptin (a dipeptidyl peptidase‐4 inhibitor) and voglibose (an α‐glucosidase inhibitor) monotherapy in Japanese patients with type 2 diabetes who have inadequate glycaemic control (HbA1c ≥6.5% and <10.0%) on diet and exercise. Methods: In a multi‐center, randomized, double‐blind, parallel‐group study, 319 patients were randomized (1:1) to 12‐week treatment with sitagliptin 50 mg once daily or voglibose 0.2 mg thrice daily before meals. The primary analysis assessed whether sitagliptin was non‐inferior to voglibose in lowering HbA1c. Results: After 12 weeks, sitagliptin was non‐inferior to voglibose for HbA1c‐lowering efficacy. Furthermore, sitagliptin was superior to voglibose, providing significantly greater reductions in HbA1c from baseline [least squares mean changes in HbA1c [95% confidence intervals (CI)] = ?0.7% (?0.8 to ?0.6) and ?0.3% (?0.4 to ?0.2), respectively; between‐group difference = ?0.4% (?0.5 to ?0.3), p < 0.001]. Sitagliptin was also superior to voglibose on other key efficacy endpoints, including change from baseline in 2‐h postmeal glucose (?2.8 mmol/l vs. ?1.8 mmol/l, p < 0.001) and fasting plasma glucose (?1.1 mmol/l vs. ?0.5 mmol/l, p < 0.001). After 12 weeks, the incidences of clinical adverse experiences (AEs), drug‐related AEs and gastrointestinal AEs in the sitagliptin group (48.5, 10.4 and 18.4%, respectively) were significantly (p < 0.05) lower than those in the voglibose group (64.7, 26.3 and 34.6%, respectively). The incidences of hypoglycaemia, serious AEs and discontinuations due to AEs were low and similar in both groups. Conclusions: In Japanese patients with type 2 diabetes, once‐daily sitagliptin monotherapy showed greater efficacy and better tolerability than thrice‐daily voglibose over 12 weeks.     

老年2型糖尿病肾病合并高血压患者应用硝苯地平控释片联合缬沙坦治疗的疗效分析

目的 分析老年2型糖尿病肾病合并高血压患者应用硝苯地平控释片联合缬沙坦治疗的疗效.方法 实验中老年2型糖尿病肾病合并高血压患者180例均在2019年2—9月期间入院治疗,抛硬币法下将患者平分为对照组和实验组,对照组(n=90)给予缬沙坦治疗,实验组(n=90)给予硝苯地平控释片联合缬沙坦治疗,对比两组疗效、血糖变化与不...     

Hypertension in Diabetes Study III. Prospective Study of Therapy of Hypertension in Type 2 Diabetic Patients: Efficacy of ACE Inhibition and β-Blockade

The Hypertension in Diabetes Study (HDS) is an ongoing, multicentre, prospective randomized intervention trial of therapy of hypertension (> 160 and/or > 90 mmHg) in Type 2 diabetic patients. It compares tight blood pressure control (aim: < 150/85 mmHg) versus less tight control (aim: < 180/105 mmHg) and, within the tight control group, an ACE inhibitor, captopril, versus a beta blocker, atenolol. We report the efficacy, side-effects of treatment, biochemical responses and incidence of hypoglycaemia in 755 patients (mean age 57 years, blood pressure 150/94 mmHg) followed for 2 years. At 2 years, blood pressure was 143/84 in the tight control and 156/90 mmHg in the less tight control group (p < 0.0001). Blood pressure reduction, adherence to therapy, incidence of side-effects and of hypoglycaemia were similar on captopril and on atenolol. Patients on atenolol had a greater increase in body weight (+ 2.3 vs + 0.7 kg, p < 0.01) and a non-significant trend to a greater increase in triglyceride than patients on captopril. A large blood pressure difference between the tight control and less tight control groups was obtained, with captopril and atenolol having similar hypotensive effects. The study has the potential to determine whether strict blood pressure control reduces the incidence of diabetic complications and whether ACE inhibitor or β-blocker therapy is clinically advantageous.     

国产苯磺酸氨氯地平降压效果及安全性的多中心随机临床对照研究

目的　比较国产苯磺酸氨氯地平 (安内真 ) 5mg与进口苯磺酸氨氯地平 (络活喜 ) 5mg每天一次口服治疗原发性轻、中度高血压的有效性和安全性。方法　多中心、随机平行对照研究 ,98例轻、中度高血压患者被随机分入安内真组和络活喜组 ,分别每天一次口服安内真 5mg或络活喜 5mg ,2周后如坐位舒张压 >90mmHg或坐位收缩压 >14 0mmHg ,则改为安内真 10mg或络活喜 10mg、每天一次口服。结果　服药 2 ,4周时 ,安内真与络活喜两组平均舒张压和收缩压均明显下降 ,两组比较无明显差异 ;治疗 4周时两组控制血压的总有效率分别为 75 56% ,77 0 8% ,两组间无明显差异 ;不良反应事件发生率低 ,两组相似。结论　国产苯磺酸氨氯地平 (安内真 ) 5mg或 10mg每日一次治疗原发性轻、中度高血压安全有效 ,其疗效与进口苯磺酸氨氯地平 (络活喜 )等同