Clinical effectiveness and safety of amlodipine/losartan‐based single‐pill combination therapy in patients with hypertension: Findings from real‐world,multicenter observational databases

Various single‐pill combinations (SPCs) have been introduced to improve drug compliance and clinical efficacy. However, there is a lack of real‐world evidence regarding the effectiveness of these SPCs for hypertension. This study evaluated the real‐world clinical efficacy and safety of amlodipine/losartan‐based SPC therapies in patients with hypertension in a real‐world setting. A total of 15 538 patients treated with amlodipine/losartan‐based SPCs [amlodipine + losartan (AL), amlodipine + losartan + rosuvastatin (ALR), and amlodipine + losartan + chlorthalidone (ALC)] were selected from the database of three tertiary hospitals in Korea. The efficacy endpoints were target blood pressure (BP) and low‐density lipoprotein cholesterol (LDL‐C) achievement rates. Safety was evaluated based on laboratory parameters. Drug adherence was defined as the proportion of medication days covered (PDC). The target BP attainment rate was above 90% and was similar among the three groups. Although many patients in the AL and ALC groups took statins, the target LDL‐C attainment rate was significantly higher in the ALR group than in the AL and ALC groups. Safety endpoints were not significantly different among the groups, except serum uric acid level and incidence rate of new‐onset hyperuricemia, which were significantly lower in the AL and ALR groups than in the ALC group. The PDC was > 90% in all groups. In the real‐world hypertensive patients, amlodipine/losartan‐based SPC therapy demonstrated good target BP achievement rates. Especially, rosuvastatin‐combination SPC showed better target LDL‐C goal achievement rate compared to the other SPCs. All three amlodipine/losartan‐based SPC had excellent drug adherence.     

A randomized,double‐blind clinical trial to evaluate the efficacy and safety of a fixed‐dose combination of amlodipine/rosuvastatin in patients with dyslipidemia and hypertension

This multicenter, randomized, double‐blind, parallel‐group phase III clinical trial aimed to investigate the efficacy and safety of a rosuvastatin + amlodipine combination compared with that of rosuvastatin or amlodipine monotherapy in hypertensive patients with dyslipidemia. A total of 106 patients of 15 institutions in Korea were randomly assigned to 1 of 3 treatment groups: rosuvastatin 20 mg + amlodipine 10 mg, amlodipine 10 mg, or rosuvastatin 20 mg. After 8 weeks of treatment, the mean ± SD of change in mean sitting systolic blood pressure (msSBP) was −22.82 ± 12.99 mm Hg in the rosuvastatin + amlodipine group, the most decreased among the treatment groups. The percentage of patients whose msSBP decreased ≥20 mm Hg or msDBP decreased ≥10 mm Hg was also highest in this group (74.29%). The mean ± SD percentage change in low‐density lipoprotein cholesterol (LDL‐C) level from baseline after 8 weeks was −52.53% ± 11.21% in the rosuvastatin + amlodipine group, the most decreased among the treatment groups. More patients in the rosuvastatin + amlodipine group achieved their target LDL‐C goal at 8 weeks, compared with the other treatment groups (97.14%). No serious adverse events or adverse drug reactions were observed in all groups. In hypertensive patients with dyslipidemia, combination treatment with rosuvastatin 20 mg + amlodipine 10 mg effectively reduced blood pressure and LDL‐C levels while maintaining safety.     

Assessment of suitable antihypertensive therapies: Combination with high‐dose amlodipine/irbesartan vs triple combination with amlodipine/irbesartan/indapamide (ASAHI‐AI study)

Angiotensin receptor blockers (ARBs) plus calcium channel blockers (CCBs) are a widely used combination therapy for hypertensive patients. In order to determine which combination was better as the next‐step therapy for standard‐dose combination of ARBs and CCBs, a combination with high‐dose CCBs or a triple combination with diuretics, the authors conducted a prospective, randomized, open‐label trial to determine which of the following combination is better as the next‐step treatment: a combination with high‐dose CCBs or a triple combination with diuretics. Hypertensive outpatients who did not achieve their target blood pressure (BP) with usual dosages of ARBs and amlodipine 5 mg were randomly assigned to treatment with irbesartan 100 mg/amlodipine 10 mg (Group 1: n = 48) or indapamide 1 mg in addition to ARBs plus amlodipine 5 mg (Group 2: n = 46). The primary end point was changes in the systolic BP (SBP) and diastolic BP (DBP) after the 12‐week treatment period, while secondary end points were changes in BP after the 24‐week treatment period and laboratory values. At 12 weeks, the SBP/DBP significantly decreased from 152.1/83.4 mm Hg to 131.5/76.1 mm Hg in Group 1 and 153.9/82.1 mm Hg to 132.7/75.9 mm Hg in Group 2. Although both groups produced a similar efficacy in reducing the SBP/DBP (−19.2/‐9.2 mm Hg in Group 1 and −21.6/‐8.8 mm Hg in Group 2; SBP P = .378, DBP P = .825), high‐dose CCBs combined with ARBs controlled hypertension without elevation of serum uric acid. These results will provide new evidence for selecting optimal combination therapies for uncontrolled hypertensive patients.     

复方替米沙坦对单药控制不良高血压患者的有效性和安全性

目的 评价复方替米沙坦在替米沙坦单药治疗无充分反应时中国高血压患者中的有效性和安全性.方法 多中心、随机、双盲、双模拟临床试验.经1周安慰剂筛选期,699例符合入选标准的轻、中度高血压患者进入80 mg替米沙坦单药开放治疗期.345例对替米沙坦单药开放治疗8周无充分反应[平均坐位舒张压≥90 mm Hg(1 mm Hg=0.133 kPa)]的患者进入为期8周的随机双盲治疗期.175例患者进入复方替米沙坦治疗组(80 mg替米沙坦加12.5 mg氢氯噻嗪),170例进入80 mg替米沙坦单药治疗组.每次随访测量坐位和立位的收缩压和舒张压谷值,记录不良事件.筛选期以及开放和随机双盲治疗期结束时进行实验室和心电图检查.结果 (1)与开放治疗期结束(基线)比较,随机双盲治疗8周后,复方替米沙坦组坐位舒张压谷值平均下降10.1 mm Hg,替米沙坦单药组平均下降7.7 mm Hg,两组间比较P=0.0017.复方替米沙坦组坐位收缩压谷值平均下降14.2 mm Hg,替米沙坦单药组平均下降7.4 mm Hg,两组间比较P＜0.0001.(2)与基线比较,随机双盲治疗8周后,复方替米沙坦组立位舒张压和收缩压谷值平均下降幅度大于替米沙坦单药组,两组间比较P=0.0350和P＜0.0001.(3)按照平均坐位舒张压谷值＜90 mm Hg和(或)与基线值相比降低≥10 mm Hg评价,随机双盲治疗8周后,复方替米沙坦组有效率为74.6%(129例患者),替米沙坦单药组为59.2%(100例患者),两组间比较P=0.0016.(4)在随机双盲期,两组与试验药物有关的不良事件发生率分别为3.5%和3.6%,两组间比较P＞0.05.结论 替米沙坦单药治疗无充分反应的中国高血压患者,复方替米沙坦每日口服一次能够进一步降低血压,且安全性良好.     

A randomized multicenter study on ambulatory blood pressure and arterial stiffness in patients treated with valsartan/amlodipine or nifedipine GITS

In a pre‐specified subgroup analysis of a 12‐week randomized multicenter study, we investigated effects of valsartan/amlodipine 80/5 mg single‐pill combination (n = 75) and nifedipine GITS 30 mg (n = 75) on ambulatory blood pressure (BP) and arterial stiffness assessed by brachial‐ankle pulse wave velocity (PWV) in patients with uncontrolled hypertension. At week 12, the between‐treatment mean differences in systolic/diastolic BP were smaller for 24‐hour and daytime (–2.1/–1.7 and −2.0/−1.5 mm Hg, respectively, P ≥ 0.22) but greater (P < 0.01) for nighttime (–4.0/‐2.8 mm Hg, P ≤ 0.09), especially in sustained uncontrolled hypertension (−5.0/−4.1 mm Hg, P ≤ 0.04) and non‐dippers (−6.5/−3.7 mm Hg, P ≤ 0.07), in favor of valsartan/amlodipine. At week 12, PWV was significantly reduced from baseline by valsartan/amlodipine (n = 59, P < 0.0001) but not nifedipine (n = 59, P = 0.06). The changes in PWV were significantly associated with that in ambulatory systolic BP and pulse pressure in the nifedipine (P ≤ 0.0008) but not valsartan/amlodipine group (P ≥ 0.57), with a significant interaction (P ≤ 0.045). The valsartan/amlodipine combination was more efficacious than nifedipine GITS in lowering nighttime BP in sustained uncontrolled hypertension and non‐dippers, and in lowering arterial stiffness independent of BP lowering.     

Blood pressure–lowering efficacy of indapamide SR/amlodipine combination in older patients with hypertension: A post hoc analysis of the NESTOR trial (Natrilix SR vs Enalapril in Hypertensive Type 2 Diabetics With Microalbuminuria)

To examine the antihypertensive efficacy and safety of indapamide sustained‐release (SR)/amlodipine compared with enalapril/amlodipine in patients 65 years and older with uncontrolled blood pressure (BP) on monotherapy, a post hoc analysis of the NESTOR trial (Natrilix SR vs Enalapril in Hypertensive Type 2 Diabetics With Microalbuminuria) was conducted. NESTOR randomized 570 patients (n=197, aged ≥65 years) with hypertension (systolic BP 140–180/diastolic BP <110 mm Hg) to indapamide SR 1.5 mg or enalapril 10 mg. If target BP (<140/85 mm Hg) was not achieved at 6 weeks, amlodipine 5 mg was added with uptitration to 10 mg if required. A total of 107 patients aged 65 years and older received dual therapy (53 indapamide SR/amlodipine and 54 enalapril/amlodipine). Amlodipine uptitration occurred in 22 and 24 patients, respectively. At 52 weeks, mean systolic BP (±SE) reduction was significantly greater with indapamide SR/amlodipine vs enalapril/amlodipine 6.2±2.7 mm Hg (P=.02). Indapamide SR/amlodipine was also associated with a greater BP response rate (88% vs 75%, respectively). Both regimens were well tolerated. Indapamide SR/amlodipine may be more effective than enalapril/amlodipine for lowering systolic BP in patients with hypertension aged 65 years and older.     

A randomized controlled trial on the blood pressure–lowering effect of amlodipine and nifedipine‐GITS in sustained hypertension

In a multicenter, randomized trial, we investigated whether the long half‐time dihydropyridine calcium channel blocker amlodipine was more efficacious than the gastrointestinal therapeutic system (GITS) formulation of nifedipine in lowering ambulatory blood pressure (BP) in sustained hypertension (clinic systolic/diastolic BP 140‐179/90‐109 mm Hg and 24‐hour systolic/diastolic BP ≥ 130/80 mm Hg). Eligible patients were randomly assigned to amlodipine 5‐10 mg/day or nifedipine‐GITS 30‐60 mg/day. Ambulatory BP monitoring was performed for 24 hours at baseline and 4‐week treatment and for 48 hours at 8‐week treatment with a dose of medication missed on the second day. After 8‐week treatment, BP was similarly reduced in the amlodipine (n = 257) and nifedipine‐GITS groups (n = 248) for both clinic and ambulatory (24‐hour systolic/diastolic BP 10.3/6.5 vs 10.9/6.3 mm Hg, P ≥ 0.24) measurements. However, after missing a dose of medication, ambulatory BP reductions were greater in the amlodipine than nifedipine‐GITS group, with a significant (P ≤ 0.04) between‐group difference in 24‐hour (–1.2 mm Hg) and daytime diastolic BP (–1.5 mm Hg). In conclusion, amlodipine and nifedipine‐GITS were efficacious in reducing 24‐hour BP. When a dose of medication was missed, amlodipine became more efficacious than nifedipine‐GITS.     

Efficacy and safety of azilsartan medoxomil/chlortalidone fixed‐dose combination in hypertensive patients uncontrolled on azilsartan medoxomil alone: A randomized trial

Patients with grade 2‐3 essential hypertension and postplacebo mean clinic systolic blood pressure (SBP) 160‐190 mm Hg and 24‐hour SBP 140‐175 mm Hg by ambulatory blood pressure monitoring (ABPM) received 40 mg azilsartan medoxomil (AZL‐M) monotherapy for 4 weeks. “Nonresponders” were then randomized to 8 weeks of double‐blind treatment with AZL‐M 40 mg, AZL‐M/chlortalidone (CLD) 40/25, or AZL‐M/CLD 40/12.5 mg. After 8 weeks, mean clinic SBP change was −21.1 (±1.04) mm Hg for AZL‐M/CLD 40/25 mg, −15.8 (±1.08) mm Hg for AZL‐M/CLD 40/12.5 mg, and −6.4 (±1.05) mm Hg for AZL‐M 40 mg (P < 0.001 for both AZL‐M/CLD vs AZL‐M, ANCOVA). Drug discontinuation rates were 8.9% (AZL‐M/CLD 40/25 mg), 7.5% (AZL‐M 40 mg), and 3.9% (AZL‐M/CLD 40/12.5 mg). Creatinine increased in 8.1% (AZL‐M/CLD 40/25), 3.1% (AZL‐M/CLD 40/12.5 mg), and 3.0% (AZL‐M 40 mg) of patients. AZL‐M/CLD was effective and well tolerated in patients not achieving blood pressure targets with AZL‐M.     

Randomized,multicenter, parallel,open, phase 4 study to compare the efficacy and safety of rosuvastatin/amlodipine polypill versus atorvastatin/amlodipine polypill in hypertension patient with dyslipidemia

The authors performed this study to investigate the efficacy and safety of a rosuvastatin (RSV)/amlodipine (AML) polypill compared with those of atorvastatin (ATV)/AML polypill. We included 259 patients from 21 institutions in Korea. Patients were randomly assigned to 1 of 3 treatment groups: RSV 10 mg/AML 5 mg, RSV 20 mg/AML 5 mg, or ATV 20 mg /AML 5 mg. The primary endpoint was the efficacy of the RSV 10.20 mg/AML 5 mg via percentage changes in LDL-C after 8 weeks of treatment, compared with the ATV 20 mg /AML 5 mg. There was a significant difference in the mean percentage change of LDL-C at 8 weeks between the RSV 10 mg/AML 5 mg and the ATV 20 mg/AML 5 mg (full analysis set [FAS]: −7.08%, 95% CI: −11.79 to −2.38, p = .0034, per-protocol analysis set [PPS]: −6.97%, 95% CI: −11.76 to −2.19, p = .0046). Also, there was a significant difference in the mean percentage change of LDL-C at 8 weeks between the RSV 20 mg/AML 5 mg and the ATV 20 mg/AML 5 mg (FAS: −10.13%, 95% CI: −15.41 to −4.84, p = .0002, PPS: −10.96%, 95% CI: −15.98 to −5.93, p < .0001). There was no significant difference in the adverse events rates between RSV 10 mg/AML 5 mg, RSV 20 mg/AML 5 mg, and ATV 20 mg/AML 5 mg. In conclusion, while maintaining safety, RSV 10 mg/AML 5 mg and the RSV 20 mg/AML 5 mg more effectively reduced LDL-C compared with the ATV 20 mg /AML 5 mg (Clinical trial: NCT03951207).     

A clinical trial evaluating the 24-hour effects of bisoprolol/hydrochlorothiazide 5 mg/6.25 mg combination in patients with mild to moderate hypertension

This study used 24-h ambulatory blood pressure (BP) monitoring to investigate the effectiveness of a novel low-dose combination of bisoprolol/hydrochlorothiazide in adult patients with mild to moderate essential hypertension. Thirty-six patients with stable mild to moderate hypertension (sitting diastolic BP 95–114 mmHg) after a placebo run-in phase received oral bisoprolol/hydrochlorothiazide 5 mg/6.25 mg once daily for 4 weeks in a single-blind regimen. At office visits, BP and pulse were measured with statistically significant reductions (p<0.01) recorded after 2 and 4 weeks of treatment Twenty-four-h ambulatory BP monitoring at the completion of therapy revealed significant reductions (p<0.01) in both systolic and diastolic 24-h, daytime, and nighttime BP, compared with the end of the placebo treatment phase. Systolic and diastolic load were also reduced (p<0.01). The combination was well tolerated, and overall quality-of-life questionnaire scores indicated an improvement after bisoprolol/hydrochlorothiazide therapy (p = 0.02). No clinically significant changes from baseline in laboratory parameters were observed; in particular, serum potassium was unchanged. This is the first study to demonstrate the 24-h effectiveness of the bisoprolol/hydrochlorothiazide 5 mg/6.25 mg combination, using 24-h ambulatory BP monitoring. In addition, antihypertensive therapy with low doses of bisoprolol/hydrochlorothiazide in combination may improve tolerability.     

The efficacy and safety of fixed-dose combination of amlodipine/benazepril in Chinese essential hypertensive patients not adequately controlled with benazepril monotherapy: a multicenter,randomized, double-blind,double-dummy,parallel-group clinical trial

This double-blind, double-dummy clinical trial evaluated the efficacy and safety of two strengths of fixed-dose combination of amlodipine/benazepril in Chinese hypertensive patients not adequately controlled with benazepril. Of 442 patients who received treatment with benazepril 10?mg for 4 weeks, 341 patients failed to achieve to diastolic blood pressure (DBP) <90?mmHg. These non-responders were randomized to receive amlodipine/benazepril 2.5/10?mg, or amlodipine/benazepril 5/10?mg, or benazepril 10?mg for 8 weeks. BP reductions with amodipinel/benazepril 2.5/10?mg (15.2/11.8?mmHg) or amlodipine/benazepril 5/10?mg (15.4/12.4?mmHg) were significantly greater than that with benazepril 10?mg (9.88/9.46?mmHg) at study end (p?p?0.01, combination versus benazepril). Three groups were generally well tolerated. Our study indicated that amlodipine/benazepril fixed-dose combination offered significant additional BP reductions and BP control rate compared with the continuation of benazepril monotherapy. No significant differences were observed in both BP reductions and BP control rate between amlodipine/benazepril 2.5/10?mg and amlodipine/benazepril 5/10?mg.     

Efficacy and safety of amlodipine/valsartan compared with amlodipine monotherapy in patients with stage 2 hypertension: a randomized,double-blind,multicenter study: the EX-EFFeCTS Study

Achieving blood pressure (BP) targets in stage 2 hypertension usually requires two or more drugs, which should be selected from different classes. This study compared the efficacy and tolerability of amlodipine/valsartan with amlodipine in patients with stage 2 hypertension. In this multicenter, randomized, double-blind, 8-week study, 646 patients with stage 2 hypertension (mean sitting systolic blood pressure [MSSBP] ≥160 mm Hg) received amlodipine/valsartan 5/160 mg or amlodipine 5 mg for 2 weeks, prior to being force-titrated to amlodipine/valsartan 10/160 mg or amlodipine 10 mg, respectively, for a further 6 weeks. Hydrochlorothiazide could be added at Week 4 if MSSBP was ≥130 mm Hg. At endpoint Week 4, reductions in MSSBP were significantly greater in patients receiving amlodipine/valsartan than in those receiving amlodipine (30.1 mm Hg vs. 23.5 mm Hg; P < .0001). Likewise, MSSBP reductions in patients with baseline MSSBP ≥180 mm Hg were also greater for amlodipine/valsartan at Week 4 (40.1 mm Hg vs. 31.7 mm Hg for amlodipine; P = .0018). Differences favoring amlodipine/valsartan were also seen for BP control. Amlodipine/valsartan was generally well tolerated. These findings support the rationale for combining agents with complementary mechanisms of action, such as amlodipine and valsartan, in the management of stage 2 hypertension.     

Combined use of amlodipine and folic acid are significantly more efficacious than amlodipine alone in lowering plasma homocysteine and blood pressure among hypertensive patients with hyperhomocysteinemia and intolerance to ACEI: A multicenter,randomized, double-blind,parallel-controlled clinical trial

Hyperhomocysteinemia with hypertension can synergistically increase the risk of stroke. The China stroke primary prevention trial showed that combining 0.8 mg folic acid (FA) with angiotensin-converting enzyme inhibitor (ACEI) can effectively lower plasma total homocysteine (tHcy) and blood pressure (BP); and reduce first stroke risk by additional 21% compared to ACEI alone. However, intolerance to ACEI is common in Asians and amlodipine can be alternative. This is a multicenter, randomized, double-blind, parallel-controlled clinical trial (RCT) which evaluated whether amlodipine combined with FA is more efficacious than amlodipine alone in lowering tHcy and BP among Chinese hypertensive with hyperhomocysteinemia and intolerance to ACEI. 351 Eligible patients were randomly assigned by 1:1:1 ratio to receive amlodipine-FA tablet daily (amlodipine 5 mg/FA 0.4 mg, A group); amlodipine 5 mg/FA 0.8 mg tablet daily (B group); amlodipine 5 mg daily (C group, control group). Follow-up was conducted at 2, 4, 6, and 8 weeks. The primary outcome was efficacy of lowering both tHcy and BP at the end of 8-week treatment. Compared with C group, A group had a significantly higher rate of lowering both tHcy and BP (23.3% vs. 6.0%; Odds Ratio [OR], 8.68; 95% CI, 3.04-24.78, P < .001); B group also had a higher rate of lowering both tHcy and BP (20.3% vs. 6.0%; OR: 5.90; 95% CI, 2.11-16.47, P < .001). This RCT showed amlodipine combined with FA compared with amlodipine alone, each had significantly higher efficacy of lowering both tHcy and BP. No difference was found in BP-lowering and occurrence of adverse events between the three groups.     

Efficacy and safety of sacubitril/valsartan compared with olmesartan in Asian patients with essential hypertension: A randomized,double‐blind, 8‐week study

This study assessed the efficacy and safety of angiotensin receptor neprilysin inhibitor sacubitril/valsartan vs olmesartan in Asian patients with mild‐to‐moderate hypertension. Patients (N = 1438; mean age, 57.7 years) with mild‐to‐moderate hypertension were randomized to receive once daily administration of sacubitril/valsartan 200 mg (n = 479), sacubitril/valsartan 400 mg (n = 473), or olmesartan 20 mg (n = 486) for 8 weeks. The primary endpoint was reduction in mean sitting systolic blood pressure (msSBP) from baseline with sacubitril/valsartan 200 mg vs olmesartan 20 mg at Week 8. Secondary endpoints included msSBP reduction with sacubitril/valsartan 400 mg, and reductions in clinic and ambulatory BP and pulse pressure (PP) vs olmesartan. In addition, changes in msBP from baseline in the Chinese subpopulation, elderly (≥65 years), and in patients with isolated systolic hypertension (ISH) were assessed. Sacubitril/valsartan 200 mg provided a significantly greater reduction in msSBP than olmesartan 20 mg at Week 8 (between‐treatment difference: −2.33 mm Hg [95% confidence interval (CI) −4.00 to −0.66 mm Hg], P < 0.05 for non‐inferiority and superiority). Greater reductions in msSBP were also observed with sacubitril/valsartan 400 mg vs olmesartan 20 mg (−3.52 [−5.19 to −1.84 mm Hg], P < 0.001 for superiority). Similarly, greater reductions in msBP were observed in the Chinese subpopulation, in elderly patients, and those with ISH. In addition, both doses of sacubitril/valsartan provided significantly greater reductions from baseline in nighttime mean ambulatory BP vs olmesartan. Treatment with sacubitril/valsartan 200 or 400 mg once daily is effective and provided superior BP reduction than olmesartan 20 mg in Asian patients with mild‐to‐moderate hypertension and is generally safe and well tolerated.     

Efficacy and safety of four doses of lumiracoxib versus diclofenac in patients with knee or hip primary osteoarthritis: a phase II, four-week, multicenter, randomized, double-blind, placebo-controlled trial

OBJECTIVE: To compare the efficacy and tolerability of the novel cyclooxygenase 2-selective inhibitor lumiracoxib with placebo and diclofenac in osteoarthritis (OA). METHODS: Adults (n=583) with knee or hip OA were randomized to receive for 4 weeks lumiracoxib 50, 100, or 200 mg twice daily or 400 mg once daily; placebo; or diclofenac 75 mg twice daily. Efficacy assessments included overall joint pain intensity and Western Ontario and McMaster Universities Osteoarthritis Index subscales; tolerability was evaluated by adverse event and physician reporting. RESULTS: All lumiracoxib doses were superior to placebo in relieving pain, improving stiffness, and improving physical function after 4 weeks. At study endpoint, pain relief was comparable among all lumiracoxib dosages and similar to diclofenac. Lumiracoxib tolerability was superior to diclofenac and comparable to placebo. CONCLUSION: Lumiracoxib provides predictable and sustained relief from pain, stiffness, and impaired physical function in OA. Lumiracoxib shows clinically comparable efficacy and superior tolerability to diclofenac.     

Efficacy of glimepiride/metformin fixed‐dose combination vs metformin uptitration in type 2 diabetic patients inadequately controlled on low‐dose metformin monotherapy: A randomized,open label,parallel group,multicenter study in Korea

Aims/Introduction

To compare the efficacy and safety of early combination therapy with glimepiride/metformin to metformin uptitration in reducing glycated hemoglobin (HbA1c) levels in Korean type 2 diabetic patients inadequately controlled on low-dose metformin monotherapy.

Materials and Methods

In a randomized, open label, parallel group, multicenter study, 209 Korean type 2 diabetic patients (HbA1c 7.0–10.0%, on metformin 500–1,000 mg/day) received glimepiride/metformin fixed-dose combination (G/M FDC) or metformin uptitration treatment (Met UP). The primary end-point was the change in HbA1c from baseline to week 24.

Results

G/M FDC therapy provided significantly greater adjusted mean decreases vs Met UP therapy in HbA1c (−1.2 vs −0.8%, P < 0.0001), and fasting plasma glucose (−35.7 vs −18.6 mg/dL, P < 0.0001). A significantly greater proportion of patients with G/M FDC therapy achieved HbA1c < 7% (74.7 vs 46.6%, P < 0.0001) at the end of the study. More patients experienced hypoglycemia with G/M FDC therapy compared with Met UP therapy (41 vs 5.6%, P < 0.0001), but there was no serious hypoglycemia in any group. A modest increase in mean bodyweight occurred in the patients who were treated with G/M FDC therapy (1.0 kg), whereas a slight decrease was observed in the patients who were treated with Met UP therapy (−0.7 kg).

Conclusion

The present study showed that glimepiride/metformin fixed-dose combination therapy was more effective in glycemic control than metformin uptitration, and was well tolerated in type 2 diabetic patients inadequately controlled by low-dose metformin monotherapy in Korea. This trial was registered with ClinicalTrial.gov (no. {"type":"clinical-trial","attrs":{"text":"NCT00612144","term_id":"NCT00612144"}}NCT00612144).     

Efficacy and safety of sacubitril/valsartan in patients with essential hypertension uncontrolled by olmesartan: A randomized,double‐blind, 8‐week study

A majority of patients with hypertension fail to achieve blood pressure (BP) control despite treatment with commonly prescribed drugs. This randomized, double‐blind phase III trial assessed the superiority of sacubitril/valsartan 200 mg (97/103 mg) to continued olmesartan 20 mg in reducing ambulatory systolic BP after 8‐week treatment in patients with mild to moderate essential hypertension uncontrolled with olmesartan 20 mg alone. A total of 376 patients were randomized to receive either sacubitril/valsartan (n = 188) or olmesartan (n = 188). Superior reductions in 24‐hour mean ambulatory systolic BP were observed in the sacubitril/valsartan group vs the olmesartan group (−4.3 mm Hg vs −1.1 mm Hg, P < .001). Reductions in 24‐hour mean ambulatory diastolic BP and pulse pressure and office systolic BP and diastolic BP were significantly greater with sacubitril/valsartan vs olmesartan (P < .014). A greater proportion of patients achieved BP control with sacubitril/valsartan vs olmesartan. The overall incidence of adverse events was comparable between the groups. Compared with continued olmesartan, sacubitril/valsartan was more effective and generally safe in patients with hypertension uncontrolled with olmesartan 20 mg.     

A multicenter, randomized, placebo-controlled, double-blind phase II trial evaluating the optimal dose, efficacy and safety of LC 15-0444 in patients with type 2 diabetes

Aim: The objective of this study was to evaluate the optimal dose, efficacy and safety of a novel dipeptidyl peptidase‐4 (DPP‐IV) inhibitor, LC15‐0444, in Korean subjects with type 2 diabetes mellitus treated by diet and exercise. Methods: This study was a double‐blind, randomized, multicenter and parallel‐group, dose‐range finding study. We enrolled 145 patients (91 men and 54 women) with a median age of 53 years and a median body mass index of 25.1 kg/m². The median baseline fasting plasma glucose (FPG) was 8.1 mmol/l, the median HbA1c was 7.9% and the median time since the diagnosis of diabetes was 3 years. After 2 weeks of an exercise/diet programme followed by 2 weeks of a placebo period, the subjects were randomized to one of the four following groups for a 12‐week active treatment period: placebo and 50, 100 or 200 mg of LC15‐0444. Results: All three doses of LC15‐0444 significantly reduced the HbA1c from baseline compared to the placebo group (?0.06 vs. ?0.98, ?0.74 and ?0.78% in the placebo and 50, 100 and 200 mg groups, respectively), without a significant difference between the doses. Subjects with a higher baseline HbA1c (≥8.5%) had a greater reduction in HbA1c. Insulin secretory function, as assessed using homeostasis model assessment‐beta cell, C‐peptide and the insulinogenic index, improved significantly with LC15‐0444 treatment. Insulin sensitivity, as assessed using homeostasis model assessment‐insulin resistance, also improved significantly after 12 weeks of treatment. The 50 and 200 mg groups had significantly reduced total cholesterol and low‐density lipoprotein cholesterol levels at 12 weeks compared to the placebo group. No dosage of LC15‐0444 affected weight or waist circumference. The incidences of adverse events were similar in all study subjects. Conclusions: LC15‐0444 monotherapy (50 mg for 12 weeks) improved the HbA1c, FPG level, oral glucose tolerance test results, β‐cell function and insulin sensitivity measures, and was well tolerated in Korean subjects with type 2 diabetes.