Efficacy and safety of alogliptin added to insulin in Japanese patients with type 2 diabetes: a randomized,double-blind, 12-week,placebo-controlled trial followed by an open-label,long-term extension phase

Objective: To evaluate the efficacy and safety of alogliptin added to insulin in Japanese patients with type 2 diabetes mellitus (T2DM) who are poorly controlled with insulin and diet or exercise.

Study design: This was a randomized, double-blind, 12-week comparative trial of alogliptin and insulin versus placebo and insulin in 179 patients with T2DM followed by a 40-week, open-label phase in 169 patients on alogliptin and insulin.

Primary outcome measure: Change in glycated hemoglobin (HbA1c) from baseline to the end of double-blind phase (week 12).

Results: The change in HbA1c (least squares means) from baseline to week 12 was ?0.96% for the alogliptin and insulin group and ?0.29% for the placebo and insulin group. The point estimate (95% confidence interval) intergroup difference was ?0.66% ([?0.824%, ?0.503%]). In the alogliptin and insulin group, HbA1c started to decrease from week 2 onward and peaked by week 12. The proportions of patients who achieved HbA1c < 8.0, < 7.0 and < 6.0% at week 12 were significantly higher in alogliptin and insulin group (73.0, 23.3 and 1.1%) than in placebo and insulin group (25.0, 5.7 and 0%). Incidences of adverse effects were comparable between groups, with no relevant increases in hypoglycemia or weight gain seen.

Conclusions: Alogliptin 25 mg/day was effective and well tolerated when added to insulin in Japanese patients with inadequately controlled T2DM.     

Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus from Latin America

Objective:

This post hoc analysis evaluated the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) from Latin America.

Research design and methods:

Analyses were performed in subgroups of patients from Latin America based on data from three individual, 26-week, placebo-controlled studies of canagliflozin (monotherapy [n?=?116/584], add-on to metformin [n?=?199/918], and add-on to metformin plus sulfonylurea [n?=?76/469]) and three individual, 52-week, active-controlled studies of canagliflozin (add-on to metformin versus sitagliptin [n?=?240/1101], add-on to metformin versus glimepiride [n?=?155/1450], and add-on to metformin plus sulfonylurea versus sitagliptin [n?=?156/755]).

Main outcome measures:

Changes from baseline in HbA_1c, body weight, and systolic blood pressure (BP) with canagliflozin 100 and 300?mg versus placebo or active comparator (i.e., sitagliptin or glimepiride) were evaluated in the overall study populations and Latin American subgroups. Safety was assessed based on adverse event (AE) reports.

Results:

Canagliflozin 100 and 300?mg provided reductions in HbA_1c, body weight, and systolic BP across studies in patients from Latin America that were generally similar to those seen in the overall populations of patients with T2DM. The AE profile in patients from Latin America was equivalent to that in the overall populations; higher rates of genital mycotic infections and osmotic diuresis–related AEs were seen with canagliflozin versus comparators. Limitations of this study include the post hoc analysis of data and the small sample size of patients from Latin America.

Conclusion:

Canagliflozin improved glycemic control, reduced body weight and systolic BP, and was generally well tolerated in patients with T2DM from Latin America.

Clinical trial registration:

NCT01081834; NCT01106677; NCT01106625; NCT00968812; NCT01137812.     

Efficacy and safety of canagliflozin monotherapy in Japanese patients with type 2 diabetes inadequately controlled with diet and exercise: a 24-week,randomized, double-blind,placebo-controlled,Phase III study

Objective: To examine the efficacy and safety of canagliflozin monotherapy, a sodium/glucose co-transporter 2 inhibitor, in Japanese type 2 diabetes patients.

Methods: In this double-blind, multi-centre Phase III study, patients aged ≥ 20 years with hemoglobin A1c (HbA1c) 7.0 – 10.0% on diet/exercise therapy alone received placebo or canagliflozin (100 or 200 mg) once daily for 24 weeks. The main outcome measure was the change in HbA1c from baseline to Week 24.

Results: The changes in HbA1c (?0.74 and ?0.76 vs + 0.29%), fasting plasma glucose (1 mg/dl = 0.0555 mmol/l; ?31.6 and ?31.9 vs + 3.7 mg/dl), 2-h plasma glucose after 75-g glucose load (?84.9 and ?79.0 vs ?0.5 mg/dl), body weight (percent change: ?3.76 and ?4.02 vs ?0.76%) and systolic blood pressure (?7.88 and ?6.24 vs ?2.72 mmHg) were significantly greater with 100 and 200 mg canagliflozin than with placebo (all, p < 0.05). Genital infections in females (6.5, 6.3 and 0%) and asymptomatic hypoglycemia (4.4, 5.6 and 2.2%), but not symptomatic hypoglycemia (2.2, 1.1 and 1.1%), were more frequent in the 100- and 200-mg groups than in the placebo group.

Conclusion: Canagliflozin significantly improved glycemic control and was well tolerated.     

Efficacy and safety of alogliptin in Japanese patients with type 2 diabetes mellitus: a randomized,double-blind,dose-ranging comparison with placebo,followed by a long-term extension study

Abstract

Objective:

To compare the efficacy and safety of different dosages of alogliptin with that of placebo and voglibose in drug-naïve Japanese patients with type 2 diabetes inadequately controlled by diet and exercise.     

Efficacy and safety of teneligliptin add-on to insulin monotherapy in Japanese patients with type 2 diabetes mellitus: a 16-week,randomized, double-blind,placebo-controlled trial with an open-label period

Objective: To assess the efficacy and safety of teneligliptin as add-on to insulin monotherapy in patients with type 2 diabetes mellitus (T2DM).

Research design and methods: In a 16-week, double-blind period, 148 Japanese T2DM patients with inadequate glycemic control with insulin and diet/exercise therapies were randomized to placebo or teneligliptin 20 mg. In a subsequent 36-week, open-label period, all patients received teneligliptin once daily. The primary outcome measure was change in HbA1c at the end of the double-blind period.

Results: The difference between placebo and teneligliptin in change in HbA1c in the double-blind period (least squares mean ± SE) was ?0.80% ± 0.11%; teneligliptin was superior (ANCOVA, P < 0.001). The HbA1c-lowering effect of teneligliptin was maintained throughout the open-label period. The incidence of adverse events was 53.5% with placebo and 44.2% with teneligliptin in the double-blind period, 66.7% in the placebo/teneligliptin group in the open-label period, and 77.9% in the teneligliptin/teneligliptin group over both double-blind/open-label periods. The incidence of hypoglycemic symptoms was 11.1% in the placebo/teneligliptin group in the open-label period and 27.3% in the teneligliptin/teneligliptin group over both double-blind/open-label periods.

Conclusion: Teneligliptin was effective and well tolerated in Japanese T2DM patients with inadequate glycemic control.

Clinical trial registration: NCT02081599     

Efficacy and safety of canagliflozin in type 2 diabetes mellitus: systematic review of randomized controlled trials

Background: Currently available antihyperglycemic agents (AHAs), despite being effective, do not provide adequate glycemic control in some cases and are associated with side effects. A sodium glucose co-transporter 2 inhibitor, canagliflozin, is a newer AHA, which acts by decreasing the reabsorption of filtered glucose thereby elevating the urinary glucose excretion in diabetics.

Areas covered: This systematic review was completed to assess the clinical effectiveness and safety of canagliflozin in T2DM. A literature search in PubMed, MEDLINE, Cochrane and ClinicalTrials.gov was conducted for randomized clinical trials of canagliflozin as an AHA by applying predetermined inclusion and exclusion criteria. Total 13 studies were included in the systematic review. The main outcomes assessed were change in HbA1c and fasting plasma glucose.

Expert opinion: Canagliflozin monotherapy or combination therapy has the potential to decrease inadequately controlled hyperglycemia in T2DM. It acts by a novel insulin independent mechanism which complements the action of the existing AHA and improves glycemic control and decreases the body weight. Safety profile of canagliflozin indicates lower number of hypoglycemic episodes. Some manageable adverse events include genital mycotic infections, urinary tract infections, osmotic diuresis-related events etc. These findings affirm the utility of canagliflozin in T2DM; however, data on long-term safety and efficacy are needed.     

Efficacy and safety of saxagliptin in patients with type 2 diabetes mellitus: a meta-analysis of randomized controlled trials

As a new oral hypoglycemic agent, saxagliptin belongs to the class of dipeptidyl peptidase-4 (DPP-4) inhibitors. However, it remains inconclusive whether saxagliptin is associated with increased risk of adverse events (AE) and efficacy as add-on treatment. Therefore, we performed an up-to-date meta-analysis to compare the efficacy and safety of saxagliptin with placebo and other oral hypoglycemic agents in adult patients with type 2 diabetes mellitus (T₂DM). Randomized clinical trials (RCTs) comparing saxagliptin with comparators were retrieved by selecting articles from Pubmed, Embase, Cochrane Library and Clinical Trials Registry Platform up to Oct. 2013. Weighted mean difference (WMD) was used to analyze the effect of hypoglycemic agents on HbA1c, weight and fasting plasma glucose (FPG). While the patients who achieved HbA1c<7.0% and had AE were analyzed as relative risks (RR).A total of 18 articles from 16 RCTs and one clinic trial from the WHO International Clinical Trials Registry Platform met the included criterion. Clinically significant decrease from baseline HbA1c compared with placebo was certified for 2.5 mg/day saxagliptin (WMD = –0.45%, 95%CI, –0.48% to –0.42%) and 5 mg/d saxagliptin (WMD = –0.52%, 95%CI, –0.60% to –0.44%). Saxagliptin as add-on therapy was superior to thiazolidinediones, up-titrated glyburide, up-titrated metformin or metformin monotherapy in achieving HbA1c<7.0%. Treatment with saxagliptin had negligible effect on weight, and it was considered weight neutral. Saxagliptin treatment did not increase the risk of hypoglycemia (RR = 1.28, 95% CI 0.72 to 2.27, P = 0.40) and serious adverse experiences (RR = 1.25, 95% CI 0.94 to 1.66, P = 0.13). No statistically significant differences were observed between saxagliptin and comparators in terms of the risk of infections.The present study showed that saxagliptinwas effective in improving glycaemic control in T₂DM with a low risk of hypoglycaemia and incidence of infections in either monotherapy or add-on treatment. This founding should be further certified by large-sample size and good-designed RCT.     

Efficacy and safety of saxagliptin in combination with insulin in Japanese patients with type 2 diabetes mellitus: a 16-week double-blind randomized controlled trial with a 36-week open-label extension

Background: We examined the efficacy and safety of saxagliptin as an add-on to insulin in Japanese patients with type 2 diabetes mellitus.

Research design and methods: We randomized 240 patients with type 2 diabetes mellitus on insulin monotherapy to 5-mg saxagliptin or placebo as add-on therapy for a 16-week, double-blind period. All patients received 5-mg saxagliptin and insulin for an additional 36 weeks (open-label extension). Change in hemoglobin A1c (HbA1c) at Week 16 was the main endpoint.

Results: At Week 16, the adjusted change in HbA1c from baseline increased by 0.51% with placebo and decreased by 0.40% with saxagliptin (difference ?0.92% [95% confidence interval ?1.07%, ?0.76%; p < 0.001]). In patients receiving saxagliptin, reductions in HbA1c at Week 16 were maintained to Week 52, while switching from placebo to saxagliptin resulted in a similar reduction in HbA1c. The incidence of hypoglycemia was not markedly increased with saxagliptin versus placebo in the double-blind period and did not increase substantially during the open-label extension period. The efficacy and safety of saxagliptin was similar between the elderly and non-elderly patient groups.

Conclusions: Adding saxagliptin to ongoing insulin therapy improved glycemic control and was well tolerated in Japanese patients with type 2 diabetes.     

Results of VERTIS SU extension study: safety and efficacy of ertugliflozin treatment over 104 weeks compared to glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin

Objective: To assess the safety and efficacy of ertugliflozin over 104?weeks in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin.

Methods: In this double-blind, multicenter, randomized, phase III study (VERTIS SU; NCT01999218), adults with T2DM and glycated hemoglobin (HbA1c) 7.0–9.0% on metformin ≥1500?mg/day received ertugliflozin 5?mg or 15?mg, or glimepiride. The primary efficacy time point was Week 52; double-blinded treatment continued until Week 104.

Results: Baseline characteristics of randomized, treated patients (n?=?1315) were similar across groups (mean age 58.2 years, HbA1c 7.8%); 76.4% completed the study; 61.6% completed on study medication. Mean glimepiride dose at 104?weeks was 3.5?mg/day. At Week 104, least squares mean change from baseline in HbA1c (95% confidence intervals) were ?0.3% (?0.4, ?0.2), ?0.4% (?0.5, ?0.3) and ?0.4% (?0.5, ?0.3) for ertugliflozin 5?mg, 15?mg, and glimepiride, respectively. Ertugliflozin provided sustained reductions in body weight and systolic blood pressure (SBP) over 104?weeks. The incidence of adverse events (AEs) and serious AEs was similar across groups. The incidence of symptomatic hypoglycemia was 3.8%, 6.4% and 22.1% in the ertugliflozin 5?mg, 15?mg, and glimepiride groups, respectively. Genital mycotic infections were reported in 5.3%, 2.6% and 0% of men, respectively, and 9.2%, 12.3% and 1.4% of women, respectively. The incidence of urinary tract infection and hypovolemia AEs was similar across groups.

Conclusions: Ertugliflozin was well tolerated and provided clinically meaningful glycemic control and durable reductions in body weight and SBP over 104?weeks.     

Efficacy and safety of ertugliflozin across racial groups in patients with type 2 diabetes mellitus

Abstract

Objective: To assess the efficacy and safety of the sodium–glucose cotransporter 2 inhibitor ertugliflozin across racial groups in patients with type 2 diabetes mellitus (T2DM).

Methods: Pooled analysis of data from randomized, double-blind studies in the ertugliflozin phase III development program. Seven placebo- and comparator-controlled studies were used to assess safety (N?=?4859) and three placebo-controlled studies were used to assess efficacy (N?=?1544). Least-squares (LS) mean change from baseline was calculated for glycated hemoglobin (HbA1c), body weight and systolic blood pressure (SBP). Safety evaluation included overall and prespecified adverse events (AEs).

Results: At Week 26, ertugliflozin provided a greater reduction in HbA1c, body weight and SBP versus placebo in all racial subgroups. The placebo-adjusted LS mean change (95% confidence interval) from baseline in HbA1c was ?0.8% (?1.0, ?0.7) and ?1.0% (?1.1, ?0.8) with ertugliflozin 5?mg and 15?mg, respectively, in the White subgroup, ?0.7% (?1.2, ?0.2) and ?0.8% (?1.3, ?0.3) in the Black subgroup, and ?0.8% (?1.1, ?0.5) and ?1.0% (?1.3, ?0.8) in the Asian subgroup. The incidences of overall AEs, serious AEs and AEs leading to discontinuation from study medication were similar between the ertugliflozin 5?mg, 15?mg and non-ertugliflozin groups within each racial subgroup. The incidence of female genital mycotic infection (GMI) was higher with ertugliflozin than non-ertugliflozin across all racial subgroups. The incidence of male GMI was higher with ertugliflozin than non-ertugliflozin in the White sub-group; however, there were few male GMI events in the non-White subgroups.

Conclusions: In patients with T2DM, treatment with ertugliflozin improved HbA1c, body weight and SBP across all racial subgroups. Ertugliflozin had a generally similar safety profile across racial subgroups and was generally well tolerated.

Clinicaltrials.gov identifiers: NCT01986855, NCT01999218, NCT01958671, NCT02099110, NCT02036515, NCT02033889, and NCT02226003.     

维格列汀联合胰岛素治疗2型糖尿病的疗效及安全性研究

目的：研究在接受胰岛素治疗的2型糖尿病患者中,联合应用维格列汀治疗的疗效及对胰岛素剂量的影响并进行安全性评价。方法：本实验为前瞻性、开放性、前后自身及空白对照的临床研究。设立试验组和对照组,试验组为110例应用胰岛素治疗的2型糖尿病患者,加用维格列汀50mg,每日2次,治疗12周,对照组为109例应用胰岛素治疗12周的患者,观察两组治疗前后糖化血红蛋白（HbA1c）及血糖变化。结果：治疗12周后,试验组HbA1c由基线的（9.27＆#177;1.42）%降至（7.82＆#177;1.36）%,下降了（1.45＆#177;1.03）%,对照组HbA1c由基线的（8.86＆#177;1.06）%降至（8.02＆#177;1.32）%,下降了（0.84＆#177;1.13）%,两组下降幅度均P＆lt;0.05。以HbA1c≤6.5%和HbA1c≤7.0%为目标值,治疗后试验组达标率为16.36%和43.63%,较治疗前增加12.76%和33.63%;试验组胰岛素用量由基线的53.9IU/d降至41.2IU/d,剂量减少23.56%,对照组胰岛素用量由基线的66.7IU/d降至58.3IU/d,剂量减少12.59%,两组胰岛素减少量P＆lt;0.05;患者空腹血糖及餐后2h血糖均有明显改善;患者平均每日药品费用较治疗前无明显增加（P＆gt;0.05）。治疗期间试验组共14例患者（12.7%）发生一般性低血糖事件（24件＆#183;次）,无严重低血糖事件发生,与对照组比较,低血糖发生率有统计学差异（P＆lt;0.05）。结论：维格列汀联合胰岛素治疗2型糖尿病,可有效降低患者空腹及餐后血糖水平,利于实现HbA1c达标,并减少胰岛素使用剂量,提高治疗的安全性及耐受性。     

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized,double-blind,placebo-controlled study

ABSTRACT

Objectives: To evaluate the efficacy and safety of alogliptin in patients with type 2 diabetes inadequately controlled by therapy with a thiazolidinedione (TZD).

Research design and methods: In a multicenter, double-blind, placebo-controlled clinical study, 493 patients 18–80 years old with inadequate glycemic control after stabilization (i.e., glycosylated hemoglobin [HbA_1c] 7.0–10.0%) despite ongoing treatment with a TZD were randomly assigned (2:2:1) to treatment with pioglitazone plus alogliptin 12.5?mg, alogliptin 25?mg or placebo once daily. Concomitant therapy with metformin or sulfonylurea at prestudy doses was permitted.

Main outcome measures: The primary efficacy endpoint was change in HbA_1c from baseline to Week 26. Secondary endpoints included changes in fasting plasma glucose (FPG) and body weight, and incidences of marked hyperglycemia (FPG?≥?200?mg/dL [11.10?mmol/L]) and rescue for hyperglycemia.

Results: Least squares (LS) mean change in HbA_1c was significantly (p?<?0.001) greater for alogliptin 12.5?mg (?0.66%) or 25?mg (?0.80%) than for placebo (?0.19%). A significantly (p?≤?0.016) larger proportion of patients achieved HbA_1c?≤?7% with alogliptin 12.5?mg (44.2%) or 25?mg (49.2%) than with placebo (34.0%). LS mean decreases in FPG were significantly (p?=?0.003) greater with alogliptin 12.5?mg (?19.7?mg/dL [?1.09?mmol/L]) or 25?mg (?19.9?mg/dL [?1.10?mmol/L]) than with placebo (?5.7?mg/dL [?0.32?mmol/L]). The percentage of patients with marked hyperglycemia was significantly (p?<?0.001) lower for alogliptin (≤25.0%) than placebo (44.3%). The incidences of overall adverse events and hypoglycemia were similar across treatment groups, but cardiac events occurred more often with active treatment than placebo.

Conclusions: Addition of alogliptin to pioglitazone therapy significantly improved glycemic control in patients with type 2 diabetes and was generally well tolerated. The study did not evaluate the effect of combination therapy on long-term clinical outcomes and safety.

Clinical trial registration: NCT00286494, clinicaltrials.gov.     

国产盐酸吡格列酮对2型糖尿病的疗效及安全性研究

目的:评价国产盐酸吡格列酮对2型糖尿病(DM)患者合用磺脲类及双胍类药物时的降糖疗效及安全性.方法:采用随机、双盲、安慰剂平行对照的临床研究方法,将48例应用磺脲类及双胍类治疗而空腹血糖(FPG)控制不佳(7.5 mmol·L-1≤FPG<12.0 mmol·L-1)的2型DM患者随机分为吡格列酮组(30 mg·d-1)与安慰剂组治疗,共12周.结果:于12周时,吡格列酮组与安慰剂组FPG较基线值分别下降1.1 mmol·L-1和0.23 mmol·L-1 (P<0.05);PPG分别下降1.7 mmol·L-1和0.23 mmol·L-1 (P＞0.05);HbAlc分别下降0.52%和0.05%(P＞0.05).结论:12周的临床观察显示,对2型DM患者饮食、运动和应用磺脲类及双胍类治疗而血糖控制不佳者联合应用盐酸吡格列酮(30 mg·d-1),改善糖代谢紊乱,且安全性和依从性好.