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.     

Once-daily sitagliptin,a dipeptidyl peptidase-4 inhibitor,for the treatment of patients with type 2 diabetes

ABSTRACT

Objective: Sitagliptin, an oral, potent, and selective dipeptidyl peptidase-4 (DPP?4) inhibitor was evaluated as once-daily monotherapy in a 12-week randomized, double-blind, placebo-controlled, parallel group, dose-ranging study. Additionally, the glycemic response to sitagliptin 100?mg daily was evaluated as a once-daily (100?mg once-daily) or twice-daily (50?mg twice-daily) dosing regimen.

Research design and methods: In a multinational, double-blind, randomized, placebo-controlled, parallel-group, dose-range finding study, 555 patients, 23–74 years of age, with HbA_1c of 6.5–10.0% were randomized to one of five treatment groups: placebo, sitagliptin 25, 50 or 100?mg once-daily, or sitagliptin 50?mg twice-daily for 12 weeks. The efficacy analysis was based on the all-patients-treated population using an ANCOVA model.

Results: Mean baseline HbA_1c ranged from 7.6 to 7.8% across treatment groups, with 29% of all patients with values ≤?7%. After 12 weeks, treatment with all doses of sitagliptin significantly (?p < 0.05) reduced HbA_1c by –0.39 to –0.56% and fasting plasma glucose by –11.0 to –17.2?mg/dLrelative to placebo, with the greatest reduction observed in the 100-mg once-daily group. Mean daily glucose was significantly (?p < 0.05) reduced by –14.0 to –22.6?mg/dL with all doses of sitagliptin relative to placebo. HOMA?β was significantly (?p < 0.05) increased by 11.3–15.2 with all sitagliptin doses relative to placebo. QUICKI and HOMA?IR were not significantly changed with sitagliptin treatment. There were no significant differences observed between the sitagliptin 100?mg once-daily and 50?mg twice-daily groups for any parameter. For sitagliptin, the incidence of adverse events of hypoglycemia was low, with one event in each of the 25- and 50-mg once-daily and 50-mg twice-daily treatment groups and two events in the 100?mg once-daily treatment group. There was no mean change in body weight with sitagliptin relative to placebo. Study duration may be a limitation because the extent of the glycemic response and the safety and tolerability may not have been fully elucidated in this 12-week study.

Conclusion: Sitagliptin monotherapy improved indices of glycemic control compared to placebo and was generally well-tolerated in patients with type 2 diabetes. The glycemic response to treatment with sitagliptin 100?mg/day was similar between the sitagliptin 100-mg once-daily and 50-mg twice-daily dose regimens.     

甘精胰岛素与西格列汀联用治疗老年2型糖尿病临床观察

目的探讨甘精胰岛素联用西格列汀治疗高龄2型糖尿病的疗效及安全性。方法将78例60岁以上的2型糖尿病患者随机分成甘精胰岛素联用西格列汀组(G组)40例和生物合成预混30/70人胰岛素组(N组)38例,根据血糖情况调整用药剂量,治疗12周后比较两组的空腹血糖、餐后2 h血糖、糖化血红蛋白(HbA1c)、低血糖发生率及体重指数(BMI)。结果 G组在空腹2 h血糖和低血糖发生率方面均低于N组,两组比较差异有统计学意义(P<0.05);在餐后血糖、HbA1c和BMI方面两组比较差异无统计学意义(P>0.05)。结论甘精胰岛素与西格列汀联用对老年2型糖尿病患者是一种安全、有效且方便的治疗方案,低血糖发生率低,尤其是对认知力较差、活动不方便、视力差或合并多种慢性病的高龄2型糖尿病患者尤为适用。     

A randomized clinical trial of the safety and efficacy of sitagliptin in patients with type 2 diabetes mellitus inadequately controlled by acarbose alone

Objective: To evaluate the safety and efficacy of sitagliptin when added to the treatment of patients with type 2 diabetes mellitus (T2DM) and inadequate glycemic control on acarbose monotherapy.

Research design and methods: This was a multicenter, randomized, placebo-controlled, double-blind clinical trial. Patients (N?=?381) with T2DM and inadequate glycemic control (glycated hemoglobin [HbA1c] ≥?7.0% and ≤10.0%) on acarbose monotherapy (at least 50?mg three times daily) were randomized in a 1:1 ratio to receive the addition of sitagliptin 100?mg or matching placebo once daily for 24 weeks.

Main outcome measures: Changes from baseline in HbA1c and fasting plasma glucose (FPG) at Week 24.

Results: The mean baseline HbA1c in randomized patients was 8.1%. At Week 24, the placebo-controlled, least squares mean changes from baseline (95% confidence interval) in HbA1c and FPG in the sitagliptin group were ?0.62% and ?0.8?mmol/L (p?p?Conclusions: Sitagliptin was generally well tolerated and provided statistically superior and clinically meaningful improvements in glycemic control after 24 weeks of treatment compared to placebo when added to treatment of patients with inadequate glycemic control on acarbose monotherapy.

Clinicaltrials.gov: NCT01177384.     

Tolerability and pharmacokinetics of metformin and the dipeptidyl peptidase-4 inhibitor sitagliptin when co-administered in patients with type 2 diabetes

ABSTRACT

Objective: As part of the clinical development of sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of type 2 diabetes, the potential for pharmacokinetic interactions with other antihyperglycemic agents used in managing patients with type 2 diabetes are being carefully evaluated. The purposes of this study were to evaluate the tolerability of co-administered sitagliptin and metformin and effects of sitagliptin on metformin pharmacokinetics as well as metformin on sitagliptin pharmacokinetics under steady-state conditions.

Methods: This placebo-controlled, multiple-dose, crossover study in patients with type 2 diabetes assessed the tolerability of co-administered sitagliptin (50?mg b.i.d.) with metformin (1000?mg b.i.d.). Patients received, in a randomized crossover manner, three treatments (each of 7 days duration): 50?mg sitagliptin twice daily and placebo to metformin twice daily; 1000?mg of metformin twice daily and placebo to sitagliptin twice daily; concomitant administration of 50?mg of sitagliptin twice daily and 1000?mg of metformin twice daily. Following dosing on Day 7 of each treatment period, these pharmacokinetic parameters were determined for plasma sitagliptin and metformin: area under the plasma concentrations–time curve over the dosing interval (AUC_{0–12 h}), maximum observed plasma concentrations (C_max), and time of occurrence of maximum observed plasma concentrations (T_max). Renal clearance was also determined for sitagliptin.

Results: In this study, no adverse experiences were reported by 11 of 13 patients. Two patients had adverse experiences, which were not related to study drugs as determined by the investigators. The mean metformin plasma concentration–time profiles were nearly identical with or without sitagliptin co-administration [metformin AUC_{0–12 h} geometric mean ratio (GMR; [metformin + sitagliptin]/metformin)] was 1.02 (90% CI 0.95, 1.09). Similarly metformin administration did not alter the plasma sitagliptin pharmacokinetics [sitagliptin AUC_{0–12 h} GMR ([sitagliptin + metformin]/sitagliptin)] was 1.02 (90% CI 0.97, 1.08) or renal clearance of sitagliptin. No efficacy measurements (glycosylated hemoglobin or fasting plasma glucose) were obtained during this study. Urinary pharmacokinetics for metformin were not determined due to the lack of effect of sitagliptin on plasma metformin pharmacokinetics.

Conclusions: In this study, co-administration of sitagliptin and metformin was generally well tolerated in patients with type 2 diabetes and did not meaningfully alter the steady-state pharmacokinetics of either agent.     

Efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes: a 54-week study

ABSTRACT

Objective: To assess the 54-week efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes and inadequate glycemic control (HbA_1c 7.5–11%) on diet and exercise.

Methods and materials: This was multinational study conducted at 140 clinical sites in 18 countries. Following an initial 24-week, double-blind, placebo-controlled period, patients entered a double-blind continuation period for an additional 30 weeks. Following the week 24 evaluation, patients remained on their previously assigned active, oral treatments: sitagliptin 50?mg b.i.d.?+?metformin 1000?mg b.i.d. (S100?+?M2000), sitagliptin 50?mg b.i.d.?+?metformin 500?mg b.i.d. (S100?+?M1000), metformin 1000?mg b.i.d. (M2000), metformin 500?mg b.i.d. (M1000), and sitagliptin 100?mg q.d. (S100). Patients initially randomized to placebo were switched to M2000 (designated PBO/M2000) at week 24. This report summarizes the overall safety and tolerability data for the 54-week study and presents efficacy results for patients randomized to continuous treatments who entered the 30-week continuation period.

Results: Of the 1091 randomized patients, 906 completed the 24-week placebo-controlled phase and 885 patients continued into the 30-week continuation period (S100?+?M2000 n?=?161, S100+M1000 n?=?160, M2000 n?=?153, M1000 n?=?147, S100 n?=?141, PBO/M2000 n?=?123). At baseline, patients included in the efficacy analysis had mean age of 54 years, mean BMI of 32?kg/m², mean HbA_1c of 8.7% (8.5–8.8% across groups), and mean duration of type 2 diabetes of 4 years. At week 54, in the all-patients-treated analysis of continuing patients, least-squares (LS) mean changes in HbA_1c from baseline were ?1.8% (S100?+?M2000), ?1.4% (S100?+?M1000), ?1.3% (M2000), ?1.0% (M1000), and ?0.8% (S100). The proportions of continuing patients with an HbA_1c?<?7% at week 54 were 67% (S100?+?M2000), 48% (S100?+?M1000), 44% (M2000), 25% (M1000), and 23% (S100). For the patients completing treatment through week 54, LS mean changes in HbA_1c from baseline were ?1.9% (S100?+?M2000), ?1.7% (S100?+?M1000), ?1.6% (M2000), ?1.2% (M1000), and ?1.4% (S100). Glycemic response was generally durable over time across treatments. All treatments improved measures of β-cell function (e.g., HOMA-β, proinsulin/insulin ratio). Mean body weight decreased from baseline in the combination and metformin monotherapy groups and was unchanged from baseline in the sitagliptin monotherapy group. The incidence of hypoglycemia was low (1–3%) across treatment groups. The incidence of gastrointestinal adverse experiences with the co-administration of sitagliptin and metformin was similar to that observed with metformin alone.

Limitations: The patient population evaluated in the 54-week efficacy analysis was a population of patients who entered the continuation period without receiving glycemic rescue therapy in the 24-week placebo-controlled period. Because the baseline HbA_1c inclusion criteria ranged from 7.5 to 11% and the glycemic rescue criterion was an HbA_1c?>?8% after week 24, there was a greater likelihood of glycemic rescue in the monotherapy groups; this led to more missing data in the continuation all-patients-treated population(CAPT) analysis and fewer patients contributing to the completers analysis in the monotherapy groups.

Conclusions: In this study, initial treatment with sitagliptin, metformin, or the combination therapy of sitagliptin and metformin provided substantial and durable glycemic control, improved markers of β-cell function, and was generally well-tolerated over 54 weeks in patients with type 2 diabetes.     

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.     

西格列汀治疗2型糖尿病疗效和安全性的Meta分析

目的对西格列汀治疗2型糖尿病的疗效和安全性进行评价。方法以“sitagliptin”为关键词检索PubMed、Embase及CochraneLibrary,以“西格列汀”为关键词检索万方数据库,收集以糖化血红蛋白〈7％和不良反应发生率为研究终点的西格列汀治疗2型糖尿病的随机对照试验（RCT）,对符合纳入标准的RCT进行质量评价,提取相关资料并应用RevMan5．2软件进行统计分析,计算比值比（OR）和95％置信区间（口）。结果共25个RCT入选。Meta分析显示,西格列汀糖化血红蛋白〈7％达标率优于安慰剂（OR=3．02,95％C／为2．48～3．67,P=0．00）,逊于噻唑烷二酮类药物（OR=0．60,95％C／为0．41～0．88,P=0．01）,类似于二甲双胍（OR=0．78,95％C／为0．51～1．19,P=0．25）、胰高血糖素样肽1（GLP-1）受体激动剂（OR=0．53,95％C／为0．15-1．92,P=0．34）和磺酰脲类药物（OR=0．93,95％CI为0．58—1．48,P=0．76）;不良反应发生率类似于安慰剂（OR=1．11,95％C／为0．89～1．39,P=0．33）,低于二甲双胍（OR=0．42,95％C／为0．32～0．55,P=0．00）、噻唑烷二酮类药物（OR=0．65,95％C／为0．45～0．94,P=0．02）、GLP一1受体激动剂（OR=0．45,95％凹为0．24—0．83,P=0．01）、磺酰脲类药物（OR=0．38,95％CI为0．32—0．47,P=0．00）。结论西格列汀治疗2型糖尿病可有效降低患者糖化血红蛋白水平,不良反应发生率低于其他降糖药。     

Hypoglycemia in patients with type 2 diabetes from India and Malaysia treated with sitagliptin or a sulfonylurea during Ramadan: a randomized,pragmatic study

Abstract

Objective:

To compare the incidence of symptomatic hypoglycemia between sitagliptin and sulfonylurea in Muslim patients with type 2 diabetes who fasted during Ramadan.     

磷酸西格列汀治疗老年2型糖尿病的临床观察

目的:评价老年2型糖尿病(T2DM)患者合并应用二肽激肽酶Ⅳ(DPP-Ⅳ)抑制剂磷酸西格列汀的疗效和安全性。方法:收集13例为调整血糖住院的65岁以上老年2型糖尿病患者,用药方案均为合并应用西格列汀100 mg,每日1次。比较治疗前后全血糖化血红蛋白(HbA1c)、空腹血糖(FBG)、餐后2 h血糖(2 h PPG)、生化指标、血常规,并记录服药后不良反应。结果:用药后HbA1c较用药前显著下降(P<0.01)。治疗后患者体重、血压、肝、肾功能、血脂、血红蛋白(Hb)、白细胞(WBC)无明显变化。用药期间均能耐受治疗。无严重低血糖事件。结论:西格列汀联合胰岛素和其他口服降糖药用于治疗老年2型糖尿病,具有较好的疗效和安全性。     

Inhibition of DPP-4: a new therapeutic approach for the treatment of type 2 diabetes

ABSTRACT

Background: Glucagon-like peptide-1 (GLP?1) and glucose-dependent insulinotropic polypeptide (GIP) are hormones secreted by the enteroendocrine cells of the gut in response to the ingestion of nutrients. These incretin hormones, so called because they increase insulin secretion, are key modulators of pancreatic islet hormone secretion and, thus, glucose homeostasis. The glucoregulatory effects of incretins are the basis for new therapies currently being developed for the treatment of type 2 diabetes mellitus (T2DM). Drugs that inhibit dipeptidyl peptidase-4 (DPP?4), a ubiquitous enzyme that rapidly inactivates both GLP-1 and GIP, increase active levels of these hormones and, in doing so, improve islet function and glycemic control in T2DM.

Scope: In this review, we briefly describe (1) the role of pancreatic islet dysfunction in the onset and progression of T2DM, (2) the rationale for developing drugs that enhance incretin activity, (3) the evidence that inhibition of DPP?4 is effective in ameliorating islet dysfunction and improving glycemic control in T2DM, (4) the efficacy, safety, and tolerability of DPP?4 inhibitors as monotherapy and in combination with other antidiabetic agents, and (5) the potential utility of DPP?4 inhibitors relative to existing oral antidiabetic agents and newer antidiabetic drugs in the pipeline. The review is based upon MEDLINE literature searches (1966–August 2006) and abstracts and presentations from the American Diabetes Association Scientific Sessions (2002–2006) and the European Association for the Study of Diabetes Annual Meetings (1998–2006). Basic science, preclinical, and clinical studies and review articles published in the English language were evaluated and selected based upon consideration of their originality, relevance, and frequency of citation.

Findings: DPP?4 inhibitors are a new class of antidiabetogenic drugs that provide comparable efficacy to current treatments. They are effective as monotherapy in patients inadequately controlled with diet and exercise and as add-on therapy in combination with metformin, thiazolidinediones, and insulin. The DPP?4 inhibitors are well tolerated, carry a low risk of producing hypoglycemia, and are weight-neutral. The long-term durability of effect on glycemic control and β?cell morphology and function remain to be established.

Conclusions: Islet cell dysfunction is central to the pathogenesis of T2DM. Incretin-based therapies, including GLP-1 analogues and DPP?4 inhibitors, have been shown to restore glucose homeostasis and improve glycemic control. The DPP?4 inhibitors, which can be used as monotherapy or in combination with other antidiabetic drugs, are a promising new treatment option, especially for patients with early-stage T2DM and more severe hyperglycemia.     

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 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.     

Effects of saxagliptin added to sub-maximal doses of metformin compared with uptitration of metformin in type 2 diabetes: the PROMPT study

Abstract

Objective:

The PROMPT study compared efficacy and tolerability of two treatment intensification strategies: adding saxagliptin or uptitrating metformin monotherapy, in patients with type 2 diabetes (T2D) and inadequate glycaemic control on a sub-maximal metformin dose.     

Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes

ABSTRACT

Objective: The purpose of this study was to evaluate the efficacy and safety of sitagliptin as an add-on to metformin therapy in patients with moderately severe (hemoglobin A_1c ≥?8.0% and ≤?11.0%) type 2 diabetes mellitus (T2DM).

Research design and methods: This was a multi­national, randomized, placebo-controlled, parallel-group, double-blind study conducted in 190 patients with T2DM. After ≥?6?weeks of stable metformin monotherapy (≥?1500?mg/day), patients were randomized to either the addition of sitagliptin 100?mg once daily or placebo to ongoing metformin for 30?weeks.

Main outcome measures: The primary efficacy endpoint was reduction in hemoglobin A_1c (HbA_1c) measured after 18?weeks of sitagliptin treatment. Key secondary end­points included reduction in fasting plasma glucose (FPG) and 2-hour (2-h) postprandial plasma glucose (PPG) at 18 weeks, and HbA_1c at 30 weeks. The proportion of patients meeting the goal of HbA_1c <?7.0% was also analyzed.

Results: Sitagliptin significantly reduced HbA_1c, FPG, and 2-h PPG, compared with placebo (all p < 0.001). The net improvement in HbA_1c was –1.0% at both 18 and 30 weeks, and a significantly greater proportion of patients treated with sitagliptin achieved HbA_1c <?7.0% by the end of the study (22.1% vs. 3.3%, p < 0.001). Sitagliptin was well-tolerated. Compared with placebo, sitagliptin had a neutral effect on body weight and did not signif­icantly increase the risk of hypoglycemia or gastro­intestinal adverse events.

Conclusions: Addition of sitagliptin 100?mg once daily to ongoing metformin therapy was well-tolerated and resulted in significant glycemic improvement in patients with moderately severe T2DM who were treated for 30 weeks.

Trial registration: ClinicalTrials.gov identifier: NCT00337610.