Robust analyzes for longitudinal clinical trials with missing and non-normal continuous outcomes.

Missing data is unavoidable in longitudinal clinical trials, and outcomes are not always normally distributed. In the presence of outliers or heavy-tailed distributions, the conventional multiple imputation with the mixed model with repeated measures analysis of the average treatment effect (ATE) based on the multivariate normal assumption may produce bias and power loss. Control-based imputation (CBI) is an approach for evaluating the treatment effect under the assumption that participants in both the test and control groups with missing outcome data have a similar outcome profile as those with an identical history in the control group. We develop a robust framework to handle non-normal outcomes under CBI without imposing any parametric modeling assumptions. Under the proposed framework, sequential weighted robust regressions are applied to protect the constructed imputation model against non-normality in the covariates and the response variables. Accompanied by the subsequent mean imputation and robust model analysis, the resulting ATE estimator has good theoretical properties in terms of consistency and asymptotic normality. Moreover, our proposed method guarantees the analysis model robust-ness of the ATE estimation in the sense that its asymptotic results remain intact even when the analysis model is misspecified. The superiority of the proposed robust method is demonstrated by comprehensive simulation studies and an AIDS clinical trial data application.

A randomized clinical trial of the efficacy and safety of sitagliptin as initial oral therapy in youth with type 2 diabetes.

OBJECTIVE: To assess the efficacy and safety of DPP-4 inhibition with sitagliptin in youth with type 2 diabetes (T2D). STUDY DESIGN: This was a 54-week, double-blind, randomized, controlled clinical trial evaluating the safety and efficacy of DPP-4 inhibition with sitagliptin 100 mg once daily as initial oral therapy in youth with T2D. The 190 participants, aged 10-17 years, had HbA1c 6.5%-10% (7.0%-10% if on insulin). All were negative for pancreatic autoantibodies and overweight/obese at screening or diagnosis. The trial was placebo controlled for the first 20 weeks, after which metformin replaced placebo. The primary efficacy endpoint was change from baseline in HbA1c at Week 20. RESULTS: Treatment groups were well balanced at baseline (mean ± SD HbA1c = 7.5% ± 1.0, BMI percentile = 97.1% ± 6.8, age = 14.0 years ± 2.0 [57.4% <15], 60.5% female). At Week 20, least squares mean changes from baseline in HbA1c were -0.01% (sitagliptin) and 0.18% (placebo); between-group difference (95% CI) = -0.19% (-0.68, 0.30), p = 0.448. At Week 54, the changes in HbA1c were 0.45% (sitagliptin) and -0.11 (placebo/metformin). There were no notable between-group differences in the adverse event profiles through Week 54. CONCLUSIONS: DPP-4 inhibition with sitagliptin did not provide significant improvement in glycemic control. In this study, sitagliptin was generally well tolerated with a safety profile similar to that reported in adults. (ClinicalTrials.gov: NCT01485614; EudraCT: 2011-002528-42).

Efficacy and safety of the addition of sitagliptin to treatment of youth with type 2 diabetes and inadequate glycemic control on metformin without or with insulin.

OBJECTIVE: To assess the efficacy and safety of sitagliptin in youth with type 2 diabetes (T2D) inadequately controlled with metformin ± insulin. STUDY DESIGN: Data were pooled from two 54-week, double-blind, randomized, placebo-controlled studies of sitagliptin 100 mg daily or placebo added onto treatment of 10- to 17-year-old youth with T2D and inadequate glycemic control on metformin ± insulin. Participants (N = 220 randomized and treated) had HbA1c 6.5%-10% (7.0%-10% if on insulin), were overweight/obese at screening or diagnosis and negative for pancreatic autoantibodies. The primary endpoint was change from baseline in HbA1c at Week 20. RESULTS: Treatment groups were well balanced at baseline (mean HbA1c = 8.0%, BMI = 30.9 kg/m2 , age = 14.4 years [44.5% <15], 65.9% female). The dose of background metformin was >1500 mg/day for 71.8% of participants; 15.0% of participants were on insulin therapy. At Week 20, LS mean changes from baseline (95% CI) in HbA1c for sitagliptin/metformin and placebo/metformin were -0.58% (-0.94, -0.22) and -0.09% (-0.43, 0.26), respectively; difference = -0.49% (-0.90, -0.09), p = 0.018; at Week 54 the LS mean (95% CI) changes were 0.35% (-0.48, 1.19) and 0.73% (-0.08, 1.54), respectively. No meaningful differences between the adverse event profiles of the treatment groups emerged through Week 54. CONCLUSIONS: These results do not suggest that addition of sitagliptin to metformin provides durable improvement in glycemic control in youth with T2D. In this study, sitagliptin was generally well tolerated with a safety profile similar to that reported in adults. (ClinicalTrials.gov: NCT01472367, NCT01760447; EudraCT: 2011-002529-23/2014-003583-20, 2012-004035-23).

Double-blind, randomized clinical trial comparing the efficacy and safety of continuing or discontinuing the dipeptidyl peptidase-4 inhibitor sitagliptin when initiating insulin glargine therapy in patients with type 2 diabetes: The CompoSIT-I Study.

AIMS: To compare the effects of continuing versus discontinuing sitagliptin when initiating and intensively titrating insulin glargine. MATERIALS AND METHODS: Eligible patients had inadequately controlled type 2 diabetes on metformin (≥1500 mg/d) in combination with a dipeptidyl peptidase-4 (DPP-4) inhibitor and/or a sulphonylurea. Those on metformin + sitagliptin were directly randomized; all others were switched to metformin + sitagliptin (discontinuing other DPP-4 inhibitors and sulphonylureas) and stabilized during a run-in period. At randomization, patients were allocated to continuing sitagliptin or discontinuing sitagliptin, with both groups initiating insulin glargine and titrating to a target fasting glucose of 4.0 to 5.6 mmol/L. RESULTS: A total of 743 participants (mean glycated haemoglobin [HbA1c] 72.6 mmol/mol [8.8%], disease duration 10.8 years), were treated. After 30 weeks, the mean HbA1c and least squares (LS) mean change from baseline in HbA1c were 51.4 mmol/mol (6.85%) and -20.5 mmol/mol (-1.88%) in the sitagliptin group and 56.4 mmol/mol (7.31%) and -15.5 mmol/mol (-1.42%) in the placebo group; the difference in LS mean changes from baseline HbA1c was -5.0 mmol/mol (-0.46%; P < 0.001). The percentage of participants with HbA1c <53 mmol/mol (<7.0%) was higher (54% vs. 35%) and the mean daily insulin dose was lower (53 vs. 61 units) in the sitagliptin group. Despite lower HbA1c, event rates and incidences of hypoglycaemia were not higher in the sitagliptin group. Adverse events overall and changes from baseline in body weight were similar between the two treatment groups. CONCLUSION: When initiating insulin glargine therapy, continuation of sitagliptin, compared with discontinuation, resulted in a clinically meaningful greater reduction in HbA1c without an increase in hypoglycaemia. ClinicalTrials.gov Identifier: NCT02738879.

Efficacy and safety of MK-1293 insulin glargine compared with originator insulin glargine (Lantus) in type 1 diabetes: A randomized, open-label clinical trial.

AIM: To compare the efficacy and safety of MK-1293 insulin glargine (Mk-Gla; 100 U/mL) with originator insulin glargine, Lantus (Sa-Gla), in people with type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS: This phase 3, randomized, active-controlled, open-label, 52-week study (ClinicalTrials.gov NCT02059161) enrolled 508 people with T1DM (HbA1c ≤11.0%; 97 mmol/mol) taking basal and prandial insulin. Participants were randomized 1:1 to once-daily Mk-Gla (n = 245) or Sa-Gla (n = 263). Dose titration of basal insulin was by a pre-breakfast plasma glucose dosing algorithm. The primary efficacy objective was assessment of the non-inferiority of HbA1c change from baseline (margin of 0.40% [4.4 mmol/mol]) for Mk-Gla compared with Sa-Gla over 24 weeks. The primary safety objective was assessment of anti-insulin antibody development over 24 weeks. RESULTS: The least squares (LS) mean HbA1c change from baseline at week 24 was -0.62 (95% CI -0.79, -0.45)% (-6.8 [-8.7, -4.9] mmol/mol) and -0.66 (-0.82, -0.50)% (-7.2 [-9.0, -5.4] mmol/mol) for Mk-Gla and Sa-Gla. The LS mean HbA1c difference was 0.04 (-0.11, 0.19)% (0.4 [-1.2, 2.0] mmol/mol) for Mk-Gla minus Sa-Gla, meeting the primary and secondary objective criteria for non-inferiority and equivalence. Week 24 mean insulin glargine dose for Mk-Gla and Sa-Gla was 0.46 and 0.48 U/kg, respectively. Similarity of HbA1c response and basal insulin dose trajectory persisted over the 52 weeks. Safety and tolerability, including anti-insulin antibody responses, hypoglycaemia, adverse events and body weight, were similar between insulins over the 52-week study duration. CONCLUSIONS: Mk-Gla and Sa-Gla exhibited similar efficacy and safety over 52 weeks in people with T1DM. ClinicalTrials.gov: NCT02059161.

Efficacy and safety of MK-1293 insulin glargine compared with originator insulin glargine (Lantus) in type 2 diabetes: A randomized, open-label clinical trial.

AIM: To compare the efficacy and safety of MK-1293 insulin glargine (Mk-Gla) and Lantus (Sa-Gla) in people with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: This Phase 3, randomized, active-controlled, open-label, 24-week clinical trial (ClinicalTrials.gov number NCT02059187) enrolled 531 participants with T2DM (HbA1c ≤11.0%) either eligible for or currently taking basal insulin (≥10 U/day). Participants were randomized 1:1 to once-daily Mk-Gla (n = 263) or Sa-Gla (n = 263). Titration of insulin was guided by a fasting plasma glucose (FPG)-based dosing algorithm. The primary efficacy objective was to demonstrate the non-inferiority of change from baseline in HbA1c (margin of 0.40% [4.4 mmol/mol]) with Mk-Gla versus Sa-Gla after 24 weeks. The primary safety objective was anti-insulin antibody development after 24 weeks. RESULTS: For Mk-Gla and Sa-Gla, the least squares (LS) mean HbA1c change from baseline (95% CI) was -1.28 (-1.41, -1.15)% (-14.0 [-15.4, -12.6] mmol/mol) and -1.30 (-1.43, -1.18)% (-14.2 [-15.6, -12.8] mmol/mol). The LS mean HbA1c difference (Mk-Gla minus Sa-Gla) was 0.03 (-0.12, 0.18)% (0.3 [-1.4, 1.9] mmol/mol), meeting non-inferiority and equivalence (secondary objective) criteria. Insulin doses, FPG, and seven-point plasma glucose profiles were similar between groups. Safety and tolerability, including anti-insulin antibody responses, hypoglycaemia, adverse events and body weight, were similar between insulins. The efficacy and safety of Mk-Gla and Sa-Gla were similar both in participants who were insulin-treated or insulin-naïve at baseline. CONCLUSIONS: Mk-Gla and Sa-Gla demonstrated similar efficacy and safety over 24 weeks of treatment in people with T2DM.

Randomized clinical trial of the safety and efficacy of sitagliptin and metformin co-administered to Chinese patients with type 2 diabetes mellitus.

INTRODUCTION: The results of a clinical trial to evaluate the efficacy and safety of initial combination therapy with sitagliptin and metformin in Chinese patients with type 2 diabetes and inadequate glycemic control are reported here. MATERIALS AND METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, parallel group, 24-week clinical trial carried out in China. Patients (n = 744) with type 2 diabetes and inadequate glycemic control (glycated hemoglobin ≥7.5 and ≤11.0%) who were either drug-naïve or washed out of previous therapy were randomized in equal ratios to sitagliptin 100 mg once daily (q.d.; S100), metformin 500 mg twice daily (b.i.d.; M1000), metformin 850 mg b.i.d. (M1700), sitagliptin 50 mg b.i.d. plus metformin 500 mg b.i.d. (S100/M1000), sitagliptin 50 mg b.i.d. plus metformin 850 mg b.i.d. (S100/M1700), or placebo. RESULTS: The mean baseline glycated hemoglobin in randomized patients was 8.7%. Least squares mean changes from baseline in glycated hemoglobin were -0.59% (placebo), -0.99% (S100), -1.29% (M1000), -1.56% (M1700), -1.67% (S100/M1000) and -1.83% (S100/M1700) (P < 0.05 for each active group vs placebo, for S100/M1700 and S100/M1000 vs S100, and for S100/M1000 vs M1000). All treatments were generally well-tolerated. The overall incidence of hypoglycemia (symptomatic or asymptomatic) was higher in the two co-administration groups (S100/M1700 and S100/M1000) compared with the placebo. The incidence of symptomatic hypoglycemia was low, and similar, across all treatment groups. The incidences of gastrointestinal adverse events were generally higher in high-dose metformin groups than in the placebo group. CONCLUSIONS: In Chinese patients with type 2 diabetes, initial combination therapy with sitagliptin and metformin was generally well-tolerated, and provided improvement in glycemic control.

A randomized clinical trial evaluating the safety and efficacy of sitagliptin added to the combination of sulfonylurea and metformin in patients with type 2 diabetes mellitus and inadequate glycemic control.

BACKGROUND: Type 2 diabetes mellitus (T2DM) treatment generally requires multiple antihyperglycemic agents. When diet, exercise, and treatment with sulfonylurea and metformin do not achieve glycemic goals, several options are available. The present study evaluated the efficacy and tolerability of sitagliptin 100 mg/day added to therapy with sulfonylurea and metformin. METHODS: Patients with HbA1c ≥7.5% and ≤10.5% while on a sulfonylurea and metformin were randomized 1: 1 to sitagliptin 100 mg/day or placebo for 24 weeks. At Week 24, patients in the placebo group switched to pioglitazone 30 mg/day and both groups continued treatment for another 30 weeks. RESULTS: Of 427 patients randomized, 339 (79.4%) completed the study. At Week 24, significantly greater (P < 0.001) mean reductions from baseline were seen in the sitagliptin versus placebo group for HbA1c (-0.84% vs -0.16%, respectively), 2-h post-meal glucose (-2.0 vs -0.2 mmol/L, respectively) and fasting plasma glucose (-0.7 vs 0.3 mmol/L, respectively). At Week 54, improvements in glycemic control continued. At Week 24, the incidence of adverse events (AEs) was numerically greater with sitagliptin than placebo, primarily because of a higher incidence of hypoglycemia. At Week 54, the incidence of AEs was similar in both groups, primarily because of a higher incidence of hypoglycemia and edema in the placebo/pioglitazone group after Week 24. The only meaningful change in body weight was an increase in the placebo/pioglitazone group at Week 54. CONCLUSIONS: In this study, sitagliptin 100 mg/day was generally well tolerated and provided improvement in glycemic control when added to the combination of sulfonylurea and metformin in patients with T2DM.

Efficacy and Tolerability of Sitagliptin Compared with Glimepiride in Elderly Patients with Type 2 Diabetes Mellitus and Inadequate Glycemic Control: A Randomized, Double-Blind, Non-Inferiority Trial.

OBJECTIVE: The aim of this study was to evaluate the efficacy and tolerability of sitagliptin compared with glimepiride in elderly patients with type 2 diabetes mellitus (T2DM) and inadequate glycemic control with diet and exercise alone. METHODS: This was a randomized, parallel-group, multinational, non-inferiority clinical trial with an active-controlled, double-blind treatment period in which patients ≥ 65 and ≤ 85 years of age with T2DM were screened at 85 sites. Patients were randomized to once-daily sitagliptin (100 or 50 mg, depending on renal function) or glimepiride (in titrated doses) for 30 weeks. The main outcome measures were change from baseline in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and body weight; and the incidence of symptomatic hypoglycemia. RESULTS: The mean baseline HbA1c was 7.8% in both the sitagliptin group (n = 197) and the glimepiride group (n = 191). After 30 weeks, the least squares (LS) mean change in HbA1c baseline was -0.32% with sitagliptin and -0.51 % with glimepiride, for a between-group difference (95% CI) of 0.19% (0.03-0.34). This result met the pre-specified criterion for declaring non-inferiority, which required that the upper 95% confidence limit lie below 0.4%. The LS mean change in FPG from baseline was -14.5 mg/dL with sitagliptin and -21.2 mg/dL with glimepiride, for a between-group difference (95% CI) of 6.7 mg/dL (0.7-12.7). The percentages of patients with adverse events of symptomatic hypoglycemia were 0.8% in the sitagliptin group and 4.7% in the glimepiride group (between-treatment difference = -3.9%, p = 0.009). The LS mean change in body weight from baseline was 0.4 kg with sitagliptin and 1.1 kg with glimepiride, for a between-group difference of -0.7 kg (p = 0.011). CONCLUSION: In elderly patients with T2DM and inadequate glycemic control with diet and exercise alone, sitagliptin provided non-inferior glycemic control after 30 weeks of treatment compared with glimepiride. Compared with glimepiride, sitagliptin had a lower risk of hypoglycemia. Sitagliptin was weight-neutral; while the between-group difference in change from baseline in body weight was statistically significant, the modest difference may not be clinically meaningful. STUDY IDENTIFIER: ClinicalTrials.gov NCT01189890.

A Randomized Clinical Trial to Evaluate the Efficacy and Safety of Co-Administration of Sitagliptin with Intensively Titrated Insulin Glargine.

INTRODUCTION: The objective of this study was to assess the effect of sitagliptin on insulin dose in patients with inadequately controlled type 2 diabetes who titrate basal insulin to a target fasting glucose level after initiating sitagliptin. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, 24-week clinical trial in which treatment with sitagliptin 100 mg/day or placebo was administered concurrently with insulin glargine titration, targeting a fasting glucose of 4.0-5.6 mmol/L (72-100 mg/dL). The trial randomized 660 patients with type 2 diabetes and inadequate glycemic control on insulin, with or without metformin (≥1500 mg/day) or sulfonylurea, for ≥10 weeks. Patients could remain on metformin but not sulfonylurea after randomization. RESULTS: The increase from baseline in the daily dose of insulin was less in the sitagliptin group (N = 329) compared to placebo (N = 329) (between group difference = -4.7 IU [95% confidence interval [CI] -8.3, -1.2]; p = 0.009). Patients in the sitagliptin group had lower glycated hemoglobin (HbA1c) levels after 24 weeks (between-group difference of -0.4% [95% CI -0.6, -0.3; -4.9 mmol/mol (95% CI -6.6, -3.2)]; p < 0.001), and more patients in the sitagliptin group reached the HbA1c goal of <7.0% (53 mmol/mol), with a between-group difference of 17.3% (95% CI 10.4%, 24.1%; p < 0.001). Fewer patients in the sitagliptin group experienced an adverse event of hypoglycemia (between-group difference = -15.5%, p < 0.001). CONCLUSION: Administration of sitagliptin prior to intensive titration of basal insulin glargine reduces the insulin dose requirement while providing superior glycemic control and less hypoglycemia, compared to an insulin-only regimen. FUNDING: Merck & Co., Inc., Kenilworth, NJ, USA.

Safety of sitagliptin in elderly patients with type 2 diabetes: a pooled analysis of 25 clinical studies.

OBJECTIVE: The aim of this study was to evaluate the safety and tolerability of sitagliptin 100 mg/day in elderly patients with type 2 diabetes. DESIGN: A post hoc pooled analysis of 25 randomized, double-blind, parallel group clinical studies with results available as of 1 December 2011. SETTING: Multicenter, international clinical trials. SUBJECTS: Patients with type 2 diabetes aged 65 years or older. INTERVENTIONS: Patients were randomized to sitagliptin 100 mg/day (n = 1,261) or a comparator (n = 1,185) for 12 weeks to 2 years. MAIN OUTCOME MEASURES: In each study, investigators reported serious and non-serious adverse events that occurred during the study, and serious adverse events occurring within 14 days following the last dose of study drug. This analysis used patient-level data from each study to assess the exposure-adjusted incidence rates of specific adverse events that occurred following initiation of study drug. RESULTS: Summary measures of adverse events overall were similar between the sitagliptin and non-exposed (active comparator or placebo) groups, except for higher incidences of deaths and drug-related adverse events in the non-exposed group. Incidence rates of specific adverse events were generally similar between the two groups, with the exception of hypoglycemia. A lower incidence rate of hypoglycemia was observed in the sitagliptin group compared with the non-exposed group [7.0 vs. 14.3 per 100 patient-years; difference -7.6 (95 % CI -11.2 to -4.3]), primarily due to greater use of sulfonylureas in the non-exposed group. CONCLUSIONS: In this pooled safety analysis of elderly patients with type 2 diabetes, treatment with sitagliptin 100 mg/day was generally well tolerated for up to 2 years.

Assessment of AACE/ACE recommendations for initial dual antihyperglycemic therapy using the fixed-dose combination of sitagliptin and metformin versus metformin.

OBJECTIVE: The American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) diabetes algorithm recommends a stratified approach to initial therapy to achieve a glycated hemoglobin (HbA1c) goal of ≤6.5% in patients with type 2 diabetes mellitus (T2DM) who have inadequate glycemic control. Data from a double-blind study in drug-naïve T2DM patients comparing initial monotherapy with metformin (MET) with initial dual therapy with a fixed-dose combination of sitagliptin and MET (SITA/MET FDC) was used to determine AACE/ACE HbA1c goal attainment in these treatment groups. METHODS: A total of 1,250 patients (mean baseline HbA1c = 9.9%) were randomized 1:1 to SITA/MET FDC 50/500 mg twice daily (b.i.d.) or MET 500 mg b.i.d. for 18 weeks. SITA/MET FDC and MET were uptitrated over 4 weeks to 50/1,000 mg b.i.d. and 1,000 mg b.i.d., respectively. RESULTS: At week 18, a higher percentage of patients receiving SITA/MET FDC had HbA1c levels ≤6.5% and <7% than those receiving MET alone within each of the 3 AACE/ACE HbA1c categories (6.5-7.5%, >7.5-9.0%, and >9.0%). Of patients with a baseline HbA1c >7.5-9.0% who initiated SITA/MET FDC, 48.6% achieved an HbA1c ≤6.5% at week 18 compared with 23.1% of patients who initiated MET monotherapy (P<.001). In patients with a baseline HbA1c >9.0%, 24.0% on SITA/MET FDC achieved an HbA1c ≤6.5% compared with 12.8% on MET alone (P<.001). CONCLUSION: In T2DM patients with a baseline HbA1c >7.5-9.0%, substantially more achieved the HbA1c goal of ≤6.5% with initial dual therapy (SITA/MET FDC) than with initial monotherapy (MET), which is in agreement with the AACE/ACE diabetes algorithm.

Safety and tolerability of sitagliptin in type 2 diabetes: pooled analysis of 25 clinical studies.

INTRODUCTION: In a previous pooled analysis of 19 double-blind clinical studies conducted by Merck, which included data available as of July 2009 on 10,246 patients with type 2 diabetes (T2DM), treatment with sitagliptin was shown to be generally well tolerated compared with treatment with control agents. As the sitagliptin clinical development program continues, additional studies with sitagliptin have been completed. The present analysis updates the safety and tolerability assessment of sitagliptin by examining pooled data from 25 double-blind clinical studies. METHODS: The present analysis included data from 14,611 patients in 25 studies with T2DM who received either sitagliptin 100 mg/day (n = 7,726; sitagliptin group) or a comparator agent (n = 6,885; non-exposed group). These studies represent all randomized, double-blind trials conducted by Merck that included patients treated with the usual clinical dose of sitagliptin (100 mg/day) for between 12 weeks and 2 years, and for which results were available as of December 2011. These studies assessed sitagliptin, versus comparator agents, taken as monotherapy, initial combination therapy with metformin or pioglitazone, or as add-on combination therapy with other antihyperglycemic agents (metformin, pioglitazone, a sulfonylurea ± metformin, insulin ± metformin, or metformin + pioglitazone or rosiglitazone). Patient-level data from each study were used to evaluate between-group differences in the exposure-adjusted incidence rates of adverse events (AEs). RESULTS: Overall incidence rates of AEs and drug-related AEs were higher in the non-exposed group compared with the sitagliptin group. Incidence rates of specific AEs were generally similar between the two groups, except for higher incidence rates of hypoglycemia related to the greater use of a sulfonylurea and diarrhea related to the greater use of metformin in the non-exposed group, and of constipation in the sitagliptin group. Treatment with sitagliptin was not associated with an increased risk of major adverse cardiovascular events, malignancy, or pancreatitis. CONCLUSION: In this updated pooled safety analysis of data from 14,611 patients with T2DM, sitagliptin 100 mg/day was generally well tolerated in clinical trials of up to 2 years in duration.

Cardiovascular safety of sitagliptin in patients with type 2 diabetes mellitus: a pooled analysis.

OBJECTIVE: To compare the incidence of cardiovascular events and mortality in patients with type 2 diabetes mellitus treated with sitagliptin or non-sitagliptin comparators. METHODS: A post hoc assessment of cardiovascular safety in 14,611 patients was performed by pooling data from 25 double-blind studies, which randomised patients at baseline to sitagliptin 100 mg/day or a non-sitagliptin comparator (i.e., non-exposed). Included studies were limited to those at least 12 weeks in duration (range: 12 to 104 weeks). Patient-level data were used in this analysis of major adverse cardiovascular events (MACE) including ischaemic events and cardiovascular deaths. Analyses were performed in three cohorts: the entire 25-study cohort, the cohort from placebo-controlled portions of studies (n=19), and the cohort from studies comparing sitagliptin to a sulphonylurea (n=3). RESULTS: In the entire cohort analysis, 78 patients had at least 1 reported MACE-related event, with 40 in the sitagliptin group and 38 in the non-exposed group. The exposure-adjusted incidence rate was 0.65 per 100 patient-years in the sitagliptin group and 0.74 in the non-exposed group (incidence rate ratio = 0.83 [95% confidence interval (CI): 0.53, 1.30]). In the analysis comparing sitagliptin to placebo, the exposure-adjusted incidence rate was 0.80 per 100-patient-years with sitagliptin and 0.76 with placebo (incidence rate ratio = 1.01 [95% CI: 0.55, 1.86]). In the analysis comparing sitagliptin to sulphonylurea, the exposure-adjusted incidence rate was 0.00 per 100 patient-years with sitagliptin and 0.86 with sulphonylurea (incidence rate ratio = 0.00 [95% CI: 0.00, 0.31]). CONCLUSION: A pooled analysis of 25 randomised clinical trials does not indicate that treatment with sitagliptin increases cardiovascular risk in patients with type 2 diabetes mellitus. In a subanalysis, a higher rate of cardiovascular-related events was associated with sulphonylurea relative to sitagliptin.

Efficacy and safety of sitagliptin in patients with type 2 diabetes and ESRD receiving dialysis: a 54-week randomized trial.

BACKGROUND: Treatment with oral antihyperglycemic agents has not been well characterized in patients with type 2 diabetes and end-stage renal disease (ESRD). The efficacy and safety of sitagliptin and glipizide monotherapy in patients with type 2 diabetes and ESRD on dialysis therapy were assessed in this study. STUDY DESIGN: 54-week, randomized, double-blind, parallel-arm study. SETTING & PARTICIPANTS: From 31 clinical sites in 12 countries, 129 patients 30 years or older with type 2 diabetes and ESRD who were on dialysis therapy and had a hemoglobin A1c (HbA1c) level of 7%-9% were randomly assigned 1:1 to treatment. INTERVENTION: Monotherapy with sitagliptin, 25 mg daily or glipizide (initiated with 2.5 mg daily and titrated up to a potential maximum dose of 10 mg twice daily or down to avoid hypoglycemia). OUTCOMES: Primary end points were 54-week change in HbA1c level from baseline and tolerability with sitagliptin. A secondary end point was the comparison of sitagliptin versus glipizide on the incidence of symptomatic hypoglycemia. RESULTS: Of 129 patients randomly assigned, 64 were in the sitagliptin group (mean baseline age, 61 years; HbA1c, 7.9%) and 65 were in the glipizide group (mean baseline age, 59 years; HbA1c, 7.8%). After 54 weeks, the least squares mean change from baseline in HbA1c level was -0.72% (95% CI, -0.95% to -0.48%) with sitagliptin and -0.87% (95% CI, -1.11% to -0.63%) with glipizide, for a difference of 0.15% (95% CI, -0.18% to 0.49%). The incidences of symptomatic hypoglycemia and severe hypoglycemia were 6.3% versus 10.8% (between-group difference, -4.8% [95% CI, -15.7% to 5.6%]) and 0% versus 7.7% (between-group difference, -7.8% [95% CI, -17.1% to -1.9%]) in the sitagliptin and glipizide groups, respectively. Higher incidences (ie, 95% CI around between-treatment difference excluded 0) of cellulitis and headache were found with sitagliptin compared to glipizide (6.3% vs 0%, respectively, for both). LIMITATIONS: Small sample size limits between-group comparisons. CONCLUSIONS: Treatment with sitagliptin or glipizide monotherapy was effective and well tolerated over 54 weeks in patients with type 2 diabetes and ESRD who were receiving dialysis.

Efficacy and safety of sitagliptin added to ongoing metformin and pioglitazone combination therapy in a randomized, placebo-controlled, 26-week trial in patients with type 2 diabetes.

AIMS: To assess efficacy and safety of sitagliptin, a dipeptidyl peptidase-4 inhibitor, in combination therapy with metformin (≥1500 mg/day) and pioglitazone (≥30 mg/day) in patients with type 2 diabetes (T2DM) with inadequate glycemic control (hemoglobin A1c [HbA1c] ≥7.5% and ≤11%). METHODS: This placebo-controlled, double-blind study included 313 patients, mean baseline HbA1c=8.7%, who were randomized to receive sitagliptin 100 mg/day or placebo for 26 weeks. RESULTS: The addition of sitagliptin led to significant (P<.001) mean changes from baseline relative to placebo in HbA1c (-0.7%), fasting plasma glucose (-1.0 mmol/L), and 2-h post-meal glucose (-2.2 mmol/L). In patients with baseline HbA1c ≥9.0%, mean changes from baseline in HbA1c were -1.6% and -0.8% for the sitagliptin and placebo groups, respectively (between-group difference -0.8%; P<.001). The incidences of reported adverse events were generally similar between the treatment groups. Incidences of symptomatic hypoglycemia were 7/157 [4.5%] and 6/156 [3.8%] in the sitagliptin and placebo groups, respectively (P=.786). Two patients, both in the placebo group, experienced an episode of hypoglycemia that required non-medical assistance. CONCLUSIONS: In this 26-week study, addition of sitagliptin to combination therapy with metformin and pioglitazone improved glycemic control and was generally well tolerated.

Efficacy and safety of sitagliptin versus glipizide in patients with type 2 diabetes and moderate-to-severe chronic renal insufficiency.

OBJECTIVE: Patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease have an increased risk of micro- and macrovascular disease, but limited options for antihyperglycemic therapy. We compared the efficacy and safety of sitagliptin with glipizide in patients with T2DM and moderate-to-severe chronic renal insufficiency and inadequate glycemic control. RESEARCH DESIGN AND METHODS: Patients (n = 426) were randomized 1:1 to sitagliptin (50 mg every day [q.d.] for moderate renal insufficiency and 25 mg q.d. for severe renal insufficiency) or glipizide (2.5 mg q.d., adjusted based on glycemic control to a 10-mg twice a day maximum dose). Randomization was stratified by: 1) renal status (moderate or severe renal insufficiency); 2) history of cardiovascular disease; and 3) history of heart failure. RESULTS: At week 54, treatment with sitagliptin was noninferior to treatment with glipizide in A1C change from baseline (-0.8 vs. -0.6%; between-group difference -0.11%; 95% CI -0.29 to 0.06) because the upper bound of the 95% CI was less than the prespecified noninferiority margin of 0.4%. There was a lower incidence of symptomatic hypoglycemia adverse events (AEs) with sitagliptin versus glipizide (6.2 and 17.0%, respectively; P = 0.001) and a decrease in body weight with sitagliptin (-0.6 kg) versus an increase (1.2 kg) with glipizide (difference, -1.8 kg; P < 0.001). The incidence of gastrointestinal AEs was low with both treatments. CONCLUSIONS: In patients with T2DM and chronic renal insufficiency, sitagliptin and glipizide provided similar A1C-lowering efficacy. Sitagliptin was generally well-tolerated, with a lower risk of hypoglycemia and weight loss versus weight gain, relative to glipizide.

Efficacy and safety of sitagliptin added to ongoing metformin and rosiglitazone combination therapy in a randomized placebo-controlled 54-week trial in patients with type 2 diabetes.

BACKGROUND: New therapeutic approaches are needed to improve glycemic control in patients with type 2 diabetes (T2D), a progressive disorder that often requires combination therapy. The present study assessed the efficacy and safety of sitagliptin as add-on therapy to metformin and rosiglitazone in patients with T2D. METHODS: The present study was a randomized double-blind placebo-controlled parallel-group 54-week study conducted at 41 sites across North and South America, Europe, and Asia in 278 patients with HbA1c ranging from ≥7.5% to ≤11.0% despite ongoing combination therapy with metformin (≥1500 mg/day) and rosiglitazone (≥4 mg/day). Patients were randomized (2:1) to receive sitagliptin 100 mg or placebo once daily. The main outcome measure was change from baseline in HbA1c at Week 18. RESULTS: Mean baseline HbA1c was 8.8%. The mean placebo-adjusted change from baseline in HbA1c with sitagliptin treatment was -0.7% (P < 0.001) at Week 18 and -0.8% (P < 0.001) at Week 54. There were also significant (P < 0.001) reductions in 2-h post-meal glucose and fasting plasma glucose compared with placebo at Weeks 18 and 54. Significantly higher proportions of sitagliptin- than placebo-treated patients had HbA1c<7.0% at Weeks 18 (22% vs 9%; P = 0.003) and 54 (26% vs 14%; P = 0.015). Changes in body weight and the rates of adverse events overall, hypoglycemia, and gastrointestinal adverse events were similar in the sitagliptin and placebo groups during the 54-week study. CONCLUSIONS: In patients with T2D, the addition of sitagliptin for 54 weeks to ongoing therapy with metformin and rosiglitazone improved glycemic control and was generally well tolerated compared with placebo.