Efficacy and safety of sitagliptin and metformin as initial combination therapy and as monotherapy over 2 years in patients with type 2 diabetes

Aim: To assess the 104‐week efficacy and safety of sitagliptin and metformin as initial combination therapy and as monotherapy in patients with type 2 diabetes and inadequate glycaemic control (HbA_1c 7.5–11%) on diet and exercise. Methods: This study was a 50‐week, double‐blind extension of a 54‐week, randomized, double‐blind, factorial study of the initial combination of sitagliptin and metformin, metformin monotherapy and sitagliptin monotherapy (104 weeks total duration). Patients assigned to active therapy in the 54‐week base study remained on those treatments in the extension study: sitagliptin 50 mg b.i.d. + metformin 1000 mg b.i.d. (higher dose combination), sitagliptin 50 mg b.i.d. + metformin 500 mg b.i.d. (lower dose combination), metformin 1000 mg b.i.d. (higher dose), metformin 500 mg b.i.d. (lower dose) and sitagliptin 100 mg q.d. Patients randomized to receive the sequence of placebo/metformin were switched, in a blinded manner, from placebo to metformin monotherapy uptitrated to 1000 mg b.i.d. beginning at week 24 and remained on higher dose metformin through the extension. Results: Amongst patients who entered the extension study without having initiated glycaemic rescue therapy, least‐squares mean changes in HbA_1c from baseline at week 104 were ?1.7% (higher dose combination), ?1.4% (lower dose combination), ?1.3% (higher dose), ?1.1% (lower dose) and ?1.2% (sitagliptin). The proportions of patients with an HbA_1c <7% at week 104 were 60% (higher dose combination), 45% (lower dose combination), 45% (higher dose), 28% (lower dose) and 32% (sitagliptin). Fasting and postmeal measures of glycaemic control and β‐cell function improved in all groups, with glycaemic responses generally maintained over the 104‐week treatment period. The incidence of hypoglycaemia was low across all groups. The incidences of gastrointestinal adverse experiences were generally lower in the sitagliptin group and similar between the metformin monotherapy and combination groups. Conclusions: Initial combination therapy with sitagliptin and metformin and monotherapy with either drug alone provided substantial and sustained glycaemic improvements and were well tolerated over 104 weeks in patients with type 2 diabetes.     

Initial therapy with the fixed-dose combination of sitagliptin and metformin results in greater improvement in glycaemic control compared with pioglitazone monotherapy in patients with type 2 diabetes

Aims: To evaluate the efficacy and safety of initial therapy with a fixed‐dose combination (FDC) of sitagliptin and metformin compared with pioglitazone in drug‐naÏve patients with type 2 diabetes. Methods: After a 2‐week single‐blind placebo run‐in period, patients with type 2 diabetes, HbA1c of 7.5–12% and not on antihyperglycaemic agent therapy were randomized in a double‐blind manner to initial treatment with a FDC of sitagliptin/metformin 50/500 mg twice daily (N = 261) or pioglitazone 30 mg per day (N = 256). Sitagliptin/metformin and pioglitazone were up‐titrated over 4 weeks to doses of 50/1000 mg twice daily and 45 mg per day, respectively. Both treatments were then continued for an additional 28 weeks. Results: From a mean baseline HbA1c of 8.9% in both groups, least squares (LS) mean changes in HbA1c at week 32 were ?1.9 and ?1.4% for sitagliptin/metformin and pioglitazone, respectively (between‐group difference = ?0.5%; p < 0.001). A greater proportion of patients had an HbA1c of <7% at week 32 with sitagliptin/metformin vs. pioglitazone (57% vs. 43%, p < 0.001). Compared with pioglitazone, sitagliptin/metformin treatment resulted in greater LS mean reductions in fasting plasma glucose (FPG) [?56.0 mg/dl (?3.11 mmol/l) vs. ?44.0 mg/dl (?2.45 mmol/l), p < 0.001] and in 2‐h post‐meal glucose [?102.2 mg/dl (?5.68 mmol/l) vs. ?82.0 mg/dl (?4.56 mmol/l), p < 0.001] at week 32. A substantially greater reduction in FPG [?40.5 mg/dl (?2.25 mmol/l) vs. ?13.0 mg/dl (?0.72 mmol/l), p < 0.001] was observed at week 1 with sitagliptin/metformin vs. pioglitazone. A greater reduction in the fasting proinsulin/insulin ratio and a greater increase in homeostasis model assessment of β‐cell function (HOMA‐β) were observed with sitagliptin/metformin than with pioglitazone, while greater decreases in fasting insulin and HOMA of insulin resistance (HOMA‐IR), and a greater increase in quantitative insulin sensitivity check index (QUICKI) were observed with pioglitazone than with sitagliptin/metformin. Both sitagliptin/metformin and pioglitazone were generally well tolerated. Sitagliptin/metformin led to weight loss (?1.4 kg), while pioglitazone led to weight gain (3.0 kg) (p < 0.001 for the between‐group difference). Higher incidences of diarrhoea (15.3% vs. 4.3%, p < 0.001), nausea (4.6% vs. 1.2%, p = 0.02) and vomiting (1.9% vs. 0.0%, p = 0.026), and a lower incidence of oedema (1.1% vs. 7.0%, p < 0.001), were observed with sitagliptin/metformin vs. pioglitazone. The between‐group difference in the incidence of hypoglycaemia did not reach statistical significance (8.4 and 4.3% with sitagliptin/metformin and pioglitazone, respectively; p = 0.055). Conclusion: Compared with pioglitazone, initial therapy with a FDC of sitagliptin and metformin led to significantly greater improvement in glycaemic control as well as a higher incidence of prespecified gastrointestinal adverse events, a lower incidence of oedema and weight loss vs. weight gain.     

The effect of initial therapy with the fixed-dose combination of sitagliptin and metformin compared with metformin monotherapy in patients with type 2 diabetes mellitus

Aims: This study was conducted to compare the glycaemic efficacy and safety of initial combination therapy with the fixed‐dose combination of sitagliptin and metformin versus metformin monotherapy in drug‐naive patients with type 2 diabetes. Methods: This double‐blind study (18‐week Phase A and 26‐week Phase B) randomized 1250 drug‐naÏve patients with type 2 diabetes [mean baseline haemoglobin A1c (HbA1c) 9.9%] to sitagliptin/metformin 50/500 mg bid or metformin 500 mg bid (uptitrated over 4 weeks to achieve maximum doses of sitagliptin/metformin 50/1000 mg bid or metformin 1000 bid). Results of the primary efficacy endpoint (mean HbA1c reductions from baseline at the end of Phase A) are reported herein. Results: At week 18, mean change from baseline HbA1c was ?2.4% for sitagliptin/metformin FDC and ?1.8% for metformin monotherapy (p < 0.001); more patients treated with sitagliptin/metformin FDC had an HbA1c value <7% (p < 0.001) versus metformin monotherapy. Changes in fasting plasma glucose were significantly greater with sitagliptin/metformin FDC (?3.8 mmol/l) versus metformin monotherapy (?3.0 mmol/l; p < 0.001). Homeostasis model assessment of β‐cell function (HOMA‐β) and fasting proinsulin/insulin ratio were significantly improved with sitagliptin/metformin FDC versus metformin monotherapy. Baseline body weight was reduced by 1.6 kg in each group. Both treatments were generally well tolerated with a low and similar incidence of hypoglycaemia. Abdominal pain (1.1 and 3.9%; p = 0.002) and diarrhoea (12.0 and 16.6%; p = 0.021) occurred significantly less with sitagliptin/metformin FDC versus metformin monotherapy; the incidence of nausea and vomiting was similar in both groups. Conclusion: Compared with metformin monotherapy, initial treatment with sitagliptin/metformin FDC provided superior glycaemic improvement with a similar degree of weight loss and lower incidences of abdominal pain and diarrhoea.     

Efficacy and safety of alogliptin added to pioglitazone in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial with an open-label long-term extension study

Aim: To assess the efficacy and safety of alogliptin added to pioglitazone versus pioglitazone monotherapy, in Japanese patients with type 2 diabetes who achieved inadequate glycaemic control on pioglitazone plus diet/exercise. Methods: Patients were stabilized on pioglitazone 15 or 30 mg/day plus diet/exercise during a 16‐week screening period. Patients with HbA1c of 6.9–10.4% were randomized to 12 weeks' double‐blind treatment with alogliptin 12.5 or 25 mg once daily or placebo, added to their stable pioglitazone regimen. The primary endpoint was the change in HbA1c from baseline to week 12. Patients had an option to continue in a 40‐week, open‐label extension study, with those originally randomized to alogliptin remaining on the same dosage regimen while patients treated with placebo were randomly allocated to alogliptin 12.5 or 25 mg (added to their stable pioglitazone). Results: The change from baseline in HbA1c after 12 weeks was significantly greater with alogliptin 12.5 mg added to pioglitazone and alogliptin 25 mg added to pioglitazone than with placebo added to pioglitazone (?0.91 and ?0.97% vs. ?0.19%; p < 0.0001). Responder rates (HbA1c <6.9% and HbA1c <6.2%) and changes in fasting and postprandial blood glucose levels showed a similar positive trend in terms of glycaemic control. The benefits seen with alogliptin were sustained during the 40‐week extension period. Alogliptin added to pioglitazone was generally well tolerated; hypoglycaemia was infrequent and increases in body weight were minor. Conclusions: Once‐daily alogliptin was effective and generally well tolerated when given as add‐on therapy to pioglitazone in Japanese patients with type 2 diabetes who achieved inadequate glycaemic control on pioglitazone plus lifestyle measures. Clinical benefits were maintained for 52 weeks.     

A treatment strategy implementing combination therapy with sitagliptin and metformin results in superior glycaemic control versus metformin monotherapy due to a low rate of addition of antihyperglycaemic agents

Aims: Combination therapy with sitagliptin and metformin has shown superior efficacy compared with metformin monotherapy. In this study, we compare two strategies: initial combination therapy with sitagliptin/metformin as a fixed‐dose combination (FDC) and initial metformin monotherapy, with the option to add additional antihyperglycaemic agents (AHAs) in either treatment arm during the second phase of the study in order to reach adequate glycaemic control. Methods: We evaluated the sitagliptin and metformin FDC compared with metformin monotherapy over 44 weeks in 1250 patients with type 2 diabetes mellitus in a two‐part, double‐blind, randomized, controlled clinical trial. The initial 18‐week portion (Phase A) of this study in which additional AHAs were only allowed based on prespecified glycaemic criteria, has been previously reported. Here, we present results from the 26‐week Phase B portion of the study during which double‐blind study medication continued; however, unlike Phase A, during Phase B investigators were unmasked to results for haemoglobin A1C (HbA1c) and fasting plasma glucose (FPG) and directed to manage glycaemic control by adding incremental AHA(s) as deemed clinically appropriate. Results: There were 1250 patients randomized in the study with 965 completing Phase A and continuing in Phase B. Among patients receiving sitagliptin/metformin FDC or metformin monotherapy, 8.8% and 16.7% received additional AHA therapy, respectively. Although glycaemic therapy in both groups was to have been managed to optimize HbA1c reductions with the option for investigators to supplement with additional AHAs during Phase B, patients randomized to initial therapy with sitagliptin/metformin FDC had larger reductions of HbA1c from baseline compared with patients randomized to initial metformin monotherapy [least squares (LS) mean change: ?2.3% and ?1.8% (p < 0.001 for difference) for sitagliptin/metformin FDC and metformin monotherapy groups, respectively]. A significantly larger reduction in FPG from baseline was observed in the sitagliptin/metformin FDC group compared with the metformin monotherapy group (p = 0.001). Significantly more patients in the sitagliptin/metformin FDC group had an HbA1c of less than 7.0% or less than 6.5% compared with those on metformin monotherapy. Both treatment strategies were generally well tolerated, with a low and similar incidence of hypoglycaemia in both groups and lower incidences of abdominal pain and diarrhoea in the sitagliptin/metformin FDC group compared with the metformin monotherapy group. Conclusions: A strategy initially implementing combination therapy with sitagliptin/metformin FDC was superior to a strategy initially implementing metformin monotherapy, even when accounting for the later addition of supplemental AHAs. Sitagliptin/metformin FDC was generally well tolerated.     

Efficacy and safety of treatment with sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy: a randomized, double-blind, non-inferiority trial

Aim: To evaluate the efficacy and safety of adding sitagliptin or glimepiride to the treatment regimen of patients with type 2 diabetes mellitus and inadequate glycaemic control on metformin monotherapy. Methods: Patients with type 2 diabetes and an HbA_1c of 6.5–9.0% while on a stable dose of metformin (≥1500 mg/day) combined with diet and exercise for at least 12 weeks were randomized in a double‐blind manner to receive either sitagliptin 100 mg daily (N = 516) or glimepiride (starting dose 1 mg/day and up‐titrated, based upon patient's self‐monitoring of blood glucose results, to a maximum dose of up to 6 mg/day) (N = 519) for 30 weeks. The primary analysis assessed whether sitagliptin is non‐inferior to glimepiride in reducing HbA_1c at week 30 (based on the criterion of having an upper bound of the 95% CI less than the prespecified non‐inferiority bound of 0.4%). Results: The mean baseline HbA_1c was 7.5% in both the sitagliptin group (n = 443) and the glimepiride group (n = 436). After 30 weeks, the least squares (LS) mean change in HbA_1c from baseline was ?0.47% with sitagliptin and ?0.54% with glimepiride, with a between‐group difference (95% CI) of 0.07% (?0.03, 0.16). This result met the prespecified criterion for declaring non‐inferiority. The percentages of patients with an HbA_1c < 7.0% at week 30 were 52 and 60% in the sitagliptin and glimepiride groups, respectively. The LS mean change in fasting plasma glucose from baseline (95% CI) was ?0.8 mmol/l (?1.0, ?0.6) with sitagliptin and ?1.0 mmol/l (?1.2, ?0.8) with glimepiride, for a between‐group difference (95% CI) of 0.2 mmol/l (?0.1, 0.4). The percentages of patients for whom hypoglycaemia was reported were 7% in the sitagliptin group and 22% in the glimepiride group (percentage‐point difference = ?15, p < 0.001). Relative to baseline, sitagliptin was associated with a mean weight loss (?0.8 kg), whereas glimepiride was associated with a mean weight gain (1.2 kg), yielding a between‐group difference of ?2.0 kg (p < 0.001). Conclusions: In patients with type 2 diabetes and inadequate glycaemic control on metformin monotherapy, the addition of sitagliptin or glimepiride led to similar improvement in glycaemic control after 30 weeks. Sitagliptin was generally well tolerated. Compared to treatment with glimepiride, treatment with sitagliptin was associated with a lower risk of hypoglycaemia and with weight loss versus weight gain ( ClinicalTrials.gov : NCT00701090).     

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin

AIM: To assess the efficacy and safety of a 24-week treatment with sitagliptin, a highly selective once-daily oral dipeptidyl peptidase-4 (DPP-4) inhibitor, in patients with type 2 diabetes who had inadequate glycaemic control [glycosylated haemoglobin (HbA(1c)) >or=7.5% and or=4 mg/day) monotherapy and 229 were on glimepiride (>or=4 mg/day) plus metformin (>or=1,500 mg/day) combination therapy. Patients exceeding pre-specified glycaemic thresholds during the double-blind treatment period were provided open-label rescue therapy (pioglitazone) until study end. The primary efficacy analysis evaluated the change in HbA(1c) from baseline to Week 24. Secondary efficacy endpoints included fasting plasma glucose (FPG), 2-h post-meal glucose and lipid measurements. RESULTS: Mean baseline HbA(1c) was 8.34% in the sitagliptin and placebo groups. After 24 weeks, sitagliptin reduced HbA(1c) by 0.74% (p < 0.001) relative to placebo. In the subset of patients on glimepiride plus metformin, sitagliptin reduced HbA(1c) by 0.89% relative to placebo, compared with a reduction of 0.57% in the subset of patients on glimepiride alone. The addition of sitagliptin reduced FPG by 20.1 mg/dl (p < 0.001) and increased homeostasis model assessment-beta, a marker of beta-cell function, by 12% (p < 0.05) relative to placebo. In patients who underwent a meal tolerance test (n = 134), sitagliptin decreased 2-h post-prandial glucose (PPG) by 36.1 mg/dl (p < 0.001) relative to placebo. The addition of sitagliptin was generally well tolerated, although there was a higher incidence of overall (60 vs. 47%) and drug-related adverse experiences (AEs) (15 vs. 7%) in the sitagliptin group than in the placebo group. This was largely because of a higher incidence of hypoglycaemia AEs (12 vs. 2%, respectively) in the sitagliptin group compared with the placebo group. Body weight modestly increased with sitagliptin relative to placebo (+0.8 vs. -0.4 kg; p < 0.001). CONCLUSIONS: Sitagliptin 100 mg once daily significantly improved glycaemic control and beta-cell function in patients with type 2 diabetes who had inadequate glycaemic control with glimepiride or glimepiride plus metformin therapy. The addition of sitagliptin was generally well tolerated, with a modest increase in hypoglycaemia and body weight, consistent with glimepiride therapy and the observed degree of glycaemic improvement.     

Saxagliptin given in combination with metformin as initial therapy improves glycaemic control in patients with type 2 diabetes compared with either monotherapy: a randomized controlled trial

Aim: The study aim was to evaluate the efficacy and safety of initial combination therapy with saxagliptin + metformin vs. saxagliptin or metformin monotherapy in treatment‐naïve patients with type 2 diabetes (T2D) and inadequate glycaemic control. Methods: In this multicentre, randomized, double‐blind, active‐controlled phase 3 trial, 1306 treatment‐naïve patients with T2D ≥18 to ≤77 years, glycosylated haemoglobin (HbA1c) ≥8 to ≤12%, fasting C‐peptide concentration ≥1.0 ng/ml, body mass index ≤40 kg/m² were randomized to receive saxagliptin 5 mg + metformin 500 mg, saxagliptin 10 mg + metformin 500 mg, saxagliptin 10 mg + placebo or metformin 500 mg + placebo for 24 weeks. From weeks 1–5, metformin was uptitrated in 500‐mg/day increments to 2000 mg/day maximum in the saxagliptin 5 mg + metformin, saxagliptin 10 mg + metformin and metformin + placebo treatment groups. The main outcome measure was HbA1c change from baseline to week 24. Selected secondary outcomes included change from baseline to week 24 in fasting plasma glucose (FPG), proportion of patients achieving HbA1c <7% and postprandial glucose area under the curve (PPG‐AUC). Results: At 24 weeks, saxagliptin 5 mg + metformin and saxagliptin 10 mg + metformin demonstrated statistically significant adjusted mean decreases vs. saxagliptin 10 mg and metformin monotherapies in HbA1c (?2.5 and ?2.5% vs. ?1.7 and ?2.0%, all p < 0.0001 vs. monotherapy) and FPG (?60 and ?62 mg/dl vs. ?31 and ?47 mg/dl, both p < 0.0001 vs. saxagliptin 10 mg; p = 0.0002 saxagliptin 5 mg + metformin vs. metformin; p < 0.0001 saxagliptin 10 mg + metformin vs. metformin). Proportion of patients achieving an HbA1c <7% was 60.3 and 59.7%, respectively, for saxagliptin 5 mg + metformin and saxagliptin 10 mg + metformin (all p < 0.0001 vs. monotherapy). PPG‐AUC was significantly reduced [?21 080 mg·min/dl (saxagliptin 5 mg + metformin) and ?21 336 mg·min/dl (saxagliptin 10 mg + metformin) vs. ?16 054 mg·min/dl (saxagliptin 10 mg) and ?15 005 mg·min/dl (metformin), all p < 0.0001 vs. monotherapy]. Adverse event occurrence was similar across all groups. Hypoglycaemic events were infrequent. Conclusion: Saxagliptin + metformin as initial therapy led to statistically significant improvements compared with either treatment alone across key glycaemic parameters with a tolerability profile similar to the monotherapy components.     

Efficacy and tolerability of initial combination therapy with vildagliptin and pioglitazone compared with component monotherapy in patients with type 2 diabetes

AIM: The aim of this study was to compare efficacy and tolerability of initial combination therapy with vildagliptin/pioglitazone to component monotherapy. METHODS: This 24-week, multicentre, randomized, double-blind, active-controlled study assessed the effects of the dipeptidyl peptidase-4 inhibitor vildagliptin (100 mg q.d.), pioglitazone (30 mg q.d.) and vildagliptin combined with pioglitazone (100/30 mg q.d. or 50/15 mg q.d.) in 607 drug-naive patients with type 2 diabetes (T2DM). The primary outcome measure was change from baseline in HbA(1c) in patients receiving initial combination therapy compared with pioglitazone monotherapy. RESULTS: After 24-week treatment, adjusted mean changes in HbA(1c) from baseline (approximately 8.7%) in patients receiving pioglitazone monotherapy, 50/15 mg combination, 100/30 mg combination and vildagliptin monotherapy were -1.4 +/- 0.1%, -1.7 +/- 0.1%, -1.9 +/- 0.1% and -1.1 +/- 0.1% respectively. Both low-dose and high-dose combinations were significantly more efficacious than pioglitazone alone (p = 0.039 and p < 0.001 respectively). Adjusted mean changes in fasting plasma glucose were -1.9 +/- 0.2, -2.4 +/- 0.2, -2.8 +/- 0.2 and -1.3 +/- 0.2 mmol/l respectively, and both combination groups were significantly more effective than pioglitazone monotherapy (p = 0.022 and p < 0.001 respectively). The overall incidence of adverse events ranged from 45.8% in the low-dose combination to 51.6% in the pioglitazone monotherapy group. The incidence of peripheral oedema was highest in patients receiving pioglitazone monotherapy (9.3%) and lowest in those receiving low-dose combination (3.5%). One mild hypoglycaemic event was reported by one patient receiving high-dose combination and one patient receiving vildagliptin monotherapy. CONCLUSIONS: First-line treatment with vildagliptin/pioglitazone combination in patients with T2DM provides better glycaemic control than either monotherapy component yet has minimal risk of hypoglycaemia and a tolerability profile comparable with component monotherapy.     

Effect of initial combination therapy with sitagliptin and metformin on β-cell function in patients with type 2 diabetes

Aim: To examine the effect of sitagliptin and metformin, alone and in combination, on modelled parameters of β‐cell function in patients with type 2 diabetes. Methods: The data used in the present analyses are from a 104‐week study, which included a 24‐week, placebo‐ and active controlled phase followed by a 30‐week, active controlled, continuation phase and an additional 50‐week, active controlled extension phase. Patients were randomised to one of six blinded treatments: sitagliptin 50 mg + metformin 1000 mg b.i.d., sitagliptin 50 mg + metformin 500 mg b.i.d., metformin 1000 mg b.i.d., metformin 500 mg b.i.d., sitagliptin 100 mg q.d. or placebo. Patients on placebo were switched in a blinded manner to metformin 1000 mg b.i.d. at week 24. Subsets of patients volunteered to undergo frequently sampled meal tolerance tests at baseline and at weeks 24, 54 and 104. β‐cell responsivity was assessed with the C‐peptide minimal model. The static component (Φ_s) estimates the rate of insulin secretion related to above‐basal glucose concentration. The dynamic component (Φ_d) is related to the rate of change in glucose. The total index (Φ_total) represents the overall response to a glycaemic stimulus and is calculated as a function of Φ_s and Φ_d. Insulin sensitivity was estimated with the Matsuda index (ISI). The disposition index, which assesses insulin secretion relative to the prevailing insulin sensitivity, was calculated based on the Φ_total and ISI. Results: At week 24, substantial reductions in postmeal glucose were observed with all active treatment groups relative to the placebo group. Φ_s, Φ_total and the disposition index were significantly improved from baseline at week 24 with all active treatments relative to placebo. Generally larger effects were observed with the initial combination of sitagliptin and metformin relative to the monotherapy groups. When expressed as median percent change from baseline, Φ_s increased from baseline by 137 and 177% in the low‐ and high‐dose combination groups and by 85, 54, 73 and ?9% in the high‐dose metformin, low‐dose metformin, sitagliptin monotherapy and placebo groups, respectively. At weeks 54 and 104, the combination treatment groups continued to demonstrate greater improvements in β‐cell function relative to their respective monotherapy groups. Conclusions: After 24 weeks of therapy, relative to placebo, initial treatment with sitagliptin or metformin monotherapy improved β‐cell function; moreover, initial combination therapy demonstrated larger improvements than the individual monotherapies. Improvements in β‐cell function were found with treatments for up to 2 years.     

Initial combination therapy with saxagliptin and metformin provides sustained glycaemic control and is well tolerated for up to 76 weeks

Aim: To assess the efficacy and safety of saxagliptin + metformin initial combination therapy compared with saxagliptin or metformin alone over 76 weeks (24‐week short‐term + 52‐week long‐term extension) in treatment‐naÏve type 2 diabetes mellitus patients with inadequate glycaemic control. Methods: In this phase 3, parallel‐group, double‐blind, active‐controlled study, 1306 patients 18–77 years of age (HbA1c 8.0–12.0%) were randomized to saxagliptin 5 mg + 500 mg metformin, saxagliptin 10 mg + 500 mg metformin, saxagliptin 10 mg + placebo or 500 mg metformin + placebo. Blinded metformin was titrated during weeks 1–5 of the short‐term treatment period in 500 mg/day increments to 2000 mg/day maximum in the metformin‐based treatment groups. No titration of metformin was permitted during the long‐term treatment period. A total of 888 patients completed the study (76 weeks), 613 without being rescued. Changes in HbA1c, fasting plasma glucose, 120‐min postprandial glucose (PPG) and PPG‐area under the curve (AUC) from baseline to week 76 were analysed using a repeated‐measures model. Results: At 76 weeks, adjusted mean changes from baseline HbA1c (95% CI) for saxagliptin 5 mg + metformin, saxagliptin 10 mg + metformin, saxagliptin 10 mg and metformin were ?2.31 (?2.44, ?2.18), ?2.33 (?2.46, ?2.20), ?1.55 (?1.70, ?1.40) and ?1.79% (?1.93, ?1.65), respectively (post hoc and nominal p < 0.0001 vs. metformin and saxagliptin monotherapies for saxagliptin 5 mg + metformin and saxagliptin 10 mg + metformin). The proportions of patients requiring rescue or discontinuation for insufficient glycaemic control were lower for saxagliptin + metformin than for either monotherapy. Little or no attenuation in PPG‐AUC or 120‐min PPG was observed between weeks 24 and 76 for saxagliptin + metformin, indicating persistent efficacy. Adverse event rates were similar across groups; hypoglycaemic events occurred at a low frequency. Conclusion: Saxagliptin + metformin initial combination therapy was well tolerated and produced sustained glycaemic control for up to 76 weeks, with greater improvements in glycaemic parameters compared with either drug alone.     

Treatment of type 2 diabetes with a combination regimen of repaglinide plus pioglitazone

The efficacy and safety of combination therapy (repaglinide plus pioglitazone) was compared to repaglinide or pioglitazone in 24-week treatment of type 2 diabetes. This randomized, multicenter, open-label, parallel-group study enrolled 246 adults (age 24-85) who had shown inadequate response in previous sulfonylurea or metformin monotherapy (HbA(1c) > 7%). Prior therapy was withdrawn for 2 weeks, followed by randomization to repaglinide, pioglitazone, or repaglinide/pioglitazone. In the first 12 weeks of treatment, repaglinide doses were optimized, followed by 12 weeks of maintenance therapy. Pioglitazone dosage was fixed at 30 mg per day. Baseline HbA(1c) values were comparable (9.0% for repaglinide, 9.1% for pioglitazone, 9.3% for combination). Mean changes in HbA(1c) values at the end of treatment were -1.76% for repaglinide/pioglitazone, -0.18% for repaglinide, +0.32% for pioglitazone. Fasting plasma glucose reductions were -82 mg/dl for combination therapy, -34 mg/dl for repaglinide, -18 mg/dl for pioglitazone. Minor hypoglycemia occurred in 5% of patients for the combination, 8% for repaglinide, and 3% for pioglitazone. Weight gains for combination therapy were correlated to individual HbA(1c) reductions. In summary, for patients who had previously failed oral antidiabetic monotherapy, the combination repaglinide/pioglitazone had acceptable safety, with greater reductions of glycemic parameters than therapy using either agent alone.     

Alogliptin as a third oral antidiabetic drug in patients with type 2 diabetes and inadequate glycaemic control on metformin and pioglitazone: a 52-week, randomized, double-blind, active-controlled, parallel-group study

Aim: To assess the efficacy and safety of adding alogliptin versus uptitrating pioglitazone in patients with type 2 diabetes and inadequate glycaemic control on metformin and pioglitazone. Methods: In this randomized, double‐blind, active‐controlled, parallel‐group study, patients with type 2 diabetes and A1c ≥7.0 and ≤10.0% on metformin (≥1500 mg or maximum tolerated dose; Met) and pioglitazone 30 mg (Pio30) received alogliptin 25 mg (Alo25; n = 404) or pioglitazone 15 mg (n = 399) added to Met+Pio30 for 52 weeks. The primary endpoint was change from baseline (CFB) in A1c at weeks 26 and 52, with sequential testing for non‐inferiority of Met+Pio30+Alo25 at weeks 26 and 52 and then for superiority at week 52. Results: Met+Pio30+Alo25 showed superior glycaemic control versus Met+Pio45 at week 52 [least squares (LS) mean CFB in A1c, ?0.70 vs. ?0.29%; p < 0.001]. At week 52, Met+Pio30+Alo25 resulted in greater CFB in A1c regardless of baseline A1c (p < 0.001); higher proportions of patients achieving A1c ≤7.0 (33.2 vs. 21.3%) and ≤6.5% (8.7 vs. 4.3%; p < 0.001); greater CFB in fasting plasma glucose (FPG; LS mean CFB, ?0.8 vs. ?0.2 mmol/L; p < 0.001); and greater improvements in measures of β‐cell function (p < 0.001). Hypoglycaemia incidence was low (Met+Pio30+Alo25, 4.5%; Met+Pio45, 1.5%), mostly mild to moderate, but with two severe events in the Met+Pio30+Alo25 group. No meaningful differences in incidences of individual adverse events were observed between treatments. Conclusions: Adding alogliptin to an existing metformin–pioglitazone regimen provided superior glycaemic control and potentially improved β‐cell function versus uptitrating pioglitazone in patients with type 2 diabetes, with no clinically important differences in safety.     

Efficacy and safety of monotherapy of sitagliptin compared with metformin in patients with type 2 diabetes

Aim: To compare the efficacy and safety of monotherapy with sitagliptin and metformin in treatment‐naïve patients with type 2 diabetes. Methods: In a double‐blind study, 1050 treatment‐naïve patients (i.e. not taking an antihyperglycaemic agent for ≥16 weeks prior to study entry) with type 2 diabetes and an HbA_1c 6.5–9% were randomized (1:1) to treatment with once‐daily sitagliptin 100 mg (N = 528) or twice‐daily metformin 1000 mg (N = 522) for 24 weeks. Metformin was up‐titrated from 500 to 2000 mg per day (or maximum tolerated daily dose ≥1000 mg) over a period of 5 weeks. The primary analysis used a per‐protocol (PP) approach to assess whether sitagliptin was non‐inferior to metformin based on HbA_1c change from baseline at week 24. Non‐inferiority was to be declared if the upper boundary of the 95% confidence interval (CI) for the between‐group difference in this endpoint was <0.40%. Results: From a mean baseline HbA_1c of 7.2% in the PP population, HbA_1c change from baseline was ?0.43% with sitagliptin (n = 455) and ?0.57% with metformin (n = 439). The between‐group difference (95% CI) was 0.14% (0.06, 0.21), thus confirming non‐inferiority. Baseline HbA_1c influenced treatment response, with larger reductions in HbA_1c observed in patients with baseline HbA_1c≥8% in the sitagliptin (–1.13%; n = 74) and metformin (–1.24%; n = 73) groups. The proportions of patients at week 24 with HbA_1c values at the goals of <7 or <6.5% were 69 and 34% with sitagliptin and 76 and 39% with metformin, respectively. Fasting plasma glucose changes from baseline were ?11.5 mg/dL (–0.6 mmol/l) and ?19.4 mg/dl (–1.1 mmol/l) with sitagliptin and metformin, respectively (difference in LS mean change from baseline [95% CI] = 8.0 mg /dl [4.5,11.4]). Both treatments led to similar improvements from baseline in measures of homeostasis model assessment‐β cell function (HOMA‐β) and insulin resistance (HOMA‐IR). The incidence of hypoglycaemia was 1.7% with sitagliptin and 3.3% with metformin (p = 0.116). The incidence of gastrointestinal‐related adverse experiences was substantially lower with sitagliptin (11.6%) compared with metformin (20.7%) (difference in incidence [95% CI] = ?9.1% [?13.6,?4.7]), primarily because of significantly decreased incidences of diarrhoea (3.6 vs. 10.9%; p < 0.001) and nausea (1.1 vs. 3.1%; p = 0.032). Body weight was reduced from baseline with both sitagliptin (LS mean change [95% CI] = ?0.6 kg [?0.9,?0.4]) and metformin (–1.9 kg [–2.2, ?1.7]) (p < 0.001 for sitagliptin vs. metformin). Conclusions: In this 24‐week monotherapy study, sitagliptin was non‐inferior to metformin in improving HbA_1c in treatment‐naïve patients with type 2 diabetes. Although both treatments were generally well tolerated, a lower incidence of gastrointestinal‐related adverse experiences was observed with sitagliptin.     

Effect of adding sitagliptin, a dipeptidyl peptidase-4 inhibitor, to metformin on 24-h glycaemic control and beta-cell function in patients with type 2 diabetes

AIM: The aim of this study was to assess the effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on 24-h glucose control when added to the regimen of patients with type 2 diabetes who had inadequate glycaemic control on metformin therapy. METHODS: In a double-blind, randomized, placebo-controlled, two-period crossover study, patients with type 2 diabetes with inadequate glycaemic control on metformin monotherapy (i.e. on a stable dose of > or = 1500 mg/day for > or = 6 weeks prior to the screening visit and an haemoglobin A(1c) (HbA(1c)) > or = 6.5% and <10% and fasting plasma glucose (FPG) < or = 240 mg/dl) were recruited for participation. A total of 28 patients (baseline HbA(1c) range = 6.5-9.6%) receiving metformin were randomized into one of two treatment sequences: the addition of placebo for 4 weeks followed by the addition of sitagliptin 50 mg twice daily (b.i.d.) for 4 weeks, or vice versa. At the end of each treatment period, patients were domiciled for frequent blood sampling over 24 h. The primary endpoint was 24-h weighted mean glucose (WMG) and secondary endpoints included change in FPG, mean of 7 daily self-blood glucose measurements (MDG) and fructosamine. beta-cell function was assessed from glucose and C-peptide concentrations were measured during the 5-h period after a standard breakfast meal by using the C-peptide minimal model. RESULTS: Despite a carryover effect from period 1 to period 2, the combined period 1 and period 2 results for glycaemic endpoints were statistically significant for sitagliptin relative to placebo when added to ongoing metformin therapy. To account for the carryover effect, the period 1 results were also compared between the groups. Following period 1, there were significant least-squares (LS) mean reductions in 24-h WMG of 32.8 mg/dl, significant LS mean reduction from baseline in MDG of 28 mg/dl, FPG of 20.3 mg/dl and fructosamine of 33.7 mmol/l in patients treated with sitagliptin relative to placebo (p < 0.05). When added to ongoing metformin therapy, parameters of beta-cell function were significantly improved with sitagliptin compared with placebo. No weight gain or increases in gastrointestinal adverse events or hypoglycaemia events were observed with sitagliptin relative to placebo during this study. CONCLUSIONS: In this study, the addition of sitagliptin 50 mg b.i.d. to ongoing metformin therapy improved 24-h glycaemic control and beta-cell function, and was generally well tolerated in patients with type 2 diabetes.     

Efficacy and tolerability of vildagliptin vs. pioglitazone when added to metformin: a 24-week, randomized, double-blind study

Aim: The aim of this study was to compare the efficacy and tolerability of vildagliptin vs. pioglitazone as add‐on therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy. Methods: This 24‐week, multicentre, double‐blind, randomized, active‐controlled study compared vildagliptin (100 mg daily, given as equally divided doses, n = 295) and pioglitazone (30 mg daily, given as a single q.d. dose, n = 281) in patients with inadequate glycaemic control (A1C 7.5–11%) while receiving a stable metformin dose (≥1500 mg daily). The adjusted mean changes from baseline to study endpoint (AMΔ) in A1C, fasting plasma glucose (FPG), fasting lipids and body weight were compared by analysis of covariance. Results: When added to a stable dose of metformin (mean dose at baseline >2000 mg/day), both vildagliptin and pioglitazone decreased A1C (AMΔ = ?0.9 ± 0.1% and ?1.0 ± 0.1%, respectively) from identical baseline values (8.4 ± 0.1%). The between‐group difference in AMΔ A1C was 0.1 ± 0.1%, and non‐inferiority of vildagliptin to pioglitazone was established at both 0.4 and 0.3% margins for upper limit of the 95% confidence intervals. Pioglitazone decreased FPG (AMΔ = ?2.1 ± 0.1 mmol/l) to a greater extent than vildagliptin (AMΔ = ?1.4 ± 0.1 mmol/l), but only pioglitazone increased body weight (AMΔ = +1.9 ± 0.2 kg: between‐group difference = ?1.6 ± 0.3 kg, p < 0.001). Adverse events (AEs) were reported by 60% of vildagliptin‐treated patients and by 56.4% of pioglitazone‐treated patients; serious AEs were reported by 2.0 and 4.6% of patients receiving vildagliptin and pioglitazone respectively. Mild hypoglycaemia was reported by one patient (0.3%) in the vildagliptin group and by no patients receiving pioglitazone. Conclusions: When added to metformin, the efficacy of vildagliptin is non‐inferior to that of pioglitazone. The treatments were similarly well tolerated, but only pioglitazone increased body weight.     

Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes

Objective: To evaluate the efficacy and tolerability of sitagliptin when added to insulin therapy alone or in combination with metformin in patients with type 2 diabetes. Methods: After a 2 week placebo run‐in period, eligible patients inadequately controlled on long‐acting, intermediate‐acting or premixed insulin (HbA1c ≥ 7.5% and ≤ 11%), were randomised 1:1 to the addition of once‐daily sitagliptin 100 mg or matching placebo over a 24‐week study period. The study capped the proportion of randomised patients on insulin plus metformin at 75%. Further, the study capped the proportion of randomised patients on premixed insulin at 25%. The metformin dose and the insulin dose were to remain stable throughout the study. The primary endpoint was HbA1c change from baseline at week 24. Results: Mean baseline characteristics were similar between the sitagliptin (n = 322) and placebo (n = 319) groups, including HbA1c (8.7 vs. 8.6%), diabetes duration (13 vs. 12 years), body mass index (31.4 vs. 31.4 kg/m²), and total daily insulin dose (51 vs. 52 IU), respectively. At 24 weeks, the addition of sitagliptin significantly (p < 0.001) reduced HbA1c by 0.6% compared with placebo (0.0%). A greater proportion of patients achieved an HbA1c level < 7% while randomised to sitagliptin as compared with placebo (13 vs. 5% respectively; p < 0.001). Similar HbA1c reductions were observed in the patient strata defined by insulin type (long‐acting and intermediate‐acting insulins or premixed insulins) and by baseline metformin treatment. The addition of sitagliptin significantly (p < 0.001) reduced fasting plasma glucose by 15.0 mg/dl (0.8 mmol/l) and 2‐h postmeal glucose by 36.1 mg/dl (2.0 mmol/l) relative to placebo. A higher incidence of adverse experiences was reported with sitagliptin (52%) compared with placebo (43%), due mainly to the increased incidence of hypoglycaemia (sitagliptin, 16% vs. placebo, 8%). The number of hypoglycaemic events meeting the protocol‐specified criteria for severity was low with sitagliptin (n = 2) and placebo (n = 1). No significant change from baseline in body weight was observed in either group. Conclusion: In this 24‐week study, the addition of sitagliptin to ongoing, stable‐dose insulin therapy with or without concomitant metformin improved glycaemic control and was generally well tolerated in patients with type 2 diabetes.     

Lack of pharmacokinetic interaction between dapagliflozin, a novel sodium-glucose transporter 2 inhibitor, and metformin, pioglitazone, glimepiride or sitagliptin in healthy subjects

Aims: Dapagliflozin increases urinary glucose excretion by selectively inhibiting renal sodium–glucose transporter 2, an insulin‐independent mechanism of action that may be complementary to that of other oral antidiabetes drugs. The current studies assessed the potential for pharmacokinetic (PK) interaction between dapagliflozin and pioglitazone, metformin, glimepiride or sitagliptin in healthy subjects following single‐dose administration. Methods: In open‐label, randomized, three‐period, three‐treatment crossover studies, 24 subjects received 50 mg dapagliflozin, 45 mg pioglitazone or the combination, while 18 subjects received 20 mg dapagliflozin, 1000 mg metformin or the combination. In an open‐label, randomized, five‐period, five‐treatment, unbalanced crossover study, 18 subjects first received 20 mg dapagliflozin, 4 mg glimepiride or the combination, and afterward 100 mg sitagliptin or sitagliptin plus 20 mg dapagliflozin. Blood samples were taken over 72 h of each treatment period. Lack of PK interaction was defined as the ratio of geometric means and 90% confidence interval (CI) for combination:monotherapy being within the range of 0.80–1.25. Results: Co‐administration of dapagliflozin with pioglitazone, metformin, glimepiride or sitagliptin had no effect on dapagliflozin maximum plasma concentration (C_max) or area under the plasma concentration‐time curve (AUC). Similarly, dapagliflozin did not affect the C_max or AUC for the co‐administered drug, except for slight extensions of the 90% CI for the ratio of geometric means for glimepiride AUC (upper limit 1.29) and pioglitazone C_max (lower limit 0.75). All monotherapies and combination therapies were well tolerated. Conclusion: Dapagliflozin can be co‐administered with pioglitazone, metformin, glimepiride or sitagliptin without dose adjustment of either drug.     

Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type 2 diabetes: a randomized, double-blind, placebo-controlled study

Aims: To compare the efficacy, safety and tolerability of linagliptin or placebo administered for 24 weeks in combination with pioglitazone in patients with type 2 diabetes mellitus (T2DM) exhibiting insufficient glycaemic control (HbA1c 7.5–11.0%). Methods: Patients were randomized to receive the initial combination of 30 mg pioglitazone plus 5 mg linagliptin (n = 259) or pioglitazone plus placebo (n = 130), all once daily. The primary endpoint was change from baseline in HbA1c after 24 weeks of treatment, adjusted for baseline HbA1c and prior antidiabetes medication. Results: After 24 weeks of treatment, the adjusted mean change (±s.e.) in HbA1c with the initial combination of linagliptin plus pioglitazone was ?1.06% (±0.06), compared with ?0.56% (±0.09) for placebo plus pioglitazone. The difference in adjusted mean HbA1c in the linagliptin group compared with placebo was ?0.51% (95% confidence interval [CI] ?0.71, ?0.30; p < 0.0001). Reductions in fasting plasma glucose (FPG) were significantly greater for linagliptin plus pioglitazone than with placebo plus pioglitazone; ?1.8 and ?1.0 mmol/l, respectively, equating to a treatment difference of ?0.8 mmol/l (95% CI ?1.2, ?0.4; p < 0.0001). Patients taking linagliptin plus pioglitazone, compared with those receiving placebo plus pioglitazone, were more likely to achieve HbA1c of <7.0% (42.9 vs. 30.5%, respectively; p = 0.0051) and reduction in HbA1c of ≥0.5% (75.0 vs. 50.8%, respectively; p < 0.0001). β‐cell function, exemplified by the ratio of relative change in adjusted mean HOMA‐IR and disposition index, improved. The proportion of patients that experienced at least one adverse event was similar for both groups. Hypoglycaemic episodes (all mild) occurred in 1.2% of the linagliptin plus pioglitazone patients and none in the placebo plus pioglitazone group. Conclusion: Initial combination therapy with linagliptin plus pioglitazone was well tolerated and produced significant and clinically meaningful improvements in glycaemic control. This combination may offer a valuable additive initial treatment option for T2DM, particularly where metformin either is not well tolerated or is contraindicated, such as in patients with renal impairment.     

Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency

Objective: To assess the safety of sitagliptin in patients with type 2 diabetes and moderate [creatinine clearance (CrCl) ≥30 to <50 ml/min] or severe renal insufficiency [CrCl <30 ml/min including patients with end‐stage renal disease (ESRD) on dialysis]. The efficacy of sitagliptin in this patient population was also assessed. Methods: In a 54‐week, randomized, double‐blind, parallel‐group study, patients with baseline glycosylated haemoglobin A_1c (HbA_1c) values of 6.5–10% were allocated (2:1) to sitagliptin (for 54 weeks) or the sequence of placebo (for 12 weeks) followed by active treatment with glipizide (for 42 weeks). To achieve plasma concentrations similar to those observed in patients with normal renal function treated with 100 mg sitagliptin once daily, patients with moderate renal insufficiency were allocated to receive sitagliptin 50 mg once daily and patients with severe renal insufficiency to receive 25 mg once daily. Glipizide treatment was initiated at 2.5 or 5 mg/day and uptitrated to a maximum of 20 mg/day. Results: Patients (N = 91) with a mean baseline HbA_1c value of 7.7% (range: 6.2–10.3%) were randomized to sitagliptin (n = 65) or placebo (n = 26). After 12 weeks, the mean change [95% confidence interval (CI)] from baseline in HbA_1c was ?0.6% (?0.8, ?0.4) in the sitagliptin group compared with ?0.2% (?0.4, 0.1) in the placebo group [between‐group difference (95% CI) = ?0.4% (?0.7, ?0.1)]. At 54 weeks, patients continuously treated with sitagliptin had a mean change (95% CI) from baseline in HbA_1c of ?0.7% (?0.9, ?0.4). The overall incidence of adverse experiences was generally similar between groups. Between‐group differences in incidences of specific clinical adverse experiences were generally small; however, the proportion of patients for whom hypoglycaemia was reported was lower in the sitagliptin group (4.6%) compared with the placebo/glipizide group (23.1%). Consistent with the high mortality risk in this patient population, there were six deaths during this 54‐week study [5 of 65 patients (7.7%) in the sitagliptin group and 1 of 26 patients (3.8%) in the placebo/glipizide group]; no death was considered by the investigator to be drug related. The overall incidences of drug‐related and serious adverse experiences and discontinuations because of adverse experiences were generally similar between groups. Conclusions: In this study, sitagliptin was generally well tolerated and provided effective glycaemic control in patients with type 2 diabetes and moderate to severe renal insufficiency, including patients with ESRD on dialysis.