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.     

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.     

The addition of sitagliptin to ongoing metformin therapy significantly improves glycemic control in Chinese patients with type 2 diabetes*(†)

Background: The present study was conducted to evaluate the efficacy, safety and tolerability of sitagliptin added to ongoing metformin therapy in Chinese patients with type 2 diabetes (T2DM) who failed to achieve adequate glycemic control with metformin monotherapy. Methods: After a metformin titration/stabilization period and a 2‐week, single‐blind, placebo run‐in period, 395 Chinese patients with T2DM aged 25–77 years (baseline HbA1c 8.5%) were randomized (1:1) to double‐blind placebo or sitagliptin 100 mg q.d. added to ongoing open‐label metformin (1000 or 1700 mg/day) for 24 weeks. Results: Significant (P < 0.001) changes from baseline in HbA1c (?0.9%), fasting plasma glucose (?1.2 mmol/L), and 2‐h post‐meal plasma glucose (?1.9 mmol/L) were seen with sitagliptin compared with placebo. There were no significant differences between sitagliptin and placebo in the incidence of hypoglycemia or gastrointestinal adverse events. A small decrease from baseline body weight was observed in the placebo group compared with no change in the sitagliptin group (between‐group difference 0.5 kg; P = 0.018). Conclusions: The addition of sitagliptin 100 mg to ongoing metformin therapy significantly improved glycemic control and was generally well tolerated in Chinese patients with T2DM who had inadequate glycemic control on metformin alone.     

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

Aim: To assess the 54‐week efficacy of initial combination therapy with sitagliptin and pioglitazone, compared with pioglitazone monotherapy, and to assess safety in these groups during the 30 weeks after the dosage of pioglitazone was increased from 30 to 45 mg/day, in drug‐naÏve patients with type 2 diabetes mellitus and inadequate glycaemic control [haemoglobin A1c (HbA1c) 8–12%]. Methods: Following a 24‐week, randomized, double‐blind, parallel‐group study (Sitagliptin Protocol 064, Clinicaltrials.gov: NCT00397631; Yoon KH, Shockey GR, Teng R et al. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase‐4 inhibitor, and pioglitazone on glycaemic control and measures of beta‐cell function in patients with type 2 diabetes. Int J Clin Pract 2011; 65: 154–164) in which patients were treated with the combination of sitagliptin 100 mg/day and pioglitazone 30 mg/day or monotherapy with pioglitazone 30 mg/day, patients entered a 30‐week extension study. In the extension study, the pioglitazone dose was increased from 30 to 45 mg/day in both groups. Depending upon treatment allocation, patients took one tablet of sitagliptin 100 mg or matching placebo daily. Pioglitazone was administered in an open‐label fashion as a single 45‐mg tablet taken once daily. Patients not meeting specific glycaemic goals in the extension study were rescued with metformin therapy. Efficacy and safety results for the extension study excluded data after initiation of rescue therapy. Results: Of the 520 patients initially randomized, 446 completed the base study and, of these, 317 entered the extension. In this extension study cohort, the mean reductions from baseline in HbA1c and fasting plasma glucose (FPG) at the end of the base study (week 24) were ?2.5% and ?62.1 mg/dl with the combination of sitagliptin 100 mg and pioglitazone 30 mg versus ?1.9% and ?48.7 mg/dl with pioglitazone monotherapy. At the end of the extension study (week 54), the mean reduction in haemoglobin A1c (HbA1c) was ?2.4% with the combination of sitagliptin 100 mg and pioglitazone 45 mg versus ?1.9% with pioglitazone monotherapy [between‐group difference (95% CI) = ?0.5% (?0.8, ?0.3)] and the mean reduction in FPG was ?61.3 mg/dl versus ?52.8 mg/dl, respectively [between‐group difference (95% CI) = ?8.5 mg/dl (?16.3, ?0.7)]. Safety and tolerability of initial treatment with the combination of sitagliptin and pioglitazone and pioglitazone monotherapy were similar. As expected, increases in body weight from baseline were observed in both treatment groups at week 54: 4.8 and 4.1 kg in the combination and monotherapy groups, respectively [between‐group difference (95% CI) = 0.7 kg (?0.7, 2.1)]. Conclusion: In this study, initial combination therapy with sitagliptin 100 mg and pioglitazone 30 mg increased to 45 mg after 24 weeks led to a substantial and durable incremental improvement in glycaemic control compared with initial treatment with pioglitazone monotherapy during a 54‐week treatment period. Both initial combination therapy with sitagliptin and pioglitazone and pioglitazone monotherapy were generally well tolerated (Clinicaltrials.gov: NCT01028391).     

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.     

Metformin extended‐release versus immediate‐release: An international,randomized, double‐blind,head‐to‐head trial in pharmacotherapy‐naïve patients with type 2 diabetes

This international, randomized, double‐blind trial (NCT01864174) compared the efficacy and safety of metformin extended‐release (XR) and immediate‐release (IR) in patients with type 2 diabetes. After a 4‐week placebo lead‐in, pharmacotherapy‐naïve adults with glycated haemoglobin (HbA1c) at 7.0% to 9.2% were randomized (1:1) to receive once‐daily metformin XR 2000 mg or twice‐daily metformin IR 1000 mg for 24 weeks. The primary endpoint was change in HbA1c after 24 weeks. Secondary endpoints were change in fasting plasma glucose (FPG), mean daily glucose (MDG) and patients (%) with HbA1c <7.0% after 24 weeks. Overall, 539 patients were randomized (metformin XR, N = 268; metformin IR, N = 271). Adjusted mean changes in HbA1c, FPG, MDG and patients (%) with HbA1c <7.0% after 24 weeks were similar for XR and IR: ?0.93% vs ?0.96%; ?21.1 vs ?20.6 mg/dL (?1.2 vs ?1.1 mmol/L); ?24.7 vs ?27.1 mg/dL (?1.4 vs ?1.5 mmol/L); and 70.9% vs 72.0%, respectively. Adverse events were similar between groups and consistent with previous studies. Overall, metformin XR demonstrated efficacy and safety similar to that of metformin IR over 24 weeks, with the advantage of once‐daily dosing.     

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial

AIM: To compare the efficacy and safety of sitagliptin vs. glipizide in patients with type 2 diabetes and inadequate glycaemic control [haemoglobin A(1c) (HbA(1c)) > or = 6.5 and < or = 10%] on metformin monotherapy. METHODS: After a metformin dose titration/stabilization period (> or = 1500 mg/day), 1172 patients were randomized to the addition of sitagliptin 100 mg q.d. (N = 588) or glipizide 5 mg/day (uptitrated to a potential maximum 20 mg/day) (N = 584) for 52 weeks. The primary analysis assessed whether sitagliptin was non-inferior to glipizide regarding HbA(1c) changes from baseline at Week 52 using a per-protocol approach. RESULTS: From a mean baseline of 7.5%, HbA(1c) changes from baseline were -0.67% at Week 52 in both groups, confirming non-inferiority. The proportions achieving an HbA(1c) < 7% were 63% (sitagliptin) and 59% (glipizide). Fasting plasma glucose changes from baseline were -0.56 mmol/l (-10.0 mg/dl) and -0.42 mmol/l (-7.5 mg/dl) for sitagliptin and glipizide, respectively. The proportion of patients experiencing hypoglycaemia episodes was significantly (p < 0.001) higher with glipizide (32%) than with sitagliptin (5%), with 657 events in glipizide-treated patients compared with 50 events in sitagliptin-treated patients. Sitagliptin led to weight loss (change from baseline =-1.5 kg) compared with weight gain (+1.1 kg) with glipizide [between-treatment difference (95% confidence interval) =-2.5 kg (-3.1, -2.0); p < 0.001]. CONCLUSIONS: In this study, the addition of sitagliptin compared with glipizide provided similar HbA(1c)-lowering efficacy over 52 weeks in patients on ongoing metformin therapy. Sitagliptin was generally well tolerated, with a lower risk of hypoglycaemia relative to glipizide and with weight loss compared with weight gain with glipizide.     

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 vildagliptin as add-on therapy to metformin in Chinese patients with type 2 diabetes mellitus

Aim: To investigate the efficacy and tolerability of vildagliptin as add‐on therapy to metformin in Chinese patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin. Methods: This was a 24‐week, randomized, double‐blind, placebo‐controlled study. Patients with T2DM (N = 438) with haemoglobin A1c (HbA1c) of 7.0–10.0% and fasting plasma glucose (FPG) <15 mmol/l (<270 mg/dl) were randomized (1 : 1 : 1) to vildagliptin 50 mg bid, vildagliptin 50 mg qd or placebo in addition to metformin. Results: The treatment groups were well balanced at baseline [mean HbA1c, 8.0%, FPG, 8.8 mmol/l (158 mg/dl); body mass index, 25.5 kg/m²]. The adjusted mean change (AMΔ) in HbA1c at endpoint was ?1.05 ± 0.08%, ?0.92 ± 0.08% and ?0.54 ± 0.08% in patients receiving vildagliptin 50 mg bid, 50 mg qd and placebo, respectively. The between‐treatment difference (vildagliptin 50 mg bid–placebo) was ?0.51 ± 0.11%, p < 0.001. A greater proportion of vildagliptin‐treated patients met at least one responder criterion (82.1 and 70.7%) compared to placebo‐treated patients (60.4%). The AMΔ at endpoint for FPG with vildagliptin 50 mg bid, ?0.95 mmol/l (?17.1 mg/dl); 50 mg qd, ?0.84 mmol/l (?15.1 mg/dl) was significantly different compared with the placebo ?0.26 mmol/l (?4.68 mg/dl) (p ≤ 0.001). Adverse events (AEs) were reported as 34.2, 36.5 and 37.5% for patients receiving vildagliptin 50 mg bid, 50 mg qd or placebo, respectively. Two patients in the vildagliptin 50 mg qd and one in the placebo group reported serious AEs, which were not considered to be related to the study drug; one incidence of hypoglycaemic event was reported in the vildagliptin 50 mg bid group. Conclusion: Vildagliptin as add‐on therapy to metformin improved glycaemic control and was well tolerated in Chinese patients who were inadequately controlled by metformin only.     

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.     

Safety and efficacy of linagliptin as add‐on therapy to metformin in patients with type 2 diabetes: a randomized,double‐blind,placebo‐controlled study

Aim: To evaluate the efficacy and safety of the potent and selective dipeptidyl peptidase‐4 (DPP‐4) inhibitor linagliptin administered as add‐on therapy to metformin in patients with type 2 diabetes with inadequate glycaemic control. Methods: This 24‐week, randomized, placebo‐controlled, double‐blind, parallel‐group study was carried out in 82 centres in 10 countries. Patients with HbA1c levels of 7.0–10.0% on metformin and a maximum of one additional antidiabetes medication, which was discontinued at screening, continued on metformin ≥1500 mg/day for 6 weeks, including a placebo run‐in period of 2 weeks, before being randomized to linagliptin 5 mg once daily (n = 524) or placebo (n = 177) add‐on. The primary outcome was the change from baseline in HbA1c after 24 weeks of treatment, evaluated with an analysis of covariance (ANCOVA). Results: Mean baseline HbA1c and fasting plasma glucose (FPG) were 8.1% and 9.4 mmol/l, respectively. Linagliptin showed significant reductions vs. placebo in adjusted mean changes from baseline of HbA1c (?0.49 vs. 0.15%), FPG (?0.59 vs. 0.58 mmol/l) and 2hPPG (?2.7 vs. 1.0 mmol/l); all p < 0.0001. Hypoglycaemia was rare, occurring in three patients (0.6%) treated with linagliptin and five patients (2.8%) in the placebo group. Body weight did not change significantly from baseline in both groups (?0.5 kg placebo, ?0.4 kg linagliptin). Conclusions: The addition of linagliptin 5 mg once daily in patients with type 2 diabetes inadequately controlled on metformin resulted in a significant and clinically meaningful improvement in glycaemic control without weight gain or increased risk of hypoglycaemia.     

Effect of gemigliptin on glycaemic variability in patients with type 2 diabetes (STABLE study)

The aim of this study was to evaluate the effect of gemigliptin vs sitagliptin or glimepiride as initial combination therapy with metformin on glycaemic variability and to assess the correlation between glycaemic variability reduction and the dipeptidyl peptidase‐4 (DPP‐4) inhibition in patients with type 2 diabetes. This multicentre, randomized, active‐controlled, open‐label exploratory study included 69 patients with HbA1c > 7.5%. Subjects were randomized to receive gemigliptin 50 mg (n = 24), sitagliptin 100 mg (n = 23) or glimepiride 2 mg (n = 22) for 12 weeks. After 12 weeks, the change in mean amplitude of glycaemic excursion (MAGE) compared with baseline was significantly lower in the DPP‐4 inhibitor groups compared with that in patients who received glimepiride. Furthermore, the standard deviation (SD) of glucose was significantly lower in patients who received gemigliptin than that in patients who received sitagliptin or glimepiride. The DPP‐4 inhibition was significantly correlated with changes in MAGE and SD of glucose. In conclusion, gemigliptin and sitagliptin were more effective than glimepiride in reducing glycaemic variability as initial combination therapy with metformin in patients with type 2 diabetes, and the DPP‐4 inhibition was associated with a reduction in glycaemic variability.     

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.     

Saxagliptin add‐on therapy in Chinese patients with type 2 diabetes inadequately controlled by insulin with or without metformin: Results from the SUPER study,a randomized,double‐blind,placebo‐controlled trial

This prospective, multicentre, phase III study (NCT02104804) evaluated the efficacy and safety of saxagliptin add‐on therapy in Chinese patients with type 2 diabetes inadequately controlled by insulin ± metformin. Patients with glycated haemoglobin (HbA1c) 7.5% to 10.5% and fasting plasma glucose (FPG) <15 mmol/L (270 mg/dL) on stable insulin therapy (20‐150 U/d) were randomized (1:1) to saxagliptin 5 mg once daily (N = 232) or placebo (N = 230) for 24 weeks, stratified by metformin use. The primary efficacy measure was change in HbA1c. Saxagliptin treatment resulted in a greater adjusted mean change in HbA1c from baseline to week 24 than placebo (?0.58%; P < .001), irrespective of metformin use, and a greater mean change in FPG (0.9 mmol/L [?15.9 mg/dL]; P < .001). More patients achieved HbA1c <7% with saxagliptin (11.4%) than with placebo (3.5%, P = .002). Adverse events and incidence of hypoglycaemia were similar in both groups. Overall, add‐on saxagliptin 5 mg once daily significantly improved glycaemic control without increasing hypoglycaemia risk and was well tolerated in Chinese patients with type 2 diabetes inadequately controlled by insulin (± metformin).     

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

Efficacy and tolerability of sitagliptin, a dipeptidyl peptidase-4 inhibitor, were assessed in Japanese patients with type 2 diabetes. In a multicenter, double-blind, randomized, placebo-controlled trial in Japan, 151 patients with inadequate glycemic control [HbA(1c) > or =6.5% to <10%, fasting plasma glucose (FPG) > or =126 to < or =240 mg/dL] were randomized to once-daily sitagliptin 100mg or placebo for 12 weeks. After 12 weeks, the least squares (LS) mean change from baseline HbA(1c) was -0.65% (95% CI: -0.80, -0.50) with sitagliptin versus 0.41% (0.26, 0.56) with placebo [between-group difference=-1.05% (-1.27, -0.84); p<0.001]. LS mean change from baseline FPG was -22.5mg/dL (95% CI: -28.0, -17.0) with sitagliptin versus 9.4 mg/dL (3.9, 14.9) with placebo [between-group difference=-31.9 mg/dL (95% CI: -39.7,-24.1); p<0.001]. More patients achieved HbA(1c) <7% or <6.5% with sitagliptin than with placebo (p<0.001). Following a meal tolerance test, 2-h postprandial glucose was significantly reduced with sitagliptin relative to placebo. Clinical and laboratory adverse experiences were similar between treatments, with no reported hypoglycemia adverse events with sitagliptin. Body weight was unchanged relative to baseline in the sitagliptin group (-0.1 kg), but significantly (p<0.01) different relative to the placebo group (-0.7 kg). In this study, once-daily sitagliptin 100mg for 12 weeks improved fasting and postprandial glycemic control and was generally well tolerated in Japanese patients with type 2 diabetes.     

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.     

Adding saxagliptin to extended-release metformin vs. uptitrating metformin dosage

Aim: To investigate whether patients taking metformin for type 2 diabetes mellitus (T2DM) have improved glycaemic control without compromising tolerability by adding an agent with a complementary mechanism of action vs. uptitrating metformin. Methods: Adults with T2DM and glycated haemoglobin (HbA1c) between 7.0 and 10.5% receiving metformin extended release (XR) 1500 mg/day for ≥8 weeks were randomized to receive saxagliptin 5 mg added to metformin XR 1500 mg (n = 138) or metformin XR uptitrated to 2000 mg/day (n = 144). Endpoints were change from baseline to week 18 in HbA1c (primary), 120‐min postprandial glucose (PPG), fasting plasma glucose (FPG) and the proportion of patients achieving HbA1c <7%. Results: At week 18, the adjusted mean reduction from baseline HbA1c was ?0.88% for saxagliptin + metformin XR and ?0.35% for uptitrated metformin XR (difference, ?0.52%; p < 0.0001). For 120‐min PPG and FPG, differences in adjusted mean change from baseline between saxagliptin + metformin XR and uptitrated metformin XR were ?1.3 mmol/l (?23.32 mg/dl) (p = 0.0013) and ?0.73 mmol/l (?13.18 mg/dl) (p = 0.0030), respectively. More patients achieved HbA1c <7.0% with saxagliptin + metformin XR than with uptitrated metformin XR (37.2 vs. 26.1%; p = 0.0459). The proportions of patients experiencing any adverse events (AEs) were generally similar between groups; neither group showed any notable difference in hypoglycaemia or gastrointestinal AEs. Conclusion: Adding saxagliptin to metformin XR provided superior glycaemic control compared with uptitrating metformin XR without the emergence of additional safety concerns (Clinical Trials.gov registration: NCT00960076).     

Twelve weeks treatment with the DPP‐4 inhibitor,sitagliptin, prevents degradation of peptide YY and improves glucose and non‐glucose induced insulin secretion in patients with type 2 diabetes mellitus

Aim: To examine the effects of 12 weeks of treatment with the DPP‐4 inhibitor, sitagliptin, on gastrointestinal hormone responses to a standardized mixed meal and beta cell secretory capacity, measured as glucose and non‐glucose induced insulin secretion during a hyperglycaemic clamp, in patients with type 2 diabetes. Method: A double‐blinded, placebo‐controlled study over 12 weeks in which 24 patients with T2DM were randomized to receive either sitagliptin (Januvia) 100 mg qd or placebo as an add‐on therapy to metformin. In week 0, 1 and 12 patients underwent a meal test and a 90‐min 20 mM hyperglycaemic clamp with 5 g of l ‐arginine infusion. Main outcome measure was postprandial total glucagon‐like peptide 1 (GLP‐1) concentration. Additional measures were insulin and C‐peptide, glycaemic control, intact and total peptide YY (PYY) and glucose‐dependent insulinotropic polypeptide (GIP), and intact glucagon‐like peptide 2 (GLP‐2) and GLP‐1. Results: All patients [sitagliptin n = 12, age: 59.5 (39–64) years, HbA1c: 8.0 (7.3–10.0)%, BMI: 33.2 (29.3–39.4); placebo n = 12, age: 60 (31–72) years, HbA1c: 7.7 (7.1–9.8)%, BMI: 30.7 (25.7–40.5)] [median (range)] completed the trial. Sitagliptin treatment improved glycaemic control, had no effect on total GLP‐1, GIP or intact GLP‐2, but reduced total PYY and PYY_{3‐ 36}, and increased PYY_{1‐ 36} and intact incretin hormones. Sitagliptin improved first and second phases of beta cell secretion and maximal secretory capacity. All effects were achieved after 1 week. No significant changes occurred in the placebo group. Conclusion: The postprandial responses of total GLP‐1 and GIP and intact GLP‐2 were unaltered. PYY degradation was prevented. Glucose and non‐glucose induced beta cell secretion was improved. There was no difference in responses to sitagliptin between 1 and 12 weeks of treatment.     

Effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on beta-cell function in patients with type 2 diabetes: a model-based approach

Purpose: The purpose of this exploratory analysis was to assess the effect of sitagliptin, a dipeptidyl peptidase‐4 inhibitor, on pancreatic beta‐cell function using a model‐based analysis. Methods: Data for this analysis were from three large, placebo‐controlled clinical studies that examined sitagliptin 100 mg q.d. as add‐on to metformin therapy or as monotherapy over 18 or 24 weeks. In these studies, subsets of patients consented to undergo extensive blood sampling as part of a nine‐point meal tolerance test performed at baseline and study end‐point. Blood samples were collected at ?10, 0, 10, 20, 30, 60, 90, 120 and 180 min relative to the start of a meal and subsequently were assayed for plasma glucose and serum C‐peptide concentrations. Parameters for beta‐cell function were calculated using the C‐peptide minimal model, which estimates insulin secretion rate (ISR) and partitions the ISR into basal (Φ_b; ISR at basal glucose concentrations), static (Φ_s; ISR at above basal glucose concentrations following a meal) and dynamic (Φ_d; ISR in response to the rate of increase in above basal glucose concentrations following a meal) components. The total responsivity index (Φ_total; average ISR over the average glucose concentration) is calculated as a function of Φ_s, Φ_d and Φ_b. Insulin sensitivity was assessed with a validated composite index (ISI). Disposition indices (DI), which assess insulin secretion in the context of changes in insulin sensitivity, were calculated as the product of Φand ISI. Results: When administered in combination with ongoing metformin therapy or as monotherapy, sitagliptin was associated with substantial reductions in postprandial glycaemic excursion following a meal challenge relative to placebo. Sitagliptin produced significant (p < 0.05 vs. placebo) improvements in Φ_s and Φ_total, regardless of treatment regimen (add‐on to metformin or as monotherapy). For Φ_d, there was a numerical, but not statistically significant, improvement with sitagliptin relative to placebo. Treatment with sitagliptin increased Φ_b, but the difference relative to placebo was only significant with monotherapy. ISI was not significantly different between sitagliptin and placebo. The DIs for the static, dynamic and total measures were significantly (p < 0.05) increased with sitagliptin treatment relative to placebo. Conclusions: In this model‐based analysis, sitagliptin improved beta‐cell function relative to placebo in both fasting and postprandial states in patients with type 2 diabetes.     

Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial

Aims/hypothesis

The aim of this work was to evaluate the efficacy and safety of canagliflozin vs placebo and sitagliptin in patients with type 2 diabetes who were being treated with background metformin.

Methods

This randomised, double-blind, four-arm, parallel-group, Phase 3 study was conducted at 169 centres in 22 countries between April 2010 and August 2012. Participants (N?=?1,284) with type 2 diabetes aged ≥18 and ≤80 years who had inadequate glycaemic control (HbA_1c ≥7.0% [53 mmol/mol] and ≤10.5% [91 mmol/mol]) on metformin therapy received canagliflozin 100 mg or 300 mg, sitagliptin 100 mg, or placebo (n?=?368, 367, 366, 183, respectively) for a 26 week, placebo- and active-controlled period followed by a 26 week, active-controlled period (placebo group switched to sitagliptin [placebo/sitagliptin]) and were included in the modified intent-to-treat analysis set. Randomisation was performed using a computer-generated schedule; participants, study centres and the sponsor were blinded to group assignment. The primary endpoint was change from baseline in HbA_1c at week 26; secondary endpoints included changes in HbA_1c (week 52) and fasting plasma glucose (FPG), body weight, and systolic blood pressure (BP; weeks 26 and 52). Adverse events (AEs) were recorded throughout the study.

Results

At week 26, canagliflozin 100 mg and 300 mg reduced HbA_1c vs placebo (?0.79%, –0.94%, –0.17%, respectively; p?<?0.001). At week 52, canagliflozin 100 mg and 300 mg demonstrated non-inferiority, and canagliflozin 300 mg demonstrated statistical superiority, to sitagliptin in lowering HbA_1c (?0.73%, –0.88%,–0.73%, respectively); differences (95% CI) vs sitagliptin were 0% (?0.12, 0.12) and ?0.15% (?0.27, –0.03), respectively. Canagliflozin 100 mg and 300 mg reduced body weight vs placebo (week 26: –3.7%, –4.2%, –1.2%, respectively; p?<?0.001) and sitagliptin (week 52: –3.8%, –4.2%, –1.3%, respectively; p?<?0.001). Both canagliflozin doses reduced FPG and systolic BP vs placebo (week 26) and sitagliptin (week 52) (p?<?0.001). Overall AE and AE-related discontinuation rates were generally similar across groups, but higher with canagliflozin 100 mg. Genital mycotic infection and osmotic diuresis-related AE rates were higher with canagliflozin; few led to discontinuations. Hypoglycaemia incidence was higher with canagliflozin.

Conclusions/interpretation

Canagliflozin improved glycaemia and reduced body weight vs placebo (week 26) and sitagliptin (week 52) and was generally well tolerated in patients with type 2 diabetes on metformin.

Clinical trial registry

ClinicalTrials.gov NCT01106677

Funding

This study was supported by Janssen Research & Development, LLC.