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 sitagliptin monotherapy compared with voglibose in Japanese patients with type 2 diabetes: a randomized,double‐blind trial

Objective: To compare the efficacy and safety of sitagliptin (a dipeptidyl peptidase‐4 inhibitor) and voglibose (an α‐glucosidase inhibitor) monotherapy in Japanese patients with type 2 diabetes who have inadequate glycaemic control (HbA1c ≥6.5% and <10.0%) on diet and exercise. Methods: In a multi‐center, randomized, double‐blind, parallel‐group study, 319 patients were randomized (1:1) to 12‐week treatment with sitagliptin 50 mg once daily or voglibose 0.2 mg thrice daily before meals. The primary analysis assessed whether sitagliptin was non‐inferior to voglibose in lowering HbA1c. Results: After 12 weeks, sitagliptin was non‐inferior to voglibose for HbA1c‐lowering efficacy. Furthermore, sitagliptin was superior to voglibose, providing significantly greater reductions in HbA1c from baseline [least squares mean changes in HbA1c [95% confidence intervals (CI)] = ?0.7% (?0.8 to ?0.6) and ?0.3% (?0.4 to ?0.2), respectively; between‐group difference = ?0.4% (?0.5 to ?0.3), p < 0.001]. Sitagliptin was also superior to voglibose on other key efficacy endpoints, including change from baseline in 2‐h postmeal glucose (?2.8 mmol/l vs. ?1.8 mmol/l, p < 0.001) and fasting plasma glucose (?1.1 mmol/l vs. ?0.5 mmol/l, p < 0.001). After 12 weeks, the incidences of clinical adverse experiences (AEs), drug‐related AEs and gastrointestinal AEs in the sitagliptin group (48.5, 10.4 and 18.4%, respectively) were significantly (p < 0.05) lower than those in the voglibose group (64.7, 26.3 and 34.6%, respectively). The incidences of hypoglycaemia, serious AEs and discontinuations due to AEs were low and similar in both groups. Conclusions: In Japanese patients with type 2 diabetes, once‐daily sitagliptin monotherapy showed greater efficacy and better tolerability than thrice‐daily voglibose over 12 weeks.     

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 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.     

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).     

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.     

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.     

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).     

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 vildagliptin and voglibose in Japanese patients with type 2 diabetes: a 12‐week,randomized, double‐blind,active‐controlled study

Aim: To confirm the efficacy of vildagliptin in patients with type 2 diabetes (T2D) by testing the hypothesis that glycosylated haemoglobin (HbA1c) reduction with vildagliptin is superior to that with voglibose after 12 weeks of treatment. Methods: In this 12‐week, randomized, double‐blind, active‐controlled, parallel‐group study, the efficacy and safety of vildagliptin (50 mg bid, n = 188) was compared with that of voglibose (0.2 mg tid, n = 192) in patients with T2D who were inadequately controlled with diet and exercise. Results: The characteristics of two groups were well matched at baseline. The mean age, body mass index (BMI) and HbA1c were 59.1 years, 24.9 kg/m² and 7.6%, respectively. At baseline, fasting plasma glucose (FPG) and 2‐h postprandial glucose (PPG) were 9.01 mmol/l (162.2 mg/dl) and 13.57 mmol/l (244.3 mg/dl), respectively. The adjusted mean change in HbA1c from baseline to endpoint was ?0.95 ± 0.04% in the vildagliptin‐treated patients and ?0.38 ± 0.04% in those receiving voglibose (between‐group change = 0.57 ± 0.06%, 95% confidence interval (CI) (?0.68 to ?0.46%), p < 0.001), showing that vildagliptin was superior to voglibose. Endpoint HbA1c ≤ 6.5% was achieved in 51% vildagliptin‐treated patients compared with 24% patients who were on voglibose (p < 0.001). Vildagliptin also exhibited significantly (p < 0.001) greater reduction compared with voglibose in both FPG [1.34 vs. 0.43 mmol/l (24.1 vs. 7.8 mg/dl)] and 2‐h PPG [2.86 vs. 1.1 mmol/l (51.5 vs. 19.8 mg/dl)]. Overall adverse events (AEs) were lower in the vildagliptin‐treated patients compared with that in the voglibose‐treated patients (61.2 vs. 71.4%), with no incidence of hypoglycaemia and serious adverse events with vildagliptin. Gastrointestinal AEs were significantly lower with vildagliptin compared with that of the voglibose (18.6 vs. 32.8%; p = 0.002). Conclusions: Vildagliptin (50 mg bid) showed superior efficacy and better tolerability compared with voglibose in Japanese patients with T2D.     

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.     

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 the addition of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sitagliptin: The VERTIS SITA2 placebo‐controlled randomized study

Aims

To assess ertugliflozin in patients with type 2 diabetes who are inadequately controlled by metformin and sitagliptin.

Materials and Methods

In this double‐blind randomized study ( Clinicaltrials.gov NCT02036515), patients (glycated haemoglobin [HbA1c] 7.0% to 10.5% [53‐91 mmol/mol] receiving metformin ≥1500 mg/d and sitagliptin 100 mg/d; estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m²) were randomized to ertugliflozin 5 mg once‐daily, 15 mg once‐daily or placebo. The primary efficacy endpoint was change from baseline in HbA1c at Week 26; treatment was continued until Week 52.

Results

A total of 464 patients were randomized (mean baseline HbA1c, 8.0% [64.3 mmol/mol]; eGFR, 87.9 mL/min/1.73 m²). After 26 weeks, placebo‐adjusted least squares (LS) mean changes in HbA1c from baseline were ?0.7% (?7.5 mmol/mol) and ?0.8% (?8.3 mmol/mol) for ertugliflozin 5 and 15 mg, respectively (both P < .001); 17.0%, 32.1% and 39.9% of patients receiving placebo, ertugliflozin 5 mg or ertugliflozin 15 mg, respectively, had HbA1c <7.0% (53 mmol/mol). Significant reductions in fasting plasma glucose, body weight (BW) and systolic blood pressure (SBP) were observed with ertugliflozin relative to placebo. The positive effects of ertugliflozin on glycaemic control, BW and SBP were maintained through Week 52. A higher incidence of genital mycotic infections was observed in male and female patients receiving ertugliflozin (3.7%‐14.1%) vs placebo (0%‐1.9%) through Week 52. The incidence of urinary tract infections, symptomatic hypoglycaemia and hypovolaemia adverse events were not meaningfully different across groups.

Conclusions

Ertugliflozin added to metformin and sitagliptin was well‐tolerated, and provided clinically meaningful, durable glycaemic control, BW and SBP reductions vs placebo over 52 weeks.     

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.     

Ertugliflozin plus sitagliptin versus either individual agent over 52 weeks in patients with type 2 diabetes mellitus inadequately controlled with metformin: The VERTIS FACTORIAL randomized trial

Aim

To evaluate the efficacy and safety of ertugliflozin and sitagliptin co‐administration vs the individual agents in patients with type 2 diabetes who are inadequately controlled with metformin.

Methods

In this study ( Clinicaltrials.gov NCT02099110), patients with glycated haemoglobin (HbA1c) ≥7.5% and ≤11.0% (≥58 and ≤97 mmol/mol) with metformin ≥1500 mg/d (n = 1233) were randomized to ertugliflozin 5 (E5) or 15 (E15) mg/d, sitagliptin 100 mg/d (S100) or to co‐administration of E5/S100 or E15/S100. The primary endpoint was change from baseline in HbA1c at Week 26.

Results

At Week 26, least squares mean HbA1c reductions from baseline were greater with E5/S100 (?1.5%) and E15/S100 (?1.5%) than with individual agents (?1.0%, ?1.1% and ?1.1% for E5, E15 and S100, respectively; P < .001 for all comparisons). HbA1c <7.0% (<53 mmol/mol) was achieved by 26.4%, 31.9%, 32.8%, 52.3% and 49.2% of patients in the E5, E15, S100, E5/S100 and E15/S100 groups, respectively. Fasting plasma glucose reductions were significantly greater with E5/S100 and E15/S100 compared with individual agents. Body weight and systolic blood pressure (SBP) significantly decreased with E5/S100 and E15/S100 vs S100 alone. Glycaemic control, body weight and SBP effects of ertugliflozin were maintained to Week 52. Genital mycotic infections were more common among ertugliflozin‐treated patients compared with those treated with S100. Incidences of symptomatic hypoglycaemia and adverse events related to hypovolaemia or urinary tract infection were similar among groups.

Conclusions

In patients with uncontrolled type 2 diabetes while using metformin, co‐administration of ertugliflozin and sitagliptin provided more effective glycaemic control through 52 weeks compared with the individual agents.     

Metformin-glibenclamide versus metformin plus rosiglitazone in patients with type 2 diabetes inadequately controlled on metformin monotherapy

AIM: This double-blind study evaluated the efficacy and safety of metformin-glibenclamide tablets vs. metformin plus rosiglitazone therapy in patients with type 2 diabetes inadequately controlled on metformin monotherapy. SUBJECTS AND METHODS: After an open-label, metformin lead-in phase, 318 patients were randomly assigned to treatment based on metformin-glibenclamide 500/2.5 mg tablets (initial daily dose 1000/5 mg) or metformin 500 mg plus rosiglitazone 4 mg (initial daily dose 1000-2000 mg + 4 mg, depending on previous treatment) for 24 weeks. Doses were titrated to achieve the therapeutic glycaemic target. The primary efficacy variable was the change in HbA1C. RESULTS: At week 24, metformin-glibenclamide tablets resulted in significantly greater reductions in HbA1C (-1.5%) and fasting plasma glucose [-2.6 mmol/l (-46 mg/dl)] than metformin plus rosiglitazone [-1.1%, p < 0.001; -2 mmol/l (-36 mg/dl), p = 0.03]. More patients receiving metformin-glibenclamide attained HbA1C <7.0% than did those in the metformin plus rosiglitazone group (60 vs. 47%) and had fasting plasma glucose levels <7 mmol/l (<126 mg/dl) by week 24 (34 vs. 25%). Both treatments were well tolerated. Frequency of adverse gastrointestinal events was comparable between groups. Four per cent of patients receiving metformin-glibenclamide withdrew because of symptomatic hypoglycaemia contrasted with 3% of patients receiving metformin plus rosiglitazone who withdrew because of persistent hyperglycaemia. Hypoglycaemic events were mild or moderate in intensity and were easily self-managed. CONCLUSIONS: Metformin-glibenclamide tablets resulted in significantly greater reductions in HbA1C and fasting plasma glucose compared with metformin plus rosiglitazone in patients with type 2 diabetes inadequately controlled on metformin monotherapy.     

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.     

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.     

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.     

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.