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.     

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus

Aims/hypothesis The aim of this study was to assess the efficacy and safety of sitagliptin (MK-0431) as monotherapy in patients with type 2 diabetes mellitus and inadequate glycaemic control (HbA_1c ≥7% and ≤10%) on exercise and diet.Methods A total of 521 patients aged 27–76 years with a mean baseline HbA_1c of 8.1% were randomised in a 1:2:2 ratio to treatment with placebo, sitagliptin 100 mg once daily, or sitagliptin 200 mg once daily, for 18 weeks. The efficacy analysis was based on an all-patients-treated population using an analysis of covariance, excluding data obtained after glycaemic rescue.Results After 18 weeks, HbA_1c was significantly reduced with sitagliptin 100 mg and 200 mg compared with placebo (placebo-subtracted HbA_1c reduction: −0.60% and −0.48%, respectively). Sitagliptin also significantly decreased fasting plasma glucose relative to placebo. Patients with higher baseline HbA_1c (≥9%) experienced greater placebo-subtracted HbA_1c reductions with sitagliptin (−1.20% for 100 mg and −1.04% for 200 mg) than those with HbA_1c <8% (−0.44% and −0.33%, respectively) or ≥8% to 8.9% (−0.61% and −0.39%, respectively). Homeostasis model assessment beta cell function index and fasting proinsulin:insulin ratio, markers of insulin secretion and beta cell function, were significantly improved with sitagliptin. The incidence of hypoglycaemia and gastrointestinal adverse experiences was not significantly different between sitagliptin and placebo. Sitagliptin had a neutral effect on body weight.Conclusions/interpretation Sitagliptin significantly improved glycaemic control and was well tolerated in patients with type 2 diabetes mellitus who had inadequate glycaemic control on exercise and diet. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible to authorised users.For the Sitagliptin Study 023 Group see electronic supplementary material for list of study investigators.     

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 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).     

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 sitagliptin when added to ongoing metformin therapy in patients with type 2 diabetes

Aim: To assess the addition of sitagliptin to ongoing metformin therapy in patients with type 2 diabetes who were inadequately controlled [haemoglobin A_1c (HbA_1c) 7–11%] on metformin monotherapy. Methods: Patients (n = 273) on metformin (≥1500 mg/day) were randomized to receive the addition of once‐daily placebo, sitagliptin 100 mg or rosiglitazone 8 mg in a 1 : 1 : 1 ratio for 18 weeks. The efficacy analysis was based on the all‐patients‐treated population using an analysis of co‐variance with change in HbA_1c from baseline as the primary endpoint. Results: The mean baseline HbA_1c was 7.7% for the entire cohort. After 18 weeks, both active add‐on therapies led to greater improvements in HbA_1c from baseline: ?0.73% for sitagliptin (p < 0.001 vs. placebo) and ?0.79% for rosiglitazone compared with ?0.22% for placebo. No difference was observed between the sitagliptin and rosiglitazone treatments (0.06% [95% confidence interval (CI): ?0.14 to 0.25]). The proportion of patients achieving an HbA_1c < 7% was greater with sitagliptin (55%) and rosiglitazone (63%) compared with placebo (38%). Body weight increased from baseline with rosiglitazone (1.5 kg) compared with body weight reduction with sitagliptin (?0.4 kg) and placebo (?0.8 kg). The difference in body weight between the sitagliptin and rosiglitazone groups was 1.9 kg (95% CI: 1.3–2.5). In a prespecified analysis, the proportion of patients experiencing a greater than 3‐kg increase in body weight was 21% in the rosiglitazone group compared with 2% in both the sitagliptin and placebo groups. Both active treatments were generally well tolerated, with no increased risk of hypoglycaemia or gastrointestinal adverse events compared with placebo. Conclusions: In this 18‐week study, the addition of sitagliptin was effective and well tolerated in patients with type 2 diabetes inadequately controlled with metformin monotherapy. Treatment with sitagliptin produced similar reductions in HbA_1c compared with the addition of rosiglitazone.     

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes inadequately controlled by glyburide monotherapy

Aim: To evaluate the efficacy and safety of alogliptin, a potent and highly selective dipeptidyl peptidase‐4 (DPP‐4) inhibitor, in combination with glyburide in patients with type 2 diabetes inadequately controlled by sulphonylurea monotherapy. Methods: After a 2‐week screening period, adult patients 18–80 years of age entered a 4‐week run‐in/stabilization period in which they were switched from their own sulphonylurea medication to an equivalent dose of glyburide (open label) plus placebo (single blind). After the run‐in period, patients were randomly assigned to double‐blind treatment with alogliptin 12.5 mg (n = 203), alogliptin 25 mg (n = 198), or placebo (n = 99) for 26 weeks. The primary end‐point was change from baseline to week 26 in glycosylated haemoglobin (HbA1c). Secondary end‐points included clinical response rates and changes in fasting plasma glucose, β‐cell function (fasting proinsulin, insulin, proinsulin/insulin ratio, and C‐peptide, and homeostasis model assessment β‐cell function), body weight, and safety end‐points [adverse events (AEs), clinical laboratory tests, vital signs and electrocardiographic readings]. Results: The study population had a mean age of 57 years and a mean disease duration of 8 years; it was well balanced for gender (52% women) and was mainly white (71%). The mean baseline HbA1c was approximately 8.1% in each group. Significantly greater least squares (LS) mean reductions in HbA1c were seen at week 26 with alogliptin 12.5 mg (?0.38%) and 25 mg (?0.52%) vs. placebo (+0.01%; p < 0.001), and more patients in the alogliptin 25‐mg group had HbA1c levels ≤7.0% at week 26 (34.8%, p = 0.002) vs. placebo (18.2%). Proportionately more patients in the alogliptin 12.5 mg (47.3%) and 25 mg (50.5%) groups had an HbA1c reduction ≥0.5% from baseline compared with patients in the placebo group (26.3%; p < 0.001). Minor improvements in individual markers of β‐cell function were seen with alogliptin, but no significant treatment group differences were noted relative to placebo. Minor LS mean changes in body weight were noted across groups (placebo, ?0.20 kg; alogliptin 12.5 mg, +0.60 kg; alogliptin 25 mg, +0.68 kg). AEs were reported for 63–64% of patients receiving alogliptin and 54% of patients receiving placebo. Few AEs were treatment limiting (2.0–2.5% across groups), and serious AEs (2.0–5.6%) were infrequent, similar across groups, and generally considered not related to treatment. The incidences of hypoglycaemia for placebo, alogliptin 12.5 mg and alogliptin 25 mg groups were 11.1, 15.8 and 9.6% respectively. Conclusions: In patients with type 2 diabetes inadequately controlled by glyburide monotherapy, the addition of alogliptin resulted in clinically significant reductions in HbA1c without increased incidence of hypoglycaemia.     

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).     

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.     

Fifty-two-week efficacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy

Aim: To examine the efficacy and safety of vildagliptin vs. glimepiride as add‐on therapy to metformin in patients with type 2 diabetes mellitus in a 52‐week interim analysis of a large, randomized, double‐blind, multicentre study. The primary objective was to demonstrate non‐inferiority of vildagliptin vs. glimepiride in glycosylated haemoglobin (HbA_1c) reduction at week 52. Methods: Patients inadequately controlled on metformin monotherapy (HbA_1c 6.5–8.5%) and receiving a stable dose of metformin (mean dose 1898 mg/day; mean duration of use 36 months) were randomized 1:1 to receive vildagliptin (50 mg twice daily, n = 1396) or glimepiride (titrated up to 6 mg/day; mean dose 4.5 mg/day, n = 1393). Results: Non‐inferiority of vildagliptin was demonstrated (97.5% confidence interval 0.02%, 0.16%) with a mean (SE) change from baseline HbA_1c (7.3% in both groups) to week 52 endpoint of ?0.44% (0.02%) with vildagliptin and ?0.53% (0.02%) with glimepiride. Although a similar proportion of patients reached a target HbA_1c level of <7% with vildagliptin and glimepiride (54.1 and 55.5%, respectively), a greater proportion of patients reached this target without hypoglycaemia in the vildagliptin group (50.9 vs. 44.3%; p < 0.01). Fasting plasma glucose (FPG) reductions were comparable between groups (mean [SE] ?1.01 [0.06] mmol/l and ?1.14 [0.06] mmol/l respectively). Vildagliptin significantly reduced body weight relative to glimepiride (mean [SE] change from baseline ?0.23 [0.11] kg; between‐group difference ?1.79 kg; p < 0.001) and resulted in a 10‐fold lower incidence of hypoglycaemia than glimepiride (1.7 vs. 16.2% of patients presenting at least one hypoglycaemic event; 39 vs. 554 hypoglycaemic events, p < 0.01). No severe hypoglycaemia occurred with vildagliptin compared with 10 episodes with glimepiride (p < 0.01), and no patient in the vildagliptin group discontinued because of hypoglycaemia compared with 11 patients in the glimepiride group. The incidence of adverse events (AEs), serious AEs and adjudicated cardiovascular events was 74.5, 7.1 and 0.9%, respectively, in patients receiving vildagliptin, and 81.1, 9.5 and 1.6%, respectively, in patients receiving glimepiride. Conclusions: When metformin alone fails to maintain sufficient glycaemic control, the addition of vildagliptin provides comparable efficacy to that of glimepiride after 52 weeks and displays a favourable AE profile, with no weight gain and a significant reduction in hypoglycaemia compared with glimepiride.     

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.     

西格列汀联合二甲双胍治疗老年2型糖尿病疗效分析

目的探讨单服二甲双胍(metformin)治疗未达标的老年2型糖尿病患者(T2DM)加用西格列汀(sitagliptin)的有效性及安全性。方法入选2015年5月至2016年9月中关村医院内分泌科单服二甲双胍控制不佳的老年T2DM患者52例,其中男性30例,女性22例,年龄65~78(68.0±8.0)岁。随机分成西格列汀组和阿卡波糖(acarbose)组,每组26例(男性15例,女性11例)。西格列汀组患者口服西格列汀100 mg/次,1次/d,阿卡波糖组患者口服阿卡波糖50 mg/次,3次/d,两组患者同时口服二甲双胍500 mg/次,3次/d,连续治疗12周。观察两组患者服药12周后空腹血糖(FPG)、餐后2h血糖(2hPG)、糖化血红蛋白(HbA1c)等指标变化,并记录低血糖、胃肠道不良反应的发生情况。结果两组患者治疗前FPG、2hPG和HbA1c差异均无统计学意义(P0.05);治疗12周后,两组患者FPG、2hPG和HbA1c较治疗前均明显降低,并且西格列汀组较阿卡波糖组2hPG和HbA1c下降更显著,差异有统计学意义(P0.05)。治疗期间两组患者无低血糖发生,阿卡波糖组4例发生腹胀,排气增加,两组患者不良反应发生差异无统计学意义(P0.05)。结论西格列汀与二甲双胍联用治疗T2DM患者疗效显著且安全。     

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 sitagliptin added to treatment of patients with type 2 diabetes inadequately controlled with premixed insulin

To improve understanding of the safety and efficacy of adding sitagliptin to treatment of patients with type 2 diabetes taking premixed insulin, data from patients using premixed insulin ± metformin (screening HbA1c ≥7.5% and ≤11%) in either of two clinical trials in which sitagliptin 100 mg once-daily or placebo was added to various formulations of insulin treatment, were analysed. In both trials, insulin doses were to remain stable throughout the 24-week trial period. At week 24, the between-group difference (sitagliptin - placebo) in the least squares mean (95% confidence intervals) change from baseline in HbA1c in patients using premixed insulin was −0.43% (−0.58, −0.28), P <0.001. Adverse events were generally similar between the treatment groups. The incidence of symptomatic hypoglycaemia was slightly higher with sitagliptin, and the incidence of hypoglycaemia requiring medical attention was slightly higher with placebo; in both cases the difference was not statistically significant. The data from this pooled analysis confirm the utility of sitagliptin used in combination with premixed insulin in patients with type 2 diabetes.