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.     

Patterns of glycaemic control in patients with type 2 diabetes mellitus initiating second‐line therapy after metformin monotherapy: Retrospective data for 10 256 individuals from the United Kingdom and Germany

Aim

To investigate determinants of change in glycated haemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2DM) at 6 months after initiating uninterrupted second‐line glucose‐lowering therapies.

Materials and Methods

This cohort study utilized retrospective data from 10 256 patients with T2DM who initiated second‐line glucose‐lowering therapy (switch from or add‐on to metformin) between 2011 and 2014 in Germany and the UK. Effects of pre‐specified patient characteristics on 6‐month HbA1c changes were assessed using analysis of covariance.

Results

Patients had a mean (standard error [SE]) baseline HbA1c of 8.68% (0.02); 28.5% of patients discontinued metformin and switched to an alternative therapy and the remainder initiated add‐on therapy. Mean (SE) unadjusted 6‐month HbA1c change was ?1.27% (0.02). When adjusted for baseline HbA1c, 6‐month changes depended markedly on the magnitude of the baseline HbA1c (HbA1c <9%, ?0.45% per unit increase in HbA1c; HbA1c ≥9%, ?0.87% per unit increase in HbA1c). Adjusted mean 6‐month HbA1c reductions showed slight treatment differences (range, 0.92–1.09%; P < .001). Greater reductions in HbA1c were associated with second‐line treatment initiation within 6 months of T2DM diagnosis (1.36% vs 1.03% [P < .001]) and advanced age (≥70 years, 1.13%; <70 years, 1.02% [P < .001]).

Conclusions

Many patients with T2DM have very high HbA1c levels when initiating second‐line therapy, indicating the need for earlier treatment intensification. Patient‐specific factors merit consideration when making treatment decisions.     

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。     

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

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

Efficacy and safety of the 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 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 replacing sitagliptin with canagliflozin in real-world patients with type 2 diabetes uncontrolled with sitagliptin combined with metformin and/or gliclazide: The SITA-CANA Switch Study

Aim

To analyze the efficacy and safety of replacing sitagliptin with canagliflozin in patients with type 2 diabetes (T2D) and poor metabolic control despite treatment with sitagliptin in combination with metformin and/or gliclazide.

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 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.     

Initial treatment with rosiglitazone/metformin fixed-dose combination therapy compared with monotherapy with either rosiglitazone or metformin in patients with uncontrolled type 2 diabetes

AIM: This study assessed the efficacy and safety of rosiglitazone and metformin (RSG/MET) fixed-dose combination (AVANDAMET) as initial therapy in patients with uncontrolled type 2 diabetes compared with monotherapy with either RSG or MET after 32 weeks of treatment. METHODS: A total of 468 drug-naive patients with uncontrolled type 2 diabetes were recruited for this multicentre, double-blind trial if their glycated haemoglobin (A1c) was greater than 7.5%, but less than or equal to 11%, and their fasting plasma glucose (FPG) was less than or equal to 15 mmol/l. Patients were randomized to 32 weeks of blinded treatment with either RSG/MET fixed-dose combination (n = 155), MET (n = 154) or RSG (n = 159). The groups were comparable at baseline, with mean A1c of 8.8% and FPG of 11 mmol/l. RSG/MET was initiated with a total daily dose of 2 mg/500 mg and could be increased up to 8 mg/2000 mg; MET therapy began with a total daily dose of 500 mg and could be increased up to 2000 mg; and RSG treatment began with a total daily dose of 4 mg and could be increased up to 8 mg. Medication was uptitrated during on-therapy visits based on failure to attain glycaemic target of mean daily glucose less than or equal to 6.1 mmol/l (unless at maximum tolerated dose). Patients were assessed for efficacy and safety at nine visits over a 32-week treatment period. This was a trial designed to show greater efficacy of RSG/MET combination therapy compared with MET or RSG monotherapy. The primary end point was change in A1c from baseline to week 32. Secondary end points included the proportion of patients achieving recommended A1c and FPG targets for glycaemic control and change from baseline in FPG, free fatty acid, lipids, insulin, insulin sensitivity, C-reactive protein and adiponectin. Safety evaluations included adverse-event (AE) monitoring, changes in weight and clinical laboratory evaluations. RESULTS: At week 32, RSG/MET showed significant improvements in A1c from a baseline of 8.9 +/- 1.1% to 6.6 +/- 1.0% at study end, and this 2.3% reduction was significantly greater than the reductions achieved individually with MET (-1.8%; p = 0.0008) and RSG (-1.6%; p < 0.0001). The greatest mean decrease in FPG was seen with RSG/MET (-4.1 mmol/l) and was significant compared with MET (-2.8 mmol/l; p < 0.0001) and RSG (-2.6 mmol/l; p < 0.0001). Target A1c of less than or equal to 6.5% and less than 7% were achieved in more patients in the RSG/MET group (60% and 77%) than with MET (39% and 57%) or RSG (35% and 58%) respectively. Treatment was well tolerated, with nausea, vomiting and diarrhoea as the most commonly reported AEs. Oedema was comparable between RSG/MET (6%) and RSG (7%) and lower in the MET group (3%). No new safety and tolerability issues were observed in the RSG/MET group. CONCLUSIONS: As first-line therapy in patients with uncontrolled type 2 diabetes, RSG/MET fixed-dose combination therapy achieved significant reductions in A1c and FPG compared with either RSG or MET monotherapy. RSG/MET was generally well tolerated as initial therapy, with no new tolerability issues identified with the fixed-dose combination.