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

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

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).     

The efficacy and safety of the dipeptidyl peptidase-4 inhibitor saxagliptin in treatment-naive patients with type 2 diabetes mellitus: a randomized controlled trial

ABSTRACT: BACKGROUND: The aim of this study was to assess efficacy and safety of saxagliptin monotherapy for up to 76 weeks in patients with type 2 diabetes mellitus (T2DM) and inadequate glycemic control, with main efficacy assessment at 24 weeks. METHODS: 365 treatment-naive patients with T2DM (HbA1c 7.0%-10.0%) were treated with saxagliptin 2.5 mg q.A.M., saxagliptin 2.5 mg q.A.M. with possible titration to saxagliptin 5 mg, saxagliptin 5 mg q.A.M., saxagliptin 5 mg q.P.M., or placebo. After week 24, patients in all groups were eligible for titration to saxagliptin 10 mg based on HbA1c [greater than or equal to]7%, and all unrescued placebo patients began blinded metformin 500 mg/day. Rescue with open-label metformin was available for patients with inadequate glycemic control. RESULTS: At week 24, placebo-subtracted mean HbA1c reduction from baseline (LOCF) was significantly greater in the saxagliptin treatment groups vs placebo, and remained greater through week 76. Serious adverse events (AEs) and discontinuations due to AEs were similar in saxagliptin and control groups; incidence of confirmed hypoglycemia was low across all treatment groups (saxagliptin-treated, 2 [0.7]; control, 1 [1.4]). CONCLUSIONS: In treatment-naive patients with T2DM, saxagliptin monotherapy demonstrated statistically significant improvement in HbA1c compared with placebo at 24 weeks and was generally well tolerated for up to 76 weeks. Trial registration ClinicalTrials.gov Identifier: NCT00316082.     

Initial combination of linagliptin and metformin improves glycaemic control in type 2 diabetes: a randomized, double-blind, placebo-controlled study

Aims: To evaluate the efficacy and safety of initial combination therapy with linagliptin plus metformin versus linagliptin or metformin monotherapy in patients with type 2 diabetes. Methods: In this 24‐week, double‐blind, placebo‐controlled, Phase III trial, 791 patients were randomized to one of six treatment arms. Two free combination therapy arms received linagliptin 2.5 mg twice daily (bid) + either low (500 mg) or high (1000 mg) dose metformin bid. Four monotherapy arms received linagliptin 5 mg once daily, metformin 500 mg or 1000 mg bid or placebo. Patients with haemoglobin A1c (HbA1c) ≥11.0% were not eligible for randomization and received open‐label linagliptin + high‐dose metformin. Results: The placebo‐corrected mean (95% confidence interval) change in HbA1c from baseline (8.7%) to week 24 was ?1.7% (?2.0, ?1.4) for linagliptin + high‐dose metformin, ?1.3% (?1.6, ?1.1) for linagliptin + low‐dose metformin, ?1.2% (?1.5, ?0.9) for high‐dose metformin, ?0.8% (?1.0, ?0.5) for low‐dose metformin and ?0.6 (?0.9, ?0.3) for linagliptin (all p < 0.0001). In the open‐label arm, the mean change in HbA1c from baseline (11.8%) was ?3.7%. Hypoglycaemia occurred at a similar low rate with linagliptin + metformin (1.7%) as with metformin alone (2.4%). Adverse event rates were comparable across treatment arms. No clinically significant changes in body weight were noted. Conclusions: Initial combination therapy with linagliptin plus metformin was superior to metformin monotherapy in improving glycaemic control, with a similar safety and tolerability profile, no weight gain and a low risk of hypoglycaemia.     

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

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

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

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

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 fixed‐dose combination therapy,alogliptin plus metformin,in Asian patients with type 2 diabetes: A phase 3 trial

This study evaluated the efficacy and safety of 26 weeks of twice‐daily (BID) alogliptin + metformin fixed‐dose combination (FDC) therapy in Asian patients with type 2 diabetes. Patients aged 18 to 75 years with hemoglobin A1c (HbA1c) of 7.5% to 10.0% after ≥2 months of diet and exercise and a 4‐week placebo run‐in were enrolled. Eligible patients were randomized (1:1:1:1) to placebo, alogliptin 12.5 mg BID, metformin 500 mg BID or alogliptin 12.5 mg plus metformin 500 mg FDC BID. The primary endpoint was change in HbA1c from baseline to end of treatment (Week 26). In total, 647 patients were randomized. The least‐squares mean change in HbA1c from baseline to Week 26 was ?0.19% with placebo, ?0.86% with alogliptin, ?1.04% with metformin and ?1.53% with alogliptin + metformin FDC. Alogliptin + metformin FDC was significantly more effective ( P < .0001) in lowering HbA1c than either alogliptin or metformin alone. The safety profile of alogliptin + metformin FDC was similar to that of the individual components alogliptin and metformin. The study demonstrated that treatment with alogliptin + metformin FDC BID resulted in better glycaemic control than either monotherapy and was well tolerated in Asian patients with type 2 diabetes.     

The effect of linagliptin on glycaemic control and tolerability in patients with type 2 diabetes mellitus: a systematic review and meta-analysis

Aim: Linagliptin is a new dipeptidyl peptidase‐4 inhibitor recently approved for use in the USA. The objective of this systematic review and meta‐analysis was to assess effect of linagliptin on glycaemic control, biomarkers and incidence of adverse events (AEs) in patients with type 2 diabetes mellitus. Methods: Five published and four unpublished randomized, clinical trials were identified from multiple databases. Qualitative assessments and quantitative analyses were performed. Results: Nine studies included 4246 participants with 53% men, 59.4% Caucasians, 38.7% Asians, and age range 45–69 years. Linagliptin was given as monotherapy (vs. placebo) or combined with metformin (vs. metformin + placebo), sulphonylurea (vs. sulphonylurea + placebo) or pioglitazone (vs. pioglitazone + placebo). Linagliptin 5 mg/day for 12–24 weeks, significantly reduced haemoglobin A1c (HbA1c) (?0.63%, p < 0.00001), fasting plasma glucose (FPG) (?1.01 mmol/l, p < 0.00001) and improved disposition index (DI, product of insulin sensitivity and acute insulin secretion) (p = 0.0001). Linagliptin monotherapy was not more effective than metformin at reducing HbA1c or FPG. Similar proportion of patients in linagliptin and placebo groups reported AEs including upper respiratory tract infections, headaches, nausea, hypertension and back pain. Conclusions: Linagliptin was associated with modest but significant reduction in HbA1c and FPG and improved DI after 12–24 weeks. Patients who would probably benefit most are those with HbA1c <9%, already on an active agent, compliant with weight reduction strategies, and can recognize and manage hypoglycaemia, fluid retention and upper respiratory tract infections. Long‐term studies are needed to determine durability of response, incidence of microvascular and macrovacular complications, cost‐effectiveness and safety.     

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.     

Liraglutide, a once-daily human glucagon-like peptide 1 analogue, provides sustained improvements in glycaemic control and weight for 2 years as monotherapy compared with glimepiride in patients with type 2 diabetes

Aims: Most treatments for type 2 diabetes fail over time, necessitating combination therapy. We investigated the safety, tolerability and efficacy of liraglutide monotherapy compared with glimepiride monotherapy over 2 years. Methods: Participants were randomized to receive once‐daily liraglutide 1.2 mg, liraglutide 1.8 mg or glimepiride 8 mg. Participants completing the 1‐year randomized, double‐blind, double‐dummy period could continue open‐label treatment for an additional year. Safety data were evaluated for the full population exposed to treatment, and efficacy data were evaluated for the full intention‐to‐treat (ITT) and 2‐year completer populations. Outcome measures included change in glycosylated haemoglobin (HbA1c), fasting plasma glucose (FPG), body weight and frequency of nausea and hypoglycaemia. Results: For patients completing 2 years of therapy, HbA1c reductions were ?0.6% with glimepiride versus ?0.9% with liraglutide 1.2 mg (difference: ?0.37, 95% CI: ?0.71 to ?0.02; p = 0.0376) and ?1.1% with liraglutide 1.8 mg (difference: ?0.55, 95% CI: ?0.88 to ?0.21; p = 0.0016). In the ITT population, HbA1c reductions were ?0.3% with glimepiride versus ?0.6% with liraglutide 1.2 mg (difference: ?0.31, 95% CI: ?0.54 to ?0.08; p = 0.0076) and ?0.9% with liraglutide 1.8 mg (difference: ?0.60, 95% CI: ?0.83 to ?0.38; p < 0.0001). For both ITT and completer populations, liraglutide was more effective in reducing HbA1c, FPG and weight. Over 2 years, rates of minor hypoglycaemia [self‐treated plasma glucose <3.1 mmol/l (<56 mg/dl)] were significantly lower with liraglutide 1.2 mg and 1.8 mg compared with glimepiride (p < 0.0001). Conclusion: Liraglutide monotherapy for 2 years provides significant and sustained improvements in glycaemic control and body weight compared with glimepiride monotherapy, at a lower risk of hypoglycaemia.     

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

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

Triple oral fixed-dose diabetes polypill versus insulin plus metformin efficacy demonstration study in the treatment of advanced type 2 diabetes (TrIED study-II)

Aim: To compare the efficacy of a fixed‐dose triple oral diabetes polypill containing 1 or 2 mg glimepiride, 500 mg sustained‐release metformin, and 15 mg pioglitazone (GMP) administered once daily with human insulin 70/30 mix and 500 mg sustained‐release metformin administered twice daily (IM) in insulin‐naÏve subjects with type 2 diabetes mellitus inadequately controlled [haemoglobin A1c (HbA1c) over 8.0%] on a combination of glimepiride and metformin. Methods: One hundred and one subjects were randomized to GMP or IM regimens for 12 weeks. The primary outcome was the change in HbA1c and secondary outcomes were changes in fasting plasma, and postprandial plasma glucoses and the number of patients achieving a drop in HbA1c of over 1%. Other secondary outcomes were changes in the lipid profile, C‐peptide level, body weight as well as physician assessments of efficacy and patient assessment of tolerability. Results: The primary outcome of a change in HbA1c showed a trend towards a lower HbA1c with GMP therapy (?1.33% vs. ?0.83%; p = 0.059). The number of subjects achieving a decrease in HbA1c of greater than 1.0% was significantly greater in the GMP therapy (72.5% vs. 22%; p = 0.0001). Both regimens equally and significantly reduced fasting and postprandial glucose levels (p = 0.05). Weight gain was nonsignificantly greater with IM (2.69 vs. 0.92 kg; p = 0.223). Investigator assessment of efficacy was significantly better with GMP (p = 0.001) as was tolerability as assessed by patients (p = 0.0001). Conclusion: When compared with suboptimally titrated IM there was a trend towards a lower HbA1c with GMP and significantly more GMP subjects obtained an HbA1c under 7%. Global assessments by investigators and subjects showed both a greater efficacy and tolerability with GMP.     

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 improves glycaemic control and is well tolerated in patients with type 2 diabetes mellitus and renal impairment

Aim: To evaluate the efficacy and safety of saxagliptin vs. placebo in patients with type 2 diabetes mellitus (T2DM) and renal impairment. Methods: In this multicentre, randomized, parallel‐group, double‐blind, placebo‐controlled study, patients with glycated haemoglobin (HbA1c) 7–11% and creatinine clearance <50 ml/min were stratified by baseline renal impairment (moderate, severe or end‐stage on haemodialysis), and randomized (1 : 1) to saxagliptin 2.5 mg once daily or placebo for 12 weeks. Oral antihyperglycaemic drugs and insulin therapy present at enrolment were continued throughout the study. The absolute change in HbA1c from baseline to week 12 (primary efficacy end‐point) was analysed using an analysis of covariance model with last observation carried forward methodology. Results: A total of 170 patients were randomized and treated. The adjusted mean decrease from baseline to week 12 in HbA1c was statistically significantly greater in the saxagliptin group than in the placebo group; the difference between treatments was ?0.42% (95% confidence interval: ?0.71 to ?0.12%, p = 0.007). Adjusted mean HbA1c decreases from baseline to week 12 were numerically greater with saxagliptin than with placebo in the subgroups of patients with moderate (?0.64 vs. ?0.05%) and severe (?0.95 vs. ?0.50%) renal impairment. HbA1c reductions were similar between saxagliptin and placebo in the subgroup with end‐stage renal disease on haemodialysis (?0.84 vs. ?0.87%). Saxagliptin was generally well tolerated; incidences of adverse events and hypoglycaemic events were similar to placebo. Conclusions: Saxagliptin 2.5 mg once daily is a well‐tolerated treatment option for patients with inadequately controlled T2DM and renal impairment.     

Linagliptin monotherapy provides superior glycaemic control versus placebo or voglibose with comparable safety in Japanese patients with type 2 diabetes: a randomized, placebo and active comparator-controlled, double-blind study

Aims: To evaluate the efficacy and safety of linagliptin 5 and 10 mg vs. placebo and voglibose in Japanese patients with type 2 diabetes mellitus (T2DM). Methods: This study enrolled patients with inadequately controlled T2DM who were previously treated with one or two oral antidiabetics or were drug naÏve. After a 2 to 4‐week washout and placebo run‐in, 561 patients were randomized (2 : 2 : 2 : 1) to double‐blind treatment with linagliptin 5 or 10 mg qd, voglibose 0.2 mg tid or placebo. The primary endpoint was the change from baseline in haemoglobin A1c (HbA1c) with linagliptin vs. placebo after 12 weeks and vs. voglibose after 26 weeks. Results: Baseline characteristics were well balanced across treatment groups (overall mean HbA1c was 8.01%). The adjusted mean (95% confidence interval) treatment differences at week 12 were ?0.87% (?1.04, ?0.70; p < 0.0001) and ?0.88% (?1.05, ?0.71; p < 0.0001) for linagliptin 5 and 10 mg vs. placebo and at week 26 were ?0.32% (?0.49, ?0.15; p = 0.0003) and ?0.39% (?0.56, ?0.21; p < 0.0001) for linagliptin 5 and 10 mg vs. voglibose. At week 12, mean HbA1c was 7.58, 7.48 and 8.34% in patients receiving linagliptin 5 mg, linagliptin 10 mg and placebo, respectively. At week 26, mean HbA1c was 7.63% with linagliptin 5 mg, 7.50% with linagliptin 10 mg and 7.91% with voglibose. Drug‐related adverse event rates were comparable across treatment groups over 12 weeks (9.4% linagliptin 5 mg, 8.8% linagliptin 10 mg and 10.0% placebo) and 26 weeks (11.3% linagliptin 5 mg, 10.6% linagliptin 10 mg and 18.5% voglibose). There were no documented cases of hypoglycaemia. Conclusions: Linagliptin showed superior glucose‐lowering efficacy and comparable safety and tolerability to both placebo and voglibose in Japanese patients with T2DM.     

Vildagliptin plus metformin combination therapy provides superior glycaemic control to individual monotherapy in treatment-naive patients with type 2 diabetes mellitus

Aim: To compare the efficacy and safety of vildagliptin and metformin initial combination therapy with individual monotherapies in treatment‐naive patients with type 2 diabetes mellitus (T2DM). Methods: This was a 24‐week, randomized, double‐blind, active‐controlled study. Treatment‐naive patients with T2DM who had a glycated haemoglobin (HbA_1c) of 7.5–11% (N = 1179) were randomized equally to receive vildagliptin plus high‐dose metformin combination therapy (50 mg + 1000 mg twice daily), vildagliptin plus low‐dose metformin combination therapy (50 mg + 500 mg twice daily), vildagliptin monotherapy (50 mg twice daily) or high‐dose metformin monotherapy (1000 mg twice daily). The primary objective was to demonstrate that HbA_1c reduction from baseline with either combination therapy is superior to both monotherapies at the week 24 endpoint. Patients who failed glycaemic‐screening criteria [HbA_1c >11% or fasting plasma glucose (FPG) >15 mmol/l (270 mg/dl)] could enter a 24‐week, single‐arm substudy. These patients (N = 94) received open‐label vildagliptin plus high‐dose metformin combination therapy (100 mg + 1000 mg twice daily). Results: From comparable baseline values (8.6–8.7%), HbA_1c decreased in all four treatment groups, to the greatest extent with vildagliptin plus high‐dose metformin combination therapy. Mean (SE) HbA_1c change from baseline was ?1.8% (0.06%), ?1.6% (0.06%), ?1.1% (0.06%) and ?1.4% (0.06%) with vildagliptin plus high‐dose metformin combination therapy, vildagliptin plus low‐dose metformin combination therapy, and vildagliptin and metformin monotherapies respectively. The between‐group difference was superior with vildagliptin plus high‐dose metformin combination therapy (p < 0.001 vs. both monotherapies) and vildagliptin plus low‐dose metformin combination therapy (p < 0.001 and p = 0.004, vs. vildagliptin and metformin monotherapies, respectively). Higher baseline HbA_1c values were linked to greater HbA_1c reductions, with changes of ?3.2% (0.22%), ?2.7% (0.22%), ?1.5% (0.24%) and ?2.6% (0.26%) respectively, occurring in patients with baseline HbA_1c≥10%. Reductions in FPG were superior with vildagliptin plus high‐dose metformin combination therapy [change from baseline ?2.63 (0.13) mmol/l] compared with both monotherapies [?1.26 (0.13) mmol/l and ?1.92 (0.13) mmol/l, respectively; p < 0.001]. There was no incidence of hypoglycaemia or severe hypoglycaemia with either combination therapy, and neither was associated with weight gain. All treatments were well tolerated and displayed a comparable incidence of adverse events overall. Despite superior HbA_1c lowering, the vildagliptin plus low‐dose metformin combination therapy group demonstrated a favourable gastrointestinal (GI) tolerability profile compared with metformin monotherapy. Conclusions: In treatment‐naive patients, combinations of vildagliptin and both high‐dose and low‐dose metformin provide superior efficacy to monotherapy treatments with a comparable overall tolerability profile and low risk of hypoglycaemia. The potential dose‐sparing effect of adding vildagliptin to low‐dose metformin in preference to the up‐titration of metformin may allow patients to achieve equivalent or superior HbA_1c lowering without the GI tolerability issues associated with higher doses of metformin.     

Comparison between a basal-bolus and a premixed insulin regimen in individuals with type 2 diabetes–results of the GINGER study

Aim: To compare the efficacy and safety of an intensified insulin regimen, using insulin glargine (glargine) once daily and pre‐meal insulin glulisine (glulisine) (basal‐bolus), with a conventional therapy, using premixed insulin (premix) twice daily. Methods: This 52‐week, open‐label, randomized, multinational, multicentre trial included 310 subjects with type 2 diabetes (T2D) on premix, with or without metformin, who were randomized to a basal‐bolus regimen with glargine and glulisine (n = 153; mean ± s.d. age 60.2 ± 7.5 years; HbA1c 8.6 ± 0.8%; weight 87.0 ± 15.1 kg; T2D duration 12.8 ± 5.8 years) or twice‐daily premix (n = 157; age 60.9 ± 7.8 years; HbA1c 8.5 ± 0.9%; weight 84.3 ± 15.0 kg; T2D duration 12.5 ± 6.8 years). The primary endpoint was change in HbA1c from baseline to endpoint. Results: Mean decrease in baseline‐to‐endpoint HbA1c for basal‐bolus vs. premix was ?1.31 vs. ?0.80% (difference: ?0.476%; 95% Cl: ?0.714, ?0.238; p = 0.0001, ancova ). More subjects reached HbA1c ≤ 7.0% in the basal‐bolus group than in the premix group [68 (46.6%) vs. 43 (27.9%); p = 0.0004], while they also experienced significantly lower mean ± s.d. daytime (?2.7 ± 2.3 vs. ?2.3 ± 2.5 mmol/l; p = 0.0033) and postprandial (?3.1 ± 2.6 vs. ?2.5 ± 2.8 mmol/l; p < 0.0001) blood glucose. Endpoint daily insulin doses were 98.0 ± 48.7 vs. 91.3 ± 44.3 IU (p = 0.2104); mean weight gain was +3.6 ± 4.0 vs. +2.2 ± 4.5 kg (p = 0.0073). Mean number of overall hypoglycaemic events with basal‐bolus and premix was 13.99 and 18.54 events/patient year, respectively (difference: ?3.90; 95% CI: ?10.40, 2.60; p = 0.2385). Conclusions: An intensified basal‐bolus regimen using glargine/glulisine results in a significantly superior glycaemic control vs. premix therapy in a population with long‐standing insulin‐treated T2D, with no increase in the rates of hypoglycaemia.     

Durability of glycaemic control with dapagliflozin,an SGLT2 inhibitor,compared with saxagliptin,a DPP4 inhibitor,in patients with inadequately controlled type 2 diabetes

Dapagliflozin is associated with greater reductions in HbA1c and weight than saxagliptin in management of type 2 diabetes mellitus (T2DM). The present post hoc analyses compared the durability of these effects over short- and long-term follow-up in patients with T2DM who were inadequately controlled with metformin (≥1500 mg/day) and who were receiving either dapagliflozin (10 mg/day) or saxagliptin (5 mg/day). Failure of glycaemiccontrol was assessed using the slope of the change in HbA1c from baseline-over-time regression line (coefficient of failure [CoF]). CoF was compared directly (dapagliflozin vs saxagliptin) over the short term (NCT01606007, 24 weeks) and indirectly (placebo-adjusted) over the long term (NCT00528879 and NCT00121667, 102 weeks). A low CoF value indicated greater durability. CoF was lower for dapagliflozin versus saxagliptin over 18–24 weeks (−1.38%/year; 95% CI, −2.41 to −0.35; P = .009) and 20–102 weeks (−0.37%/year; 95% CI, −0.73 to −0.02; P = .04). Fewer dapagliflozin-treated patients versus saxagliptin-treated patients required rescue medication or discontinued the study because of failure to achieve glycaemic control at 24 weeks (3.4% vs 9.4%; P = .0191). In patients with T2DM who were inadequately controlled with metformin, dapagliflozin was associated with greater durability of glycaemic control than saxagliptin over 18–24 and 20–102 weeks.     

Glucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naive patients with type 2 diabetes

Aim: Enhancing the physiologic actions of the endogenous incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, by inhibiting dipeptidyl peptidase-4 (DPP-4), the enzyme responsible for their degradation, is an emerging treatment for type 2 diabetes mellitus (T2DM). The aim of this study was to evaluate the safety and efficacy of dose ranges of the DPP-4 inhibitor saxagliptin (BMS-477118) in patients with T2DM. Methods: In a 12-week, multicentre, randomized, parallel-group, double-blind, placebo-controlled trial conducted at 152 out-patient US study centres, 338 (low-dose cohort) and 85 (high-dose cohort) drug-naive patients with T2DM and inadequate glycaemic control (baseline HbA1c ≥6.8 and ≤9.7%) were randomized. Following a 2-week washout, patients received saxagliptin 2.5, 5, 10, 20 or 40 mg once daily, or placebo, for 12 weeks (low-dose cohort). In a second cohort, patients received saxagliptin 100 mg once daily, or placebo, for 6 weeks (high-dose cohort). The main outcome measure was saxagliptin dose response assessed as change from baseline in HbA1c following double-blind treatment. Results: In all treatment arms, saxagliptin significantly reduced HbA1c by 0.7–0.9% from an average baseline of 7.9% vs. placebo (0.3% reduction) in the low-dose cohort. Placebo-subtracted HbA1c reductions were 0.45–0.63% (low-dose cohort). Saxagliptin had significant placebo-subtracted reductions in fasting serum glucose (14–25 mg/dl). Postprandial glucose levels at 60 min following a standard liquid meal test were reduced by 24–41 mg/dl vs. placebo. Saxagliptin was weight neutral. Adverse events were similar across treatment groups, including placebo, with a very low incidence of confirmed hypoglycaemia in saxagliptin treatment arms. Conclusions: Saxagliptin effectively improved glycaemic control in drug-naive patients with T2DM and was generally safe, with a tolerability profile similar to placebo.