Once-daily sitagliptin,a dipeptidyl peptidase-4 inhibitor,for the treatment of patients with type 2 diabetes

ABSTRACT

Objective: Sitagliptin, an oral, potent, and selective dipeptidyl peptidase-4 (DPP?4) inhibitor was evaluated as once-daily monotherapy in a 12-week randomized, double-blind, placebo-controlled, parallel group, dose-ranging study. Additionally, the glycemic response to sitagliptin 100?mg daily was evaluated as a once-daily (100?mg once-daily) or twice-daily (50?mg twice-daily) dosing regimen.

Research design and methods: In a multinational, double-blind, randomized, placebo-controlled, parallel-group, dose-range finding study, 555 patients, 23–74 years of age, with HbA_1c of 6.5–10.0% were randomized to one of five treatment groups: placebo, sitagliptin 25, 50 or 100?mg once-daily, or sitagliptin 50?mg twice-daily for 12 weeks. The efficacy analysis was based on the all-patients-treated population using an ANCOVA model.

Results: Mean baseline HbA_1c ranged from 7.6 to 7.8% across treatment groups, with 29% of all patients with values ≤?7%. After 12 weeks, treatment with all doses of sitagliptin significantly (?p < 0.05) reduced HbA_1c by –0.39 to –0.56% and fasting plasma glucose by –11.0 to –17.2?mg/dLrelative to placebo, with the greatest reduction observed in the 100-mg once-daily group. Mean daily glucose was significantly (?p < 0.05) reduced by –14.0 to –22.6?mg/dL with all doses of sitagliptin relative to placebo. HOMA?β was significantly (?p < 0.05) increased by 11.3–15.2 with all sitagliptin doses relative to placebo. QUICKI and HOMA?IR were not significantly changed with sitagliptin treatment. There were no significant differences observed between the sitagliptin 100?mg once-daily and 50?mg twice-daily groups for any parameter. For sitagliptin, the incidence of adverse events of hypoglycemia was low, with one event in each of the 25- and 50-mg once-daily and 50-mg twice-daily treatment groups and two events in the 100?mg once-daily treatment group. There was no mean change in body weight with sitagliptin relative to placebo. Study duration may be a limitation because the extent of the glycemic response and the safety and tolerability may not have been fully elucidated in this 12-week study.

Conclusion: Sitagliptin monotherapy improved indices of glycemic control compared to placebo and was generally well-tolerated in patients with type 2 diabetes. The glycemic response to treatment with sitagliptin 100?mg/day was similar between the sitagliptin 100-mg once-daily and 50-mg twice-daily dose regimens.     

Efficacy and safety of saxagliptin in combination with insulin in Japanese patients with type 2 diabetes mellitus: a 16-week double-blind randomized controlled trial with a 36-week open-label extension

Background: We examined the efficacy and safety of saxagliptin as an add-on to insulin in Japanese patients with type 2 diabetes mellitus.

Research design and methods: We randomized 240 patients with type 2 diabetes mellitus on insulin monotherapy to 5-mg saxagliptin or placebo as add-on therapy for a 16-week, double-blind period. All patients received 5-mg saxagliptin and insulin for an additional 36 weeks (open-label extension). Change in hemoglobin A1c (HbA1c) at Week 16 was the main endpoint.

Results: At Week 16, the adjusted change in HbA1c from baseline increased by 0.51% with placebo and decreased by 0.40% with saxagliptin (difference ?0.92% [95% confidence interval ?1.07%, ?0.76%; p < 0.001]). In patients receiving saxagliptin, reductions in HbA1c at Week 16 were maintained to Week 52, while switching from placebo to saxagliptin resulted in a similar reduction in HbA1c. The incidence of hypoglycemia was not markedly increased with saxagliptin versus placebo in the double-blind period and did not increase substantially during the open-label extension period. The efficacy and safety of saxagliptin was similar between the elderly and non-elderly patient groups.

Conclusions: Adding saxagliptin to ongoing insulin therapy improved glycemic control and was well tolerated in Japanese patients with type 2 diabetes.     

Efficacy and safety of canagliflozin monotherapy in Japanese patients with type 2 diabetes inadequately controlled with diet and exercise: a 24-week,randomized, double-blind,placebo-controlled,Phase III study

Objective: To examine the efficacy and safety of canagliflozin monotherapy, a sodium/glucose co-transporter 2 inhibitor, in Japanese type 2 diabetes patients.

Methods: In this double-blind, multi-centre Phase III study, patients aged ≥ 20 years with hemoglobin A1c (HbA1c) 7.0 – 10.0% on diet/exercise therapy alone received placebo or canagliflozin (100 or 200 mg) once daily for 24 weeks. The main outcome measure was the change in HbA1c from baseline to Week 24.

Results: The changes in HbA1c (?0.74 and ?0.76 vs + 0.29%), fasting plasma glucose (1 mg/dl = 0.0555 mmol/l; ?31.6 and ?31.9 vs + 3.7 mg/dl), 2-h plasma glucose after 75-g glucose load (?84.9 and ?79.0 vs ?0.5 mg/dl), body weight (percent change: ?3.76 and ?4.02 vs ?0.76%) and systolic blood pressure (?7.88 and ?6.24 vs ?2.72 mmHg) were significantly greater with 100 and 200 mg canagliflozin than with placebo (all, p < 0.05). Genital infections in females (6.5, 6.3 and 0%) and asymptomatic hypoglycemia (4.4, 5.6 and 2.2%), but not symptomatic hypoglycemia (2.2, 1.1 and 1.1%), were more frequent in the 100- and 200-mg groups than in the placebo group.

Conclusion: Canagliflozin significantly improved glycemic control and was well tolerated.     

A randomized clinical trial evaluating the efficacy and safety of the once-weekly dipeptidyl peptidase-4 inhibitor omarigliptin in patients with type 2 diabetes inadequately controlled on metformin monotherapy

Objective: To examine the efficacy and safety of the once-weekly (q.w.) dipeptidyl peptidase-4 inhibitor, omarigliptin, in patients with type 2 diabetes (T2DM) and inadequate glycemic control on metformin monotherapy.

Methods: In a randomized, double-blind trial, patients with T2DM on a stable dose of metformin monotherapy (≥1500?mg/day) with glycated hemoglobin (HbA1c) of 7.0–10.5% were randomized to omarigliptin 25?mg q.w. or matching placebo (n?=?201 in both) for 24 weeks (primary timepoint) followed by an additional 80-week treatment period.

Results: At week 24, from a mean baseline HbA1c of 8.0–8.1%, the least squares (LS) mean (95% CI) change from baseline in HbA1c (primary end-point) was –0.54% (–0.69%, –0.40%) in the omarigliptin group and 0.00% (–0.14%, 0.15%) in the placebo group, for a between-group difference of –0.55% (–0.75%, –0.34%); p?p?=?.011) and –0.5 mmol/L (–0.9, –0.1) (p?=?.010), respectively. At week 24, the incidences of symptomatic hypoglycemia and subjects with one or more adverse event (AE), serious AEs, and discontinuations due to an AE were similar in the omarigliptin and placebo groups. Over 104 weeks, omarigliptin treatment provided a clinically meaningful reduction in HbA1c.

Conclusions: In patients with T2DM, adding omarigliptin 25?mg q.w. to metformin monotherapy improved glycemic control over 104 weeks and was generally welltolerated with a low risk of hypoglycemia.     

Effects of sitagliptin or mitiglinide as an add-on to acarbose on daily blood glucose fluctuations measured by 72 h subcutaneous continuous glucose monitoring in Japanese patients with type 2 diabetes: a prospective randomized study

Objective: Postprandial hyperglycemia and blood glucose fluctuations increase the risk of macroangiopathy in patients with type 2 diabetes mellitus (T2DM). However, few studies have examined the effects of oral hypoglycemic drugs on blood glucose fluctuations in daily life.

Methods: Twenty-nine T2DM patients treated with acarbose were randomized to receive either sitagliptin (14 patients) or mitiglinide (15 patients) together with acarbose for 4 weeks. Patients were then switched to a combination of 10 mg mitiglinide and 0.2 mg voglibose for 4 weeks. All patients wore a continuous glucose monitoring (CGM) device for 5 – 7 days in week 3 of each treatment period.

Results: The percentage of blood glucose levels in the hyperglycemic range, blood glucose indices derived from 24-h CGM profiles and the glycemic parameters (HbA1c, glycated albumin and fasting plasma glucose) were significantly improved by adding sitagliptin or mitiglinide to ongoing acarbose therapy. These parameters also tended to improve in the mitiglinide/voglibose combination period.

Conclusion: Daily blood glucose fluctuations were significantly improved by adding sitagliptin or mitiglinide to acarbose, and improved after switching to the mitiglinide/voglibose combination. Larger controlled studies are needed to verify the effects of adding sitagliptin or mitiglinide to acarbose on glucose fluctuations.     

Efficacy and safety of teneligliptin add-on to insulin monotherapy in Japanese patients with type 2 diabetes mellitus: a 16-week,randomized, double-blind,placebo-controlled trial with an open-label period

Objective: To assess the efficacy and safety of teneligliptin as add-on to insulin monotherapy in patients with type 2 diabetes mellitus (T2DM).

Research design and methods: In a 16-week, double-blind period, 148 Japanese T2DM patients with inadequate glycemic control with insulin and diet/exercise therapies were randomized to placebo or teneligliptin 20 mg. In a subsequent 36-week, open-label period, all patients received teneligliptin once daily. The primary outcome measure was change in HbA1c at the end of the double-blind period.

Results: The difference between placebo and teneligliptin in change in HbA1c in the double-blind period (least squares mean ± SE) was ?0.80% ± 0.11%; teneligliptin was superior (ANCOVA, P < 0.001). The HbA1c-lowering effect of teneligliptin was maintained throughout the open-label period. The incidence of adverse events was 53.5% with placebo and 44.2% with teneligliptin in the double-blind period, 66.7% in the placebo/teneligliptin group in the open-label period, and 77.9% in the teneligliptin/teneligliptin group over both double-blind/open-label periods. The incidence of hypoglycemic symptoms was 11.1% in the placebo/teneligliptin group in the open-label period and 27.3% in the teneligliptin/teneligliptin group over both double-blind/open-label periods.

Conclusion: Teneligliptin was effective and well tolerated in Japanese T2DM patients with inadequate glycemic control.

Clinical trial registration: NCT02081599     

A randomized,double-blind,placebo-controlled trial evaluating sitagliptin action on insulin resistance parameters and β-cell function

Aim: To evaluate the impact on glycemic control, insulin secretion and on insulin resistance of a sitagliptin + metformin combination compared to metformin monotherapy in type 2 diabetic, naïve to treatment, patients.

Materials and methods: A total of 178 Caucasian type 2 diabetic patients were randomized to take sitagliptin 100 mg once a day or placebo in addition to previously taken metformin, for 12 months. The authors evaluated at 3, 6, 9, and 12 months: body mass index (BMI), glycemic control, fasting plasma insulin (FPI), HOMA-IR, HOMA-β, fasting plasma proinsulin (FPPr), proinsulin/fasting plasma insulin ratio (Pr/FPI ratio), C-peptide, glucagon, retinol binding protein-4 (RBP-4), visfatin, and chemerin. Before and 12 months after the addition of sitagliptin, patients underwent tests to assess insulin sensitivity and insulin secretion.

Results: Sitagliptin + metformin gave a better decrease of glycemic control, HOMA-IR and glucagon levels compared to placebo + metformin; sitagliptin + metformin also better increased HOMA-β and all β-cell measurements recorded after the clamp. Regarding adipocytokines, sitagliptin + metformin better reduced RBP-4, visfatin and chemerin levels, compared to placebo + metformin.

Conclusion: When metformin alone is not enough to reach an adequate glycemic control, sitagliptin can be a valid option, because of its effects in reducing insulin resistance and in preserving β-cell function.     

Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes

ABSTRACT

Objective: The purpose of this study was to evaluate the efficacy and safety of sitagliptin as an add-on to metformin therapy in patients with moderately severe (hemoglobin A_1c ≥?8.0% and ≤?11.0%) type 2 diabetes mellitus (T2DM).

Research design and methods: This was a multi­national, randomized, placebo-controlled, parallel-group, double-blind study conducted in 190 patients with T2DM. After ≥?6?weeks of stable metformin monotherapy (≥?1500?mg/day), patients were randomized to either the addition of sitagliptin 100?mg once daily or placebo to ongoing metformin for 30?weeks.

Main outcome measures: The primary efficacy endpoint was reduction in hemoglobin A_1c (HbA_1c) measured after 18?weeks of sitagliptin treatment. Key secondary end­points included reduction in fasting plasma glucose (FPG) and 2-hour (2-h) postprandial plasma glucose (PPG) at 18 weeks, and HbA_1c at 30 weeks. The proportion of patients meeting the goal of HbA_1c <?7.0% was also analyzed.

Results: Sitagliptin significantly reduced HbA_1c, FPG, and 2-h PPG, compared with placebo (all p < 0.001). The net improvement in HbA_1c was –1.0% at both 18 and 30 weeks, and a significantly greater proportion of patients treated with sitagliptin achieved HbA_1c <?7.0% by the end of the study (22.1% vs. 3.3%, p < 0.001). Sitagliptin was well-tolerated. Compared with placebo, sitagliptin had a neutral effect on body weight and did not signif­icantly increase the risk of hypoglycemia or gastro­intestinal adverse events.

Conclusions: Addition of sitagliptin 100?mg once daily to ongoing metformin therapy was well-tolerated and resulted in significant glycemic improvement in patients with moderately severe T2DM who were treated for 30 weeks.

Trial registration: ClinicalTrials.gov identifier: NCT00337610.     

Incretin mimetics and dipeptidyl peptidase 4 inhibitors in clinical trials for the treatment of type 2 diabetes

Background: Exenatide is an incretin mimetic, while sitagliptin and vildagliptin are incretin enhancers used as adjunctive therapy in patients with type 2 diabetes failing oral agents. Sitagliptin and vildagliptin can also be used as monotherapy in patients with type 2 diabetes uncontrolled by diet. Objective: To provide a critical review of clinical trials of exenatide, sitagliptin and vildagliptin. Method: Review of Phase III clinical trials based on Medline search published up to April 2008. Results: The use of exenatide is associated with reduction in average hemoglobin A1c (HbA1c) levels of approximately 0.8% compared with baseline. The corresponding reduction with either sitagliptin or vildagliptin is 0.7%. The actions of incretin-based drugs predominantly target postprandial hyperglycemia. Treatment-related hypoglycemia is generally mild, and mainly occurs when used with sulfonylureas (SUs). Exenatide treatment leads to a mild weight loss of around 2 kg after 30 weeks, whereas sitagliptin and vildagliptin have generally neutral effect on weight. Sitagliptin and vildagliptin are well tolerated in trials lasting up to 52 weeks. Meanwhile, 5 – 10% of patients cannot tolerate exenatide due to adverse effects, mainly nausea and vomiting. The three drugs are limited by the lack of long-term safety and efficacy data, as well as by their high cost. Conclusion: Exenatide, sitagliptin and vildagliptin are useful add-on therapy for type 2 diabetes that is suboptimally controlled on oral agents, particularly when there is concern about weight gain and hypoglycemia, or when postprandial hyperglycemia is the major cause of inadequate glycemic control. Sitagliptin and vildagliptin may be used as monotherapy in patients who cannot tolerate metformin or SU, and sitagliptin may be used as alternative to metformin in renal insufficiency.     

Comparison of acarbose and metformin therapy in newly diagnosed type 2 diabetic patients with overweight and/or obesity

Objective: To compare the efficacy of acarbose and metformin in overweight and/or obese patients with newly diagnosed type 2 diabetes mellitus (T2DM).

Methods: A total of 108 drug-naïve patients with newly diagnosed T2DM, whose hemoglobin A1c (HbA1c) was between 7% and 10% and body mass index was greater than 24?kg/m², were enrolled in the First People’s Hospital and Municipal Central Hospital of Xiangtan City, Xiangtan, China, from 1 February 2010 to 1 August 2011. Patients were randomly assigned to acarbose (100?mg three times a day) and metformin (1.5?g/day) groups for a predictive follow-up period of 24 weeks. Plasma glucose, insulin, and glucagons at 0, 0.5, and 2?hours after a standardized meal, and HbA1c were measured at baseline and 24 weeks.

Results: Baseline characteristics of the acarbose and metformin groups were similar. Glucose control improved significantly in both groups at 24 weeks. The percentage of patients achieving HbA1C <6.5% was comparable for acarbose and metformin therapy at 24 weeks. Body weight reduction from baseline to 24 weeks was 3.3?kg in the acarbose group and 2.7?kg in the metformin group, whereas the change in HbA1c and body weight was similar in both groups. The early-phase insulin secretion index improved only in the acarbose group at 24 weeks. After 24 weeks of therapy, fasting glucagon and 0.5?hour postprandial glucagon levels decreased markedly in the acarbose group compared to the metformin group.

Conclusions: Twenty-four weeks of therapy with acarbose and metformin induced similar reductions in HbA1c and body weight, but acarbose showed superior efficacy in improving islet α-cell function compared with metformin in overweight/obese patients with newly diagnosed T2DM. However, more large-sample, multicenter, randomized controlled trials are needed to evaluate the efficacy, safety, cost-effectiveness, and glycemic variability of the two drugs.     

西格列汀联合治疗单一口服药治疗效果不佳的2型糖尿病观察

目的：评价联合西格列汀治疗血糖控制不佳的2型糖尿病患者的有效性及安全性。方法：54例单一口服药治疗（二甲双胍16例,磺脲类38例）的2型糖尿病患者,糖化血红蛋白未达标（HbA1c〉6.5%）,联合西格列汀100 mg,po qd治疗24周,比较治疗前后血糖控制情况,不良反应及体质量增加情况。结果：治疗后HbA1c较治疗前降低了0.91%,FPG降低了1.3mmol·L-1,PPG降低了3.8 mmol·L-1,差异均有统计学意义（P〈0.01）。24周发生低血糖1人次,其他不良反应3例。体质指数与治疗前比差异无统计学意义（P〉0.05）。结论：西格列汀联合治疗可明显改善血糖控制,低血糖发生少,不良反应少。     

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

ABSTRACT

Objective: To assess the 54-week efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes and inadequate glycemic control (HbA_1c 7.5–11%) on diet and exercise.

Methods and materials: This was multinational study conducted at 140 clinical sites in 18 countries. Following an initial 24-week, double-blind, placebo-controlled period, patients entered a double-blind continuation period for an additional 30 weeks. Following the week 24 evaluation, patients remained on their previously assigned active, oral treatments: sitagliptin 50?mg b.i.d.?+?metformin 1000?mg b.i.d. (S100?+?M2000), sitagliptin 50?mg b.i.d.?+?metformin 500?mg b.i.d. (S100?+?M1000), metformin 1000?mg b.i.d. (M2000), metformin 500?mg b.i.d. (M1000), and sitagliptin 100?mg q.d. (S100). Patients initially randomized to placebo were switched to M2000 (designated PBO/M2000) at week 24. This report summarizes the overall safety and tolerability data for the 54-week study and presents efficacy results for patients randomized to continuous treatments who entered the 30-week continuation period.

Results: Of the 1091 randomized patients, 906 completed the 24-week placebo-controlled phase and 885 patients continued into the 30-week continuation period (S100?+?M2000 n?=?161, S100+M1000 n?=?160, M2000 n?=?153, M1000 n?=?147, S100 n?=?141, PBO/M2000 n?=?123). At baseline, patients included in the efficacy analysis had mean age of 54 years, mean BMI of 32?kg/m², mean HbA_1c of 8.7% (8.5–8.8% across groups), and mean duration of type 2 diabetes of 4 years. At week 54, in the all-patients-treated analysis of continuing patients, least-squares (LS) mean changes in HbA_1c from baseline were ?1.8% (S100?+?M2000), ?1.4% (S100?+?M1000), ?1.3% (M2000), ?1.0% (M1000), and ?0.8% (S100). The proportions of continuing patients with an HbA_1c?<?7% at week 54 were 67% (S100?+?M2000), 48% (S100?+?M1000), 44% (M2000), 25% (M1000), and 23% (S100). For the patients completing treatment through week 54, LS mean changes in HbA_1c from baseline were ?1.9% (S100?+?M2000), ?1.7% (S100?+?M1000), ?1.6% (M2000), ?1.2% (M1000), and ?1.4% (S100). Glycemic response was generally durable over time across treatments. All treatments improved measures of β-cell function (e.g., HOMA-β, proinsulin/insulin ratio). Mean body weight decreased from baseline in the combination and metformin monotherapy groups and was unchanged from baseline in the sitagliptin monotherapy group. The incidence of hypoglycemia was low (1–3%) across treatment groups. The incidence of gastrointestinal adverse experiences with the co-administration of sitagliptin and metformin was similar to that observed with metformin alone.

Limitations: The patient population evaluated in the 54-week efficacy analysis was a population of patients who entered the continuation period without receiving glycemic rescue therapy in the 24-week placebo-controlled period. Because the baseline HbA_1c inclusion criteria ranged from 7.5 to 11% and the glycemic rescue criterion was an HbA_1c?>?8% after week 24, there was a greater likelihood of glycemic rescue in the monotherapy groups; this led to more missing data in the continuation all-patients-treated population(CAPT) analysis and fewer patients contributing to the completers analysis in the monotherapy groups.

Conclusions: In this study, initial treatment with sitagliptin, metformin, or the combination therapy of sitagliptin and metformin provided substantial and durable glycemic control, improved markers of β-cell function, and was generally well-tolerated over 54 weeks in patients with type 2 diabetes.     

A randomized,double-blind,non-inferiority trial evaluating the efficacy and safety of omarigliptin,a once-weekly DPP-4 inhibitor,or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy

Objective: To evaluate the efficacy and safety of adding the once-weekly DPP-4 inhibitor omarigliptin or the sulfonylurea glimepiride to the treatment regimen of patients with type 2 diabetes (T2DM) and inadequate glycemic control on metformin monotherapy.

Methods: Patients with T2DM and HbA1c ≥6.5% to ≤9.0% while on a stable dose of metformin (≥1500?mg/day) were randomized to omarigliptin 25?mg once-weekly (n?=?376) or glimepiride up to 6?mg once daily (n?=?375) for 54 weeks. The primary hypothesis was that omarigliptin is non-inferior to glimepiride in reducing HbA1c at week 54.

Results: The mean baseline HbA1c was 7.5% in the omarigliptin group and 7.4% in the glimepiride group. After 54 weeks, the least squares (LS) mean change from baseline in HbA1c was –0.30% in the omarigliptin group and –0.48% in the glimepiride group, with a between-group difference (95% CI) of 0.18% (0.06, 0.30), which met the pre-specified criterion for declaring non-inferiority. The incidence of symptomatic hypoglycemia was 5.3% in the omarigliptin group and 26.7% in the glimepiride group. With the exception of hypoglycemia, the incidences of adverse events and discontinuations were similar between treatment groups. Relative to baseline, omarigliptin was associated with a mean weight loss (?0.4?kg) and glimepiride a mean weight gain (+1.5?kg).

Conclusions: After 54 weeks, as add-on therapy to metformin, once-weekly omarigliptin was generally well tolerated and non-inferior to glimepiride in improving glycemic control, with a lower incidence of hypoglycemia and with weight loss vs weight gain.     

Results of VERTIS SU extension study: safety and efficacy of ertugliflozin treatment over 104 weeks compared to glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin

Objective: To assess the safety and efficacy of ertugliflozin over 104?weeks in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin.

Methods: In this double-blind, multicenter, randomized, phase III study (VERTIS SU; NCT01999218), adults with T2DM and glycated hemoglobin (HbA1c) 7.0–9.0% on metformin ≥1500?mg/day received ertugliflozin 5?mg or 15?mg, or glimepiride. The primary efficacy time point was Week 52; double-blinded treatment continued until Week 104.

Results: Baseline characteristics of randomized, treated patients (n?=?1315) were similar across groups (mean age 58.2 years, HbA1c 7.8%); 76.4% completed the study; 61.6% completed on study medication. Mean glimepiride dose at 104?weeks was 3.5?mg/day. At Week 104, least squares mean change from baseline in HbA1c (95% confidence intervals) were ?0.3% (?0.4, ?0.2), ?0.4% (?0.5, ?0.3) and ?0.4% (?0.5, ?0.3) for ertugliflozin 5?mg, 15?mg, and glimepiride, respectively. Ertugliflozin provided sustained reductions in body weight and systolic blood pressure (SBP) over 104?weeks. The incidence of adverse events (AEs) and serious AEs was similar across groups. The incidence of symptomatic hypoglycemia was 3.8%, 6.4% and 22.1% in the ertugliflozin 5?mg, 15?mg, and glimepiride groups, respectively. Genital mycotic infections were reported in 5.3%, 2.6% and 0% of men, respectively, and 9.2%, 12.3% and 1.4% of women, respectively. The incidence of urinary tract infection and hypovolemia AEs was similar across groups.

Conclusions: Ertugliflozin was well tolerated and provided clinically meaningful glycemic control and durable reductions in body weight and SBP over 104?weeks.     

Sitagliptin/metformin fixed-dose combination: in patients with type 2 diabetes mellitus

Sitagliptin/metformin is a single-tablet, fixed-dose combination of the dipeptidyl peptidase-4 inhibitor sitagliptin and the biguanide antihyperglycaemic metformin that achieves greater improvements in glycaemic control than either component alone in patients with type 2 diabetes mellitus. Recommended dosages of sitagliptin plus metformin, either as the fixed-dose tablet or a combination of the individual agents, significantly reduced glycosylated haemoglobin (HbA(1c)) levels in two well designed clinical trials in treatment-naive patients with type 2 diabetes. The improvements in glycaemic control seen with sitagliptin plus metformin therapy after 18 or 24 weeks were greater than those observed with the individual components alone and/or placebo, and sustained over treatment durations of up to 2 years. As add-on therapy in treatment-experienced patients with inadequate glycaemic control, the HbA(1c)-lowering efficacy of sitagliptin plus metformin was noninferior to that of glimepiride plus metformin in a 30-week, double-blind trial. Sitagliptin plus metformin and glipizide plus metformin lowered HbA(1c) levels by generally similar magnitudes, with the noninferiority of sitagliptin plus metformin to glipizide plus metformin being established in one 52-week study. As part of triple combination therapy, also in treatment-experienced patients with inadequate glycaemic control, sitagliptin added to ongoing glimepiride with or without metformin or ongoing insulin with or without metformin significantly improved glycaemic control over 24 weeks. Sitagliptin plus metformin, as the fixed-dose tablet or a combination of the individual agents, was generally well tolerated in patients with type 2 diabetes, and was associated with a low risk of hypoglycaemia.     

Fixed-dose combination therapy for type 2 diabetes: sitagliptin plus pioglitazone

Importance of the field: Type 2 diabetes is typically associated with insulin resistance and dysfunction of insulin-secreting pancreatic beta-cells. Addressing these defects often requires therapy with a combination of differently acting antidiabetic agents. A potential novel combination in development brings together the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin with the thiazolidinedione pioglitazone into a fixed-dose single-tablet combination. The former component acts mainly to increase prandial insulin secretion; the latter improves insulin sensitivity.

Areas covered in this review: To date, clinical trials conducted in type 2 diabetes patients have used combinations of sitagliptin (100 mg/day) and pioglitazone (30 – 45 mg/day) as separate tablets. These trials have shown that the combinations offer additive efficacy in reducing blood glucose when given as initial antidiabetic therapy and as add-on therapy when pioglitazone alone fails to maintain glycemic control.

What the reader will gain: Initial therapy with a combination of sitagliptin (100 mg/day) and pioglitazone (30 mg/day) reduced HbA1c by > 2% starting from a baseline > 9%. Adding sitagliptin (50 – 100 mg/day) to patients inadequately controlled on pioglitazone reduced HbA1c by 0.7 – 1.4% from a baseline of 8 – 8.5%. The combination did not increase the risk of hypoglycemia and produced similar or slightly more weight gain than pioglitazone alone when introduced as initial antidiabetic therapy.

Take home message: The combination of sitagliptin and pioglitazone was well tolerated in these trials, and would appear to be suited to a fixed-dose single-tablet combination for once-daily administration.     

Factors that influence the efficacy of acarbose and metformin as initial therapy in Chinese patients with newly diagnosed type 2 diabetes: a subanalysis of the MARCH trial

Objective To conduct a subanalysis of the randomized MARCH (Metformin and AcaRbose in Chinese as the initial Hypoglycemic treatment) trial to investigate whether specific characteristics are associated with the efficacy of either acarbose or metformin as initial therapy.

Research design and methods A total of 657 type 2 diabetes patients who were randomly assigned to 48 weeks of therapy with either acarbose or metformin in the MARCH trial were divided into two groups based upon their hemoglobin A1c (HbA1c) levels at the end of follow-up: HbA1c?<7% (<53?mmol/mol) and ≥7% (≥53?mmol/mol). Univariate, multivariate, and stepwise linear regression analyses were applied to identify the factors associated with treatment efficacy.

Main outcome measures Because this was a subanalysis, no measurement was performed.

Results Univariate analysis showed that the efficacy of acarbose and metformin was influenced by HbA1c, fasting blood glucose (FBG), and 2 hour postprandial venous blood glucose (2hPPG) levels, as well as by changes in body mass index (BMI) (p?≤?0.006). Multivariate analysis and stepwise linear regression analyses indicated that lower baseline 2hPPG values and greater changes in BMI were factors that positively influenced efficacy in both treatment groups (p?≤?0.05). Stepwise regression model analysis also revealed that a lower baseline homeostasis model assessment-estimated insulin resistance (HOMA-IR) and higher serum insulin area under the curve (AUC) were factors positively influencing HbA1c normalization in all patients (p?≤?0.032).

Conclusions Newly diagnosed type 2 diabetes patients with lower baseline 2hPPG and HOMA-IR values are more likely to achieve glucose control with acarbose or metformin treatment. Furthermore, the change in BMI after acarbose or metformin treatment is also a factor influencing HbA1c normalization. A prospective study with a larger sample size is necessary to confirm our results as well as measure β cell function and examine the influence of the patients’ dietary habits.     

Sitagliptin

Sitagliptin, an oral dipeptidyl peptidase-4 (DPP-4) inhibitor, improves glycaemic control by inhibiting DPP-4 inactivation of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. This increases active incretin and insulin levels, and decreases glucagon levels and post-glucose-load glucose excursion. In large, well designed phase III trials in patients with type 2 diabetes mellitus, sitagliptin 100 or 200mg once daily alone or in combination with other antihyperglycaemics was associated with significant improvements relative to placebo in overall glycaemic control and indices for insulin response and beta-cell function. Improvements from baseline in mean glycosylated haemoglobin (HbA(1c)) were significantly greater with sitagliptin monotherapy than with placebo in patients with type 2 diabetes. As add-on therapy in patients with suboptimal glycaemic control despite oral antihyperglycaemic treatment, sitagliptin improved HbA(1c) to a significantly greater extent than placebo when added to metformin or pioglitazone and was noninferior to glipizide when added to metformin. Sitagliptin was well tolerated when administered alone or in combination with other antihyperglycaemics, with an adverse event profile similar to that shown with placebo. The incidence of hypoglycaemia with sitagliptin was similar to that with placebo and, in combination with metformin, lower than that with glipizide. Sitagliptin had a generally neutral effect on bodyweight.     

Real-world evaluation of glycemic control among patients with type 2 diabetes mellitus treated with canagliflozin versus dipeptidyl peptidase-4 inhibitors

Objective To evaluate glycemic control among patients with type 2 diabetes mellitus (T2DM) treated with canagliflozin (CANA) vs. dipeptidyl peptidase-4 (DPP-4) inhibitors.

Methods Using integrated claims and lab data from a US health plan of commercial and Medicare Advantage enrollees, this matched-control cohort study assessed adult T2DM patients receiving treatment with CANA or DPP-4 inhibitors (1 April 2013–31 December 2013). Cohorts were chosen hierarchically; the first pharmacy claim for CANA was identified as the index date; then the first pharmacy claim for a DPP-4 inhibitor was identified and index date set. Eligible patients had 6 months of continuous health plan enrollment before the index date (baseline) and 9 months after (follow-up) and no evidence of index drug in baseline. Patients were matched 1:1 using propensity score matching. Changes in glycated hemoglobin (HbA1c) and percentages of patients with HbA1c <8% and <7% during the follow-up were evaluated.

Results The matched CANA and DPP-4 inhibitor cohorts (53.2% treated with sitagliptin) included 2766 patients each (mean age: 55.7 years). Among patients with baseline and follow-up HbA1c results, mean baseline HbA1c values were similar, 8.62% and 8.57% (p?=?0.615) for the CANA (n?=?729) and DPP-4 inhibitor (n?=?710) cohorts, respectively. Change in HbA1c was greater among patients in the CANA cohort than for those in the DPP-4 inhibitor cohort (?0.92% vs. ?0.63%, p?<?0.001), and also among the subset of patients with baseline HbA1c ≥7% (-1.07% [n?=?624] vs. ?0.79% [n?=?603], p?=?0.004). During follow-up, greater percentages of the CANA cohort relative to the DPP-4 inhibitor cohort achieved HbA1c of <8% (66.0% vs. 58.6%, p?=?0.004) and <7% (35.4% vs. 29.9%, p?=?0.022).

Limitations This study was observational and residual confounding remains a possibility.

Conclusions In this real-world study of patients with T2DM, CANA use was associated with greater HbA1c reduction and higher percentages of patients attaining HbA1c goals than those treated with DPP-4 inhibitors.