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.     

A randomized clinical trial of the safety and efficacy of sitagliptin in patients with type 2 diabetes mellitus inadequately controlled by acarbose alone

Objective: To evaluate the safety and efficacy of sitagliptin when added to the treatment of patients with type 2 diabetes mellitus (T2DM) and inadequate glycemic control on acarbose monotherapy.

Research design and methods: This was a multicenter, randomized, placebo-controlled, double-blind clinical trial. Patients (N?=?381) with T2DM and inadequate glycemic control (glycated hemoglobin [HbA1c] ≥?7.0% and ≤10.0%) on acarbose monotherapy (at least 50?mg three times daily) were randomized in a 1:1 ratio to receive the addition of sitagliptin 100?mg or matching placebo once daily for 24 weeks.

Main outcome measures: Changes from baseline in HbA1c and fasting plasma glucose (FPG) at Week 24.

Results: The mean baseline HbA1c in randomized patients was 8.1%. At Week 24, the placebo-controlled, least squares mean changes from baseline (95% confidence interval) in HbA1c and FPG in the sitagliptin group were ?0.62% and ?0.8?mmol/L (p?p?Conclusions: Sitagliptin was generally well tolerated and provided statistically superior and clinically meaningful improvements in glycemic control after 24 weeks of treatment compared to placebo when added to treatment of patients with inadequate glycemic control on acarbose monotherapy.

Clinicaltrials.gov: NCT01177384.     

Efficacy and tolerability of initial combination therapy with nateglinide and metformin in treatment-naïve patients with type 2 diabetes

SUMMARY

Objective: To assess the efficacy and tolerability of the combination of nateglinide (120?mg, ac) and metformin (500?mg, tid) as initial treatment in drug-naïve patients with type 2 diabetes mellitus (T2DM).

Research design and methods: This study reports data from the treatment-naïve (TN) subgroup of patients in a previously published, randomized, multicenter, placebo-controlled, 24-week trial that compared nateglinide, metformin, and the combination therapy (CT) in 701 patients with T2DM with baseline HbA_1c between 6.8% and 11.0%. Of the 401 TN patients, 104, 104, 89, and 104 patients received nateglinide (120?mg, ac), metformin (500?mg, tid), CT, and placebo, respectively. The baseline characteristics of each group were similar, with mean age, BMI, duration of diabetes, HbA_1c, and fasting plasma glucose (FPG) levels of approximately 58 years, 30?kg/m², 4 years, 8.2%, and 10.2?mmol/L, respectively.

Results: In patients receiving initial CT, HbA_1c decreased substantially (? = –1.6 ± 0.1%, p < 0.0001 vs. baseline or placebo) from a mean baseline of 8.2 ± 0.1%, an effect significantly greater than the 0.8% reduction observed with both monotherapies (?p < 0.001); whereas, in placebo-treated patients, HbA_1c increased modestly (? = +0.3 ± 0.1%, p < 0.05) from an identical baseline value. Seventy percent of CT-treated patients achieved a target HbA_1c of < 7.0%. Both fasting plasma glucose (FPG) and the 2-hour postprandial glucose excursion (PPGE) after a liquid meal challenge decreased by 2.3?mmol/L in patients receiving CT, while the changes from baseline values in FPG and PPGE were +0.2 ± 0.3?mmol/L and –0.5 ± 0.2?mmol/L, respectively, in placebo-treated patients. The incremental 30-minute post-load insulin levels increased by 88 ± 32?pmol/L (?p = 0.006) in patients receiving CT and did not change significantly in placebo-treated patients. Gastrointestinal side effects occurred in 27% of patients receiving CT (vs. 27.9% in the metformin monotherapy, and 14.4% in the placebo groups). Confirmed hypoglycemia (glucose ≤ 2.8?mmol/L) occurred in 3.4% of patients receiving CT.

Conclusions: Initial CT with the rapid-acting insulinotropic agent, nateglinide, and metformin, an agent with insulin-sensitizing effects in the liver and periphery, is a safe and effective means of achieving glycemic targets in TN patients with T2DM.     

Effectiveness and safety of vildagliptin and vildagliptin add-on to metformin in real-world settings in Egypt – results from the GUARD study

Objective: The GUARD study evaluated the effectiveness, safety, and tolerability of vildagliptin treatment with or without metformin in patients with type 2 diabetes mellitus (T2DM) in real-life settings. Here we present the results of the GUARD study for the patient subset from Egypt.

Research design and methods: This was a 24?±?6 weeks, prospective, non-interventional study that enrolled adult patients with T2DM receiving vildagliptin or vildagliptin?+?metformin combination therapy as per local prescribing information.

Main outcome measures: The primary effectiveness endpoint was change in HbA1c levels from baseline to week 24?±?6 endpoint. Safety was assessed by reporting of adverse events and serious adverse events (SAEs).

Results: Of 2786 patients enrolled from Egypt, 655 received vildagliptin and 2131 received vildagliptin?+?metformin. Overall, at baseline, mean (± standard deviation [SD]) age was 49.5?±?9.49 years, BMI was 31.5?±?4.85?kg/m², HbA1c was 8.4?±?0.86%, and duration of T2DM was 2.3?±?3.78 years. At week 24, significant reductions in mean (±SD) HbA1c were observed in the vildagliptin (?1.47?±?0.79%) and vildagliptin?+?metformin (?1.62?±?0.82%) groups (both p?Conclusion: In a real-world setting, vildagliptin, with or without metformin, resulted in significant reductions in HbA1c and was well tolerated in patients with T2DM from Egypt. Limitations of the study include non-randomization and the open-label, observational nature of the study.     

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     

Consequences of delaying treatment intensification in type 2 diabetes: evidence from a UK database

Objective: Type 2 diabetes mellitus (TD2M) treatment focuses on achieving glycemic control, with HbA1c targeted at 6.5–7.5%. Clinicians commonly delay treatment intensification despite patients failing glycemic targets. This study evaluated longitudinal clinical and cost outcomes in patients failing metformin monotherapy using electronic medical records. Research design and methods: Adults with incident T2DM were identified in the UK Clinical Practice Research Datalink (CPRD) from 1 January 2000 to 31 March 2014. Patients were initiated on metformin monotherapy but had not reached target (HbA1c <7%). Patients were grouped by time to intensification of second-line therapy from first recorded HbA1c ≥7%: Group A, rapid intensification within 365 days; Group B, delayed intensification days 366–1824; Group C, never intensified. Patients were followed from day 366 for 5 years until end of study, switch to insulin, migration or death. Main outcome measures: The study evaluated baseline clinical and medication characteristics which were re-evaluated each year, including HbA1c, weight, cholesterol and concomitant prescribing. Results: A total of 6710 patients were included (Group A 2647, Group B 2452, Group C 1611). Group A achieved a significant decline in HbA1c at 1 year post-index date compared to Groups B and C (?1.13% Group A; +0.26% Group B, +0.16% Group C). A significantly higher proportion of patients achieved HbA1c target?<?7% in Group A (Group A [45.8%]; Group B [19.1%], p?<?0.0001). Using an adjusted hazard model, Group A was found to achieve the HbA1c target from the index date significantly faster than Group B (hazard ratio 3.25 [95% CI 2.87–3.69]). The most commonly prescribed second-line medications were sulfonylureas in Groups A and B throughout observation and were associated with significant weight gain (+1.3?kg per patient) in the adjusted models. Conclusions: Patients who were rapidly intensified achieved a maintained reduction in HbA1c faster than those with delayed intensification or no second-line therapy, despite a higher baseline HbA1c.     

Evaluating the costs of glycemic response with canagliflozin versus dapagliflozin and empagliflozin as add-on to metformin in patients with type 2 diabetes mellitus in the United Arab Emirates

Objective: This study evaluates the cost of achieving glycemic control with three sodium glucose co-transporter 2 (SGLT2) inhibitors, canagliflozin, dapagliflozin, and empagliflozin, in patients with type 2 diabetes mellitus (T2DM) from the payer perspective in the United Arab Emirates (UAE).

Methods: A systematic literature review identified randomized controlled trials of antihyperglycemic agents as add-on to metformin in patients with T2DM of 26?±?4 weeks in duration, published by 10 September 2014. A Bayesian network-meta analysis (NMA) compared HbA1c changes with canagliflozin 100 and 300?mg versus dapagliflozin 10?mg and empagliflozin 10 and 25?mg. The cost associated with a 1% placebo-adjusted HbA1c reduction with each SGLT2 inhibitor as add-on to metformin was calculated based on NMA results and UAE drug costs.

Results: In the NMA, canagliflozin 100 and 300?mg were associated with HbA1c reductions (?0.67% and ?0.79%) compared with dapagliflozin 10?mg (?0.41%) and empagliflozin 10 and 25?mg (?0.57% and ?0.64%). Probabilities of canagliflozin 100?mg performing better were 79%, 60%, and 53% versus dapagliflozin 10?mg and empagliflozin 10 and 25?mg, respectively; probabilities for canagliflozin 300?mg performing better were 88%, 72%, and 65%, respectively. The cost per 1%-point reduction in HbA1c was projected to be lower with canagliflozin 100 and 300?mg ($448 and $422) compared with dapagliflozin 10?mg ($785) and empagliflozin 10 and 25?mg ($527 and $563).

Conclusions: Canagliflozin may provide a greater glycemic response at a lower effective cost than dapagliflozin or empagliflozin for patients with T2DM inadequately controlled with metformin from the payer perspective in the UAE.     

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.     

Longer-term safety and tolerability of canagliflozin in patients with type 2 diabetes: a pooled analysis

Objective: To evaluate the longer-term safety of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes mellitus (T2DM).

Methods: The safety/tolerability of canagliflozin 100 and 300?mg were assessed using data pooled from seven placebo- and active-controlled studies of 52–104 weeks in duration that enrolled a broad range of patients with T2DM (N?=?5598). Canagliflozin 100 and 300?mg as monotherapy or in combination with various background antihyperglycemic agents (AHAs) were compared with pooled non-canagliflozin treatments (i.e. placebo, sitagliptin, glimepiride). Safety was assessed based on adverse event (AE) reports, including the incidence of AEs related to the mechanism of SGLT2 inhibition.

Results: Overall AE incidence was similar with canagliflozin 100 and 300?mg and non-canagliflozin (73.7%, 74.5%, and 73.7%). The incidence of AE-related discontinuations and serious AEs was low and balanced across groups. The incidence of male and female genital mycotic infections, urinary tract infections, and AEs related to osmotic diuresis or volume depletion was higher with canagliflozin versus non-canagliflozin; these AEs generally occurred early with decreased incidence over time and incidence was similar across baseline HbA1c subgroups. The incidence of fractures and diabetic ketoacidosis was low and similar across groups. Canagliflozin was associated with a low incidence of hypoglycemia when used with background AHAs that are not associated with hypoglycemia; the incidence was higher among patients on background AHAs associated with hypoglycemia (i.e. insulin, sulfonylurea, glinide).

Limitations: Limitations of this analysis include its post hoc nature. While this analysis included a broad population of patients, including those with a history or risk of cardiovascular disease or chronic kidney disease, the longer-term safety in these patient populations was not specifically evaluated. Ongoing outcome studies will provide data on the long-term safety of canagliflozin in these populations.

Conclusions: Longer-term exposure to canagliflozin as monotherapy or in combination with other agents was generally well tolerated in patients with T2DM.

Trial registration: ClinicalTrials.gov identifiers: NCT01106625, NCT01081834, NCT01106677, NCT00968812, NCT01106651, NCT01106690, NCT01137812.     

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.     

Efficacy and safety of ertugliflozin across racial groups in patients with type 2 diabetes mellitus

Abstract

Objective: To assess the efficacy and safety of the sodium–glucose cotransporter 2 inhibitor ertugliflozin across racial groups in patients with type 2 diabetes mellitus (T2DM).

Methods: Pooled analysis of data from randomized, double-blind studies in the ertugliflozin phase III development program. Seven placebo- and comparator-controlled studies were used to assess safety (N?=?4859) and three placebo-controlled studies were used to assess efficacy (N?=?1544). Least-squares (LS) mean change from baseline was calculated for glycated hemoglobin (HbA1c), body weight and systolic blood pressure (SBP). Safety evaluation included overall and prespecified adverse events (AEs).

Results: At Week 26, ertugliflozin provided a greater reduction in HbA1c, body weight and SBP versus placebo in all racial subgroups. The placebo-adjusted LS mean change (95% confidence interval) from baseline in HbA1c was ?0.8% (?1.0, ?0.7) and ?1.0% (?1.1, ?0.8) with ertugliflozin 5?mg and 15?mg, respectively, in the White subgroup, ?0.7% (?1.2, ?0.2) and ?0.8% (?1.3, ?0.3) in the Black subgroup, and ?0.8% (?1.1, ?0.5) and ?1.0% (?1.3, ?0.8) in the Asian subgroup. The incidences of overall AEs, serious AEs and AEs leading to discontinuation from study medication were similar between the ertugliflozin 5?mg, 15?mg and non-ertugliflozin groups within each racial subgroup. The incidence of female genital mycotic infection (GMI) was higher with ertugliflozin than non-ertugliflozin across all racial subgroups. The incidence of male GMI was higher with ertugliflozin than non-ertugliflozin in the White sub-group; however, there were few male GMI events in the non-White subgroups.

Conclusions: In patients with T2DM, treatment with ertugliflozin improved HbA1c, body weight and SBP across all racial subgroups. Ertugliflozin had a generally similar safety profile across racial subgroups and was generally well tolerated.

Clinicaltrials.gov identifiers: NCT01986855, NCT01999218, NCT01958671, NCT02099110, NCT02036515, NCT02033889, and NCT02226003.     

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.     

Network meta-analysis of liraglutide versus dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes in Japanese patients

Aims: To determine the comparative efficacy and safety of liraglutide and dipeptidyl peptidase-4 (DPP-4) inhibitors as antidiabetics for Japanese patients with uncontrolled type 2 diabetes (T2DM).

Methods and materials: We searched for randomized controlled trials (RCTs) evaluating outcomes among Japanese adults with uncontrolled T2DM and including liraglutide or DPP-4 inhibitors up to August 2016. We extracted data on trial and patient characteristics, and the following outcomes: HbA1c, weight, patients meeting HbA1c <7%, patients experiencing hypoglycemic events, microalbuminuria, estimated glomerular filtration rate (eGFR) and creatinine. We synthesized data using network meta-analyses (NMA) using a Bayesian framework. Continuous outcomes were modeled using normal likelihoods and an identity link, while dichotomous outcomes were modeled using a binomial likelihood and a logit link.

Results: The systematic literature review yielded 39 publications pertaining to 38 trials. A total of 27 trials (5032 patients) reported change in HbA1c at 12 weeks and at 24 weeks 9 trials (2091 patients). All treatments showed statistically significant reductions in HbA1c relative to placebo at 12 and 24 weeks. Liraglutide 0.9?mg was statistically superior to all DPP-4 interventions (vildagliptin, sitagliptin, linagliptin, alogliptin, teneligliptin, trelagliptin and omarigliptin) at 12 weeks and 24 weeks among those reporting. Treatments were not statistically differentiable with respect to weight change and risk of hypoglycemia. Finally, no comparisons of eGFR and microalbuminuria were conducted, as this data was reported in too few trials to conduct analyses.

Limitations: Some important outcomes were limited by poor reporting (eGFR and microalbuminuria) or low event rates (hypoglycemia). The follow-up time was relatively short. Clinically, the 24 week time point is more important as it demonstrates more sustained results.

Conclusions: Our research suggests that liraglutide 0.9?mg offers a more efficacious treatment option for T2DM than the DPP-4 inhibitors among adult Japanese patients and that it is a viable option for this population.     

The effect of vildagliptin relative to sulfonylurea as dual therapy with metformin (or as monotherapy) in Muslim patients with type 2 diabetes fasting during Ramadan in the Middle East: the VIRTUE study

Objective: To assess the effect of vildagliptin relative to sulfonylurea (SU) on hypoglycemic events, in Muslim patients from the Middle East with type 2 diabetes who fast during Ramadan. The primary endpoint was the proportion of patients with at least one hypoglycemic event (HE) during the fasting period. Secondary endpoints included change in weight, HbA1c levels, treatment adherence and overall safety.

Design and methods: This multicenter, prospective, observational cohort study enrolled Muslim adult T2DM patients from Middle Eastern countries who received treatment with vildagliptin or SU as add on to metformin or monotherapy. During a ～16 week observation period, data was collected up to 6 weeks before and 6 weeks after Ramadan fasting.

Results: A total of 584 patients from the Middle East enrolled in the study; 308 patients received vildagliptin and 265 received SU. Significantly fewer vildagliptin patients reported at least one HE (3.7% vildagliptin vs. 25.5% SU; p?p?=?.128). Mean change in HbA1c at the end of study showed ?0.18% between treatment difference in favor of vildagliptin, p?=?.001. Mean body weight change at the end of study showed ?0.68?kg between treatment difference in favor of vildagliptin, p?Limitations: Being observational and not mandating HE confirmation with blood glucose measurement (though it was done in a large number of patients) were key limitations.

Conclusion: Anti-hyperglycemic treatment with vildagliptin led to significantly fewer hypoglycemia events compared to sulfonylurea treatment among Muslim diabetic patients who fast during Ramadan. Good glycemic control, weight control and safety results supported this outcome.     

二甲双胍血糖控制不佳的2型糖尿病患者联合应用沙格列汀或吡格列酮疗效观察

目的 探讨二甲双胍血糖控制不佳的2型糖尿病患者联合沙格列汀或吡格列酮的疗效。方法 选择2015年1月至2016年1月安徽医科大第二附属医院内分泌门诊符合入选条件的2型糖尿病患者70例,随机被分为两组,观察组35例采用沙格列汀+二甲双胍治疗,对照组35例患者采用吡格列酮+二甲双胍治疗,观察两组治疗前后的空腹血糖（FPG）、餐后2 h血糖（2 hPG）、糖化血红蛋白（HbA1c）、空腹血清胰岛素水平、胰岛素抵抗指数（HOMA-IR）、体质指数（BMI）等。结果 与治疗前比较,治疗16周后观察组、对照组患者的FPG、餐后 2 hPG与HbA1c明显降低,HOMA-IR改善,差异有统计学意义（P<0.05）;但两组间差异无统计学意义（P>0.05）。与治疗前比较,治疗16周后观察组BMI无明显变化,差异无统计学意义（P>0.05）,对照组患者BMI明显上升,差异有统计学意义（P<0.05）,两组间差异有统计学意义（P<0.05）。结论 沙格列汀或吡格列酮联合二甲双胍可有效控制2型糖尿病患者血糖、改善胰岛素敏感性,沙格列汀不增加体质量且不良反应小,联合二甲双胍治疗是一种安全可靠的治疗方法。     

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.     

Initial combination therapy with vildagliptin plus metformin in drug-naïve patients with T2DM: a 24-week real-life study from Asia

Aims: To assess the effectiveness and safety of vildagliptin/metformin initial combination therapy in drug-naïve patients with type 2 diabetes mellitus (T2DM).

Methods: INITIAL was a 24-week prospective, observational study in T2DM patients with glycated hemoglobin (HbA1c)?≥?7.5%, and prescribed vildagliptin/metformin as initial combination therapy. The primary endpoint was change in HbA1c from baseline to week 24. Key secondary endpoints were HbA1c change from baseline to week 12, proportion of patients achieving HbA1c ≤7.0%, change in body weight at 12 and 24 weeks, change in HbA1c by sub-groups (baseline HbA1c, age, body mass index [BMI], dosage strength, co-morbidities) from baseline to week 24, and safety.

Results: A total of 532 patients were enrolled. The mean age, HbA1c, and BMI were 49.6?±?11.27 years, 9.3?±?1.57%, and 26.7?±?4.50?kg/m², respectively. Cardiovascular risk factors present at baseline were dyslipidemia (30.1%), hypertension (29.7%), and obesity (20.9%). The mean reductions in HbA1c from baseline to week 12 (?1.6?±?1.59%) and 24 (?1.9?±?1.70%) were statistically significant (p?Conclusions: Overall, in a relatively young drug-naïve T2DM Asian study population with high baseline HbA1c and often associated with cardiovascular risk factors, vildagliptin/metformin combination therapy was associated with significant and clinically relevant HbA1c reduction from baseline. This effect was seen at week 12, was maintained over 24 weeks, and was accompanied by good tolerability.     

Efficacy and safety of alogliptin added to insulin in Japanese patients with type 2 diabetes: a randomized,double-blind, 12-week,placebo-controlled trial followed by an open-label,long-term extension phase

Objective: To evaluate the efficacy and safety of alogliptin added to insulin in Japanese patients with type 2 diabetes mellitus (T2DM) who are poorly controlled with insulin and diet or exercise.

Study design: This was a randomized, double-blind, 12-week comparative trial of alogliptin and insulin versus placebo and insulin in 179 patients with T2DM followed by a 40-week, open-label phase in 169 patients on alogliptin and insulin.

Primary outcome measure: Change in glycated hemoglobin (HbA1c) from baseline to the end of double-blind phase (week 12).

Results: The change in HbA1c (least squares means) from baseline to week 12 was ?0.96% for the alogliptin and insulin group and ?0.29% for the placebo and insulin group. The point estimate (95% confidence interval) intergroup difference was ?0.66% ([?0.824%, ?0.503%]). In the alogliptin and insulin group, HbA1c started to decrease from week 2 onward and peaked by week 12. The proportions of patients who achieved HbA1c < 8.0, < 7.0 and < 6.0% at week 12 were significantly higher in alogliptin and insulin group (73.0, 23.3 and 1.1%) than in placebo and insulin group (25.0, 5.7 and 0%). Incidences of adverse effects were comparable between groups, with no relevant increases in hypoglycemia or weight gain seen.

Conclusions: Alogliptin 25 mg/day was effective and well tolerated when added to insulin in Japanese patients with inadequately controlled T2DM.     

Effects of vildagliptin versus saxagliptin on daily acute glucose fluctuations in Chinese patients with T2DM inadequately controlled with a combination of metformin and sulfonylurea

Objective The present study aimed to compare the effects of the dipeptidyl peptidase-4 (DPP-4) inhibitors vildagliptin and saxagliptin on 24?hour acute glucose fluctuations in Chinese patients with type 2 diabetes mellitus (T2DM) inadequately controlled with a combination of metformin and sulfonylurea.

Research design and methods This was a 24 week, prospective, randomized, open-label, active-controlled study. Patients (N?=?73) with T2DM who had inadequate glycemic control (HbA1c 7.0%–10.0%) with a stable dosage of metformin plus gliclazide for more than 3 months were randomized to receive either vildagliptin 50?mg twice daily (BID, n?=?37) or saxagliptin 5?mg once daily (QD, n?=?36). Change in mean amplitude of glycemic excursions (MAGE) was assessed at the end of 24 weeks.

Results At baseline, the mean (±SD) age was 62.9?±?6.55 years, disease duration was 7.0?±?2.33 years, and HbA1c was 8.4?±?0.68%. After 24 weeks of treatment, the MAGE decreased from 5.81?±?1.16?mmol/L to 4.06?±?0.86?mmol/L (p<0.001) in the vildagliptin group and from 5.66?±?1.14?mmol/L to 4.79?±?1.25?mmol/L (p?=?0.003) in the saxagliptin group. The mean change in MAGE in the vildagliptin group was significantly greater than that in the saxagliptin group (1.74?±?0.48?mmol/L vs. 0.87?±?0.40?mmol/L, p<0.001). The mean change in HbA1c, from baseline to the study endpoint, in the vildagliptin and saxagliptin groups, was 1.22?±?0.40% and 1.07?±?0.36%, respectively, with no significant difference between the groups (p?=?0.091). The overall safety and tolerability of vildagliptin and saxagliptin were similar. The limitations of the study were a small number of patients and open-label administration of the study drug.

Conclusion Vildagliptin produced a significantly greater reduction in acute glucose fluctuations compared with saxagliptin when added to a dual combination of metformin and sulfonylurea in Chinese patients with T2DM.

Chinese clinical trial registration number ChiCTR-TRC-13003858.     

Long-term safety and effectiveness of biosimilar insulin glargine in Japanese patients with diabetes mellitus in routine clinical practice: results of a post-marketing safety study

Abstract

Objective: To evaluate the long-term safety and effectiveness of biosimilar insulin glargine (GLY) in real-world clinical practice.

Methods: This prospective, non-interventional, multicenter, observational, post-marketing safety study (PMSS) enrolled Japanese patients with type 1 or 2 diabetes mellitus (T1DM or T2DM) starting GLY therapy, and was required by Japanese Pharmaceutical Affairs Law mandating post-marketing safety surveillance to acquire safety and effectiveness data of biosimilar products. Data collected from the 12-month observation included patient characteristics, adverse events, and blood glucose control.

Results: The study enrolled 141 patients with T1DM and 1104 patients with T2DM. Pre-study insulin was used by 94.1% of patients with T1DM and 75.0% with T2DM. 65.4% of patients with T1DM and 64.3% with T2DM switched from the reference product (GLY-switched), while 25.0% with T2DM were insulin-naive. Adverse events were reported by 5.7% and 8.5% in T1DM and T2DM, respectively. Similar incidences were reported in GLY-switched. Adverse events were reported by 10.7% in insulin-naive T2DM. Baseline mean hypoglycemic events/month were 1.8 and 0.1 in T1DM and T2DM, respectively: the mean change from baseline (CFB) was –1.2 (p?=?.066) and 0.0 (p?=?.915), respectively. Baseline mean HbA1c was 8.4% and 8.7% in T1DM and T2DM, respectively; the mean CFB was –0.5% (p?<?.001) and –0.9% (p?<?.001), respectively, and –1.5% (p?<?.001) in insulin-naive T2DM.

Conclusions: This first long-term Japanese PMSS of GLY demonstrated adverse events, hypoglycemia, and glycemic control consistent with the known GLY profile for T1DM and T2DM patients, in routine clinical practice.