Efficacy and safety of therapy with metformin plus pioglitazone in the treatment of patients with type 2 diabetes: a double-blind,placebo-controlled,clinical trial

ABSTRACT

Objective: To assess the efficacy and safety of combination therapy with pioglitazone and metformin in Japanese patients with type 2 diabetes.

Research design and methods: During a 12-week observation period 236 patients were treated with metformin 500 or 750?mg/day. 169 patients with a confirmed HbA_1c level ≥ 6.5% were randomized (stratified according to metformin dosage) to receive pioglitazone 15?mg/day for 12 weeks then increased to 30?mg/day for a further 16 weeks (n?=?83), or placebo (n?=?86). Outcome measures included HbA_1c, fasting blood glucose (FBG), percentage of patients achieving HbA_1c?<?6.5%, lipid profile, and other metabolic parameters.

Results: Mean HbA_1c was reduced by 0.67% in patients receiving pioglitazone plus metformin versus an increase of 0.25% in those receiving metformin alone (p?<?0.0001). After 8 weeks’ treatment and until the end of the study, HbA_1c was significantly lower with pioglitazone plus metformin and more patients in this group achieved an HbA_1c?<?6.5% (38.6% vs. 8.1%; p?<?0.0001). FBG was also reduced by a significantly greater amount in patients receiving pioglitazone plus metformin compared with metformin monotherapy (?20.5 vs. 1.9?mg/dl; p?<?0.0001). Combination therapy was associated with significantly increased HDL-cholesterol, total cholesterol, and adiponectin, and significantly decreased levels of fasting insulin, free fatty acids, and homeostasis model assessment insulin resistance (HOMA-R) compared with metformin monotherapy. Overall, combination therapy and monotherapy were equally well tolerated and the incidence of adverse effects ‘possibly’ related to therapy was 15.7% and 11.6% (p?=?0.505), respectively. Edema occurred slightly more often in the combination group (6.0 vs. 1.2%).

Conclusion: Pioglitazone plus metformin significantly improved glycemic control (HbA_1c and FBG), and markers associated with increased insulin resistance and cardiovascular risk compared with metformin monotherapy.

Clinical trial registration number: UMIN 000001110.     

Achieving glycemic goal with initial versus sequential combination therapy using metformin and pioglitazone in type 2 diabetes mellitus

Abstract

Objective:

To compare glycemic goal achievement (HbA_1c?<?7%) in type 2 diabetes patients receiving initial metformin plus pioglitazone combination therapy and initial metformin monotherapy augmented with pioglitazone in a cohort follow-up study.     

Glycemic control and treatment failure with pioglitazone versus glibenclamide in type 2 diabetes mellitus: a 42-month,open-label,observational, primary care study

ABSTRACT

Background: Insulin resistance and declining β-cell function are the core defects in type2 diabetes mellitus. It has been suggestedthat deteriorating glycemic control is relatedto baseline hemoglobin A_1c (HbA_1c) values andremaining β-cell function.

Patients and methods: We report glycemic data from a 3.5‐year, open-label, observational, primary care study comparing 30?mg/day pioglitazone with 3.5?mg/day glibenclamide add-on to stable metformin monotherapy in 500 patients with type 2 diabetes. Insulin commencement was considered for patients with HbA_1c ≥ 8.0% or when vascular complications occurred. The change in HbA_1c compared with baseline and the difference in time to failure to maintain glycemic control were calculated.

Results: At endpoint, HbA_1c had decreased by 1.0% in the pioglitazone group (?p < 0.005) and by 0.6% in the glibenclamide group (?p < 0.05). Annual progression rates to insulin treatment were 6.6% (pioglitazone) and 16.4% (glibenclamide; p < 0.001 between-group difference). Mean weight increases of 3.5 ± 0.42?kg in the pioglitazone group and 3.3 ± 0.38?kg in the glibenclamide group were noted. Overall, both treatments were well tolerated.

Conclusions: Pioglitazone add-on to metformin revealed significant benefits in long-term glycemic control compared with glibenclamide. This difference may be explained by a large between-group difference in HOMA-S, which was shown to correlate significantly to the change in HbA_1c. This suggests that a strategy to reduce insulin resistance to lower the burden of the β‐cell is superior to treatment with glibenclamide.     

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized,double-blind,placebo-controlled study

ABSTRACT

Objectives: To evaluate the efficacy and safety of alogliptin in patients with type 2 diabetes inadequately controlled by therapy with a thiazolidinedione (TZD).

Research design and methods: In a multicenter, double-blind, placebo-controlled clinical study, 493 patients 18–80 years old with inadequate glycemic control after stabilization (i.e., glycosylated hemoglobin [HbA_1c] 7.0–10.0%) despite ongoing treatment with a TZD were randomly assigned (2:2:1) to treatment with pioglitazone plus alogliptin 12.5?mg, alogliptin 25?mg or placebo once daily. Concomitant therapy with metformin or sulfonylurea at prestudy doses was permitted.

Main outcome measures: The primary efficacy endpoint was change in HbA_1c from baseline to Week 26. Secondary endpoints included changes in fasting plasma glucose (FPG) and body weight, and incidences of marked hyperglycemia (FPG?≥?200?mg/dL [11.10?mmol/L]) and rescue for hyperglycemia.

Results: Least squares (LS) mean change in HbA_1c was significantly (p?<?0.001) greater for alogliptin 12.5?mg (?0.66%) or 25?mg (?0.80%) than for placebo (?0.19%). A significantly (p?≤?0.016) larger proportion of patients achieved HbA_1c?≤?7% with alogliptin 12.5?mg (44.2%) or 25?mg (49.2%) than with placebo (34.0%). LS mean decreases in FPG were significantly (p?=?0.003) greater with alogliptin 12.5?mg (?19.7?mg/dL [?1.09?mmol/L]) or 25?mg (?19.9?mg/dL [?1.10?mmol/L]) than with placebo (?5.7?mg/dL [?0.32?mmol/L]). The percentage of patients with marked hyperglycemia was significantly (p?<?0.001) lower for alogliptin (≤25.0%) than placebo (44.3%). The incidences of overall adverse events and hypoglycemia were similar across treatment groups, but cardiac events occurred more often with active treatment than placebo.

Conclusions: Addition of alogliptin to pioglitazone therapy significantly improved glycemic control in patients with type 2 diabetes and was generally well tolerated. The study did not evaluate the effect of combination therapy on long-term clinical outcomes and safety.

Clinical trial registration: NCT00286494, clinicaltrials.gov.     

A cost-effectiveness analysis of pioglitazone plus metformin compared with rosiglitazone plus metformin from a third-party payer perspective in the US*

ABSTRACT

Objective: The long-term cost-effectiveness of using pioglitazone plus metformin (Actoplusmet^?) compared with rosiglitazone plus metformin (Avandamet^?) in treating type 2 diabetes (T2DM) was assessed from a US third-party payer perspective.

Research design and methods: Clinical efficacy (change in HbA_1c and lipids) and baseline cohort parameters were extracted from a 12-month, randomized clinical trial (Derosa et al., 2006) evaluating the efficacy and tolerability of pioglitazone versus rosiglitazone, both in addition to metformin, in adult T2DM patients with insufficient glucose control (n?=?96). A Markov-based model was used to project clinical and economic outcomes over 35 years, discounted at 3% per annum. Costs for complications were taken from published sources. Base-case assumptions were assessed through several sensitivity analyses.

Main outcome measures: Outcomes included incremental life-years, quality-adjusted life-years (QALYs), total direct medical costs, cumulative incidence of complications and associated costs, and incremental cost–effectiveness ratios (ICERs).

Results: Compared to rosiglitazone plus metformin, pioglitazone plus metformin was projected to result in a modest improvement in 0.187 quality-adjusted life-years. Over patients’ lifetimes, total direct medical costs were projected to be marginally lower with pioglitazone plus metformin (difference –$526.), largely due to reduced CVD complication costs. While costs were higher among renal, ulcer/amputation/neuropathy, and eye complications in the pioglitazone plus metformin group, the cost savings for CVD complications outweighed their economic impact. Pioglitazone plus metformin was found to be a dominant long-term treatment strategy in the US compared to rosiglitazone plus metformin. Sensitivity analyses showed findings to be robust under almost all scenarios, including short-term time horizons, 6% discounting, removal of individual lipid parameters, and modifications of patient cohort to more closely represent a US T2DM population. Pioglitazone plus metformin was no longer dominant with 0% discounting, with 25% reduction in its HbA_1c effects, or with a 15% increase in its acquisition price.

Conclusions: Under a range of assumptions and study limitations around cohorts, clinical effects, and treatment patterns, this long-term analysis showed that pioglitazone plus metformin, when compared to rosiglitazone plus metformin, was a dominant treatment strategy within the US payer setting. Results were driven by the combination of modest differences in QALYs and modest savings in total complication costs over 35 years.     

Metabolic effect of repaglinide or acarbose when added to a double oral antidiabetic treatment with sulphonylureas and metformin: a double-blind,cross-over,clinical trial

ABSTRACT

Objective: To compare the metabolic effects of acarbose and repaglinide in type 2 diabetic patients who are being treated with a sulphonylurea–metformin combination therapy. The primary endpoint of the study was to evaluate which add-on treatment between acarbose and repaglinide is more efficacious in reducing PPG. The second endpoint was to evaluate which of these two treatment is more efficacious in the global management of glucose homeostasis in the enrolled patients.

Research design and methods: After a 4-week run-in period with a suplonylurea–metformin combination, 103 patients were randomised to receive in addition either repaglinide, up to 6?mg/day (2?mg three times a day) or acarbose, up to 300?mg/day (100?mg three times a day) with forced titration (independently of their glycaemic control, unless side-effects developed due to the drug dosage) for 15 weeks. The treatment was then crossed-over for further 12 weeks until the 27th week. We assessed body mass index (BMI), glycosylated haemoglobin (HbA_1c), fasting plasma glucoe (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), postprandial plasma insulin (PPI), homeostatic model assesssment (HOMA) index, systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (Tg), at baseline and at 1, 2, 15 and 27 weeks of treatment.

Results: Seven patients did not complete the study, comprising one patient who was lost to follow-up and a further six through side-effects (two in week 1, one in week 15 and three after cross-over) Side-effects were classified as nausea (one in acarbose group), gastrointestinal events (four in acarbose group), and hypoglycaemia (one in repaglinide group). After 15 weeks of therapy, the repaglinide-treated patients experienced a significant decrease in HbA_1c (?1.1%, p?<?0.05), FPG (?9.5%, p?<?0.05), and PPG (?14.9%, p?<?0.05), when compared to the baseline values. However, the same treatment was associated with a significant increase in body weight (+2.3%, p?<?0.05), BMI (+3.3%, p?<?0.05) and FPI (+22.5%, p?<?0.05); The increase was reversed during the cross-over phase. After 15 weeks of therapy, the acarbose-treated patients experienced a significant decrease in body weight (?1.9%, p?<?0.05), BMI (?4.1%, p?<?0.05), HbA_1c (?1.4%, p?<?0.05), FPG (?10.7%, p?<?0.05), PPG (?16.2%, p?<?0.05), FPI (?16.1%, p?<?0.05), PPI (?26.9%, p?<?0.05), HOMA index (?30.1%, p?<?0.05), when compared to the baseline values. All these changes were reversed during the cross-over study phase, except those relating to HbA_1c, FPG and PPG. The only changes that significantly differed when directly comparing acarbose- and repaglinide-treated patients were those relating to FPI (?16.1% vs. +22.5%, respectively, p?<?0.05) and HOMA index (?30.1% vs. +2.7%, p?<?0.05).

Conclusion: In addition from having a similar effect to repaglinide on PPG, acarbose appeared to have a more comprehensive positive effect on glucose metabolism compared to repaglinide in this relatively small sample of type 2 diabetic patients when used as add-on therapy to sulphonylureas and metformin.     

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.     

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 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.     

Randomized study of repaglinide alone and in combination with metformin in Chinese subjects with type 2 diabetes naive to oral antidiabetes therapy

Objective: The aim of this research is to determine efficacy and safety of repaglinide alone and in combination with metformin in Chinese subjects with type 2 diabetes naive to oral antidiabetes therapy.

Methods: A 16-week, open-label, randomized, active-controlled, parallel-group trial was carried out. Subjects were randomized (1:1) to repaglinide 1 mg t.i.d. (maximum dose, 4 mg t.i.d.) or repaglinide plus metformin 1 mg/500 mg t.i.d. (maximum dose, 4 mg/500 mg t.i.d.). Eligible subjects (18 – 75 years old) had type 2 diabetes, A1C > 8.5%, BMI ≤ 35 kg/m², and were naive to oral antidiabetes agents.

Results: The primary outcome was A1C reduction. Secondary end points included fasting plasma glucose (FPG), 2-h postprandial glucose (PPG), and 7-point plasma glucose. Baseline characteristics (repaglinide/metformin, n = 218; repaglinide-only, n = 214) were similar between groups. Mean A1C reduction (± SD) was 4.51 ± 1.64% (combination) and 4.05 ± 1.59% (monotherapy). Estimated mean treatment difference for repaglinide/metformin versus repaglinide-only was -0.30% (95% CI -0.49 to -0.11; p < 0.01). Combination treatment demonstrated significant improvements versus monotherapy in FPG, 7-point plasma glucose, and lunchtime and dinnertime 2-h PPG (all p < 0.05). Hypoglycemia rates were 2.04 (combination) versus 1.35 (monotherapy) events/subject-year (p = 0.058). Adverse events were comparable between groups.

Conclusions: Repaglinide plus metformin and repaglinide alone provided significant improvements in glycemic control and were well tolerated in Chinese patients naive to treatment with oral antidiabetes agents. Combination therapy with repaglinide plus metformin showed superiority to repaglinide monotherapy in this population. Limitations of this study are that subjects were newly diagnosed and had high mean baseline A1C, which may affect generalizability of results.     

Transferring type 2 diabetes patients with uncontrolled glycaemia from biphasic human insulin to biphasic insulin aspart 30: experiences from the PRESENT study

ABSTRACT

Aim: The Physician's Routine Evaluation of Safety and Efficacy of NovoMix* 30 Therapy (PRESENT) aims to assess the safety and efficacy of biphasic insulin aspart (BIAsp30) used in routine clinical practice.

Methods: This was a large, multi-national, multi-centre, prospective, 6-month study in type 2 diabetes mellitus patients who were prescribed BIAsp30. Efficacy endpoints included changes in HbA_1c, fasting plasma glucose (FPG), postprandial plasma glucose (PPPG), and proportion who achieved target HbA_1c <?7%. Changes from baseline were analysed using paired t-test. Safety endpoints were incidence and rate of hypoglycaemic episodes. A subgroup of patients previously uncontrolled (HbA_1c ≥?7.0%) on biphasic human insulin (BHI) were analysed.

Results: Glycaemia improved significantly (mean ± SD): HbA_1c by 1.58 ± 1.69% points (from 9.32 ± 1.64% to 7.70 ± 1.29%), FPG by 2.92 ± 3.71?mmol/L and PPPG by 4.75 ± 4.87?mmol/L. The incidence of hypoglycaemic episodes decreased over time, from 38.7% (baseline) to 20.8% (6?months). Episodes were mostly minor (reduced from 37.7 to 20.6% at 6?months), occurring during the day (reduced from 31.5 to 17.1% at 6?months). Major episodes were less frequently reported (reduced from 5.0 to 0.4% at 6?months). The rate of hypoglycaemia (episodes/patient year) from baseline to end of study decreased over time for overall (8.9–2.2), major (0.7–0.1), minor (8.2–2.2) and nocturnal (2.9–0.5) episodes.

Conclusions: In this observational study, in the type 2 diabetes mellitus patients who were poorly controlled on BHI, glycaemia improved when transferred to BIAsp30, and a lower incidence or rate of hypoglycaemia was observed in these patients.     

吡格列酮、瑞格列奈和二甲双胍对初发2型糖尿病患者血尿酸及肾功能的影响

目的比较吡格列酮、瑞格列奈和二甲双胍对初发2型糖尿病患者的血糖、血尿酸及肾功能的影响。方法选取75名初发2型糖尿病合并高尿酸血症患者,每组25人,监测、分析3种药物12周治疗前后空腹血糖、餐后2 h血糖、糖化血红蛋白（HbA1c）、血尿酸、尿微量白蛋白（MAU）、尿素氮（BUN）、肌酐（Cr）、总胆固醇（TC）和甘油三酯（TG）。结果吡格列酮组试验后空腹血糖、餐后2 h血糖、HbA1c、血尿酸、MAU、BUN、Cr、TC和TG均较试验前下降（P〈0.05）。瑞格列奈组试验后空腹血糖、餐后2 h血糖、HbA1c均较试验前显著下降（P〈0.05）。二甲双胍组试验后空腹血糖、餐后2 h血糖、HbA1c、TC、TG和MAU较试验前下降（P〈0.05）。瑞格列奈组试验后空腹血糖、餐后2 h血糖和HbA1c均低于吡格列酮组和二甲双胍组（P〈0.05）。吡格列酮组降低血尿酸改善肾功能的作用显著高于瑞格列奈组和二甲双胍组（P〈0.05）。吡格列酮组对尿微量白蛋白的影响比二甲双胍组显著（P〈0.05）。结论瑞格列奈的降糖作用最强。吡格列酮显著降低血尿酸,改善肾功能。2型糖尿病初发患者,同时伴有肾病、高尿酸血症或痛风时,宜选用吡格列酮。     

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.     

Time to pharmacotherapy change in response to elevated HbA1c test results

ABSTRACT

Objective: This study describes the clinical management of type 2 diabetes among a cohort of patients receiving oral antidiabetic monotherapy.

Study design and setting: A retrospective study was conducted within an integrated Midwestern health system that included all individuals receiving oral antidiabetic monotherapy during the period June 1, 1999 to November 30, 2002 (?n = 9335). Among patients with elevated hemoglobin A_1c (HbA_1c) test result(s), Kaplan-Meier estimates of median time until pharmacotherapy change were calculated.

Results: Among the 8068 patients who had ≥ 1 HbA_1c measurement during the study period, 21.4% were at goal (i.e. HbA_1c < 7%). Among patients with at least one elevated test result (≥ 7%), the median time to pharmacotherapy change following an HbA_1c test result of between 7–10% was just over 1 year (372 days, 95% confidence interval [CI] 358–393 days) and 160 days for patients with HbA_1c > 10%. Among patients with at least two elevated tests, the median time to pharmacotherapy change was 275 days from the second test result of between 7–10%, and 70 days among patients with a second HbA_1c > 10%. The median time between HbA_1c testing was 166 days overall, and 154 days among patients with at least one elevated result.

Conclusion: Despite the known benefits of glycemic control among patients with diabetes, the time between elevated HbA_1c results and pharmacotherapy change exceeds 12 months for those with HbA_1c test results between 7–10% and 9 months for those with results over 10%.     

Long-term efficacy of insulin glargine therapy with an educational programme in type 1 diabetes patients in clinical practice

ABSTRACT

Objective: To investigate the effect of initiating insulin glargine (glargine: LANTUS*), a once-daily basal insulin analogue, plus an educational programme, on glycaemic control and body weight in patients with type 1 diabetes in clinical practice.

Research design and methods: A retrospective analysis of the medical records of 65 patients (mean age: 40.7 ± 13.3 years) with type 1 diabetes was performed. Patients had previously been treated with NPH insulin (NPH; n = 54) or NPH insulin + lente insulin (NPH + lente; n = 11) and then received glargine once daily (bedtime), plus short-acting prandial insulin, for 30 months. Before initiation of glargine, patients participated in a diabetes educational programme and then received physician consultations throughout the study. Metabolic control, body weight and severe hypoglycaemia data were analysed at 9 and 30 months.

Results: Following initiation of glargine, patients showed a decrease in HbA_1c from 7.29 ± 1.1% to 7.06 ± 1.0%; p < 0.01 at 30 months. When the results were analysed by pre-treatment, both NPH-pre-treated and NPH+lente-pre-treated patients showed a significant reduction in HbA_1c of 0.14% and 0.82%, respectively, at 30 months (7.27 ± 1.2% to 7.13 ± 1.1% and 7.42 ± 1.2 to 6.60 ± 0.3%, respectively; p < 0.01). No change in body weight was observed in the overall group. No episodes of severe hypoglycaemia (blood glucose <?40?mg/dL [<?2.2?mmol/L] occurred.

Conclusions: In this retrospective study of medical records, patients with type 1 diabetes treated with insulin glargine over 30 months in combination with educational support and close clinical supervision decreased their HbA_1c levels without weight gain versus previous treatment with NPH insulin or insulin lente. Further studies in a larger cohort of patients would help to confirm these results.     

The efficacy and safety of teneligliptin added to ongoing metformin monotherapy in patients with type 2 diabetes: a randomized study with open label extension

Objective: The study investigated the efficacy and tolerability of teneligliptin co-administered to patients with type 2 diabetes mellitus (T2DM) who were inadequately controlled by stable metformin monotherapy ≥ 1000 mg/day.

Methods: A total of 447 patients from 55 European centers who completed a 14-day screening and 14-day run-in phase, received randomized double-blind treatment with 5, 10, 20 or 40 mg teneligliptin or placebo once daily, for 24 weeks. 364 patients continued treatment in a 28-week open label extension during which they received teneligliptin 20 mg once daily.

Results: Co-administration of teneligliptin (5 to 40 mg) with metformin demonstrated dose-related and statistically significant reductions in HbA_1c after 24 weeks (-0.30 to -0.63% placebo adjusted) of double-blind treatment. The greatest reduction in HbA_1c was seen with teneligliptin at 40 mg (-0.63%) at Week 24. There was also a dose-dependent increase in proportion of responders achieving HbA_1c < 7.0% at this endpoint. Responses were maintained throughout 28 weeks open label treatment with 20 mg teneligliptin. Treatment was well tolerated to Week 52 and the overall incidence of hypoglycemia during 52 weeks was 2.3%.

Conclusions: Teneligliptin co-administered with metformin produced significant reductions in HbA_1c in patients with T2DM without increasing the risk of hypoglycemia.     

Factors associated with the effect-size of thiazolidinedione (TZD) therapy on HbA1c:a meta-analysis of published randomized clinical trials

ABSTRACT

Objective: To examine factors affecting the size of the HbA^1c response to thiazolidinedione (TZD) therapy.

Research design and methods: Meta-analysis of randomized TZD controlled trials which were identified using PubMed, EBSCO and Sci-lit databases and were published in English. Sociodemographic and clinical data were extracted from each trial. HbA_1c effect size was defined as either a placebo-subtracted change in HbA_1c or a change in HbA_1c from baseline. Weighted multivariable regression was used to examine factors associated with changes in HbA_1c. Bootstrapped smearing estimates were computed to obtain reliable estimates of HbA_1c effect size.

Results: Forty-two trials yielded 60 trial arms which represented 8322 patients treated with thiazolidinediones. Weighted placebo-subtracted change in HbA_1c was –0.99% ± 0.02% with an average baseline HbA_1c of 9.1% ± 1.0%. Weighted bootstrapped smearing estimate of the placebo-subtracted change in HbA_1c was –1.02% ± 0.004%. After controlling for other variables, the baseline HbA_1c level had a significant negative association with placebo-subtracted HbA_1c change (?p = 0.004) and also with change in HbA_1c from baseline (?p = 0.002). Longer trial duration was associated with greater placebo-subtracted HbA_1c change (?p = 0.01) but not with the change in HbA_1c from baseline. The multivariable models explained 72% of the variation in placebo-subtracted HbA_1c change. It was not possible to estimate effects of the run-in period and obesity on TZD effect size.

Conclusion: Baseline HbA_1c and trial duration significantly impacted the effect size of TZD therapy on HbA_1c. Age, gender, duration of diabetes and prior use of anti-diabetic therapy were not associated with the TZD effect size.     

Pioglitazone, an in vitro inhibitor of CYP2C8 and CYP3A4, does not increase the plasma concentrations of the CYP2C8 and CYP3A4 substrate repaglinide

Objective Pioglitazone, a thiazolidinedione antidiabetic, inhibits cytochrome P450 (CYP) 2C8 and CYP3A4 enzymes in vitro. Repaglinide, a meglitinide analogue antidiabetic, is metabolised by CYP2C8 and CYP3A4. In patients with type 2 diabetes, the pioglitazone-repaglinide combination has acted synergistically on glycaemic parameters. Our aim was to determine whether pioglitazone increases the plasma concentrations of repaglinide. Methods In a randomized, 2-phase cross-over study, 12 healthy volunteers received 30 mg pioglitazone or placebo once daily for 5 days. On day 5, they ingested a single 0.25 mg dose of repaglinide 1 h after the last pretreatment dose. Plasma repaglinide and pioglitazone, and blood glucose concentrations were measured for 12 h. Results During the pioglitazone phase, the mean peak plasma repaglinide concentration (C_max) and the total area under the concentration-time curve [AUC(0-∞)] of repaglinide were 100% (range 53–157%, P=0.99) and 90% (range 63–120%, P=0.22), respectively, of those during the placebo phase. Also the half-life of repaglinide was unaffected, but the median peak time of repaglinide was shortened from 40 min to 20 min by pioglitazone (P=0.014). The short-term pioglitazone administration did not modify the blood glucose-lowering effect of a single dose of repaglinide. Conclusions Pioglitazone does not increase the plasma concentrations of repaglinide, indicating that the inhibitory effect of pioglitazone on CYP2C8 and CYP3A4 is very weak in vivo, probably due to its extensive plasma protein binding. The synergistic effect of repaglinide and pioglitazone on the glycaemic parameters, seen in patients with type 2 diabetes during their long-term use, is unlikely to be caused by inhibition of repaglinide metabolism by pioglitazone.     

Effect of non-persistent use of oral glucose-lowering drugs on HbA1c goal attainment

ABSTRACT

Objectives: The aim of this study was to quantify the effect of non-persistence with oral glucose-lowering drugs (OGLD) on HbA_1c goal attainment (<?7%) in daily practice.

Methods: From the PHARMO Record Linkage System comprising among others linked drug dispensing and clinical laboratory data from approximately 2.5 million individuals in the Netherlands, new users of OGLD in the period 1999–2004 were identified. Patients with a baseline HbA_1c ≥?7% and at least one HbA_1c measurement in the period of 6–12?months after treatment onset were included in the study cohort. Persistence with OGLD in the first year of treatment was determined using the method of Catalan. In case the first treatment episode overlapped the first HbA_1c measurement within 6–12?months after treatment onset, a patient was considered persistent at that measurement. Patients with a HbA_1c <?7% were defined as having attained goal.

Results: The study cohort included 2023 patients with a mean baseline HbA_1c of 8.9?±?1.8%. Three-quarters (1512 patients) were persistent with any OGLD at the first HbA_1c measurement within 6–12?months after treatment onset; of these, 861 (57%) were at goal. Of the 511 non-persistent patients, 239 (47%) were at goal. Non-persistent patients were about 20% less likely to attain goal (RRadj 0.82; 95%CI 0.74–0.91), compared to persistent OGLD users.

Conclusion: Non-persistent use of OGLD leads to a 20% decreased probability of HbA_1c goal attainment in daily practice. This effect of non-persistence seems modest, but represents around 12?000 new and 10?000 prevalent OGLD users a year in the Netherlands in whom OGLD use could be better controlled.     

Efficacy and safety of exenatide administered before the two largest daily meals of Latin American patients with type 2 diabetes

ABSTRACT

Objective: To evaluate whether exenatide administered before breakfast and dinner (BD) or before lunch and dinner (LD) provided similar glycemic control in Latin American patients with type 2 diabetes mellitus (T2DM) who consume a small breakfast.

Methods: In this open-label, 2-arm study, patients taking metformin, sulfonylureas, and/or thiazolidinediones were randomized to exenatide before BD or before LD (5-μg exenatide for 4 weeks, then 10-μg exenatide for 8 weeks). Treatment assignment was determined by a computer-generated random sequence using an interactive response system. Patients were eligible for study inclusion if they consumed <15% of their total caloric intake at breakfast. The primary endpoint was HbA_1c change from baseline to endpoint. Secondary endpoints included fasting serum glucose (FSG) level, 7-point SMBG profile, and safety. Clinicaltrials.gov Identifier: NCT00359879.

Results: 377 participants (55% female, age 54 ± 10 years, weight 82 ± 15 kg, BMI 31 ± 4 kg/m2, HbA_1c 8.4 ± 0.9% mean ± SD) from Brazil and Mexico were randomized to study treatment. HbA_1c reduction with exenatide administration before BD was non-inferior to administration before LD (mean difference between (LD–BD) treatments: 0.14% 95% CI –0.04 to 0.32%,p = 0.120). Both treatments resulted in statistically significant HbA_1c reductions at endpoint (BD –1.2% and LD –1.1%, respectively, p < 0.001). In Brazil, the non-inferiority criteria were met for HbA_1c reduction between treatment arms (?0.12% CI ?0.37 to 0.13%, p = 0.344), whereas in Mexico, there was a difference favoring exenatide administration before BD (0.41% CI 0.16 to 0.66%, p = 0.002). At endpoint, there were no statistical significant differences between the BD and LD arms in mean change in FSG (0.50 mmol/L; CI ?0.02 to 1.02 mmol/L, p = 0.058) and daily mean change in SMBG (0.19 mmol/L; CI ?0.17 to 0.54 mmol/L, p = 0.295). The rates of symptomatic hypoglycemia (5.2 events/patient-year vs. 6.1 events/patient-year) and nausea (23% vs. 25%), were similar between the BD and LD arms, respectively. A limitation of the study design was that caloric intake of patients and meal times were not monitored.

Conclusions: In T2DM patients who consume a small breakfast, exenatide administration before breakfast or lunch resulted in significant improvement in glycemic control.