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PMID29446523  : Safety and tolerability of dapagliflozin, saxagliptin and metformin in combination: Post-hoc analysis of concomitant add-on versus sequential add-on to metformin and of triple versus dual therapy with metformin.

Abstract

The safety of triple oral therapy with dapagliflozin plus saxagliptin plus metformin versus dual therapy with dapagliflozin or saxagliptin plus metformin was compared in a post-hoc analysis of 3 randomized trials of sequential or concomitant add-on of dapagliflozin and saxagliptin to metformin. In the concomitant add-on trial, patients with type 2 diabetes on stable metformin received dapagliflozin 10 mg/d plus saxagliptin 5 mg/d. In sequential add-on trials, patients on metformin plus either saxagliptin 5 mg/d or dapagliflozin 10 mg/d received dapagliflozin 10 mg/d or saxagliptin 5 mg/d, respectively, as add-on therapy. After 24 weeks, incidences of adverse events and serious adverse events were similar between triple and dual therapy and between concomitant and sequential add-on regimens. Urinary tract infections were more common with sequential than with concomitant add-on therapy; genital infections were reported only with sequential add-on of dapagliflozin to saxagliptin plus metformin. Hypoglycaemia incidence was <2.0% across all analysis groups. In conclusion, the safety and tolerability of triple therapy with dapagliflozin, saxagliptin and metformin, as either concomitant or sequential add-on, were similar to dual therapy with either agent added to metformin.

Structured Findings

Dapagliflozin plus saxagliptin plus metformin and Dapagliflozin or saxagliptin plus metformin had no significant difference on Incidences of adverse events and serious adverse events

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Intervention	Comparator	Outcome	Label
Dapagliflozin plus saxagliptin plus metformin	Dapagliflozin or saxagliptin plus metformin	Incidences of adverse events and serious adverse events	no significant difference

PMID33135865  : Bioequivalence of Metformin in Ertugliflozin/Metformin Fixed-Dose Combination Tablets to Canadian-Sourced Metformin Coadministered With Ertugliflozin Under Fasted and Fed States.

Abstract

A fixed-dose combination (FDC) product of a selective sodium-glucose cotransporter 2 inhibitor ertugliflozin and immediate-release metformin is approved for type 2 diabetes mellitus in the United States, European Union countries, Canada, and other countries. Two studies were conducted to assess the bioequivalence of metformin in the ertugliflozin/metformin FDC tablets to the corresponding doses of Canadian-sourced metformin (Glucophage) coadministered with ertugliflozin. Both studies were phase 1 randomized, open-label, 2-period, single-dose crossover studies (n = 32) in which healthy subjects received an ertugliflozin/metformin FDC tablet (2.5/500 mg or 7.5/850 mg) and the respective doses of the individual components (ertugliflozin coadministered with Canadian-sourced metformin) under fasted (n = 18) or fed (n = 14) conditions. Blood samples were collected 72 hours postdose to determine metformin concentrations. The 90% confidence intervals were within the bioequivalence acceptance criteria for the adjusted geometric mean ratios (FDC:coadministered) for metformin area under the plasma concentration-time curve from time zero to time t, where t is the last point with a measurable concentration and peak observed plasma concentration for both dose strengths under fasted and fed conditions. All study medications were well tolerated. Bioequivalence was demonstrated for the metformin component of the ertugliflozin/metformin FDC tablets and the corresponding doses of the Canadian-sourced metformin coadministered with ertugliflozin.

Structured Findings

ertugliflozin/metformin FDC tablet (2.5/500 mg or 7.5/850 mg) and ertugliflozin coadministered with Canadian-sourced metformin had no significant difference on methoform concentration

Structured Markup

Intervention	Comparator	Outcome	Label
ertugliflozin/metformin FDC tablet (2.5/500 mg or 7.5/850 mg)	ertugliflozin coadministered with Canadian-sourced metformin	methoform concentration	no significant difference

PMID25546164  : Pharmacokinetic study of metformin to compare voglibose/metformin fixed-dose combination with coadministered voglibose and metformin.

Abstract

The aim of this study was to compare the pharmacokinetic characteristics of metformin between a fixed-dose combination (FDC) of voglibose/metformin and coadministered individual voglibose and metformin tablets in healthy Korean volunteers under fasting conditions. A randomized, open-label, single-dose, two-treatment, two-way crossover study with a 7-day wash-out period was conducted. Plasma samples were collected for up to 24 hours and were analyzed for metformin using a validated liquid chromatography tandem mass-spectrometry (LC/MS). A noncompartmental method was used to calculate the pharmacokinetic parameters. Vital signs and adverse events were monitored, and physical examinations and laboratory tests were conducted to evaluate safety. In total, 28 subjects completed the study. The geometric mean ratio (GMR) and the 90% confidence interval (CIs) of Cmax and AUC0-t of metformin were 102.4 (94.5-111.0) and 107.1 (100.1-114.7), respectively. In total, 7 adverse drug reactions occurred in 4 subjects during the study; of these, 3 cases were from 3 subjects in the test treatment group, and 4 cases were from 3 subjects in the reference treatment group. All adverse drug reactions had been reported previously, and all subjects recovered fully without any sequelae. In conclusion, the pharmacokinetic profiles of metformin in two different study treatments, a voglibose/metformin FDC vs. the coadministration of the individual formulations, met the regulatory criteria for bioequivalence in healthy Korean subjects under fasting conditions. There was no significant difference in safety profiles between the two treatments.

Structured Findings

Voglibose/Metformin fixed-dose combination (FDC) and Voglibose/Metformin individual formulations had no significant difference on Safety profiles

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Intervention	Comparator	Outcome	Label
Voglibose/Metformin fixed-dose combination (FDC)	Voglibose/Metformin individual formulations	Safety profiles	no significant difference

PMID23704674  : Effects of metformin, metformin plus rosiglitazone, and metformin plus lifestyle on insulin sensitivity and β-cell function in TODAY.

Abstract

OBJECTIVE The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) trial demonstrated that combination therapy with metformin plus rosiglitazone provided superior durability of glycemic control compared with metformin alone, with significantly lower treatment failure rates (38.6 vs. 51.7%), and metformin plus lifestyle was intermediate. Herein we describe the temporal changes in measures of β-cell function and insulin sensitivity over a 4-year period among the three treatments. RESEARCH DESIGN AND METHODS TODAY participants (699) were tested periodically with an oral glucose tolerance test to determine insulin sensitivity (1/fasting insulin [1/IF]), insulinogenic index (ΔI(30)/ΔG(30)) or C-peptide index (ΔC(30)/ΔG(30)), and β-cell function relative to insulin sensitivity (oral disposition index [oDI]). RESULTS During the first 6 months, metformin plus rosiglitazone exhibited a significantly greater improvement in insulin sensitivity and oDI versus metformin alone and versus metformin plus lifestyle; these improvements were sustained over 48 months of TODAY. Irrespective of treatment, those who failed to maintain glycemic control had significantly lower β-cell function (~50%), higher fasting glucose concentration, and higher HbA1c at randomization compared with those who did not fail. CONCLUSIONS The beneficial change in insulin sensitivity and the resultant lower burden on β-cell function achieved in the first 6 months with metformin plus rosiglitazone appear to be responsible for its superior glycemic durability over metformin alone and metformin plus lifestyle. However, initial β-cell reserve and HbA1c at randomization are independent predictors of glycemic durability. Therefore, efforts to preserve β-cell function before significant loss occurs and to reduce HbA1c may be beneficial in the treatment of youth with type 2 diabetes.

Structured Findings

Metformin plus rosiglitazone significantly increased Improvement in insulin sensitivity and oral disposition index compared to Metformin alone

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Intervention	Comparator	Outcome	Label
Metformin plus rosiglitazone	Metformin alone	Improvement in insulin sensitivity and oral disposition index	significantly increased

PMID29790415  : A gene variant near ATM affects the response to metformin and metformin plasma levels: a post hoc analysis of an RCT.

Abstract

AIM To determine the influence of polymorphisms on the effects of metformin on HbA1c, daily dose of insulin and metformin plasma concentration. Methods: In a post hoc analysis of a 4.3 year placebo-controlled randomized trial with 390 patients with Type 2 diabetes already on insulin, we analyzed the influence of polymorphisms in genes coding for ATM and the transporters OCT1 and MATE1. Outcome measures were a combined HbA1c + daily dose of insulin Z score and metformin plasma concentrations. RESULTS rs11212617 (ATM) was associated with an improved Z score and a lower metformin plasma concentration. In addition, the major allele of rs2289669 (MATE1) was also associated with an improved Z score. CONCLUSION The ATM SNP rs11212617 significantly affected the effect of metformin and metformin plasma concentration. Further research is needed to determine the clinical importance of these findings, in particular the effects on metformin plasma concentration.

Structured Findings

rs11212617 (ATM) significantly decreased metformin plasma concentration compared to placebo

Structured Markup

Intervention	Comparator	Outcome	Label
rs11212617 (ATM)	placebo	metformin plasma concentration	significantly decreased

PMID16448519  : Metformin-glibenclamide versus metformin plus rosiglitazone in patients with type 2 diabetes inadequately controlled on metformin monotherapy.

Abstract

AIM This double-blind study evaluated the efficacy and safety of metformin-glibenclamide tablets vs. metformin plus rosiglitazone therapy in patients with type 2 diabetes inadequately controlled on metformin monotherapy. SUBJECTS AND METHODS After an open-label, metformin lead-in phase, 318 patients were randomly assigned to treatment based on metformin-glibenclamide 500/2.5 mg tablets (initial daily dose 1000/5 mg) or metformin 500 mg plus rosiglitazone 4 mg (initial daily dose 1000-2000 mg + 4 mg, depending on previous treatment) for 24 weeks. Doses were titrated to achieve the therapeutic glycaemic target. The primary efficacy variable was the change in HbA1C. RESULTS At week 24, metformin-glibenclamide tablets resulted in significantly greater reductions in HbA1C (-1.5%) and fasting plasma glucose [-2.6 mmol/l (-46 mg/dl)] than metformin plus rosiglitazone [-1.1%, p < 0.001; -2 mmol/l (-36 mg/dl), p = 0.03]. More patients receiving metformin-glibenclamide attained HbA1C <7.0% than did those in the metformin plus rosiglitazone group (60 vs. 47%) and had fasting plasma glucose levels <7 mmol/l (<126 mg/dl) by week 24 (34 vs. 25%). Both treatments were well tolerated. Frequency of adverse gastrointestinal events was comparable between groups. Four per cent of patients receiving metformin-glibenclamide withdrew because of symptomatic hypoglycaemia contrasted with 3% of patients receiving metformin plus rosiglitazone who withdrew because of persistent hyperglycaemia. Hypoglycaemic events were mild or moderate in intensity and were easily self-managed. CONCLUSIONS Metformin-glibenclamide tablets resulted in significantly greater reductions in HbA1C and fasting plasma glucose compared with metformin plus rosiglitazone in patients with type 2 diabetes inadequately controlled on metformin monotherapy.

Structured Findings

metformin-glibenclamide 500/2.5 mg tablets (initial daily dose 1000/5 mg) significantly increased reductions in HbA1C and fasting plasma glucose compared to metformin 500 mg plus rosiglitazone 4 mg (initial daily dose 1000-2000 mg + 4 mg, depending on previous treatment) for 24 weeks

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Intervention	Comparator	Outcome	Label
metformin-glibenclamide 500/2.5 mg tablets (initial daily dose 1000/5 mg)	metformin 500 mg plus rosiglitazone 4 mg (initial daily dose 1000-2000 mg + 4 mg, depending on previous treatment) for 24 weeks	reductions in HbA1C and fasting plasma glucose	significantly increased

PMID31869430  : Pharmacodynamics of Glyburide, Metformin, and Glyburide/Metformin Combination Therapy in the Treatment of Gestational Diabetes Mellitus.

Abstract

In gestational diabetes mellitus (GDM), women are unable to compensate for the increased insulin resistance during pregnancy. Data are limited regarding the pharmacodynamic effects of metformin and glyburide during pregnancy. This study characterized insulin sensitivity (SI), β-cell responsivity, and disposition index (DI) in women with GDM utilizing a mixed-meal tolerance test (MMTT) before and during treatment with glyburide monotherapy (GLY, n = 38), metformin monotherapy (MET, n = 34), or GLY and MET combination therapy (COMBO; n = 36). GLY significantly decreased dynamic β-cell responsivity (31%). MET and COMBO significantly increased SI (121% and 83%, respectively). Whereas GLY, MET, and COMBO improved DI, metformin (MET and COMBO) demonstrated a larger increase in DI (P = 0.05) and a larger decrease in MMTT peak glucose concentrations (P = 0.03) than subjects taking only GLY. Maximizing SI with MET followed by increasing β-cell responsivity with GLY or supplementing with insulin might be a more optimal strategy for GDM management than monotherapy.

Structured Findings

glyburide monotherapy (GLY) significantly decreased dynamic -cell responsivity compared to metformin monotherapy (MET)

glyburide monotherapy (GLY) significantly increased insulin sensitivity (SI) compared to metformin monotherapy (MET)

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Intervention	Comparator	Outcome	Label
glyburide monotherapy (GLY)	metformin monotherapy (MET)	dynamic -cell responsivity	significantly decreased
glyburide monotherapy (GLY)	metformin monotherapy (MET)	insulin sensitivity (SI)	significantly increased

PMID33776461  : Comparison Between Pioglitazone/Metformin Combination Therapy and Sitagliptin/Metformin Combination Therapy on the Efficacy in Chinese Type 2 Diabetic Adults Insufficiently Controlled with Metformin: Study Protocol of an Open-Label, Multicenter, Non-Inferiority Parallel-Group Randomized Controlled Trial.

Abstract

INTRODUCTION The prevalence of type 2 diabetes (T2D) has risen substantially in China, where its pathophysiology is primarily characterized by insulin resistance (IR). Alleviating IR may help with the management of T2D in the Chinese population. Pioglitazone and sitagliptin are two hypoglycemic medications with different pharmacological actions, both of which are optimal choices for use in combination with metformin. Previous studies have yielded mixed findings regarding the differences in hypoglycemic effects between the two agents. Though pioglitazone is associated with weight gain, both drugs have been shown to decrease visceral adipose tissue (VAT) and improve IR in individuals with T2D. There is a lack of direct comparisons between pioglitazone and sitagliptin among Chinese individuals with T2D. Therefore, this paper describes a protocol for a randomized controlled trial (RCT) that investigates the differences in hypoglycemic efficacy, IR improvement, and safety profiles between these drugs. METHODS AND ANALYSIS This is a 24-week, open-label, multicenter, non-inferiority parallel-group RCT with a 1:1 allocation ratio. It compares pioglitazone/metformin (15 mg/500 mg) combination therapy with sitagliptin/metformin (50 mg/500 mg) combination therapy in Chinese adults with T2D insufficiently controlled with metformin. The primary outcomes are HbA1c reduction, insulin level increase, and IR index change. The secondary outcomes are body weight and abdominal VAT decreases, lipid profiles, and inflammatory indicators. Tolerability and safety data will also be collected. CONCLUSION It is believed that the direct comparisons of the hypoglycemic effects, VAT reductions, and safety profiles between pioglitazone and sitagliptin will help to optimize treatments for Chinese adults with T2D who are primarily characterized by IR. TRIAL REGISTRATION NUMBER Chinese Clinical Trial Registry (ChiCTR1900021861).

Structured Findings

Pioglitazone/metformin (15 mg/500 mg) combination therapy significantly decreased HbA1c reduction, insulin level increase, and IR index change compared to Sitagliptin/metformin (50 mg/500 mg) combination therapy

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Intervention	Comparator	Outcome	Label
Pioglitazone/metformin (15 mg/500 mg) combination therapy	Sitagliptin/metformin (50 mg/500 mg) combination therapy	HbA1c reduction, insulin level increase, and IR index change	significantly decreased

PMID25422771  : Efficacy of glimepiride/metformin fixed-dose combination vs metformin uptitration in type 2 diabetic patients inadequately controlled on low-dose metformin monotherapy: A randomized, open label, parallel group, multicenter study in Korea.

Abstract

AIMS/INTRODUCTION To compare the efficacy and safety of early combination therapy with glimepiride/metformin to metformin uptitration in reducing glycated hemoglobin (HbA1c) levels in Korean type 2 diabetic patients inadequately controlled on low-dose metformin monotherapy. MATERIALS AND METHODS In a randomized, open label, parallel group, multicenter study, 209 Korean type 2 diabetic patients (HbA1c 7.0-10.0%, on metformin 500-1,000 mg/day) received glimepiride/metformin fixed-dose combination (G/M FDC) or metformin uptitration treatment (Met UP). The primary end-point was the change in HbA1c from baseline to week 24. RESULTS G/M FDC therapy provided significantly greater adjusted mean decreases vs Met UP therapy in HbA1c (-1.2 vs -0.8%, P < 0.0001), and fasting plasma glucose (-35.7 vs -18.6 mg/dL, P < 0.0001). A significantly greater proportion of patients with G/M FDC therapy achieved HbA1c < 7% (74.7 vs 46.6%, P < 0.0001) at the end of the study. More patients experienced hypoglycemia with G/M FDC therapy compared with Met UP therapy (41 vs 5.6%, P < 0.0001), but there was no serious hypoglycemia in any group. A modest increase in mean bodyweight occurred in the patients who were treated with G/M FDC therapy (1.0 kg), whereas a slight decrease was observed in the patients who were treated with Met UP therapy (-0.7 kg). CONCLUSION The present study showed that glimepiride/metformin fixed-dose combination therapy was more effective in glycemic control than metformin uptitration, and was well tolerated in type 2 diabetic patients inadequately controlled by low-dose metformin monotherapy in Korea. This trial was registered with ClinicalTrial.gov (no. NCT00612144).

Structured Findings

glimepiride/metformin fixed-dose combination (G/M FDC) significantly increased HbA1c compared to metformin uptitration treatment (Met UP)

glimepiride/metformin fixed-dose combination (G/M FDC) significantly increased fasting plasma glucose compared to metformin uptitration treatment (Met UP)

Structured Markup

Intervention	Comparator	Outcome	Label
glimepiride/metformin fixed-dose combination (G/M FDC)	metformin uptitration treatment (Met UP)	HbA1c	significantly increased
glimepiride/metformin fixed-dose combination (G/M FDC)	metformin uptitration treatment (Met UP)	fasting plasma glucose	significantly increased

PMID30171747  : Which is better, high-dose metformin monotherapy or low-dose metformin/linagliptin combination therapy, in improving glycemic variability in type 2 diabetes patients with insufficient glycemic control despite low-dose metformin monotherapy? A randomized, cross-over, continuous glucose monitoring-based pilot study.

Abstract

AIMS/INTRODUCTION The present study investigated the effect of high-dose metformin or low-dose metformin/linagliptin combination therapy on glycemic variability (GV) in type 2 diabetes patients with insufficient glycemic control despite low-dose metformin monotherapy in a cross-over study using continuous glucose monitoring. MATERIALS AND METHODS The present study was carried out with 11 type 2 diabetes outpatients (7% < glycated hemoglobin < 10%) receiving low-dose metformin monotherapy (500-1,000 mg). All patients were assigned to either metformin 1,500 mg monotherapy (HMET) or combination therapy of low-dose (750 mg) metformin and linagliptin 5 mg (LMET + dipeptidyl peptidase-4 [DPP4]). GV was evaluated by continuous glucose monitoring after >4 weeks of the initial treatment and again after cross-over to the other treatment. GV metrics were compared between the treatments using the Wilcoxon signed-rank test. RESULTS Of the continuous glucose monitoring-derived GV metrics for the HMET versus LMET + DPP4, mean glucose levels, standard deviations and mean amplitude of glucose excursions were not significantly different. Although the pre-breakfast glucose levels were not significantly different among the treatments (P = 0.248), the 3-h postprandial glucose area under the curve (>160 mg/dL) after breakfast was significantly larger with HMET versus LMET + DPP4 (9,550 [2,075-11,395] vs 4,065 [1,950-8,895]; P = 0.041). CONCLUSIONS A comparison of GV with HMET versus LMET + DPP4 suggested that LMET + DPP4 might reduce post-breakfast GV to a greater degree than HMET in type 2 diabetes patients receiving low-dose metformin monotherapy.

Structured Findings

Low-dose metformin + dipeptidyl peptidase-4 (DPP4) and High-dose metformin (HMET) had no significant difference on Glycemic variability (GV)

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Intervention	Comparator	Outcome	Label
Low-dose metformin + dipeptidyl peptidase-4 (DPP4)	High-dose metformin (HMET)	Glycemic variability (GV)	no significant difference