rosiglitazone-metformin-combination and Diabetes-Mellitus--Type-2

Type 2 diabetes is a common disease associated with an increased risk of long-term complications, in particular cardiovascular disease. Intervention trials have provided evidence that strict metabolic control can substantially reduce the burden of the disease. However, in order to accomplish this, the pathogenetic defects must be tackled by appropriate therapy. Insulin resistance is a common defect in these patients and it is even more severe in those who are obese. Insulin resistance not only contributes to impaired glucose homeostasis, but also to the development of dyslipidaemia, hypertension, inflammatory response and endothelial dysfunction, thus exacerbating the cardiovascular risk. Improvement of insulin sensitivity can be obtained with metformin and thiazolidinediones. These drugs act through different mechanisms with metformin exerting a prevalent effect on the liver and glitazones improving insulin sensitivity in peripheral tissue. Because of different mechanisms, the association of the two compounds is likely to result in an additive effect. Clinical trials available indicate that the combination of the two drugs results in greater improvement in plasma glucose concentration and HbA(1c) as compared to single therapy, without increasing the occurrence of specific side effects. More recently, the two compounds have been associated in the same tablet, thus providing the opportunity for a more convenient treatment that may encourage patient compliance and, at the same time, provide a tool to assess whether a more aggressive intervention on insulin resistance may produce favourable effects on the cardiovascular risk.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Combinations; Humans; Hypoglycemic Agents; Metformin; Rosiglitazone; Thiazoles; Thiazolidinediones

Insulin resistance is a major endocrinopathy underlying the development of hyperglycaemia and cardiovascular disease in type 2 diabetes. Metformin (a biguanide) and rosiglitazone (a thiazolidinedione) counter insulin resistance, acting by different cellular mechanisms. The two agents can be used in combination to achieve additive glucose-lowering efficacy in the treatment of type 2 diabetes, without stimulating insulin secretion and without causing hypoglycaemia. Both agents also reduce a range of atherothrombotic factors and markers, indicating a lower cardiovascular risk. Early intervention with metformin is already known to reduce myocardial infarction and increase survival in overweight type 2 patients. Recently, a single-tablet combination of metformin and rosiglitazone, Avandamet, has become available. Avandamet is suitable for type 2 diabetic patients who are inadequately controlled by monotherapy with metformin or rosiglitazone. Patients already receiving separate tablets of metformin and rosiglitazone may switch to the single-tablet combination for convenience. Also, early introduction of the combination before maximal titration of one agent can reduce side effects. Use of Avandamet requires attention to the precautions for both metformin and rosiglitazone, especially renal, cardiac and hepatic competence. In summary, Avandamet is a single-tablet metformin-rosiglitazone combination that doubly targets insulin resistance as therapy for hyperglycaemia and vascular risk in type 2 diabetes.

Topics: Contraindications; Diabetes Mellitus, Type 2; Drug Combinations; Humans; Hypoglycemic Agents; Insulin Resistance; Metformin; Thiazoles; Treatment Outcome

Low-calorie sweetened beverages (LCSBs) are commonly used as a lower-calorie alternative to sugar-sweetened beverages (SSBs) by individuals with type 2 diabetes. However, little is known about how intake of LCSBs is related to dietary intake and cardiometabolic health, particularly among youth.. To test the hypothesis that having higher baseline LCSB intake and increasing LCSB intake over 2 years of follow-up are associated with poorer dietary intake and higher cardiometabolic risk factors among youth enrolled in the Treatment Option for Type 2 Diabetes in Adolescents and Youth (TODAY) study.. Secondary, exploratory, analysis of baseline and longitudinal data from the TODAY study, which was a randomized, multisite trial conducted from 2004 to 2012, to compare effects of 3 interventions (metformin alone, metformin + rosiglitazone, and metformin + intensive lifestyle intervention) on glycemic control in youth with type 2 diabetes.. The study included 476 children and adolescents (10-17 years, mean body mass index 34.9 ± 7.8 kg/m. Diet was assessed using a food frequency questionnaire. Differences in energy intake, macronutrients, food group intakes, and cardiometabolic biomarkers were evaluated in 3 groups of LCSB consumers at baseline (low [1-4 servings/wk], medium [5-11 servings/wk], and high [≥12 servings/wk]), each compared with nonconsumers, and between 4 groups of change in LCSB intake (nonconsumption at start of study and nonconsumption after 2 years, increase in consumption after 2 years, decrease in consumption after 2 years, and high consumption at start of study and high consumption after 2 years).. Multivariable linear regression was performed at baseline and longitudinally over 2 years of follow-up.. Energy (kilocalories), fiber, carbohydrate, total fat, saturated fat, and protein intake (grams) were higher among high LCSB consumers compared with nonconsumers at baseline. No associations were observed between LCSB consumption and cardiometabolic risk factors at baseline. Change in LCSB intake between baseline and follow-up was not associated with change in energy intake or cardiometabolic risk factors. Participants who decreased LCSB consumption reported greater increases in sugar intake (18.4 ± 4.8 g) compared with those who increased LCSB consumption (5.7 ± 4.9 g) or remained high LCSB consumers (5.9 ± 7.4 g), but this trend was not statistically significant after a correction for multiple testing.. LCSB consumption was associated with higher energy intake in youth with type 2 diabetes, with the highest energy intakes reported in high LCSB consumers. Those who reduced LCSB consumption tended to report greater increases in sugar intake during follow-up, but further studies are needed to better understand this trend.

Topics: Adolescent; Beverages; Body Mass Index; Cardiometabolic Risk Factors; Child; Diabetes Mellitus, Type 2; Diet; Diet Records; Dietary Sugars; Drug Combinations; Energy Intake; Female; Humans; Life Style; Longitudinal Studies; Male; Metformin; Rosiglitazone; Surveys and Questionnaires; Sweetening Agents; Thiazoles

In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, metformin plus rosiglitazone (M + R) maintained glycemic control better than metformin alone (M) or metformin plus lifestyle (M + L) in youth with type 2 diabetes (T2D). We hypothesized that changes in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) would explain the differential treatment effects on glycemia.. In 626 youth ages 11-17 years with T2D duration <2 years, VAT and SAT were estimated by DXA at baseline and at 6 and 24 months. Changes from baseline were analyzed in linear mixed models.. Baseline mean age was 13.9 years, 66.4% were female, 72.2% were Hispanic/non-Hispanic black, and 20.3% were non-Hispanic white (NHW). Mean BMI was 33.7 kg/m. In contrast to the existing reports in adults with T2D, in TODAY, M + R resulted in the most VAT accumulation compared with M + L or M. Differential effects on depot-specific indirect measures of adiposity are unrelated to treatment effects in sustaining glycemic control. Additional studies are needed to understand the clinical markers of metabolic risk profile in youth with T2D on rosiglitazone.

Topics: Adiposity; Adolescent; Blood Glucose; Body Fat Distribution; Child; Combined Modality Therapy; Diabetes Mellitus, Type 2; Drug Combinations; Exercise Therapy; Female; Humans; Insulin Resistance; Intra-Abdominal Fat; Life Style; Male; Metformin; Obesity; Sex Factors; Subcutaneous Fat; Thiazoles

The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial documented that metformin plus rosiglitazone, but not metformin plus lifestyle intervention, provided superior durability of glycemic control relative to metformin monotherapy.. We examined weight changes among TODAY participants that completed at least 6 months of treatment, evaluated predictors of lifestyle outcome, and examined whether weight changes were related to cardiometabolic outcomes across treatment arms.. The 595 youth with type 2 diabetes, (85.1% of randomized participants aged 11-17 years) completed assessments of weight-related and cardiometabolic measures at months 0, 6, 12 and 24. Repeated measures models were used to investigate associations over time.. Lifestyle intervention did not enhance outcome relative to metformin alone and no predictors of response to lifestyle treatment were identified. However, changes in percent overweight across treatment arms were associated with changes in multiple cardiometabolic risk factors, and decreases of ≥ 7% in overweight were associated with significant benefits over 24 months.. Although adjunctive intensive lifestyle intervention did not improve weight-related outcomes, weight changes in the full TODAY sample were associated with small, but significant improvements in cardiometabolic status, highlighting the importance of optimizing weight management in youth with T2DM.

Topics: Adolescent; Anthropometry; Blood Glucose; Body Weight; Child; Diabetes Mellitus, Type 2; Drug Combinations; Female; Humans; Hypoglycemic Agents; Life Style; Male; Metformin; Risk Factors; Thiazoles; Treatment Outcome

At present, China has listed the compound tablet containing a fixed dose of rosiglitazone and metformin, Avandamet, which may improve patient compliance. The aim of this study was to evaluate the efficacy and safety of Avandamet or uptitrated metformin treatment in patients with type 2 diabetes inadequately controlled with metformin alone.. This study was a 48-week, multicenter, randomized, open-labeled, active-controlled trial. Patients with inadequate glycaemic control (glycated hemoglobin [HbA1c] 7.5-9.5%) receiving a stable dose of metformin (≥1500 mg) were recruited from 21 centers in China (from 19 November, 2009 to 15 March, 2011). The primary objective was to compare the proportion of patients who reached the target of HbA1c ≤7% between Avandamet and metformin treatment.. At week 48, 83.33% of patients reached the target of HbA1c ≤7% in Avandamet treatment and 70.00% in uptitrated metformin treatment, with significantly difference between groups. The target of HbA1c ≤6.5% was reached in 66.03% of patients in Avandamet treatment and 46.88% in uptitrated metformin treatment. The target of fasting plasma glucose (FPG) ≤6.1 mmol/L was reached in 26.97% of patients in Avandamet treatment and 19.33% in uptitrated metformin treatment. The target of FPG ≤7.0 mmol/L was reached in 63.16% of patients in Avandamet treatment and 43.33% in uptitrated metformin treatment. Fasting insulin decreased 3.24 ± 0.98 μU/ml from baseline in Avandamet treatment and 0.72 ± 1.10 μU/ml in uptitrated metformin treatment. Overall adverse event (AE) rates and serious AE rates were similar between groups. Hypoglycaemia occurred rarely in both groups.. Compared with uptitrated metformin, Avandamet treatment provided significant improvements in key parameters of glycemic control and was generally well tolerated.. ChiCTR-TRC-13003776.

Topics: Adult; Blood Glucose; C-Reactive Protein; Diabetes Mellitus, Type 2; Drug Combinations; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Thiazoles

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.. 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]).. 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.. 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.

Topics: Adolescent; Child; Diabetes Mellitus, Type 2; Drug Combinations; Female; Humans; Hypoglycemic Agents; Insulin Resistance; Insulin-Secreting Cells; Life Style; Male; Metformin; Thiazoles

The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) trial showed superiority of metformin plus rosiglitazone (M+R) over metformin alone (M), with metformin plus lifestyle (M+L) intermediate in maintaining glycemic control. We report here treatment effects on measures of body composition and their relationships to demographic and metabolic variables including glycemia.. Measures of adiposity (BMI, waist circumference, abdominal height, percent and absolute fat, and bone mineral content [BMC] and density [BMD]) were analyzed as change from baseline at 6 and 24 months.. Measures of fat accumulation were greatest in subjects treated with M+R and least in M+L. Although fat measures in M+L were less than those of M+R and M at 6 months, differences from M were no longer apparent at 24 months, whereas differences from M+R persisted at 24 months. The only body composition measure differing by race and/or ethnicity was waist circumference, greater in M+R than either M or M+L at both 6 and 24 months in whites. BMD and BMC increased in all groups, but increased less in M+R compared with the other two groups by 24 months. Measures of adiposity (increases in BMI, waist circumference, abdominal height, and fat) were associated with reduced insulin sensitivity and increased hemoglobin A1c (HbA1c), although effects of adiposity on HbA1c were less evident in those treated with M+R.. Despite differential effects on measures of adiposity (with M+R resulting in the most and M+L in the least fat accumulation), group differences generally were small and unrelated to treatment effects in sustaining glycemic control.

Topics: Adolescent; Body Composition; Body Mass Index; Child; Diabetes Mellitus, Type 2; Drug Combinations; Female; Glycated Hemoglobin; Humans; Life Style; Male; Metformin; Thiazoles

Data related to the safety and tolerability of treatments for pediatric type 2 diabetes are limited. The TODAY clinical trial assessed severe adverse events (SAEs) and targeted nonsevere adverse events (AEs) before and after treatment failure, which was the primary outcome (PO).. Obese 10- to 17-year-olds (N = 699) with type 2 diabetes for <2 years and hemoglobin A1c (A1C) ≤ 8% on metformin monotherapy were randomized to one of three treatments: metformin, metformin plus rosiglitazone (M + R), or metformin plus lifestyle program (M + L). Participants were followed for 2-6.5 years.. Gastrointestinal (GI) disturbance was the most common AE (41%) and was lower in the M + R group (P = 0.018). Other common AEs included anemia (20% before PO, 14% after PO), abnormal liver transaminases (16, 15%), excessive weight gain (7, 9%), and psychological events (10, 18%); the AEs were similar across treatments. Permanent medication reductions/discontinuations occurred most often because of abnormal liver transaminases and were lowest in the M + R group (P = 0.005). Treatment-emergent SAEs were uncommon and similar across treatments. Most (98%) were unrelated or unlikely related to the study intervention. There were no deaths and only 18 targeted SAEs (diabetic ketoacidosis, n = 12; severe hypoglycemia, n = 5; lactic acidosis, n = 1). There were 62 pregnancies occurring in 45 participants, and 6 infants had congenital anomalies.. The TODAY study represents extensive experience managing type 2 diabetes in youth and found that the three treatment approaches were generally safe and well tolerated. Adding rosiglitazone to metformin may reduce GI side effects and hepatotoxicity.

Topics: Adolescent; Blood Glucose; Child; Diabetes Mellitus, Type 2; Drug Combinations; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Thiazoles

Increased myocardial lipid delivery is a determinant of myocardial substrate metabolism and function in animal models of type 2 diabetes (T2DM). Sex also has major effects on myocardial metabolism in the human heart. Our aims were to determine whether 1) sex affects the myocardial metabolic response to lipid lowering in T2DM, 2) altering lipid [fatty acid (FA) or triglyceride] delivery to the heart would lower the elevated myocardial lipid metabolism associated with T2DM, and 3) decreasing lipid delivery improves diastolic dysfunction in T2DM. To this end, we studied 78 T2DM patients (43 women) with positron emission tomography, echocardiography, and whole body tracer studies before and 3 mo after randomization to metformin (MET), metformin + rosiglitazone (ROSI), or metformin + Lovaza (LOV). No treatment main effects were found for myocardial substrate metabolism, partly because men and women often had different responses to a given treatment. In men, MET decreased FA clearance, which was linked to increased plasma FA levels, myocardial FA utilization and oxidation, and lower myocardial glucose utilization. In women, ROSI increased FA clearance, thereby decreasing plasma FA levels and myocardial FA utilization. Although LOV did not change triglyceride levels, it improved diastolic function, particularly in men. Group and sex also interacted in determining myocardial glucose uptake. Thus, in T2DM, different therapeutic regimens impact myocardial metabolism and diastolic function in a sex-specific manner. This suggests that sex should be taken into account when designing a patient's diabetes treatment.

Topics: Analysis of Variance; Chi-Square Distribution; Diabetes Mellitus, Type 2; Diastole; Dietary Supplements; Docosahexaenoic Acids; Double-Blind Method; Drug Combinations; Echocardiography, Doppler; Eicosapentaenoic Acid; Energy Metabolism; Fatty Acids; Fatty Acids, Omega-3; Female; Health Status Disparities; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Missouri; Myocardium; Positron-Emission Tomography; Recovery of Function; Sex Factors; Stroke Volume; Thiazoles; Time Factors; Treatment Outcome; Triglycerides; Ventricular Function, Left; Ventricular Pressure

Alanine aminotransferase (ALT) predicts incident type 2 diabetes (T2DM), possibly reflecting early fatty liver and hepatic insulin resistance. Thiazolidinediones and metformin can improve fatty liver and hepatic insulin resistance, respectively. In the Canadian Normoglycemia Outcome Evaluation trial, rosiglitazone/metformin (Rosi/Met, 4/1000 mg) reduced incident T2DM by 66% in subjects with impaired glucose tolerance. For insight on the hepatic effects of this therapy in relation to T2DM, we evaluated the temporal changes in waist, hepatic insulin sensitivity (1/Homeostasis Model Assessment of Insulin Resistance) and ALT in the Rosi/Met (n = 103) and placebo (n = 104) arms over median of 3.9 years. Waist did not differ between the arms. Hepatic insulin sensitivity improved in the Rosi/Met arm in year 1, but deteriorated thereafter as in the placebo arm. In contrast, Rosi/Met lowered ALT in year 1 and maintained this effect throughout the trial. Thus, low-dose Rosi/Met had no effect on central obesity, a transient effect on hepatic insulin sensitivity, and a sustained effect on ALT.

Topics: Alanine Transaminase; Blood Glucose; Diabetes Mellitus, Type 2; Drug Combinations; Fatty Liver; Female; Glucose Intolerance; Humans; Hypoglycemic Agents; Insulin Resistance; Liver; Male; Metformin; Obesity, Abdominal; Thiazoles; Waist-Hip Ratio

The purpose of this study was to evaluate if superior glycaemic control could be achieved with Avandamet® (rosiglitazone/metformin/AVM) compared with metformin (MET) monotherapy, and if glycaemic effects attained with AVM are durable over 18 months of treatment. Bone mineral density (BMD) and bone biomarkers were evaluated in a subgroup of patients.. This was a phase IV, randomized, double-blind, multi-centre study in 688, drug naÏve, male and female patients who had an established clinical diagnosis of type 2 diabetes mellitus (T2DM). Patients were randomized in a 1 : 1 ratio either to AVM or MET.. As initial therapy in patients with T2DM, AVM was superior to MET in achieving statistically significant reductions in glycated haemoglobin (HbA1c) (p < 0.0001) and fasting plasma glucose (FPG) (p < 0.001), with more patients reaching recommended HbA1c and FPG targets for intensive glycaemic control. The glycaemic effects attained with AVM compared to MET monotherapy were durable over 18 months of treatment. In the bone substudy, AVM was associated with a significantly lower BMD in comparison with MET at week 80 in the lumbar spine and total hip (p < 0.0012 and p = 0.0005, respectively). Between-treatment differences were not statistically significant for distal one-third of radius BMD, femoral neck BMD or total BMD.. Superior glycaemic control was achieved with AVM compared with MET monotherapy. The superior glycaemic effects were shown to be durable over 18 months of treatment. AVM was associated with a significantly reduced BMD in comparison with MET at week 80 in the lumbar spine and total hip.

Topics: Adolescent; Adult; Aged; Biomarkers; Blood Glucose; Bone Density; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Combinations; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Thiazoles; Treatment Outcome; Young Adult

To compare the efficacy and safety of either continuing or discontinuing rosiglitazone + metformin fixed-dose combination when starting insulin therapy in people with Type 2 diabetes inadequately controlled on oral therapy.. In this 24-week double-blind study, 324 individuals with Type 2 diabetes inadequately controlled on maximum dose rosiglitazone + metformin therapy were randomly assigned to twice-daily premix insulin therapy (target pre-breakfast and pre-evening meal glucose < or = 6.5 mmol/l) in addition to either rosiglitazone + metformin (8/2000 mg) or placebo.. Insulin dose at week 24 was significantly lower with rosiglitazone + metformin (33.5 +/- 1.5 U/day, mean +/- se) compared with placebo [59.0 +/- 3.0 U/day; model-adjusted difference -26.6 (95% CI -37.7, -15,5) U/day, P < 0.001]. Despite this, there was greater improvement in glycaemic control [HbA(1c) rosiglitazone + metformin vs. placebo 6.8 +/- 0.1 vs. 7.5 +/- 0.1%; difference -0.7 (-0.8, -0.5)%, P < 0.001] and more individuals achieved glycaemic targets (HbA(1c) < 7.0% 70 vs. 34%, P < 0.001). The proportion of individuals reporting at least one hypoglycaemic event during the last 12 weeks of treatment was similar in the two groups (rosiglitazone + metformin vs. placebo 25 vs. 27%). People receiving rosiglitazone + metformin in addition to insulin reported greater treatment satisfaction than those receiving insulin alone. Both treatment regimens were well tolerated but more participants had oedema [12 (7%) vs. 4 (3%)] and there was more weight gain [3.7 vs. 2.6 kg; difference 1.1 (0.2, 2.1) kg, P = 0.02] with rosiglitazone + metformin.. Addition of insulin to rosiglitazone + metformin enabled more people to reach glycaemic targets with less insulin, and was generally well tolerated.

Topics: Adolescent; Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Europe; Female; Humans; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Thiazoles; Treatment Outcome

Traditional first-line intervention in patients with type 2 diabetes and very poor glycaemic control is insulin therapy or high doses of sulfonylureas if there is no evidence of volume depletion. This study explored the safety and efficacy of open-label treatment with rosiglitazone and metformin (RSG/MET) fixed-dose combination therapy (AVANDAMET) in patients with type 2 diabetes with very poor glycaemic control, to better characterize the magnitude of glycated haemoglobin (A1c) reduction after 24 weeks of therapy.. In this multicentre, open-label trial, 190 patients with an A1c greater than 11% or fasting plasma glucose (FPG) greater than 15 mmol/l were included after failing to meet glycaemic entry criteria for a primary double-blind, controlled, randomized study. Unless tolerability issues arose, eligible patients initiated RSG/MET 4 mg/1000 mg fixed-dose combination therapy and were up-titrated in increments of 2 mg/500 mg at 4-week intervals to a daily dose of 8 mg/2000 mg or the maximum tolerated dose. Patients were assessed for efficacy and safety at five visits over a 24-week period. The primary efficacy end point was change from baseline in A1c at week 24. Secondary efficacy end points included the proportion of patients achieving defined A1c targets, change from baseline to week 24 in FPG and insulin sensitivity.. The majority of patients (78%) completed 24 weeks of open-label treatment. At week 24, clinically significant mean reduction in A1c from 11.8 to 7.8% (mean reduction, 4.0 +/- 2.2%; p < 0.0001) and mean FPG reduction from 16.9 to 9.2 mmol/l (mean reduction, 7.7 +/- 4.4 mmol/l; p < 0.0001) were observed. A clinically significant reduction in FPG (5.2 mmol/l) was observed after 4 weeks of treatment with RSG/MET fixed-dose combination therapy. Despite a high mean baseline A1c of 11.8%, 33% of patients achieved treatment goal of A1c less than or equal to 6.5% at week 24, and 44% achieved an A1c less than 7% at week 24. RSG/MET fixed-dose combination was well tolerated, with a low incidence of hypoglycaemia (2%) and mean increase in weight from baseline of 2.6 +/- 5.2 kg, and few patients withdrew (2.6%) because of an adverse event.. RSG/MET fixed-dose combination therapy was effective as initial therapy in patients with type 2 diabetes and very high levels of A1c and/or FPG, as demonstrated by robust and relatively rapid improvements in glycaemic control. RSG/MET fixed-dose combination was well tolerated as first-line therapy with no new tolerability issues identified.

Topics: Adolescent; Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Combinations; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Resistance; Lipids; Male; Metformin; Middle Aged; Thiazoles; Treatment Outcome

This study assessed the efficacy and safety of rosiglitazone and metformin (RSG/MET) fixed-dose combination (AVANDAMET) as initial therapy in patients with uncontrolled type 2 diabetes compared with monotherapy with either RSG or MET after 32 weeks of treatment.. A total of 468 drug-naive patients with uncontrolled type 2 diabetes were recruited for this multicentre, double-blind trial if their glycated haemoglobin (A1c) was greater than 7.5%, but less than or equal to 11%, and their fasting plasma glucose (FPG) was less than or equal to 15 mmol/l. Patients were randomized to 32 weeks of blinded treatment with either RSG/MET fixed-dose combination (n = 155), MET (n = 154) or RSG (n = 159). The groups were comparable at baseline, with mean A1c of 8.8% and FPG of 11 mmol/l. RSG/MET was initiated with a total daily dose of 2 mg/500 mg and could be increased up to 8 mg/2000 mg; MET therapy began with a total daily dose of 500 mg and could be increased up to 2000 mg; and RSG treatment began with a total daily dose of 4 mg and could be increased up to 8 mg. Medication was uptitrated during on-therapy visits based on failure to attain glycaemic target of mean daily glucose less than or equal to 6.1 mmol/l (unless at maximum tolerated dose). Patients were assessed for efficacy and safety at nine visits over a 32-week treatment period. This was a trial designed to show greater efficacy of RSG/MET combination therapy compared with MET or RSG monotherapy. The primary end point was change in A1c from baseline to week 32. Secondary end points included the proportion of patients achieving recommended A1c and FPG targets for glycaemic control and change from baseline in FPG, free fatty acid, lipids, insulin, insulin sensitivity, C-reactive protein and adiponectin. Safety evaluations included adverse-event (AE) monitoring, changes in weight and clinical laboratory evaluations.. At week 32, RSG/MET showed significant improvements in A1c from a baseline of 8.9 +/- 1.1% to 6.6 +/- 1.0% at study end, and this 2.3% reduction was significantly greater than the reductions achieved individually with MET (-1.8%; p = 0.0008) and RSG (-1.6%; p < 0.0001). The greatest mean decrease in FPG was seen with RSG/MET (-4.1 mmol/l) and was significant compared with MET (-2.8 mmol/l; p < 0.0001) and RSG (-2.6 mmol/l; p < 0.0001). Target A1c of less than or equal to 6.5% and less than 7% were achieved in more patients in the RSG/MET group (60% and 77%) than with MET (39% and 57%) or RSG (35% and 58%) respectively. Treatment was well tolerated, with nausea, vomiting and diarrhoea as the most commonly reported AEs. Oedema was comparable between RSG/MET (6%) and RSG (7%) and lower in the MET group (3%). No new safety and tolerability issues were observed in the RSG/MET group.. As first-line therapy in patients with uncontrolled type 2 diabetes, RSG/MET fixed-dose combination therapy achieved significant reductions in A1c and FPG compared with either RSG or MET monotherapy. RSG/MET was generally well tolerated as initial therapy, with no new tolerability issues identified with the fixed-dose combination.

Topics: Adolescent; Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Combinations; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Lipids; Male; Metformin; Middle Aged; Rosiglitazone; Thiazoles; Thiazolidinediones; Treatment Outcome

The effect of pioglitazone was compared with that of other second-line glucose-lowering drugs on the risk of dementia among individuals with type 2 diabetes receiving metformin-based dual therapy.. A total of 204,323 individuals with type 2 diabetes aged ≥18 years who were stable metformin users and dementia-free before the initiation of second-line glucose-lowering medication were identified in the period 2000-2011 from Taiwan's National Health Insurance Research Database and followed to the end of 2013. Primary analyses included 51,415 individuals aged ≥65 years without dementia events in the first year of second-line glucose-lowering treatment. Study subjects were classified into mutually exclusive groups according to various second-line glucose-lowering drugs to metformin. Cox proportional hazards models were applied to assess the time-to-event between propensity score-matched glucose-lowering treatment groups.. Individuals aged ≥65 years on metformin + pioglitazone had a significantly lower risk of dementia compared with those on metformin + sulfonylurea (HR 0.56; 95% CI 0.34, 0.93), and a lower, but insignificant, risk of dementia compared with those on other metformin-based dual regimens (i.e. metformin + acarbose, metformin + meglitinide, metformin + insulin or metformin + dipeptidyl peptidase 4 inhibitors). Among individuals aged ≥18 years, there was also a decreased risk of dementia in those taking pioglitazone compared with those taking other second-line glucose-lowering drugs. A lower incidence of dementia was found in users of metformin + pioglitazone compared with users of metformin + rosiglitazone.. Pioglitazone as a second-line treatment after metformin might provide a protective effect on dementia risk among individuals with type 2 diabetes.

Topics: Aged; Dementia; Diabetes Mellitus, Type 2; Drug Combinations; Female; Humans; Hypoglycemic Agents; Longitudinal Studies; Male; Metformin; Pioglitazone; Thiazoles; Thiazolidinediones

The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study demonstrated that glycemic failure rates in the three treatments combined-metformin plus rosiglitazone, metformin alone, and metformin plus lifestyle-were higher in non-Hispanic blacks (NHB; 52.8%) versus non-Hispanic whites (NHW; 36.6%) and Hispanics (H; 45.0%). Moreover, metformin alone was less effective in NHB versus NHW versus H youth. This study describes treatment-associated changes in adiponectin, insulin sensitivity, and β-cell function over time among the three racial/ethnic groups to understand potential mechanism(s) responsible for this racial/ethnic disparity.. TODAY participants underwent periodic oral glucose tolerance tests to determine insulin sensitivity, C-peptide index, and oral disposition index (oDI), with measurements of total and high-molecular-weight adiponectin (HMWA).. At baseline NHB had significantly lower HMWA than NHW and H and exhibited a significantly smaller increase (17.3% vs. 33.7% vs. 29.9%, respectively) during the first 6 months overall. Increases in HMWA were associated with reductions in glycemic failure in the three racial/ethnic groups combined (hazard ratio 0.61, P < 0.0001) and in each race/ethnicity separately. Over time, HMWA was significantly lower in those who failed versus did not fail treatment, irrespective of race/ethnicity. There were no differences in treatment-associated temporal changes in insulin sensitivity, C-peptide index, and oDI among the three racial/ethnic groups.. HMWA is a reliable biomarker of treatment response in youth with type 2 diabetes. The diminutive treatment-associated increase in HMWA in NHB (∼50% lower) compared with NHW and H may explain the observed racial/ethnic disparity with higher therapeutic failure rates in NHB in TODAY.

Topics: Adiponectin; Adolescent; Black People; Blood Glucose; C-Peptide; Child; Diabetes Mellitus, Type 2; Drug Combinations; Ethnicity; Female; Glucose Tolerance Test; Health Status Disparities; Hispanic or Latino; Humans; Hypoglycemic Agents; Insulin Resistance; Life Style; Male; Metformin; Thiazoles; Treatment Failure; White People

Commercialization of rosiglitazone, an oral blood glucose-lowering drug of the thiazolidinedione class, was recently suspended in Europe and significantly restricted in the United States due to a possibly increased risk of ischemic heart disease; the drug is still being marketed in Mexico. This study was aimed to analyze the post-marketing occurrence of adverse drug reactions (ADRs) with rosiglitazone when used in combination therapy in Mexican Type 2 Diabetes patients.. A prospective observational study was conducted at a primary health-care clinic in Mexico City. Eligible subjects were adult patients with Type 2 diabetes inadequately controlled with maximal doses of oral monotherapy, in which one of two combined therapeutic schemes was prescribed: rosiglitazone/glibenclamide (R/G), or rosiglitazone/metformin (R/M). Patients' blood pressure, weight, treatment adherence and occurrence of ADRs were monitored during a 6-month follow-up period.. 174 patients received treatment with R/M or R/G (112 and 62 patients, respectively). At least one ADR was observed in about 75%, of patients. Prior to the end of the follow-up period, moderate ADRs leading to discontinuation of the treatment occurred in 29.5% and 14.5% of patients treated with R/M and R/G, respectively. The ADRs most frequently observed were peripheral edema and moderate weight gain.. The use of rosiglitazone in combination with other oral anti-diabetic drugs was associated with a high frequency of ADRs in Mexican patients with Type 2 diabetes. Post-marketing studies are relevant to identify drug-associated risks to patients in clinical practice.

Topics: Administration, Oral; Adult; Aged; Diabetes Mellitus, Type 2; Drug Combinations; Edema; Female; Follow-Up Studies; Glyburide; Humans; Hypoglycemic Agents; Male; Medication Adherence; Metformin; Mexico; Middle Aged; Pharmacovigilance; Prospective Studies; Rosiglitazone; Thiazoles; Thiazolidinediones; Weight Gain

Clinical practice guidelines from around the world have continued to highlight the importance of glycemic control in the prevention of diabetes complications. Despite the many tools available to achieve these targets, it remains a constant challenge for healthcare providers and patients alike. Rosiglitazone maleate + metformin hydrochloride extend is a new compound that has the advantage of the clinical experience and knowledge about the current version and the added benefit of being a once daily, single pill option. The existing version of rosiglitazone + metformin has been shown to effectively lower hemoglobin A1C, improve insulin sensitivity and minimize weight gain. It is expected that the new compound will also have similar features, with the added benefit of improved patient adherence given its once daily formulation.

Topics: Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Drug Combinations; Gluconeogenesis; Humans; Hypoglycemic Agents; Metformin; Molecular Structure; Thiazoles; Treatment Outcome

To study effects of avandia and its combination with metformine (avandamet) on secretion of fat tissue hormones.. The examination protocol for 42 patients with type 2 diabetes mellitus (DM) aged 62.4 +/- 7.7 years comprised tests for blood levels of leptin, soluble receptor to leptin, insulin, grelin, resistin and adiponectine.. The treatment resulted in reduction of fasting glycemia from 10.69 +/- 2.54 to 8.42 +/- 1.73 mmol/l, of glycosilated hemoglobin--from 8.1 + 1.6 to 7.75%, immunoreactive insulin--from 19.1 +/- 8.3 to 12.0 +/- 6.5 mg/ml, grelin--from 21.7 +/- 14.6 to 17.3 +/- 13.7 mg/ml, leptin--from 40.3 +/- 24.2 to 26.9 +/- 15.4 mg/ml, soluble receptor to leptin--from 17.9 +/- 4.5 to 13.1 +/- 3.5 mg/ml. LDLP and HDLP cholesterol was high.. Avandia and avandamet are effective antidiabetic drugs with a beneficial effect on secretion of fat tissue hormones.

Topics: Adiponectin; Adipose Tissue; Diabetes Mellitus, Type 2; Drug Combinations; Female; Fibrinolytic Agents; Ghrelin; Humans; Hypoglycemic Agents; Insulin; Leptin; Male; Metformin; Middle Aged; Resistin; Rosiglitazone; Thiazoles; Thiazolidinediones

Topics: Confounding Factors, Epidemiologic; Data Interpretation, Statistical; Diabetes Mellitus, Type 2; Drug Combinations; Humans; Hypoglycemic Agents; Metformin; Rosiglitazone; Thiazoles; Thiazolidinediones

Topics: Diabetes Mellitus, Type 2; Drug Combinations; Humans; Hypoglycemic Agents; Metformin; Randomized Controlled Trials as Topic; Rosiglitazone; Thiazoles; Thiazolidinediones

Topics: Body Mass Index; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Combinations; Drug Therapy, Combination; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Metformin; Patient Compliance; Placebos; Rosiglitazone; Thiazoles; Thiazolidinediones; Time Factors

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Fees, Pharmaceutical; Glipizide; Humans; Hypoglycemic Agents; Metformin; Thiazoles