Rosiglitazone Combination Therapy Research Articles

Rosiglitazone and imidapril alone or in combination alleviate muscle and adipose depletion in a murine cancer cachexia model

Rosiglitazone (RGZ) and imidapril improve cancer cachexia via different mechanisms. Therefore, we hypothesized that combination therapy of RGZ+imidapril would further attenuate cancer cachexia in vivo. After injection with colon-26 adenocarcinoma for 9 days, BALB/c mice were randomly divided into the following four treatment groups for 7 days (n = 8 per group): (1) placebo, (2) RGZ, (3) imidapril, and (4) RGZ+imidapril. Eight healthy control animals were also assessed. Body weight, tumor volume, gastrocnemius muscle and epididymal adipose mass, serum metabolic markers and cytokines, and the expression of nuclear factor-κB and two E3 ubiquitin ligases, atrogin-1 and MuRF-1, were measured. From days 14 to 16, all treatments significantly reduced tumor volume (P < 0.05). From days 10 to 16, improvements in the tumor-free body weight were observed in the RGZ and RGZ+imidapril groups. In addition, significant improvements in both gastrocnemius muscle and epididymal adipose mass were observed in all treatment groups (all, P < 0.05). Furthermore, all treatments significantly increased tumor necrosis factor alpha levels as compared to those observed in the healthy control animals (P < 0.001). Insulin levels significantly increased in the placebo group as compared to those in the healthy control group (P < 0.05), which were reduced in all the treatment groups (P < 0.05). Finally, whereas all treatments significantly reduced atrogin-1 levels as compared to the placebo group (all, P < 0.05), significant reductions in MuRF-1 levels were only observed in the RGZ and RGZ+imidapril groups (both, P < 0.05). Thus, all three treatments reduce tumor growth and alleviate cancer cachexia; however, synergistic effects of RGZ+imidapril combination therapy were not observed.

Efficacy and safety of sitagliptin added to ongoing metformin and rosiglitazone combination therapy in a randomized placebo‐controlled 54‐week trial in patients with type 2 diabetes (一项为期54周的对持续使用二甲双胍与罗格列酮联合治疗的2型糖尿病患者加用西格列汀治疗的有效性与安全性的随机安慰剂对照研究)*

AbstractBackground: New therapeutic approaches are needed to improve glycemic control in patients with type 2 diabetes (T2D), a progressive disorder that often requires combination therapy. The present study assessed the efficacy and safety of sitagliptin as add‐on therapy to metformin and rosiglitazone in patients with T2D.Methods: The present study was a randomized double‐blind placebo‐controlled parallel‐group 54‐week study conducted at 41 sites across North and South America, Europe, and Asia in 278 patients with HbA1c ranging from ≥7.5% to ≤11.0% despite ongoing combination therapy with metformin (≥1500 mg/day) and rosiglitazone (≥4 mg/day). Patients were randomized (2:1) to receive sitagliptin 100 mg or placebo once daily. The main outcome measure was change from baseline in HbA1c at Week 18.Results: Mean baseline HbA1c was 8.8%. The mean placebo‐adjusted change from baseline in HbA1c with sitagliptin treatment was −0.7% (P &lt; 0.001) at Week 18 and −0.8% (P &lt; 0.001) at Week 54. There were also significant (P &lt; 0.001) reductions in 2‐h post‐meal glucose and fasting plasma glucose compared with placebo at Weeks 18 and 54. Significantly higher proportions of sitagliptin‐ than placebo‐treated patients had HbA1c&lt;7.0% at Weeks 18 (22% vs 9%; P = 0.003) and 54 (26% vs 14%; P = 0.015). Changes in body weight and the rates of adverse events overall, hypoglycemia, and gastrointestinal adverse events were similar in the sitagliptin and placebo groups during the 54‐week study.Conclusions: In patients with T2D, the addition of sitagliptin for 54 weeks to ongoing therapy with metformin and rosiglitazone improved glycemic control and was generally well tolerated compared with placebo.

Effects of Metformin and Rosiglitazone on Peripheral Insulin Resistance and β-Cell Function in Obesity: A Double-Blind, Randomized, Controlled Study

Metformin and rosiglitazone combination therapy is known to improve insulin resistance and postpone diabetes mellitus development in subjects with impaired glucose tolerance. This double-blind, randomized, controlled study assessed this combination therapy for preventing type 2 diabetes in obese subjects with hyperinsulinaemia. Subjects received metformin (500 mg three times daily, orally) plus either rosiglitazone (4 mg once daily, orally; n = 94) or placebo (n = 95) and were followed for 6 months. Blood pressure, body fat, body mass index (BMI), lipid and insulin levels were recorded pre- and post-treatment. Metformin plus rosiglitazone significantly decreased blood pressure, lipids, BMI, and fasting and postmeal insulin levels. Metformin plus placebo led to a significant decrease in blood pressure, BMI and lipid levels, but fasting and postmeal insulin levels were unchanged. Adverse events were similar between the two groups. The metformin and rosiglitazone combination increased insulin sensitivity and β-cell function recovered. This approach may represent a therapeutic option for preventing development of type 2 diabetes in obese subjects with hyperinsulinaemia.

Inhibitory effect on hepatitis B virus in vitro by a peroxisome proliferator-activated receptor-γ ligand, rosiglitazone

Although chronic infection of hepatitis B virus (HBV) is currently managed with nucleot(s)ide analogues or interferon-α, the control of HBV infection still remains a clinical challenge. Peroxisome proliferator-activated receptor (PPAR) is a ligand-activated transcription factor, that plays a role in glucose and lipid metabolism, immune reactions, and inflammation. In this study, the suppressive effect of PPAR ligands on HBV replication was examined in vitro using a PPARα ligand, bezafibrate, and a PPARγ ligand, rosiglitazone. The effects were examined in HepG2 cells transfected with a plasmid containing 1.3-fold HBV genome. Whereas bezafibrate showed no effect against HBV replication, rosiglitazone reduced the amount of HBV DNA, hepatitis B surface antigen, and hepatitis B e antigen in the culture supernatant. Southern blot analysis showed that the replicative intermediates of HBV in the cells were also inhibited. It was confirmed that GW9662, an antagonist of PPARγ, reduced the suppressive effect of rosiglitazone on HBV. Moreover, rosiglitazone showed a synergistic effect on HBV replication with lamivudine or interferon-α-2b. In conclusion, this study showed that rosiglitazone inhibited the replication of HBV in vitro, and suggested that the combination therapy of rosiglitazone and nucleot(s)ide analogues or interferon could be a therapeutic option for chronic HBV infection.

Spirulina protects against Rosiglitazone induced osteoporosis in insulin resistance rats

Aim The study was undertaken to assess the protective effect of Spirulina fusiformis extract against Rosiglitazone induced osteoporosis and pharmacodynamic effects of Rosiglitazone with Spirulina in treating hyperglycemia and hyperlipidemia of insulin resistance rat. Method For this aim, 30 Wistar albino rats were equally divided into five groups as control (C), diabetes mellitus (DM), diabetes mellitus + Rosiglitazone (DM + R), diabetes mellitus + Spirulina (DM + S), and diabetes mellitus + Rosiglitazone + Spirulina (DM + R + S). Serum glucose, triglyceride, HDL, LDL and insulin concentrations were estimated by routine standard methods in blood samples collected on 21th day. Integrity of the bone surface was examined by scanning electronic microscopy, and bone strength was measured by micro-hardness test on 45th day. Results A significant decrease in total bone mineral density was observed in group DM + R rats ( p < 0.05). The number and depth of resorptive pits on surface of the bone in Rosiglitazone treated rats improved clearly with Spirulina administration. The intactness and integrity of the bone surface as well as the bone strength improved due to the high content of calcium and phosphorous in Spirulina. Besides, chromium and gamma-linoleic acid in Spirulina helped to decrease the fasting serum glucose, HDL, LDL and triglycerides levels in insulin resistance rats. Conclusion These findings suggest that combination therapy of Rosiglitazone with Spirulina reduced the risk of osteoporosis in insulin resistance rats. Additionally, Spirulina complemented the antihyperglycemic and antilipidemic activity of Rosiglitazone.

Cost-effectiveness of Rosiglitazone Oral Combination for the Treatment of Type 2 Diabetes in Germany

To assess the cost-effectiveness of rosiglitazone in combination with other oral agents for the treatment of overweight and obese patients with type 2 diabetes in Germany. The Diabetes Decision Analysis of Cost--type 2 model was adapted for clinical practice and healthcare financing rules in Germany. The model was calibrated using Cost of Diabetes in Europe Type 2 study data and national statistics. The perspective is that of the sickness funds, and includes all hospital inpatient, ambulatory, rehabilitation, and diabetes therapy, other medications, and sickness leave. The model simulates lifetime treatment histories and associated health outcomes and costs for age and sex-matched cohorts of 1000 overweight and obese patients. The measures of effectiveness used in the analysis were life-years and quality adjusted life-years (QALYs). The combination therapy of rosiglitazone with metformin or sulfonylurea produces better glycaemic control than conventional care of metformin with sulfonylurea and insulin in most patients, extends the viability of oral therapy before requiring insulin, and typically leads to lifetime cost increases across all treatment types. The improvements in glycaemic control lead to survival gains and reductions in morbidity, because of the reduced risk of developing or progressing to later stages of complications. Improvements in morbidity and mortality generate additional QALYs. Costs and health outcomes combine to yield favourable incremental cost-effectiveness ratios, which fall below international 'willingness-to-pay' thresholds in the medium term. The model predicts that rosiglitazone in combination with other oral agents is a cost-effective intervention for the treatment of normal weight, overweight and obese patients with type 2 diabetes when compared with conventional care in Germany.

Cost-effectiveness of Rosiglitazone Combination Therapy for the Treatment of Type 2 Diabetes Mellitus in the UK

Recent clinical trial results have demonstrated that, in patients with type 2 diabetes, second-line treatment of rosiglitazone in combination with metformin can lead to significant improvements in the control of fasting plasma glucose/ glycosylated haemoglobin A1c (HbA1c) after the failure of metformin monotherapy. Our objective was to assess the cost-effectiveness of the use of rosiglitazone in combination with metformin in overweight and obese patients with type 2 diabetes in the UK, failing to maintain glycaemic control with metformin monotherapy compared with conventional care using metformin in combination with sulfonylurea. The Diabetes Decision Analysis of Cost--type 2 (DiDACT) model, an established long-term economic model of type 2 diabetes, which projects the relationship between treatment and HbA1c over extended periods, was used to determine the health outcomes and economic impact for matched age and sex cohorts of 1000 patients with type 2 diabetes. The perspective was that of the UK National Health Service and all costs were in UK pounds sterling. Treatment with rosiglitazone in combination with metformin provides better glycaemic control over the remaining lifetime of patients than metformin and sulfonylurea combination therapy. Patients treated with rosiglitazone combination therapy were predicted to have a longer life expectancy, gaining 123 and 140 additional life years per 1000 patients in the obese and overweight cohorts, respectively. Improvements in morbidity and a delay in the start of insulin therapy resulted in a projected improvement in quality of life. These effects combine with projected improved survival to yield 131 and 209 additional quality-adjusted life-years (QALYs) per 1000 patients in the obese and overweight cohorts, respectively. Discounted incremental cost-effectiveness ratios were estimated at pounds 16,700 per QALY gained for the obese cohort and pounds 11,600 per QALY gained for the overweight cohort. The model predicts that rosiglitazone in combination with metformin is a cost-effective treatment in the UK for both obese and overweight patients failing on metformin monotherapy, compared with conventional therapy using metformin in combination with sulfonylurea.

Effects of Rosiglitazone Alone and in Combination With Atorvastatin on Nontraditional Markers of Cardiovascular Disease in Patients With Type 2 Diabetes Mellitus

Combination therapy of rosiglitazone and atorvastatin has been shown to have beneficial effects on glycemic control and lipid profiles in patients with type 2 diabetes mellitus. This study investigated the effects of the combination of rosiglitazone and atorvastatin on vascular inflammation by studying their effects on levels of biomarkers in patients with type 2 diabetes mellitus. Thirty patients with type 2 diabetes mellitus and hyperlipidemia were enrolled to receive rosiglitazone monotherapy at 4 mg/day for 3 months and then atorvastatin at 10 mg/day was added for 3 more months as combined therapy. Inflammatory biomarkers, including high-sensitivity C-reactive protein (hs-CRP), matrix metalloproteinase-9 (MMP-9), soluble CD40 ligand (sCD40L), and adiponectin, and lipid profiles were measured at the time of initiation, after rosiglitazone monotherapy and after combination therapy with rosiglitazone and atorvastatin. With treatment of rosiglitazone at 4 mg/day monotherapy for 3 months, hs-CRP levels decreased significantly by 26% (p <0.05) and adiponectin levels increased significantly by 192% (p <0.05), but no significant changes in levels of MMP-9 and sCD40L were demonstrated. After combination therapy, hs-CRP levels further significantly decreased by another 23% (p <0.05) and adiponectin further increased by another 124%. In addition, serum levels of MMP-9, sCD40L, total cholesterol, and low-density lipoprotein cholesterol decreased significantly compared with baseline levels. In conclusion, combination therapy with rosiglitazone and atorvastatin not only significantly improved lipid profiles but also decreased levels of vascular biomarkers, such as hs-CRP, MMP-9, and sCD40L, and increased serum adiponectin levels in patients with type 2 diabetes mellitus.

Metformin plus rosiglitazone had more effective glycemic control than metformin alone in type 2 diabetes mellitus

Source Citation Fonseca V, Rosenstock J, Patwardhan R, Salzman A. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. JAMA. 2000 Apr 5;283:1695-702. 10755495