IMPORTANCE Numerous glucose-lowering drugs are used to treat type 2 diabetes. OBJECTIVE To estimate the relative efficacy and safety associated with glucose-lowering drugs including insulin. DATA SOURCES Cochrane Library Central Register of Controlled Trials, MEDLINE, and EMBASE databases through March 21, 2016. STUDY SELECTION Randomized clinical trials of 24 weeks' or longer duration. DATA EXTRACTION AND SYNTHESIS Random-effects network meta-analysis. MAIN OUTCOMES AND MEASURES The primary outcome was cardiovascular mortality. Secondary outcomes included all-cause mortality, serious adverse events, myocardial infarction, stroke, hemoglobin A 1c (HbA 1C) level, treatment failure (rescue treatment or lack of efficacy), hypoglycemia, and body weight. RESULTS A total of 301 clinical trials (1 417 367 patient-months) were included; 177 trials (56 598 patients) of drugs given as monotherapy; 109 trials (53 030 patients) of drugs added to metformin (dual therapy); and 29 trials (10 598 patients) of drugs added to metformin and sulfonylurea (triple therapy). There were no significant differences in associations between any drug class as monotherapy, dual therapy, or triple therapy with odds of cardiovascular or all-cause mortality. Compared with metformin, sulfonylurea (standardized mean difference [SMD], 0.18 [95% CI, 0.01 to 0.34]), thiazolidinedione (SMD, 0.16 [95% CI, 0.00 to 0.31]), DPP-4 inhibitor (SMD, 0.33 [95% CI, 0.13 to 0.52]), and α-glucosidase inhibitor (SMD, 0.35 [95% CI, 0.12 to 0.58]) monotherapy were associated with higher HbA 1C levels. Sulfonylurea (odds ratio [OR], 3.13 [95% CI, 2.39 to 4.12]; risk difference [RD], 10% [95% CI, 7% to 13%]) and basal insulin (OR, 17.9 [95% CI, 1.97 to 162]; RD, 10% [95% CI, 0.08% to 20%]) were associated with greatest odds of hypoglycemia. When added to metformin, drugs were associated with similar HbA 1C levels, while SGLT-2 inhibitors offered the lowest odds of hypoglycemia (OR, 0.12 [95% CI, 0.08 to 0.18]; RD, −22% [−27% to −18%]). When added to metformin and sulfonylurea, GLP-1 receptor agonists were associated with the lowest odds of hypoglycemia (OR, 0.60 [95% CI, 0.39 to 0.94]; RD, −10% [95% CI, −18% to −2%]). CONCLUSIONS AND RELEVANCE Among adults with type 2 diabetes, there were no significant differences in the associations between any of 9 available classes of glucose-lowering drugs (alone or in combination) and the risk of cardiovascular or all-cause mortality. Metformin was associated with lower or no significant difference in HbA 1C levels compared with any other drug classes. All drugs were estimated to be effective when added to metformin. These findings are consistent with American Diabetes Association recommendations for using metformin monotherapy as initial treatment for patients with type 2 diabetes and selection of additional therapies based on patient-specific considerations.
Background and Objectives No evaluation of sex and race influences on MPA pharmacokinetics and adverse effects (AE) during enteric coated mycophenolate sodium (ECMPS) and tacrolimus immunosuppression are available. MPA and MPA glucuronide(MPAG) pharmacokinetics with gastrointestinal AE were investigated in 67 stable renal transplant recipients: 22 African American males(AAM); 13 AA females(AAF); 16 Caucasian males(CM) and 16 Caucasian females(CF) receiving ECMPS and tacrolimus. Methods Validated gastrointestinal AE rating included diarrhea, dyspepsia, vomiting and acid suppressive therapy was completed. Apparent clearance, clearance normalized to body mass index (BMI), area under concentration time curve 0-12 (AUC0-12) and dose normalized AUC 0-12 (AUC*) were determined using a statistical model that incorporated gastrointestinal AE and clinical covariates. Results Males had more rapid apparent MPA clearance (CM: 13.8 ± 6.27 L/h vs. AAM: 10.2 ± 3.73 L/h) compared to females (CF: 8.70 ± 3.33 L/h and AAF: 9.71 ± 3.94 L/hr; P=0.014) with a race-sex interaction (P=0.043). Sex differences were observed in MPA clearance/BMI (P=0.033) and AUC* (P=0.033). MPA AUC0-12 was greater than 60 mg•h/L in 57% of RTR with 71% of patients demonstrating gastrointestinal AE and a higher score noted in females. In all patients, females exhibited 1.40-fold increased gastrointestinal AE scores compared to males (P=0.024). Race (P=0.044) and sex (P=0.005) differences were evident with greater MPAG AUC0-12 in AAF and CF. Conclusion Sex and race differences were evident with females having slower MPA clearance, higher MPAG AUC0-12 and more severe gastrointestinal AE. These findings suggest consideration of sex and race during MPA immunosuppression.
Study Objective: This study investigated race and sex differences in tacrolimus pharmacokinetics and pharmacodynamics in stable kidney transplant recipients. Design andSetting: A cross-sectional, open-label, single center, 12-h pharmacokineticpharmacodynamic study was conducted. Tacrolimus pharmacokinetic parameters included area under the concentration-time curve (AUC 0-12 ), AUC 0-4 , 12-h troughs (C 12 h ), maximum concentrations (C max ), oral clearance (Cl), with dose-normalized AUC 0-12 , troughs, and C max with standardized adverse effect scores. Statistical models were used to analyze end points with individual covariate-adjustment including clinical factors, genotypic variants CYP3A5*3, CYP3A5*6, CYP3A5*7(CYP3A5*3*6*7) metabolic composite, and ATP binding cassette gene subfamily B member 1 (ABCB1) polymorphisms.Patients: 65 stable, female and male, Black and White kidney transplant recipients receiving tacrolimus and mycophenolic acid ≥6 months post-transplant were evaluated.Measurements and Main Results: Black recipients exhibited higher tacrolimus AUC 0-12
Race influences MPA exposure between MMF and EC-MPS and may warrant therapeutic monitoring during formulation conversion.
In an effort to address the need to include both sexes in studies of effects of the SSRI fluoxetine, the NRI reboxetine and the SNRI venlafaxine on anxiety-related behavior and memory along with the use of chronic drug administration, male and female PVG/c rats were fed diets containing two doses of each drug for 21 days. The rats' anxiety level was then assessed in an open field. Short-term spatial memory for a brightness change in a Y maze was also measured. While there was little evidence of anxiolytic effects of any of the drugs, both fluoxetine and, to a lesser extent, venlafaxine appeared to be mainly anxiogenic in their action depending on both dose and sex. Reboxetine was relatively ineffective in this respect. Ability to locate the Y-maze arm that had changed (from white to black) seemed to be impaired for male (but not female) rats by both fluoxetine and venlafaxine and, to a much lesser extent, by reboxetine. Given the relative ineffectiveness of reboxetine in either test, it is possible that the effects of the other two drugs on both anxiety and memory were mainly due to their serotonin reuptake inhibiting properties. The differences that occurred between males and females in responsiveness to all three drugs supported the long-held view that both sexes should be investigated in studies of this sort, especially in view of reports of sex differences in effects of clinically prescribed antidepressants.
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