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BMJ (Clinical Research Ed.) Jan 2015To summarize short term outcomes in randomized controlled trials comparing glibenclamide or metformin versus insulin or versus each other in women with gestational... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To summarize short term outcomes in randomized controlled trials comparing glibenclamide or metformin versus insulin or versus each other in women with gestational diabetes requiring drug treatment.
DESIGN
Systematic review and meta-analysis.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES
Randomized controlled trials that fulfilled all the following: (1) published as full text; (2) addressed women with gestational diabetes requiring drug treatment; (3) compared glibenclamide v insulin, metformin v insulin, or metformin v glibenclamide; and (4) provided information on maternal or fetal outcomes.
DATA SOURCES
Medline, CENTRAL, and Embase were searched up to 20 May 2014.
OUTCOMES MEASURES
We considered 14 primary outcomes (6 maternal, 8 fetal) and 16 secondary (5 maternal, 11 fetal) outcomes.
RESULTS
We analyzed 15 articles, including 2509 subjects. Significant differences for primary outcomes in glibenclamide v insulin were obtained in birth weight (mean difference 109 g (95% confidence interval 35.9 to 181)), macrosomia (risk ratio 2.62 (1.35 to 5.08)), and neonatal hypoglycaemia (risk ratio 2.04 (1.30 to 3.20)). In metformin v insulin, significance was reached for maternal weight gain (mean difference -1.14 kg (-2.22 to -0.06)), gestational age at delivery (mean difference -0.16 weeks (-0.30 to -0.02)), and preterm birth (risk ratio 1.50 (1.04 to 2.16)), with a trend for neonatal hypoglycaemia (risk ratio 0.78 (0.60 to 1.01)). In metformin v glibenclamide, significance was reached for maternal weight gain (mean difference -2.06 kg (-3.98 to -0.14)), birth weight (mean difference -209 g (-314 to -104)), macrosomia (risk ratio 0.33 (0.13 to 0.81)), and large for gestational age newborn (risk ratio 0.44 (0.21 to 0.92)). Four secondary outcomes were better for metformin in metformin v insulin, and one was worse for metformin in metformin v glibenclamide. Treatment failure was higher with metformin than with glibenclamide.
CONCLUSIONS
At short term, in women with gestational diabetes requiring drug treatment, glibenclamide is clearly inferior to both insulin and metformin, while metformin (plus insulin when required) performs slightly better than insulin. According to these results, glibenclamide should not be used for the treatment of women with gestational diabetes if insulin or metformin is available.Systematic review registration NCT01998113.
Topics: Adult; Birth Weight; Diabetes, Gestational; Female; Fetal Macrosomia; Glyburide; Humans; Hypoglycemia; Hypoglycemic Agents; Infant, Newborn; Insulin; Metformin; Pregnancy; Pregnancy Outcome; Randomized Controlled Trials as Topic; Regression Analysis
PubMed: 25609400
DOI: 10.1136/bmj.h102 -
Expert Opinion on Therapeutic Targets Nov 2021Cerebral edema is a key contributor to death and disability in several forms of brain injury. Current treatment options are limited, reactive, and associated with... (Review)
Review
INTRODUCTION
Cerebral edema is a key contributor to death and disability in several forms of brain injury. Current treatment options are limited, reactive, and associated with significant morbidity. Targeted therapies are emerging based on a growing understanding of the molecular underpinnings of cerebral edema.
AREAS COVERED
We review the pathophysiology and relationships between different cerebral edema subtypes to provide a foundation for emerging therapies. Mechanisms for promising molecular targets are discussed, with an emphasis on those advancing in clinical trials, including ion and water channels (AQP4, SUR1-TRPM4) and other proteins/lipids involved in edema signaling pathways (AVP, COX2, VEGF, and S1P). Research on novel treatment modalities for cerebral edema [including recombinant proteins and gene therapies] is presented and finally, insights on reducing secondary injury and improving clinical outcome are offered.
EXPERT OPINION
Targeted molecular strategies to minimize or prevent cerebral edema are promising. Inhibition of SUR1-TRPM4 (glyburide/glibenclamide) and VEGF (bevacizumab) are currently closest to translation based on advances in clinical trials. However, the latter, tested in glioblastoma multiforme, has not demonstrated survival benefit. Research on recombinant proteins and gene therapies for cerebral edema is in its infancy, but early results are encouraging. These newer modalities may facilitate our understanding of the pathobiology underlying cerebral edema.
Topics: Brain Edema; Glyburide; Humans; Sulfonylurea Receptors; TRPM Cation Channels
PubMed: 34844502
DOI: 10.1080/14728222.2021.2010045 -
Einstein (Sao Paulo, Brazil) 2022To compare the major outcomes of use of metformin and glyburide in treatment of gestational diabetes mellitus. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To compare the major outcomes of use of metformin and glyburide in treatment of gestational diabetes mellitus.
METHODS
Studies published in English, in the last 10 years, in the databases MEDLINE®, SciELO, LILACS and Cochrane Library were analyzed, and randomized controlled trials were selected. Health Sciences Descriptors were used to compose the search phrase, and the keywords "Gestational diabetes", "Glyburide", "Metformin" and their variations were searched in the Medical Subject Headings. PRISMA systematization was used to prepare this review, and a meta-analysis was conducted aiming to mathematically show the results of fasting blood glucose, postprandial blood glucose, birth weight and weight gain during pregnancy after using metformin and glyburide.
RESULTS
The studies evaluated birth weight, neonatal hypoglycemia, mode of delivery, need for intensive care, Apgar score, macrosomia, fasting glucose, postprandial glucose and weight gain during pregnancy. In 60% of studies, there were no statistically significant differences regarding safety and efficacy of administration of metformin and glyburide. Meta-analysis demonstrated the absence of statistical differences between these drugs in fasting blood glucose (p=0.821), postprandial blood glucose (p=0.217) and birth weight (p=0.194). However, significant differences were shown in weight gain during pregnancy (p=0.036).
CONCLUSION
The methods are effective, but the adverse effects of glyburide are more common; therefore, the use of metformin should be recommended, if in monotherapy.
Topics: Blood Glucose; Diabetes, Gestational; Female; Glyburide; Humans; Hypoglycemic Agents; Infant, Newborn; Insulin; Metformin; Pregnancy
PubMed: 35195193
DOI: 10.31744/einstein_journal/2022RW6155 -
Clinical Pharmacology and Therapeutics Jun 2020In gestational diabetes mellitus (GDM), women are unable to compensate for the increased insulin resistance during pregnancy. Data are limited regarding the... (Comparative Study)
Comparative Study Randomized Controlled Trial
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.
Topics: Adolescent; Adult; Blood Glucose; Diabetes, Gestational; Drug Therapy, Combination; Female; Glyburide; Humans; Hypoglycemic Agents; Insulin Resistance; Insulin-Secreting Cells; Longitudinal Studies; Metformin; Pregnancy; Prospective Studies; Young Adult
PubMed: 31869430
DOI: 10.1002/cpt.1749 -
PloS One 2020In pregnant women with gestational diabetes, glyburide can be an alternative to insulin despite concerns about its transplacental transfer. However, transplacental... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In pregnant women with gestational diabetes, glyburide can be an alternative to insulin despite concerns about its transplacental transfer. However, transplacental transfer of glyburide is poorly quantified and the relationship between cord blood glyburide concentration and hypoglycemia has not been studied. Our objective was to quantify the transplacental transfer of glyburide at delivery and to study the association between the cord blood glyburide concentration and the risk of neonatal hypoglycemia in patients with gestational diabetes treated with glyburide.
METHODS AND FINDINGS
INDAO was a multicenter, noninferiority, randomized trial conducted between May 2012 and November 2016 in 914 women with singleton pregnancies and gestational diabetes. An ancillary study was conducted in the 87 patients of the Bicêtre University Hospital Center. The sample consisted of 46 patients with utilizable assays at delivery. The relationships between glyburide concentration and the time since the last intake of glyburide and between fetal glyburide concentration and neonatal hypoglycemia were modeled with linear or logistic regressions using fractional polynomials. There was placental transfer of glyburide at a fetal to maternal ratio of 62% (95% CI [50; 74]). Umbilical cord blood glyburide concentration decreased steeply after the last maternal glyburide intake. After 24 hours, the mean umbilical cord blood concentration was less than 5 ng/mL. Neonatal hypoglycemia risk was increased with an odds ratio of hypoglycemia equal to 3.70 [1.40-9.77] for each 10 ng/mL increase in the cord blood glyburide concentration. However, no newborns were admitted to the NICU because of clinical signs of hypoglycemia or for treatment of hypoglycemia.
CONCLUSION
Considering that neonatal glyburide exposure may be limited by stopping treatment a sufficient time before labor, there may still be a place for glyburide in the management of gestational diabetes.
Topics: Administration, Oral; Adult; Diabetes, Gestational; Dose-Response Relationship, Drug; Female; Fetal Blood; Glyburide; Humans; Hypoglycemia; Hypoglycemic Agents; Infant, Newborn; Infant, Newborn, Diseases; Linear Models; Logistic Models; Maternal-Fetal Exchange; Odds Ratio; Pregnancy
PubMed: 32379777
DOI: 10.1371/journal.pone.0232002 -
Neurocritical Care Apr 2014The sulfonylurea receptor 1 (Sur1)-transient receptor potential 4 (Trpm4) channel is an important molecular element in focal cerebral ischemia. The channel is... (Review)
Review
The sulfonylurea receptor 1 (Sur1)-transient receptor potential 4 (Trpm4) channel is an important molecular element in focal cerebral ischemia. The channel is upregulated in all cells of the neurovascular unit following ischemia, and is linked to microvascular dysfunction that manifests as edema formation and secondary hemorrhage, which cause brain swelling. Activation of the channel is a major molecular mechanism of cytotoxic edema and "accidental necrotic cell death." Blockade of Sur1 using glibenclamide has been studied in different types of rat models of stroke: (i) in conventional non-lethal models (thromboembolic, 1-2 h temporary, or permanent middle cerebral artery occlusion), glibenclamide reduces brain swelling and infarct volume and improves neurological function; (ii) in lethal models of malignant cerebral edema, glibenclamide reduces edema, brain swelling, and mortality; (iii) in models with rtPA, glibenclamide reduces swelling, hemorrhagic transformation, and death. Retrospective studies of diabetic patients who present with stroke have shown that those whose diabetes is managed with a sulfonylurea drug and who are maintained on the sulfonylurea drug during hospitalization for stroke have better outcomes at discharge and are less likely to suffer hemorrhagic transformation. Here, we provide a comprehensive review of the basic science, preclinical experiments, and retrospective clinical studies on glibenclamide in focal cerebral ischemia and stroke. We also compare the preclinical work in stroke models to the updated recommendations of the Stroke Therapy Academic Industry Roundtable (STAIR). The findings reviewed here provide a strong foundation for a translational research program to study glibenclamide in patients with ischemic stroke.
Topics: Animals; Brain Edema; Brain Ischemia; Glyburide; Humans; Hypoglycemic Agents; Stroke
PubMed: 24132564
DOI: 10.1007/s12028-013-9923-1 -
International Journal of Molecular... Mar 2015Ischemic and hemorrhagic strokes are associated with severe functional disability and high mortality. Except for recombinant tissue plasminogen activator, therapies... (Review)
Review
Ischemic and hemorrhagic strokes are associated with severe functional disability and high mortality. Except for recombinant tissue plasminogen activator, therapies targeting the underlying pathophysiology of central nervous system (CNS) ischemia and hemorrhage are strikingly lacking. Sur1-regulated channels play essential roles in necrotic cell death and cerebral edema following ischemic insults, and in neuroinflammation after hemorrhagic injuries. Inhibiting endothelial, neuronal, astrocytic and oligodendroglial sulfonylurea receptor 1-transient receptor potential melastatin 4 (Sur1-Trpm4) channels and, in some cases, microglial KATP (Sur1-Kir6.2) channels, with glibenclamide is protective in a variety of contexts. Robust preclinical studies have shown that glibenclamide and other sulfonylurea agents reduce infarct volumes, edema and hemorrhagic conversion, and improve outcomes in rodent models of ischemic stroke. Retrospective studies suggest that diabetic patients on sulfonylurea drugs at stroke presentation fare better if they continue on drug. Additional laboratory investigations have implicated Sur1 in the pathophysiology of hemorrhagic CNS insults. In clinically relevant models of subarachnoid hemorrhage, glibenclamide reduces adverse neuroinflammatory and behavioral outcomes. Here, we provide an overview of the preclinical studies of glibenclamide therapy for CNS ischemia and hemorrhage, discuss the available data from clinical investigations, and conclude with promising preclinical results that suggest glibenclamide may be an effective therapeutic option for ischemic and hemorrhagic stroke.
Topics: Animals; Blood-Brain Barrier; Glyburide; Humans; Hypoglycemic Agents; KATP Channels; Stroke; Sulfonylurea Receptors
PubMed: 25749474
DOI: 10.3390/ijms16034973 -
Diabetes & Metabolism Jul 2021The recommended first-line treatment for women with gestational diabetes mellitus (GDM) in the case of failure of diet is insulin. Recent results suggest that there is a... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
The recommended first-line treatment for women with gestational diabetes mellitus (GDM) in the case of failure of diet is insulin. Recent results suggest that there is a potential role for glyburide therapy and highlight the need for better knowledge of glycaemic control with glyburide. The objective of this study was to describe and quantify in women with GDM the quality of glycaemic control, including the risk of maternal hypoglycaemia and of therapy failure.
METHODS
This is a secondary analysis of the French INDAO non-inferiority trial from 2012 to 2016, in which 890 women with GDM randomized to receive glyburide or insulin treatment were compared for perinatal outcomes. Blood glucose concentrations were assessed prospectively during pregnancy. Optimal glycaemic control was defined as less than 20% of blood glucose values exceeding the targets.
RESULTS
More than 50% of the women had optimal glycaemic control with glyburide, similar to that with insulin. Around 40% of the women had at least one episode of hypoglycaemia, more than with insulin. However, those hypoglycaemic episodes were mostly moderate and the rate of severe hypoglycaemia decreased significantly during the course of the trial. Failure of glyburide treatment (switch to insulin therapy) occurred in 18% of women and had few predictors. However, when failure occurred, glycaemic control was improved after switching to insulin.
CONCLUSIONS
Glyburide is an effective treatment for reaching glycaemic goals during pregnancy in women with GDM. The risk of maternal hypoglycaemia may be minimized by clinical practice experience. These findings could be taken into account in the management of GDM.
Topics: Diabetes, Gestational; Female; Glyburide; Glycemic Control; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Pregnancy; Treatment Failure
PubMed: 33249198
DOI: 10.1016/j.diabet.2020.11.002 -
The Use of Non-insulin Agents in Gestational Diabetes: Clinical Considerations in Tailoring Therapy.Current Diabetes Reports Dec 2019To assess evidence to date for use of non-insulin agents in treatment of gestational diabetes mellitus. (Review)
Review
PURPOSE OF REVIEW
To assess evidence to date for use of non-insulin agents in treatment of gestational diabetes mellitus.
RECENT FINDINGS
There has been increasing interest in the use of non-insulin agents, primarily metformin and glyburide (which both cross the placenta). Metformin has been associated with less maternal weight gain; however, recent studies have shown a trend toward increased weight in offspring exposed to metformin in utero. Glyburide has been associated with increased neonatal hypoglycemia. Glycemic control during pregnancy is essential to optimize both maternal and fetal outcomes. There are a myriad of factors to consider when designing treatment programs including patient preference, phenotype, and glucose patterns. While insulin is typically recommended as first-line, some women refuse or cannot afford insulin and in those cases, non-insulin agents may be used. Further studies are needed to assess treatment in pregnancy, perinatal outcomes, and particularly long-term metabolic profiles in mothers and offspring.
Topics: Acarbose; Diabetes, Gestational; Female; Glyburide; Healthy Lifestyle; Humans; Hypoglycemic Agents; Insulin; Metformin; Pregnancy; Prenatal Exposure Delayed Effects
PubMed: 31811400
DOI: 10.1007/s11892-019-1243-1 -
Scientific Reports Jan 2018Chronic inflammation underlies the development of metabolic diseases and individuals with metabolic disease often also suffer from delayed wound healing due to prolonged...
Chronic inflammation underlies the development of metabolic diseases and individuals with metabolic disease often also suffer from delayed wound healing due to prolonged inflammation. Resolving inflammation provides a therapeutic strategy in treating metabolic diseases. We previously showed that during an anti-inflammatory response when macrophages were alternatively (M2) polarized, retinoic acid (RA) dramatically activated arginase 1 gene (Arg1), a gene crucial for wound healing. Here we report that a widely used sulfonylurea drug for type 2 diabetes mellitus (T2DM), glyburide, enhances the anti-inflammatory response and synergizes with RA to promote wound healing. Our data also delineate the mechanism underlying glyburide's anti-inflammatory effect, which is to stimulate the degradation of a pro-inflammatory regulator, Receptor Interacting Protein 140 (RIP140), by activating Ca2+/calmodulin-dependent protein kinase II (CamKII) that triggers specific ubiquitination of RIP140 for degradation. By stimulating RIP140 degradation, glyburide enhances M2 polarization and anti-inflammation. Using a high-fat diet induced obesity mouse model to monitor wound healing effects, we provide a proof-of-concept for a therapeutic strategy that combining glyburide and RA can significantly improve wound healing. Mechanistically, this study uncovers a new mechanism of action of glyburide and a new pathway modulating RIP140 protein degradation that is mediated by CamKII signaling.
Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cells, Cultured; Diet, High-Fat; Drug Synergism; Glyburide; Macrophages, Peritoneal; Male; Mice; Mice, Inbred C57BL; Nuclear Receptor Co-Repressor 1; Obesity; Phosphorylation; RAW 264.7 Cells; Signal Transduction; Tretinoin; Ubiquitination; Wound Healing
PubMed: 29339732
DOI: 10.1038/s41598-017-18785-x