Combined administration of gallic acid and glibenclamide mitigate systemic complication and histological changes in the cornea of diabetic rats induced with streptozotocin.

PURPOSE: To determine the effect of gallic acid or its combination with glibenclamide on some biochemical markers and histology of the cornea of streptozotocin (STZ) induced diabetic rats. METHODS: Following induction of diabetes, 24 male albino rats were divided into four groups of six rats each. Groups 1 and 2 (control and diabetic) received rat pellets and distilled water; group 3 (gallic acid) received rat pellets and gallic acid (10 mg/kg, orally) dissolved in the distilled water; and group 4 (gallic acid + glibenclamide) received rat pellets, gallic acid (10 mg/kg, orally), and glibenclamide (5 mg/kg, orally) dissolved in the distilled water. The treatments were administered for three months after which the rats were sacrificed after an overnight fast. Blood and sera were collected for the determination of biochemical parameters, while their eyes were excised for histology. RESULTS: STZ administration to the rats induced insulin resistance, hyperglycemia, microprotenuria, loss of weight, oxidative stress, inflammation, and alteration of their cornea histology, which was abolished following supplementation with gallic acid or its combination with glibenclamide. CONCLUSIONS: The study showed the potentials of gallic acid and glibenclamide in mitigating systemic complication and histological changes in the cornea of diabetic rats induced with STZ.

Pharmacological Basis for the Antidiarrheal and Antispasmodic Effects of Cuminaldehyde in Experimental Animals: In Silico, Ex Vivo and In Vivo Studies.

BACKGROUND: Medicinal herbs are frequently used for the management of gastrointestinal disorders because they contain various compounds that can potentially amplify the intended therapeutic effects. Cuminaldehyde is a plant-based constituent found in oils derived from botanicals such as cumin, eucalyptus, myrrh, and cassia and is responsible for its health benefits. Despite the utilization of cuminaldehyde for several medicinal properties, there is currently insufficient scientific evidence to support its effectiveness in treating diarrhea. Hence, the present investigation was carried out to evaluate the antidiarrheal and antispasmodic efficacy of cuminaldehyde, with detailed pharmacodynamics explored. METHODS: An in vivo antidiarrheal test was conducted in mice following the castor oil-induced diarrhea model, while an isolated small intestine obtained from rats was used to evaluate the detailed mechanism(s) of antispasmodic effects. RESULTS: Cuminaldehyde, at 10 and 20 mg/kg, exhibited 60 and 80% protection in mice from episodic diarrhea compared to the saline control group, whereas this inhibitory effect was significantly reversed in the pretreated mice with glibenclamide, similar to cromakalim, an ATP-dependent K+ channel opener. In the ex vivo experiments conducted in isolated rat tissues, cuminaldehyde reversed the glibenclamide-sensitive low K+ (25 mM)-mediated contractions at significantly higher potency compared to its inhibitory effect against high K+ (80 mM), thus showing predominant involvement of ATP-dependent K+ activation followed by Ca++ channel inhibition. Cromakalim, a standard drug, selectively suppressed the glibenclamide-sensitive low K+-induced contractions, whereas no relaxation was observed against high K+, as expected. Verapamil, a Ca++ channel inhibitor, effectively suppressed both low and high K+-induced contractions with similar potency, as anticipated. At higher concentrations, the inhibitory effect of cuminaldehyde against Ca++ channels was further confirmed when the preincubated ileum tissues with cuminaldehyde (3 and 10 mM) in Ca++ free medium shifted CaCl2-mediated concentration-response curves (CRCs) towards the right with suppression of the maximum peaks, similar to verapamil, a standard Ca++ ion inhibitor. CONCLUSIONS: Present findings support the antidiarrheal and antispasmodic potential of cuminaldehyde, possibly by the predominant activation of ATP-dependent K+ channels followed by voltage-gated Ca++ inhibition. However, further in-depth assays are recommended to know the precise mechanism and to elucidate additional unexplored mechanism(s) if involved.

Ameliorative effects of Scutellaria Pinnatifida subsp. pichleri (Stapf) Rech.f. Extract in streptozotocin-induced diabetic rats: chemical composition, biochemical and histopathological evaluation.

BACKGROUNDS: Scutellaria Pinnatifida subsp. pichleri (Stapf) Rech.f. (SP) is used in folk medicine for the treatment of diabetes. The aim of the study was to determine the phenolic profile of SP extract (SPE) by LC-MS/MS and to investigate the antidiabetic, hepatoprotective and nephroprotective effects of SPE in streptozotosin (STZ)-induced diabetic rat model. METHODS: Forty-two rats were randomly divided into six groups (n = 7): Control (nondiabetic), diabetes mellitus (DM), DM + SP-100 (diabetic rats treated with SPE, 100 mg/kg/day), DM + SP-200 (diabetic rats treated with SPE, 200 mg/kg/day), DM + SP-400 (diabetic rats treated with SPE, 400 mg/kg/day) and DM + Gly-3 (diabetic rats treated with glibenclamide, 3 mg/kg/day). Live body weight, fasting blood glucose (FBG) level, antidiabetic, serum biochemical and lipid profile parameters, antioxidant defense system, malondyaldehyde (MDA) and histopathological examinations in liver, kidney and pancreas were evaluated. RESULTS: Apigenin, luteolin, quinic acid, cosmosiin and epigallocatechin were determined to be the major phenolic compounds in the SPE. Administration of the highest dose of SP extract (400 mg/kg) resulted in a significant reduction in FBG levels and glycosylated hemoglobin levels in STZ-induced diabetic rats, indicating an antihyperglycemic effect. SPE (200 and 400 mg/kg) and glibenclamide significantly improved MDA in liver and kidney tissues. In addition, SPE contributed to the struggle against STZ-induced oxidative stress by stimulating antioxidant defense systems. STZ induction negatively affected liver, kidney and pancreas tissues according to histopathological findings. Treatment with 400 mg/kg and glibenclamide attenuated these negative effects. CONCLUSIONS: In conclusion, the extract of the aerial part of Scutellaria pinnatifida subsp. pichleri has hepatoprotective, nephroprotective and insulin secretion stimulating effects against STZ-induced diabetes and its complications due to its antidiabetic and antioxidant phytochemicals such as apigenin, luteolin, quinic acid, cosmosiin and epigallocatechin.

Insulin Detemir Versus Glibenclamide in Gestational Diabetes Mellitus: A Retrospective Cohort Study.

BACKGROUND: Treatment of gestational diabetes mellitus (GDM) has been shown to improve both maternal and neonatal outcomes. For women with GDM who require glucose-lowering medication, insulin is regarded as the drug of choice by most medical societies. Oral therapy, with metformin or glibenclamide, is a reasonable alternative in certain medical circumstances. OBJECTIVES: To compare the efficacy and safety of insulin detemir (IDet) vs. glibenclamide for GDM when glycemic control cannot be achieved through lifestyle modification and diet. METHODS: We conducted a retrospective cohort analysis of 115 women with singleton pregnancy and GDM treated with IDet or glibenclamide. GDM was diagnosed via the two-step oral glucose tolerance test (OGTT) of 50 grams glucose, followed by 100 grams. Maternal characteristics and outcomes (preeclampsia and weight gain) and neonatal outcomes (birth weight and percentile, hypoglycemia, jaundice, and respiratory morbidity) were compared between groups. RESULTS: In total, 67 women received IDet and 48 glibenclamide. Maternal characteristics, weight gain, and the incidence of preeclampsia were similar in both groups. Neonatal outcomes were also similar. The proportion of large for gestational age (LGA) infants was 20.8% in the glibenclamide group compared to 14.9% in the IDet group (P = 0.04). CONCLUSIONS: In pregnant women with GDM, glucose control on IDet yielded comparable results as on glibenclamide, except for a significantly lower rate of LGA neonates.

Co-administration of metformin and/or glibenclamide with losartan reverse NG-nitro-l-arginine-methyl ester-streptozotocin-induced hypertensive diabetes and haemodynamic sequelae in rats.

Over the years, there have been opinions on whether to reduced blood pressure (BP) to a different levels in patients with diabetes mellitus. Hence, this study investigated the efficacy of the co-administration of losartan (angiotensin receptor blocking antihypertensive agent) with metformin and/or glibenclamide (antidiabetic agents) on hypertensive-diabetic experimental rats induced by NG-nitro-l-arginine-methyl-ester hydrochloride (l-NAME), and streptozotocin (STZ). STZ (45 mg/kg, i.p.)-induced diabetic rats combined with l-NAME (40 mg/kg, p.o.)-induced hypertension were allotted into different groups. Group 1 received distilled water (10 mL/kg) and served as normal control, group 2 comprised hypertensive diabetic rats with distilled water, groups 3-5 were hypertensive-diabetic rats but received combination treatments of losartan + metformin, losartan + glibenclamide, and losartan + metformin + glibenclamide daily for 8 weeks, respectively. Our finding revealed no changes in the body weights, but there was a significant increase in fasting blood sugar levels in l-NAME - STZ-induced hypertensive-diabetes, which were lowered by losartan + metformin, losartan + glibenclamide, and losartan + metformin + glibenclamide treatments. Moreover, the increased systolic-BP, mean arterial pressure but not diastolic-BP and heart rate by l-NAME + STZ were attenuated more significantly by losartan + metformin + glibenclamide between weeks 2-8 relative to hypertensive-diabetic control. l-NAME + STZ-induced elevated levels of lactate dehydrogenase and creatinine kinase, were differentially reversed by losartan + metformin, losartan + glibenclamide, and losartan + metformin + glibenclamide. However, l-NAME + STZ-induced decreased nitrite level was significantly restored by all treatments, suggesting increased nitrergic transmission. Additionally, l-NAME + STZ-induced degeneration of pancreatic islet and myocardial cells were dramatically alleviated by losartan + metformin + glibenclamide treatments. Our findings suggest hyperglycemia with raised systolic-BP should be managed with losartan combined with both metformin and glibenclamide than single combination of losartan with antidiabetics.

Medications for Managing Preexisting and Gestational Diabetes in Pregnancy.

Persons with gestational and pregestational diabetes during pregnancy may require pharmacologic agents to achieve pregnancy glycemic targets, and the available medications for use in pregnancy are limited. Insulin is the only FDA-approved medication for use in pregnancy and has the greatest evidence for safety and efficacy. Metformin and glyburide are the most commonly used oral agents in pregnancy. Understanding each medication's unique pharmacokinetics, potential side effects, fetal or childhood risks, gestational age of medication initiation and patient's diabetes care barriers are important aspects of shared decision-making and choosing a regimen that will achieve glycemic and pregnancy goals.

Efficiency comparison of an isoeugenol-derivated compound, eugenosedin-A, with glibenclamide and pioglitazone in protecting cardiovascular dysfunction of diabetic SHR.

This study was to investigate three agents possible protective effect against DM-induced cardiovascular dysfunction in spontaneously hypertensive rats (SHR). Control group was fed normal diet, DM group was injected with STZ/NA and fed high fat diet (HFD), and treatment groups were given STZ/NA, fed HFD, and then oral gavaged with eugenosedin-A (Eu-A), glibenclamide (Gli), or pioglitazone (Pio) 5 mg/kg/per day for 4-week, respectively. Eu-A, Gli, and Pio clearly ameliorated the changes of body weight, cardiac weight, and the biochemical parameters, cardiovascular disorders and inflammation. Like Gli and Pio, Eu-A may be effectively to control DM and the cardiovascular dysfunction.

Co-administration of Pterocarpus marsupium Extract and Glibenclamide Exhibits Better Effects in Regulating Hyperglycemia and Associated Changes in Alloxan-induced Diabetic Mice.

BACKGROUND: Diabetes mellitus (DM) is a well-known global metabolic disorder. For its treatment, glibenclamide (GLB) is very often prescribed. However, herbal drugs are considered effective and better alternatives due to their low risk of side effects. This study was conducted to determine the combined effects of GLB and Pterocarpus marsupium (PM, a commonly available Indian herb) extract for the effective and safe treatment of hyperglycemia in the mouse model. METHODS: Healthy adult male mice were distributed into five groups (n=7 in each group). Group I acted as the control, whereas groups II, III, IV, and V were considered experimental groups which received a single dosage (150 mg/kg body weight) of alloxan (ALX) intraperitoneally (i.p.). In addition, groups III, IV, and V received a pre-standardized dose of GLB (500 µg/kg body weight), PM extract (150 mg/kg body weight), and GLB+PM, respectively, at the same doses as used in individual treatment, after the seventh day of ALX administration for 15 days and the alterations in different DM related parameters were evaluated. RESULTS: ALX-induced hyperglycemia and other adverse effects were nearly normalized by GLB and PM co-treatment as evidenced by marked suppression in glucose, triglyceride, total-cholesterol, lipid-peroxidation, and lipid-hydroperoxides with an increase in antioxidants status and liver glycogen content. The positive effects were more pronounced when both GLB and PM were given, as compared to that of either of the drugs, administered alone. Liver ultra-structure, analyzed through histology and transmission electron microscopy revealed normalization of the ALX-induced damaged hepatocytes. The presence of epicatechin, the major phytoconstituent of the PM extract, as confirmed by high-performance liquid chromatography (HPLC), is responsible for its antioxidative and glucose-lowering activities. CONCLUSION: These findings reveal that PM, along with GLB, exhibits synergistic and better effects than the individual drug in regulating hyperglycemia and associated changes in alloxan-induced mice.

Comparative efficacy and safety of glyburide, metformin, and insulin in treatment of gestational diabetes mellitus: A protocol for systematic review and meta-analysis.

BACKGROUND: The increased prevalence of gestational diabetes mellitus (GDM) has caused a huge societal economic and healthy burden at both the population and individual levels. We aimed to assess the comparative efficiency and safety of the use of glyburide, metformin, and insulin in GDM from a protocol for systematic review and meta-analysis. METHODS: Two individual researchers conducted the platform searches on the PubMed, Cochrane Library, and Embase databases from inception to February 2022. Literature retrieving was carried out through a combined searching of subject terms ("MeSH" on PubMed and "Emtree" on "Embase") and free terms on the platforms of PubMed and Embase, and through keywords searching on platform of Cochrane Library. Systematic review and meta-analysis of the data will be performed in STATA13.0 software according to the Preferred Reporting Items of Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Two authors independently performed the literature searching, data extraction, and quality evaluation. Risk of bias was assessed using the Cochrane Risk of Bias Tool for randomized controlled trials. RESULTS: The results will be submitted to a peer-reviewed journal. CONCLUSION: This meta-analysis will provide a comprehensive analysis and synthesis that can be used as an evidence map to inform practitioners and policy makers about the effectiveness of glyburide, metformin, and insulin for patients with GDM.

Association of Glyburide and Subcutaneous Insulin With Perinatal Complications Among Women With Gestational Diabetes.

Importance: Nearly 30% of individuals with gestational diabetes (GDM) do not achieve glycemic control with lifestyle modification alone and require medication treatment. Oral agents, such as glyburide, have several advantages over insulin for the treatment of GDM, including greater patient acceptance; however, the effectiveness of glyburide for the treatment of GDM remains controversial. Objective: To compare the perinatal and neonatal outcomes associated with glyburide vs insulin using causal inference methods in a clinical setting with information on glycemic control. Design, Setting, and Participants: The population-based cohort study included patients with GDM who required medication treatment from 2007 to 2017 in Kaiser Permanente Northern California. Machine learning and rigorous casual inference methods with time-varying exposures were used to evaluate associations of exposure to glyburide vs insulin with perinatal outcomes. Data analysis was conducted from March 2018 to July 2017. Exposures: Time-varying exposure to glyburide vs insulin during pregnancy. Main Outcomes and Measures: Outcomes evaluated separately included neonatal hypoglycemia, jaundice, shoulder dystocia, respiratory distress syndrome (RDS), neonatal intensive care unit (NICU) admission, size-for-gestational age, and cesarean delivery. Inverse probability weighting (IPW) estimation was used to separately compare perinatal outcomes between those initiating glyburide and insulin. This approach was combined with Super Learning for propensity score estimation to account for both baseline and time-dependent confounding in both per-protocol (primary) and intention-to-treat (secondary) analyses to evaluate sustained exposure to the same therapy. Results: From 2007 to 2017, 11 321 patients with GDM (mean [SD] age, 32.9 [4.9] years) initiated glyburide or insulin during pregnancy. In multivariate models, the risk of neonatal respiratory distress was 2.03 (95% CI, 0.13-3.92) per 100 births lower and the risk of NICU admission was 3.32 (95% CI, 0.20-6.45) per 100 births lower after continuous exposure to glyburide compared with insulin. There were no statistically significant differences in glyburide vs insulin initiation in risk for neonatal hypoglycemia (0.85 [95% CI, -1.17 to 2.86] per 100 births), jaundice (0.02 [95% CI, -1.46 to 1.51] per 100 births), shoulder dystocia (-1.05 [95% CI, -2.71 to 0.62] per 100 births), or large-for-gestational age categories (-2.75 [95% CI, -6.31 to 0.80] per 100 births). Conclusions and Relevance: Using data from a clinical setting and contemporary causal inference methods, our findings do not provide evidence of a difference in the outcomes examined between patients with GDM initiating glyburide compared with those initiating insulin.

Antenatal maternal hypoglycemia in women with gestational diabetes mellitus and neonatal outcomes.

OBJECTIVE: To examine the prevalence of antenatal maternal hypoglycemia after initiation of pharmacotherapy for gestational diabetes mellitus (GDMA2) and its association with pregnancy outcomes. STUDY DESIGN: Retrospective cohort of GDMA2 women receiving either insulin or oral hypoglycemic agents. Composite neonatal outcome included macrosomia, jaundice, respiratory distress syndrome, large for gestational age, shoulder dystocia, birth trauma, 5-minute Apgar < 7, and neonatal hypoglycemia, and was compared between women with and without hypoglycemia using bivariate and multivariate analyses. RESULTS: Of 489 women included in the study, 95 (19.4%) had at least one episode of hypoglycemia, most often in the setting of glyburide. Newborns exposed to maternal hypoglycemia had higher rates of the composite neonatal outcome (54.7% vs. 38.3%, p = 0.004). After controlling for confounding factors, maternal hypoglycemia remained independently associated with the composite neonatal outcome (aOR = 1.69, 95% CI 1.04-2.72). CONCLUSION: Maternal hypoglycemia in GDMA2 was associated with higher rates of adverse neonatal outcomes.

Metformin versus glyburide in treatment and control of gestational diabetes mellitus: a systematic review with 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.

Pharmacological therapy in gestational diabetes - a comparison between insulin and oral therapy.

BACKGROUND: The appropriate medical treatment for gestational diabetes mellitus (GDM) is controversial and recommendations vary between different organizations. OBJECTIVE: To compare the safety and efficacy of glyburide and insulin as treatments for GDM. METHODS: Retrospective analysis of all pregnant women diagnosed with GDM and treated with either glyburide or insulin. Demographic features, clinical characteristics, maternal and neonatal outcomes were compared according to type of pharmacological treatment. RESULTS: Included in the study were 323 women, of whom 269 (83.28%) were treated with glyburide and 54 (16.72%) with insulin. There were no significant differences between the groups, apart from a higher one-hour oral glucose tolerance test (OGTT) value (191.80 mg/dl in the glyburide group, 204.33 in the insulin group, p = .01). Optimal glucose control was achieved in 130 women in the glyburide group (48.32%) and 15 in the insulin group (27.77%), p = .007. This difference remained significant after adjustment for age, BMI, and fasting glucose during OGTT (aOR = 2.22). Mean gestational weight gain was lower in the glyburide group vs. insulin group (10.01 vs. 11.99 kg, p = .048). Apart from higher maternal hypoglycemia rate (12.64% in glyburide group vs. 1.85% in insulin group, p = .016), there were no other differences in maternal and neonatal outcomes between the groups. Glyburide failure rate was 13.38%, and associated with higher fasting OGTT value (100.70 mg/dl in glyburide failure group vs. 94.67 mg/dl in the glyburide treatment until delivery group, p = .041). CONCLUSIONS: Glyburide is at least as safe and effective as insulin except for higher rates of maternal hypoglycemia. Considering its advantages compared to insulin (ease of use and storage, increased patient responsiveness, and lower cost), it may be considered as first line treatment in GDM, especially when fasting OGTT value is not high.

Comparison of the effectiveness and safety of insulin and oral hypoglycemic drugs in the treatment of gestational diabetes mellitus: a meta-analysis of 26 randomized controlled trials.

OBJECTIVE: Oral hypoglycemic drugs for the treatment of gestational diabetes mellitus (GDM) are still controversial because they can pass through the placenta. The purpose of this meta-analysis is to evaluate the safety and effectiveness of oral hypoglycemic drugs. METHODS: PubMed, Ovid Embase, Web of Science, and Cochrane databases were systematically searched (inception to 20 April 2021). Rev Man 5.0 was used to analyze the data. A random-effects model was used to compute the summary risk estimates. RESULTS: There were 26 randomized controlled trials (RCTs) involving 4921 GDM patients which were included in this meta-analysis. Compared with metformin, insulin had a significant increase in the risk of preeclampsia (odds ratio [OR], 1.61; 95% confidence interval [CI], 1.06 to 2.45; I2=40%; p < .05), hypertension (OR, 1.42; 95% CI, 1.02 to 1.99; I2=0%; p < .05), hypoglycemia (OR, 3.93; 95% CI, 1.27 to 12.19; I2=0%; p < .05), neonatal hypoglycemia (OR, 1.92; 95% CI, 1.34 to 2.76; I2=41%; p < .0001), neonatal jaundice (OR, 2.70; 95% CI, 1.12 to 6.52; I2=0%; p < .05), and Neonatal Intensive Care Unit Admission (OR, 1.46; 95% CI, 1.09 to 1.95; I2=39%; p < .05), but the risk of neonatal macrosomia (OR, 1.67; 95% CI, 1.12 to 2.40; I2=0%; p < .05) and neonatal injury (OR, 0.70; 95% CI, 0.55 to 0.89; I2=0%; p < .01) is lower. CONCLUSIONS: Metformin is comparable with insulin in glycemic control and neonatal outcomes and has the potential to replace insulin therapy in clinical practice. Glyburide is behind metformin and insulin, and more RCTs are needed to verify its safety.

Angiotensin-Converting Enzyme Inhibitors Used Concomitantly with Insulin Secretagogues and the Risk of Serious Hypoglycemia.

Serious hypoglycemia is a major adverse event associated with insulin secretagogues. Previous studies have suggested a potential relationship between angiotensin-converting enzyme inhibitors (ACEIs) used with sulfonylureas and serious hypoglycemia, and widely used drug compendia warn of this potential drug-drug interaction. We investigated the association between serious hypoglycemia and concomitant use of ACEIs in patients receiving insulin secretagogues, using the self-controlled case series design and Medicaid claims data from 5 US states linked to Medicare claims from 1999-2011. The exposure of interest was active prescription for ACEIs during insulin secretagogue or metformin (negative control object drug) episodes. The outcome was hospital presentation for serious hypoglycemia, identified by discharge diagnosis codes in inpatient and emergency department claims (positive predictive value ~ 78-89%). We calculated confounder-adjusted rate ratios (RRs) and 95% confidence internals (CIs) of outcome occurrence during ACEI-exposed vs. ACEI-unexposed time using conditional Poisson regression. The RRs for ACEIs were not statistically elevated during observation time of glipizide (RR, 1.06; CI, 0.98-1.15), glyburide (RR, 1.05; CI, 0.96-1.15), repaglinide (RR, 1.15; CI, 0.94-1.41), or metformin (RR, 1.02; CI, 0.97-1.06); but was modestly elevated with glimepiride (RR, 1.23; CI, 1.11-1.37) and modestly reduced with nateglinide (RR, 0.73; CI, 0.56-0.96). The overall pattern of results do not suggest that ACEIs used with insulin secretagogues were associated with increased rates of serious hypoglycemia, with the possible exception of glimepiride.

Metformin versus glyburide in treatment and control of gestational diabetes mellitus: a systematic review with meta-analysis

ABSTRACT 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.

Comparison of Insulin, Metformin, and Glyburide on Perinatal Complications of Gestational Diabetes Mellitus: A Systematic Review and Meta-Analysis.

AIM: This systematic and meta-analysis was conducted to evaluate the efficacy and safety of insulin, metformin, and glyburide on perinatal complications for gestational diabetes mellitus (GDM). METHODS: Medline (PubMed), EMBASE, The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials [CENTRAL], and Cochrane Methodology Register), Web of Science (Science and Social Science Citation Index), and ClinicalTrials (Clinicaltrials.gov) were searched, as well as manual searching. We included randomized controlled trials comparing efficacy and safety of metformin versus glyburide, metformin versus insulin, and glyburide versus insulin in patients with GDM. RESULTS: We included 32 articles including 5,964 patients published from inception to July 2020. Compared with insulin, metformin was more effective at lower incidence of macrosomia (RR: 0.66, 95% CI: 0.50-0.88, p = 0.005), lower incidence of neonatal intensive care unit admission (RR: 0.78, 95% CI: 0.67-0.91, p = 0.002), less neonatal hypoglycemia (RR: 0.67, 95% CI: 0.56-0.80, p < 0.0001), decreased birth weight (BW) (SMD: -0.37, 95% CI: -0.62 to -0.12, p = 0.004), lower incidence of large for gestational age (RR: 0.76, 95% CI: 0.50-0.90, p = 0.002), shorter gestation age at delivery (MD: -0.22, 95% CI: -0.34 to -0.10, p = 0.0002), lower maternal weight gain (MD: -1.41, 95% CI: -2.28 to -0.55, p = 0.001), less incidence of caesarean section delivery (RR: 0.86, 95% CI: 0.78-0.95, p = 0.0004), lower maternal postprandial blood glucose (SMD: -0.41, 95% CI: -0.72 to -0.11, p = 0.008), and lower incidence of pregnancy-induced hypertension (RR: 0.47, 95% CI: 0.27-0.83, p = 0.01). However, glyburide, compared with insulin, was associated with higher BW (MD: 54.95, 95% CI: 3.87-106.03, p = 0.03) and increased the incidence of neonatal hypoglycemia (RR: 1.52, 95% CI: 1.12-2.07, p = 0.007). Meanwhile, compared to glyburide, metformin was associated with higher maternal fasting blood glucose (SMD: 0.20, 95% CI: 0.05-0.36, p = 0.01) and lower incidence of induction of labor (RR: 0.76, 95% CI: 0.59-0.97, p = 0.03). CONCLUSIONS: This review suggests that metformin can decrease the incidence of perinatal complications, and it should be considered as a generally safe alternative to insulin.

Effectiveness and safety of glibenclamide for stroke: protocol for a systematic review and meta-analysis.

INTRODUCTION: Despite the continuous improvement in modern medical treatment, stroke is still a leading cause of death and disability worldwide. How to effectively improve the survival rate and reduce disability in patients who had a stroke has become the focus of many investigations. Recent findings concerning the benefits of glibenclamide as a neuroprotective drug have initiated a new area for prospective studies on the effects of sulfonylureas. Given the high mortality and disability associated with stroke, it is essential to weigh the benefits of neuroprotective drugs against their safety. Therefore, the objective of the current study is to conduct a systematic review using meta-analysis to assess the benefits and safety of glibenclamide as a neuroprotective drug. METHODS AND ANALYSIS: This study will analyse randomised clinical trials (RCTs) and observational studies published up to 31 December 2020 and include direct or indirect evidence. Studies will be retrieved by searching PubMed, EMBASE, Web of Science, the Cochrane Library and China National Knowledge Infrastructure (CNKI) and WanFang Databases. The outcomes of this study will be mortality, scores from the Modified Rankin Scale and the occurrence of hypoglycaemic events. The risk of bias will be assessed using the Cochrane risk of bias assessment instrument for RCTs. A random-effect/fixed-effect model will be used to summarise the estimates of the mean difference/risk ratio using a 95% CI. ETHICS AND DISSEMINATION: This meta-analysis is a secondary research project, which is based on previously published data. Therefore, ethical approval and informed consent were not required for this meta-analysis. The results of this study will be submitted to a peer-reviewed journal for publication. PROSPERO REGISTRATION NUMBER: CRD42020144674.

Dapagliflozin effect on endothelial dysfunction in diabetic patients with atherosclerotic disease: a randomized active-controlled trial.

BACKGROUND: The glucose-lowering independent effect of sodium glucose cotransporter-2 inhibitors (SGLT2i) on arterial wall function has not yet been clarified. This study aims to assess whether SGLT2i treatment can attenuate endothelial dysfunction related to type 2 diabetes mellitus (T2D) compared with glucose-lowering equivalent therapy. METHODS: In a prospective, open-label, single-center, randomized clinical trial, 98 patients with T2DM and carotid intima-media thickness above the 75th percentile were randomized 1:1 to 12 weeks of therapy with dapagliflozin or glibenclamide in addition to metformin in glucose-lowering equivalent regimens. The coprimary endpoints were 1-min flow-mediated dilation (FMD) at rest and 1-min FMD after 15 min of ischemia followed by 15 min of reperfusion time (I/R). RESULTS: Ninety-seven patients (61% males, 57 ± 7 years) completed the study. The median HbA1c decreased by - 0.8 (0.7)% and -0.7 (0.95)% following dapagliflozin and glibenclamide, respectively. The first coprimary endpoint, i.e., rest FMD changed by + 3.3(8.2)% and - 1.2(7.5)% for the dapagliflozin and glibenclamide arms, respectively (p = 0.0001). Differences between study arms in the second coprimary endpoint were not significant. Plasma nitrite 1 min after rest FMD was higher for dapagliflozin [308(220) nmol/L] than for glibenclamide (258[110] nmol/L; p = 0.028). The resistive indices at 1 min [0.90 (0.11) vs. 0.93 (0.07); p = 0.03] and 5 min [0.93 (0.07) vs. 0.95 (0.05); p = 0.02] were higher for the glibenclamide group than for the dapagliflozin group. Plasma biomarkers for inflammation and oxidative stress did not differ between the treatments. CONCLUSIONS: Dapagliflozin improved micro- and macrovascular endothelial function compared to glibenclamide, regardless of glycemic control in patients with T2DM and subclinical carotid atherosclerotic disease.

Hypoglycemia and Glycemic Control With Glyburide in Women With Gestational Diabetes and Genetic Variants of Cytochrome P450 2C9 and/or OATP1B3.

Glyburide is mainly metabolized by the cytochrome P450 2C9 (CYP2C9) enzyme and enters the liver via the transporter OATP1B3. The variants OATP1B3*4 (699 G>A; rs7311358) and CYP2C9*2 and *3 are known to have a significant influence on the hepatic uptake and metabolism of glyburide, with lower clearance than in the wild type. In an ancillary study of the INDAO trial, we selected 117 pregnant women with gestational diabetes treated by glyburide and assessed the role of the combined CYP2C9 and OATP1B3 genetic polymorphisms in hypoglycemia and glycemic control. Three groups were constituted: (1) the wild-type genotype group (wild-type allele genotype for both CYP2C9*1 and OATP1B3*1 (699G)), (2) the intermediate group (carriers of CYP2C9*2 allele or OATP1B3*4 (699G>A) heterozygous), and (3) the variant group (carriers of CYP2C9*3 allele and/or OATP1B3*4 (699G>A) homozygous variant). We found that the risk of hypoglycemia was significantly higher in the variant genotype at the second week of treatment: 20.0% (4/20) vs. 8.1% (3/37) in the intermediate group and 4.1% (2/49) in the wild-type genotype group (P = 0.03). The last daily dose of glyburide during pregnancy was lower for patients in the variant genotype group: 4.7 mg (SD 3.5) vs. 8.7 mg (SD 5.7) in the wild-type group and 5.7 mg (SD 3.7) in the intermediate group (P < 0.01). In conclusion, the no-function variants CYP2C9*3 and OATP1B3*4 are associated with a higher risk of hypoglycemia and a lower dose of glyburide in women with gestational diabetes treated with glyburide, which is consistent with the pharmacokinetic roles of both CYP2C9 and OATP1B3.