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ABSTRACT Introduction: Remote ischemic preconditioning (RIPC) is a new noninvasive myocardial protection strategy that uses blood pressure cuf inflation to simulate transient non-fatal ischemia to protect the myocardium and reduce ischemia-reperfusion injury. Sulfonylureas may mask the effects of RIPC due to their cardioprotec-tive effect. This meta-analysis aimed to evaluate whether RIPC, in the absence of sulfonylureas, reduces troponin release in patients undergoing cardiac surgery. Methods: We conducted a meta-analysis of randomized controlled clinical trials to determine whether RIPC can reduce postoperative troponin release in cardiac surgery patients undergoing cardiopulmonary bypass without treatment with sulfonylureas. The data were normalized to equivalent units prior to the analysis. A random-effects model was used to provide more conservative estimate of the effects in the presence of known or unknown heterogeneity. Results: Six studies with a total of 570 participants were included. The analysis showed that troponin release was lower in the RIPC group than in the control group at six hours (test of standardized mean differences = 0, Z=3.64, P<0.001) and 48 hours (Z=2.72, P=0.007) postoperatively. When the mean of cross-clamping time was > 60 minutes, RIPC reduced troponin release at six hours (Z=2.84, P=0.005), 24 hours (Z=2.64, P=0.008), and 48 hours (Z=2.87, P=0.004) postoperatively. Conclusion: In cardiac surgery patients who are not taking sulfonylureas, RIPC can reduce troponin release at six and 48 hours postoperatively; hence, RIPC may serve significant benefits in certain cardiac surgery patients.
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@#Iatrogenic hypoglycaemia is a common acute presentation; either because of misuse, self-harm or criminal intent. The most common culprits are insulin and oral hypoglycaemics (sulfonylurea, biguanides) although aspirin, fluoroquinolone and beta blockers can be causative agents. Common symptoms include sweating, anxiety, tremors, and palpitations. Neuroglycopenic symptoms usually arise at serum glucose concentrations of <2.8 mmol/L and include dizziness, confusion, blurred vision, somnolence and more serious symptoms can be convulsions, coma and potentially death.
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Sulfonylureas are widely used oral anti-diabetic drugs. However, its long-term usage effects on patients' lifespan remain controversial, with no reports of influence on animal longevity. Hence, the anti-aging effects of chlorpropamide along with glimepiride, glibenclamide, and tolbutamide were studied with special emphasis on the interaction of chlorpropamide with mitochondrial ATP-sensitive K+ (mitoK-ATP) channels and mitochondrial complex II. Chlorpropamide delayed aging in Caenorhabditis elegans, human lung fibroblast MRC-5 cells and reduced doxorubicin-induced senescence in both MRC-5 cells and mice. In addition, the mitochondrial membrane potential and ATP levels were significantly increased in chlorpropamide-treated worms, which is consistent with the function of its reported targets, mitoK-ATP channels. Increased levels of mitochondrial reactive oxygen species (mtROS) were observed in chlorpropamide-treated worms. Moreover, the lifespan extension by chlorpropamide required complex II and increased mtROS levels, indicating that chlorpropamide acts on complex II directly or indirectly via mitoK-ATP to increase the production of mtROS as a pro-longevity signal. This study provides mechanistic insight into the anti-aging effects of sulfonylureas in C. elegans.
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Recent studies revealed a number of interesting extrapancreatic actions of sulfonylureas (SUs),and there existed various mechanisms and targets of extrapancreatic effects among different SUs.We try to explore the impact of extrapancreatic effects on the clinical outcome of patients with type 2 diabetes mellitus (T2DM) based on the data from basic and clinical researches,including the effects of SUs on atherosclerosis,cognitive impairment,risk factors associated with abnormal bone metabolism,as well as the safety of treatment.All together,extrapancreatic effects of novel sulphonylureas (e.g.glimepiride) are associated with the improved clinical outcomes and less adverse effects in patients with T2DM.
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OBJECTIVE： To investigate sulfonamide allergy item annotation in drug instructions of sulfonylureas， and to provide reference for the promoting rational clinical use of the drugs. METHODS： In Oct. 2018， the drug instructions of commonly-used sulfonylureas at home and abroad were collected by MCDEX software （online version）， Drugs@FDA of the US Food and Drug Administration website， DailyMed website， European Medicines Agency website and UK electronic Medicines Compendium website. The annotation of sulfonamide allergy was analyzed statistically in respects of non-labeled sulfonamide allergy， only labeled sulfonamide allergy contraindication， only labeled sulfonylureas allergy contraindication， labeled sulfonamide and sulfonylureas allergy contraindication. The proportion of sulfonamide allergy contraindication labelling was calculated. RESULTS： Among 174 pieces of domestic drug instructions， 67 pieces of drug instructions were gliclazide， 48 were glipizide， 23 were glibenclamide， 23 were glimepiride and 13 were gliquidone. Different pharmaceutical manufacturers reached a consensus on the sulfonamide allergy of gliquidone and glibenclamide. The proportions of sulfonamide allergy contraindication labelling were 100％ and 95.65％， respectively. However， there were great differences on the sulfonamide allergy of glipizide， glimepiride and gliclazide， and the proportions of sulfonamide allergy contraindication labelling were 70.83％， 65.22％ and 49.25％， respectively. Among 13 foreign drug instructions， 4 pieces of drug instructions were glibenclamide， 3 were glipizide， 3 were glimepiride， and 3 were gliclazide， among which 7 drug instructions were sulfonamide allergy contraindication. However， there were great differences in the sulfonamide allergy annotation of drug instructions between US and Europe. CONCLUSIONS： There are great differences in the annotation for sulfonamide allergy in drug instructions of sulfonylureas at home and abroad， which indicates that there are different opinions on the clinical significance of sulfa cross-reaction in patients with sulfonamide allergy， and sulfonamide cross-allergy is a controversial issue. It is necessary to promote the research of sulfonamide cross-allergy from the perspectives of scientific researchers， medical associations， pharmaceutical manufacturers， medical staff and patients， and to clarify its mechanism and clinical significances.
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Background: Diabetes increases the risk of macrovascular complications and is often associated with angina in patient. Currently nicorandil, a potassium channel opener is being frequently used for the prevention and long-term treatment of angina pectoris. Glibenclamide exerts its antidiabetic action by closing the ATP sensitive potassium channels. Simultaneous use of nicorandil may antagonizes this action and may worsens the existing diabetes. To evaluate the pharmacodynamic interaction present study has been taken to study the effect of Nicorandil, a potassium channel opener on blood glucose level of alloxan induced diabetic rats and its pharmacodynamics interaction with Glibenclamide.Methods: Albino rats, weighing 150-200gm of male sex were used for the study. Diabetes was induced by injecting alloxan monohydrate 2% solution intra peritoneally in a dose of 150mg/kg body weight. Animal with Fasting Blood Sugar level between 250-300g/dl was selected for study and they were divided into 4 groups of 5 animals each. Group I- serving as control received 0.5ml normal saline orally for 28 days. Group II was given glibenclamide (0.5mg/kg body wt) for 28 days. Group III was treated orally with nicorandil (0.3mg/kg body wt) for 28 days. Group IV was given glibenclamide (0.5mg/kg) and nicorandil (0.3mg/kg) for 28 days. Fasting Blood Sugar level was recorded in all rats on 1st,3rd,7th,14th,21st and 28th day of the treatments.Results: results showed that glibenclamide significantly reduce blood sugar level (p <0.05) Wherase nicorandil showed rise in blood glucose level (p <0.05) While the combination (glibenclamide + nicorandil) showed rise in blood glucose (p <0.05) overall.Conclusions: Nicorandil worsen the existing diabetes and to be avoided or replaced with alternative drug in case of diabetes being treated with sulfonyl urease group of drugs.
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Background: Sulfonylureas are primarily used in the treatment of diabetes mellitus act by inhibiting ATP sensitive potassium ATP (K-ATP) channels. Similar channels are also present are also present in heart venticular muscle. Previous studies reveal that these drugs are able to reduce the electrocardiographic ST- segment elevation changes during an acute myocardial infarction. Hence, the present study was designed to evaluate the attenuating effect of sulfonylureas on ST- segment elevation in diabetic patients presenting with acute myocardial infarction.Methods: This cross sectional study included 73 diabetic patients presenting with the signs and symptoms of acute myocardial infarction of less than 24 hours duration along with CPK levels of more than 25 IU/L. Of them 5 were excluded from the study. The remaining 68 patients were included in the study, out of which 36 patients were in the study group (sulfonylurea group), and 32 patients were in the control group (non-sulfonylurea group).Results: No statistically significant difference was seen in the demographic parameters like age, sex, duration of diabetes mellitus and CPK levels (p>0.05). Among 68 patients 38 patients were diagnosed as STEMI. The mean magnitude of ST-elevation in the study group (n=16) was 2.3�12 and in control group (n=22) patients it was 3.7�33. The percentage of NSTEMI was significantly higher in study group compared to control. Statistically significant difference (p<0.05) was seen only between CPK level of range 25 and 100IU/L and mean magnitude of ST-segment elevation in STEMI patients. Significant difference in the mean magnitude of ST-segment elevation was observed in case of females among the study and control groups (p<0.05).Conclusions: Sulfonylureas drugs play a significant role in attenuation of ST-segment in diabetic patients presenting with acute myocardial infarction. Further, large multicentric studies are required to confirm the exact correlation between sulfonylureas and ST-segment.
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The relationship between Sulfonylureas(SUs) and cardiovascular (CV) risks has attracted great attention.Previous studies have illustrated that some SUs increase CV risk in type 2 diabetes (T2DM) patients;while others do not.Clinical studies have found that the CV risks of different SUs may be different.Compared with other SUs;glimepiride and gliclazide may have lower CV risks.Here we reviewed evidence-based CV safety of SUs and the recent research progress.
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The clinical practice of diabetes management is facing challenge in China,old anti-diabetic drugs such as sulfonylureas have been used for more than 60 years, and they are still valuable in diabetes management because of their remarkable hypoglycemic effect,as well as good safety,clear adverse events and cost-effectiveness.
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[Summary]_ Transient neonatal diabetes mellitus is a kind of rare special types of diabetes. It should be distinguished from type 1 diabetes. Genetic analysis can be used to define the subtype of neonatal diabetes mellitus, which helps us to select the most appropriate treatment and to predict the disease recurrence. Sulfonylureas is able to improve insulin secretion in most patients with transient neonatal diabetes mellitus and provide effective glycemic control. A case of transient neonatal diabetes mellitus is reported in order to call attention to the diagnosis and treatment of this disease.
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Objective To investigate whether sulfonylurea ( SU) increases the risk of stroke in patients with type 2 diabetes mellitus(T2DM). Methods A systemic meta-analysis including 17 random control trails(RCT) was performed to compare the risk of stroke between type 2 diabetic patients treated with SUs and comparators. Results 1 612 articles were retrieved, and finally 17 articles were included. Patients receiving SUs treatment had a higher relative risk of stroke (RR 1. 35, 95% CI 1. 13-1. 60) than those who received comparators. The I2 statistic for heterogeneity between 17 trails was 0. 0%(P=0. 687). No major asymmetry appeared in the funnel plot and Begg′adjusted rank correlation test(kendall′s score=22, P=0. 387). Conclusion The use of SUs may raise the risk of stroke which is already high in patients with T2DM.
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Neonatal diabetes mellitus(NDM)occurs within the first 6 months of life. Depending on clinical outcomes,it is classified into transient neonatal diabetes mellitus(TNDM)and permanent neonatal diabetes mellitus (PNDM). TNDM,which accounts for 50% of NDM goes into remission after treatment for an average period of 12 weeks,but relapse in puberty and early adulthood. PNDM,on the other hand,is a lifelong disease without remission. The clinical features of TNDM and PNDM overlap,and the typing is based on clinical remission on follow - up. More than 20 pathogenic genes have been identified in PNDM,of which the most common are KCNJII and ABCC8 encoding the Kir6. 2 and SUR1 subunits of KATP channel accounting for 50% . TNDM is caused by defects associated with overexpres-sion of paternally expressed genes in the imprinted region of chromosome 6q24 in 70% cases. About 26% of the defects contain mutations in KCNJII,ABCC8,INS or HNFIB. In vitro and clinical studies suggest that treatment with oral sul-fonylurea can close KATP channel and improve glycemic control and neuropsychological development. However,10% of patients with KCNJII and 15% ABCC8 mutations fail to achieve glycemic control when insulin therapy is switched to o-ral sulfonylureas. Therefore,molecular diagnosis is vital not only in accurate typing but also for better prognostication.
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Background: Diabetes mellitus is a major public health problem with many complications. The Global Burden of Diabetes Study has projected that there will be a 122% increase in the number of people with diabetes mellitus worldwide in 2025 compared to 1995. Despite the availability of new agents for the treatment of type 2 diabetes mellitus oral sulfonylureas remain a cornerstone of therapy. Glibenclamide and glimepiride are widely used sulfonylurea antidiabetic drugs. Methods: A randomized, open, parallel group study was conducted by the Department of Pharmacology in association with Department of Medicine at Maharishi Markandeshwar Institute of Medical Sciences & Research (MMIMSR), Mullana, Ambala. Total 50 patients were divided into two groups I & II. In Group I (n=25) glibenclamide (5-15 mg/day) & in Group II (n=25) glimepiride (1-6mg/day) was administered for a period of 24 weeks and data analyzed by Student’s “t”- test. Results: There was a significant improvement in the post prandial blood sugar score (p<0.05) in both the study groups (I&II) after 24 weeks but post prandial blood level did not differ significantly (p>0.05) between the two groups. Conclusions: Both the drugs glibenclamide and glimepiride were effectively reduced post prandial blood sugar in both the groups. But these sulfonylurea drugs lowered post prandial blood sugar to a similar degree without significant difference between the two groups.
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Background: Type 2 diabetes is associated with significant cardiovascular morbidity and mortality. Dyslipidemia, which affects almost 50% of patients with type 2 diabetes, is a cardiovascular risk factor characterized by elevated triglyceride levels, low high-density lipoprotein (HDL) cholesterol levels, and a preponderance of small, dense, low-density lipoprotein (LDL) particles. In addition to their glucose-lowering properties, oral anti-diabetic agents may have effects on lipid levels, especially triglycerides (TGs), HDL-C, LDL-C and total cholesterol levels. Methods: A prospective, open-labeled, randomized, parallel-group study was carried out in sizable number of patients (n=40) of established type 2 diabetes on combined oral anti-diabetic drugs, to investigate the effects of combined oral anti-diabetic on lipid parameters who was not receiving any hypolipidemic agent in addition. Results: Statistically significant mean reduction of triglycerides (TGs) of 25.1mg/dl (a 15.30% reduction from baseline value) and by 13.5 mg/dl (a 8.94% reduction from baseline value) in the SU (sulfonylurea) plus PIO (pioglitazone) and SU plus MET (metformin) group respectively. Present study also shows improvement in HDL cholesterol with SU plus PIO group by 13.18% which is almost twice that observed in SU plus MET group (8.06%). Present study also shows increase in LDL cholesterol with SU plus PIO group by 2.10%, is just opposite to SU plus MET group (4.92 % decrease). With SU plus PIO group, a statistically significant mean reduction of total cholesterol (TC) of 8.33mg/dl (5.14 % decrease) and by 7.62 mg/dl (4.28% decrease) in the SU plus MET group. Conclusions: Pioglitazone, a thiazolidinedione, has been shown to improve the lipid profile in patients with type 2 diabetes by increasing HDL-C levels and by decreasing triglyceride and total cholesterol levels in monotherapy or combination regimens with sulfonylurea. Metformin also has been shown to reduce LDL-C, TC, and TG levels and increase HDL-C levels in monotherapy and in combination regimens with sulfonylurea. In contrast, LDL cholesterol levels mild increase with pioglitazone monotherapy or with SU combination therapy. Thus the results of this study have demonstrated that SU plus pioglitazone is an effective combination regimen for patients insufficiently treated with SU monotherapy and may provide possible positive effects on other coronary risk factors/ dyslipidemias associated with the type 2 diabetes.
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Objective To reveal the clinical features of children with transient neonatal diabetes mellitus (TNDM) in order to provide a basis for the TNDM treatment strategy formulation.Methods Four patients diagnosed as TNDM hospitalized in Beijing Children's Hospital Affiliated to Capital Medical University from Dec.2008 to Dec.2010 were chosen as research subjects.Their clinical data were analyzed retrospectively.Results The 4 patients diagnosed as TNDM started insulin therapy.Two cases of the 4 patients transferred from insulin to oral Sulfonylureas for 2-3 weeks after their conditions became steady.One patient was treated with Sulfonylureas successfully and the other one was partially effective with this therapy.After 2 to 3 years follow-up,3 cases remitted in 1 month after birth with no other severe complications,one case lost.Conclusions Infants with TNDM had unique clinical features.The patients develop diabetes in the first few weeks of life but go into remission in a few months.So the follow-up for those TNDM patient is very essential for clinical classification.Oral glibenclamide therapy seems highly effective and safe for some TNDM patients.
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The sulfonylureas as insulin secretagogues,have formed a cornerstone of pharmacotherapy for type 2 diabetes over 50 years.Although sulfonylureas are effective antihyperglycemic agents,individual variability exists in drug response (i.e.,pharmacodynamics) and adverse effects which may be related to some genes.This article mainly reviews the advance of recent studies about drug metabolism and pharmacogenomics of sulfonylureas.
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Objective: To observe effects of different sulfonylurea compounds on expression of sulfonylurea receptor 2 (SUR2) in myocardium of the Goto-Kakizaki (GK) rats. Methods: Spontaneous diabetic GK rat models were divided into 6 groups: the diabetes model group, the Glibenclamide group, the Glipizide group, the Gliclazide group, the Glimepiride group and the positive control group(treated with insulin), with 12 rats in each group. A normal control group was also set up for comparison. The expression of SUR2 in myocardium of the GK rats was investigated by radioligand binding assay. SUR2 mRNA expression in the myocardial cells of rats was detected through reverse transcriptase-polymerase chain reaction (RT-PCR). Results: Twelve weeks later, no significant difference was found in the SUR2 receptor density(Bmax)and affinity(Kd) between the sulfonylurea treated groups and the other 3 groups (P>0.05). There was no significant difference in SUR2 mRNA expression between the diabetic, insulin-treated diabetic and control groups(P>0.05). Cardiac SUR2 mRNA levels were not significantly different between sulfonylureas-treated diabetic and non-treated diabetic rats (P>0.05). Conclusion: The diabetes itself does not affect the sulfonylurea receptor(SUR2) expression in myocardial tissues. Sulfonylureas at treatment dosage have no effect on receptor expression of SUR2.
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Previous studies have showed that sulfonylureas possess a bidirectional effect on cardiovascular system: they can raise the coronary artery tone, aggravate ischemic injury to the cardiovascular tissues, and accelerate cardiac hypertrophy through closing cardiovascular ATP-sensitive K+ channels; meanwhile, they can also regulate glucolipid metabolism, modulate inflammatory reaction and inhibit atherosclerosis through activating peroxisome proliferator-activated receptors. Clinical-epidemiological study showed different opinions on whether sulfonylureas can increase the mortality of patients with cardiovascular diseases.
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La diabetes de tipo MODY (maturity-onset diabetes of the young) afecta entre 1 y 5% de los pacientes con diabetes en los Estados Unidos y otras naciones industrializadas. Las tres características más importantes de esta entidad son: desarrollo de diabetes antes de la edad de 25 a 30 años en ausencia de autoanticuerpos pancreáticos, transmisión genética autosómica dominante y evidencia de secreción residual de insulina. Existen seis subtipos de MODY de los cuales, el tipo 2 (mutación de la glucoquinasa-GKS) y el tipo 3 (mutación del factor nuclear hepático 1 alfa (HNF-1-alfa) son los más prevalentes (70% de todos los casos de diabetes de tipo MODY). Las sulfonilureas son la medicación de primera línea tanto en los niños como en los adultos, cuando la terapia dietética no es suficiente para normalizar la glicemia. Aunque los pacientes con subtipos 1, 3, y 4 usualmente responden bien a la terapia oral con sulfonilureas, un porcentaje significativo de pacientes con los subtipos 1 y 3 necesitan terapia con insulina debido a un deterioro progresivo de las células beta del páncreas. El mantenimiento de un estilo de vida activo y un peso normal, son recomendaciones esenciales en todos los pacientes con diabetes de tipo MODY.
Maturity-Onset Diabetes of the Young (MODY) affects 1-5% of people with diabetes in the USA and other industrialized countries. The three main features of MODY include: Development of diabetes before the age of 25 to 30 in absence of pancreatic antibodies, autosomal dominant inheritance, and evidence of residual insulin secretion. There are six subtypes of MODY of which, MODY2 (GCK mutation) and MODY3 (HNF1-alphanmutation) are the most prevalent, accounting for more than 70% of cases. Sulfonylureas (SUs) remain the medication of first choice in children and adults when dietary therapy is insufficient to maintain normoglycemia. Although patients with MODY1, 3, and 4 usually respond very well to oral SUs, due to progressive beta-cell failure, a significant proportion of MODY1 and MODY3 patients may eventually require insulin therapy. Leading an active lifestyle and maintaining a normal weight are essential recommendations for all MODY patients.
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Sulfonylurea Compounds , Diabetes Mellitus , InsulinABSTRACT
OLETF (Otsuka Long-Evans Tokushima Fatty) rats are characterized by obesity-related insulin resistance, which is a phenotype of type 2 diabetes. Sulfonylurea drugs or benzoic acid derivatives as inhibitors of the ATP-sensitive potassium (KATP) channel are commercially available to treat diabetes. The present study compared sulfonylurea drugs (glimepiride and gliclazide) with one of benzoic acid derivatives (repaglinide) in regard to their long-term effect on ameliorating insulin sensitivity in OLETF rats. Each drug was dissolved and fed with drinking water from 29 weeks of age. On high glucose loading at 45 weeks of age, response of blood glucose recovery was the greatest in the group treated with glimepiride. On immunohistochemistry analysis for the Kir6.2 subunit of KATP channels, insulin receptor beta-subunits, and glucose transporters (GLUT) type 2 and 4 in liver, fat and skeletal muscle tissues, the sulfonylurea drugs (glimepiride and gliclazide) were more effective than repaglinide in recovery from their decreased expressions in OLETF rats. From these results, it seems to be plausible that KATP-channel inhibitors containing sulfonylurea moiety may be much more effective in reducing insulin resistance than those with benzoic acid moiety. In contrast to gliclazide, non-tissue selectivity of glimepiride on KATP channel inhibition may further strengthen an amelioration of insulin sensitivity unless considering other side effects.