Effects Of Sulphonylureas Research Articles

382-P: Is Sulphonylurea-Induced Hypoglycaemia Hyped among Clinicians?

Aim: To assess the risk of hypoglycaemia (TBR) in persons with diabetes who are on SUs with fairly controlled diabetes (HbA1c between 7 to 8%) . Background: Sulphonylurea (SU) is conventionally used as a powerful glucose lowering agent and is known to increase the risk of hypoglycaemia. This paper is an attempt to study the effect of SUs on persons with diabetes by introducing continous glucose monitoring (CGM/AGP) which can help clinicians optimise diabetes treatment along with nutrition which can reduce the risk of hypoglycaemia. Methodology: A retrospective analysis was done at our diabetes care centre. A total of 300 persons with type 2 diabetes on AGP and on SU therapy were studied. Only those persons with HbA1c between 7 to 8%, indicating fairly controlled diabetes were included. Results: It was observed that no hypoglycaemia was present in 74% of the persons under study as per AGP data. Only 26% had hypoglycaemia grade 1 with less than 5% TBR; 2% had hypoglycaemia in TBR more than 5%, out of which only one person reported symptoms of severe hypoglycaemia. One of the AGP data of person with diabetes is attached in the image. Conclusion: Judicious use of sulphonylureas does not increase risk of hypoglycaemia (Time Below Range) in type 2 diabetics as traditionally believed. Disclosure T.C.Vyas: None. B.D.Saboo: None. K.Chennamsetti: None. J.Kesavadev: None. B.Saboo: None. D.Hasnani: None. V.Chavda: None. D.Panchal: None.

Exploring the influence of extrapancreatic effect of sulphonylureas on clinical outcomes in patients with type 2 diabetes

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. Key words: Diabetes mellitus, type 2; Sulfonylureas; Extrapancreatic effect; Clinical outcome

Abstract T P318: Impact of Pre-stroke Sulphonylurea and Metformin Use on Outcome of Intracerebral Hemorrhage

Background and Purpose: There is currently no effective treatment for intracerebral hemorrhage (ICH). Preliminary evidence suggests sulphonylurea may be protective in ischemic stroke. Metformin reduced post stroke lactate generation in an animal model. Our objective was to assess the effects of sulphonylurea and metformin use at time of stroke onset on ICH outcome. Methods: We merged patient data from the consecutive single-center Helsinki ICH Study and the ICH arm of the pooled repository of trials Virtual International Trials Archive (VISTA-ICH). Logistic regression adjusting for known predictors of ICH outcome estimated the association of pre-stroke exposure to metformin and sulphonylurea with all-cause 90-day mortality. Ordinal shift analysis for 90-day mRS was performed with the same covariates in the VISTA dataset only. Results: After excluding cases with missing data (n=190) we included 1810 patients (Helsinki n=961, VISTA-ICH n=849), of whom 478 (26%) died by 90 days. Of the 289 (16%) diabetic patients, 100 (34.6%) used metformin and 78 (27%) sulphonylurea at ICH onset. After adjusting for age, sex, baseline GCS, NIHSS, volume, infratentorial location, intraventricular extension, and pre-ICH warfarin use, there was no association with sulphonylurea (OR 1.22; 95% CI 0.63-2.40;p=0.55) or metformin (OR 0.69;0.36-1.33;p=0.27) use with 90-day mortality. When restricted to the diabetic subgroup, metformin use was associated with lower 90-day mortality (OR 0.44;0.20-0.97;p=0.041) while sulphonylurea was not (OR 0.90;0.41-1.96;p=0.79). In the ordinal shift analysis neither metformin nor sulphonylurea influenced 90-day mRS in the whole dataset (p>0.5), although in the diabetic subgroup there was a trend towards improved outcome with metformin use (0.7 point reduction;-0.1-1.5;p=0.09). Conclusion: Sulphonylurea or metformin use at time of stroke was not associated with outcome in all ICH patients but there was a signal of lower mortality and possibly improved functional outcome with metformin use in diabetic patients. The protective effect of metformin might be a result of improved glycemic control or reduced lactate generation. Our results generate hypotheses which after further validation may be tested in clinical trials.

A meta‐analysis of the hypoglycaemic risk in randomized controlled trials with sulphonylureas in patients with type 2 diabetes

To assess hypoglycaemic risk with sulphonylureas in comparison with other drugs in randomized controlled trials. Randomized trials with a duration ≥ 24 weeks, enrolling patients with type 2 diabetes, comparing sulphonylureas with placebo or active drugs different from other sulphonylureas. The principal outcome was the effect of sulphonylureas on the incidence of any or severe hypoglycaemia. Cumulative incidence of hypoglycaemia was estimated combining sulphonylurea groups of different trials with a random effect model and used for meta-regression analyses. The incidence of severe hypoglycaemia in patients treated with sulphonylureas was 1.2 [1.0-1.6]%. The overall risk of severe hypoglycaemia was increased more than threefold with sulphonylureas than with comparators. The proportion of patients with at least one hypoglycaemia while on sulphonylureas was 17.4 [14.5-20.8]%. The overall risk (Mantel-Haenszel Odds Ratio) of any hypoglycaemia with sulphonylureas versus comparators was 3.69 [3.47-3.93] (p < 0.001). Meta-regression analysis suggested that the incidence of any hypoglycaemia was higher in trials enrolling patients with higher body mass index (BMI) and lower haemoglobin A1c (HbA1c). In conclusion, hypoglycaemia, including severe hypoglycaemia, is frequent in patients treated with sulphonylureas, particularly when baseline HbA1c levels are lower and BMI levels higher. Further studies are needed to characterize predictors for the identification of patients at higher risk.

Glitazone-like action of glimepiride and glibenclamide in primary human adipocytes

Sulphonylureas (SUs) are among the most widely used oral hypoglycaemic drugs that stimulate insulin secretion. In addition, SUs have pleiotropic effects on other tissues. Conflicting findings have been reported regarding the effects of SUs on adipocytes. We have now investigated the actions of glimepiride and glibenclamide (=glyburide) in primary human adipocytes. Primary cultured human white pre-adipocytes were differentiated in vitro according to a standard protocol. Lipid accumulation was assessed by Oil Red O staining and determination of triglyceride content; gene expression was measured by RT PCR and Western blotting. Initially, we characterized the genes regulated during human pre-adipocyte differentiation by performing global microarray analysis. Treatment with glimepiride and glibenclamide caused an increased accumulation of lipid droplets and triglycerides. In addition, genes involved in lipid metabolism were induced and chemokine expression was decreased. Interestingly, the effects of SUs were generally qualitatively and quantitatively similar to those of pioglitazone. In direct comparison, glibenclamide was more potent than glimepiride with respect to the induction of fatty acid binding protein 4 (FABP4) (EC(50) 0.32 vs. 2.8 µM), an important adipocyte marker gene. SU-induced differentiation was virtually completely blocked by the peroxisome proliferator-activated receptor γ (PPARγ)-antagonist T0070907 but not affected by diazoxide, indicating PPARγ activation by SUs. Repaglinide had no effect on adipogenesis, although it causes insulin liberation like SUs. In primary human pre-adipocytes, glibenclamide and glimepiride strongly induced differentiation, apparently by activating PPARγ. Thus, SUs but not repaglinide may be used to influence insulin resistance beyond their effect on insulin liberation.

Effects of sulphonylureas on spontaneous motility and induced contractions in rat isolated uterus.

To clarify the action of sulphonylureas on calcium, the effect of tolbutamide and glibenclamide has been investigated on a Ca-dependent process, the contractile activity of uterine smooth muscle. Both sulphonylureas antagonized the contractions evoked by CaCl2 in a non-competitive manner when the uterus was maintained in depolarizing solution and did not affect the spontaneous contractions of rat uterus. The capacity of tolbutamide and glibenclamide to relax vanadate-induced contraction of rat uterus in Ca-free medium suggests that sulphonylureas may have an intracellular site of action related to cytosolic free Ca levels, or effect a reduction in Ca action.

Future perspectives for insulinotropic agents in the treatment of type 2 diabetes–DPP-4 inhibitors and sulphonylureas

The introduction of dipeptidyl-peptidase IV inhibitors (DPP-4 inhibitors) brought a novel class of insulinotropic agents into the treatment options for type 2 diabetes. This paper compares the actions, clinical efficacy and safety of sulphonylureas with those of the DPP-4 inhibitors. First, the mode of action of both classes of antidiabetic agents is described. Then clinical studies for both substances in monotherapy and combination therapies are compared concerning their effects on glycaemic parameters and long-term duration of action. Hypoglycaemia incidence and other adverse effects are compared and data on cardiovascular parameters and endpoints are summarized. The effects of sulphonylureas and DPP-4 inhibitors on beta-cell function and beta-cell mass are highlighted. The present and future indications for both sulphonylureas and DPP-4 inhibitors are discussed.

The Effect of Sulphonylureas on the Microvascular and Macrovascular Complications of Diabetes

Type 2 diabetes mellitus is a chronic progressive disease that is characterised by hyperglycaemia and is associated with an increased risk of the development of microvascular complications, such as retinopathy, nephropathy and neuropathy, and cardiovascular disease. With the introduction of newer oral hypoglycaemic agents, there is a need to re-evaluate critically the effectiveness and safety of the older agents, including sulphonylureas, to assess their place in the modern management of type 2 diabetes. Though no clear benefit of sulphonylureas has been shown with respect to large vessel disease, long term studies have, however, shown benefits in patients with microvascular complications. Studies such as the University Group Diabetes Project raised concerns about the safety profile of sulphonylureas, but large prospective studies such as the UK Prospective Diabetes Study have helped to assuage such concerns to a large degree. Their utility in the peri-infarct period continues to be debatable because of the potential effect on cardiac pre-conditioning. Though sulphonylureas continue to be a mainstay of treatment in type 2 diabetes, future clinical trials addressing clinically relevant outcomes are indicated with the newer generation of sulphonylureas that are more beta cell-specific to address the concerns raised about sulphonylureas and cardiac myocytes.

Effects of sulphonylureas on the volume-sensitive anion channel in rat pancreatic beta-cells.

1. The volume-sensitive anion conductance in rat pancreatic beta-cells was studied directly using the conventional whole-cell and perforated patch recording techniques, and indirectly by measuring 3H-taurine efflux from pre-loaded, perifused islets. 2. Using the conventional whole-cell recording configuration, activation of the outwardly-rectifying, DIDS-sensitive conductance was induced by glibenclamide (10 microM) but not by tolbutamide (100 microM) nor by meglitinide (20 microM). A high concentration of glibenclamide (100 microM) caused a voltage-and time-dependent inhibition of the conductance. Tolbutamide had a modest inhibitory effect on swelling-induced inward currents. 3. In perforated patch recordings, glibenclamide, tolbutamide and meglitinide were all without effect on the conductance, although activation could be induced under these conditions by exposure to a hypotonic bath solution. 4. The rate of efflux of 3H-taurine, a marker for activity of the volume-sensitive anion channel, from preloaded, perifused islets was markedly stimulated by exposure to a hypotonic solution. However, glibenclamide and tolbutamide were both without effect. 5. Electrical activity of beta-cells in response to glibenclamide or tolbutamide was not inhibited by 4,4'-dithiocyanatostilbene-2,2'-disulphonic acid (DIDS), an inhibitor of the volume-sensitive anion channel. 6. It is concluded that activity of the volume-sensitive anion conductance in rat pancreatic beta-cells is not modulated by the sulphonylurea receptor. The activation of the conductance by glibenclamide in whole-cell recordings could be the result of a non-specific interaction of the drug with plasma membrane lipids.

Effects of sulphonylureas on cAMP-stimulated Cl- transport via the cystic fibrosis gene product in human epithelial cells.

The cystic fibrosis gene product (CFTR) is a Cl- channel that possesses specific binding sites for cytosolic adenosine triphosphate (ATP) and is activated by cyclic adenosine monophosphate (cAMP)-dependent protein kinases. We explored the possibility that CFTR shares a common pharmacology with another ATP-regulated channel protein, the ATP-sensitive K+ channel that is blocked by sulphonylureas and activated by diazoxide. cAMP-stimulated Cl- effluxes were measured with 36Cl- in the epithelial cell line T84 which stably expresses CFTR. Neither glibenclamide (30 microM), tolbutamide (1 mM) nor diazoxide (100 microM) significantly affected forskolin-activated 36Cl- effluxes in T84 cells. In patch-clamp experiments, glibenclamide exerted only weak inhibitory effects on the whole-cell currents through CFTR with an IC50 of around 0.1 mM. Tolbutamide at 1 mM, but not at 0.1 mM, blocked a current of small amplitude which reversed near the equilibrium potential for K+ ions. We conclude that sulphonylureas and diazoxide are not effective antagonists of endogenous CFTR Cl- channels.

Sulphonylureas reduce the slowly inactivating D-type outward current in rat hippocampal neurons.

1. Using intracellular recording in hippocampal slices, we have examined, in CA3 pyramidal neurons, the effects of sulphonylureas (blockers of ATP-sensitive K+ channels) on the slowly inactivating D-type K+ current (ID). 2. In the presence of TTX (1 microM) to block Na+ currents, ID had the following characteristics: activation by large depolarizing pulses from membrane potentials negative to -75 mV, slow inactivation kinetics, high sensitivity to 4-aminopyridine (4-AP, 3-40 microM), insensitivity to tetraethylammonium (TEA, 10 mM), Cs+ (3 mM) and carbachol (50 microM). 3. Applications of glibenclamide (10 microM) did not modify the input conductance of the cell, but reduced the amplitude of ID by 31.2 +/- 5.6% (n = 16), without altering its voltage dependence and inactivation kinetics. The effects were usually reversible. 4. Glibenclamide also reduced ID in the presence of TEA (10 mM), Cs+ (3 mM) and carbachol (50 microM), to block several K+ currents (IK, IC, IQ, IM), as well as kynurenate (1 mM) and bicuculline (10 microM) to block on-going synaptic currents mediated by activation of non-NMDA (N-methyl-D-aspartate) and GABA (gamma-aminobutyrate)-A receptors, respectively. 5. Comparable depressions of ID were produced by two other sulphonylureas: gliquidone (10 microM), 42.6 +/- 7.9% (n = 13) and tolbutamide (500 microM), 39.1 +/- 12.8 (n = 8). 6. It is concluded that, in the central nervous system, sulphonylureas can modulate K+ currents which are not generated by ATP-sensitive K+ channels.

The Influence of Hypoglycaemic Agents on the Growth and Metabolism of Human Endothelial Cells

Using human umbilical vein endothelial cells, and human microvascular endothelial cells from omental and subcutaneous fat obtained at laparotomy, we studied the effects of sulphonylureas and the biguanide metformin on endothelial cell proliferation, prostacyclin production, ecto-5'-nucleotidase activity, and von Willebrand factor release. Each drug produced a concentration-dependent proliferation of umbilical vein but not of microvascular endothelial cells. The stimulation of umbilical vein endothelial cell proliferation by sulphonylureas, but not by metformin, was serum- and insulin-dependent. Sulphonylureas and metformin had no effect on the proliferation of human dermal fibroblasts, smooth muscle cells derived from the umbilical artery, or 3T3 cells, until concentrations greater than 100 fold those found in vivo were reached, when there was inhibition of proliferation. These agents had no effect on prostacyclin or von Willebrand factor production, or on ecto-5'-nucleotidase activity, until high concentrations were used, at levels which also inhibited proliferation. The results suggest that the sulphonylureas and metformin, may, at concentrations found in vivo, induce changes in the turnover of endothelial cells from large vessels, but not of microvascular endothelial cells.

The relationships between dose and concentration of tolbutamide and insulin and glucose responses in patients with non-insulin-dependent diabetes

It is uncertain how the hypoglycaemic effect of sulphonylureas varies with drug concentration in patients with non-insulin-dependent diabetes mellitus. The inter-relationship of tolbutamide dosage and concentration, and glucose and insulin concentrations were therefore examined in 54 out-patients (the observational group) and in 20 patients studied under controlled conditions (the experimental group). In the observational group, tolbutamide concentration depended significantly on the daily dose, time from dose to sampling, body weight, and age. Blood glucose and insulin concentration were related, but were independent of tolbutamide concentration. In the experimental group, peak, but not pre-dose, tolbutamide concentration, depended on dose and on body mass index. Fasting and maximum post-prandial blood glucose concentration were positively correlated with maximum tolbutamide concentration, probably because tolbutamide dosage was highest in those with the poorest response. In the subset with a fasting blood glucose concentration of less than 8 mmol.l-1, neither glucose nor insulin concentrations depended significantly on tolbutamide concentrations. Tolbutamide concentration does not directly determine hypoglycaemic response in outpatients, and therapeutic monitoring of drug concentrations would not improve the management of such patients.

Effect of sulphonylurea on glucose-stimulated insulin secretion in healthy and non-insulin dependent diabetic subjects: a dose-response study

The effect of a rapid-acting sulphonylurea, glipizide, on the dose-response relationship between the beta-cell response (insulin and C-peptide secretion) and the ambient plasma glucose concentration was examined in 12 healthy and 6 non-insulin-dependent diabetic subjects. The subjects participated in two sets of experiments which were performed in random order: (A) four hyperglycaemic clamp studies, during which the plasma glucose concentration was raised for 120 min by 1 (only in healthy subjects), 3, 7, and 17 mmol/l; and (B) the same four hyperglycaemic clamp studies preceded by ingestion of 5 mg glipizide. All subjects participated in a further study, in which glipizide was ingested and the plasma glucose concentration was maintained at the basal level. In control subjects in the absence of glipizide, the first-phase plasma insulin response (0-10 min) increased progressively with increasing plasma glucose concentration up to 10 mmol/l, above which it tended to plateau. Glipizide augmented the first-phase insulin response without changing the slope of the regression line relating plasma insulin to glucose concentrations. The second-phase plasma insulin response (20-120 min) increased linearly with increasing hyperglycaemia (r = 0.997). Glipizide alone increased the plasma insulin response by 180 pmol/l. A similar increase in plasma insulin response following glipizide was observed at each hyperglycaemic step, indicating that glipizide did not affect the sensitivity of the beta-cell to glucose. First-phase insulin secretion was reduced in the type 2 (non-insulin-dependent) diabetic patients, and was not influenced by glipizide.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of sulphonylureas and diazoxide on insulin secretion and nucleotide‐sensitive channels in an insulin‐secreting cell line

1. The effects of various sulphonylureas and diazoxide on insulin secretion and the activity of various channels have been studied using tissue culture and patch-clamp methods in an insulin-secreting cell line derived from a rat islet cell tumour. 2. Tolbutamide, glibenclamide and HB699 increased the rate of insulin release by 2-5 fold. The concentrations of tolbutamide and glibenclamide giving half-maximum effects on insulin secretion were approximately 40 microM and 0.2 microM, respectively. 3. Diazoxide (0.6-1.0 mM) per se, had either no effect or produced a small increase in insulin secretion, whereas when secretion was maximally stimulated by the combination of glucose (3 mM) and leucine (20 mM), it produced inhibition. Tolbutamide-induced release was also inhibited by diazoxide. 4. Tolbutamide, glibenclamide, HB699 and HB985 reduced the open-state probability of the ATP-K+ channel in a dose-dependent manner. Tolbutamide and glibenclamide were shown to be effective regardless of which side of the membrane they were applied. 5. In whole cell recording, in which the total ATP-sensitive K+ conductance of the cell could be measured, dose-inhibition curves for tolbutamide and glibenclamide were constructed, resulting in Ki values of 17 microM and 27 nM, respectively. The value of Ki for tolbutamide was unchanged when ATP (0.1 mM) was present in the electrode. 6. Diazoxide (0.6 mM) activated the ATP-K+ channels only when they had first been inhibited by intracellular ATP (0.1 mM) or bath applied tolbutamide (3-30 microM). The inhibition produced by glibenclamide could not be reversed by diazoxide. 7. Neither tolbutamide (1.0 mM) nor glibenclamide (10 microM) altered the open-state probability of the Ca2+-activated K+ channel or the Ca2+-activated non-selective cation channel which are present in this cell line. 8. It is concluded that the sulphonylureas and related hypoglycaemic drugs and diazoxide regulate insulin secretion by direct effects on the ATP-K+ channel or a protein closely associated with this channel.

The effects of sulphonylureas on the dog heart and relationship to their pharmacokinetic aspects

The effects of sulphonylureas on the dog heart and relationship to their pharmacokinetic aspects

Effect of sulphonylurea on insulin response during intravenous glucose tolerance test in noninsulin-dependent diabetics

Effect of sulphonylurea on insulin response during intravenous glucose tolerance test in noninsulin-dependent diabetics

The Effect of Glibenclamide on Insulin Receptors in Normal Man: Comparative Studies of Insulin Binding to Monocytes and Erythrocytes*

In vivo studies in noninsulin-dependent diabetic patients have indicated that sulphonylurea drugs have an extra-pancreatic effect. To further elucidate the mechanisms of this action, we studied the effect of glibenclamide on in vivo and in vitro cellular insulin receptor binding in normal subjects. Oral administration of glibenclamide in dose of 2.5 mg/day increased insulin binding to monocytes by 70% (P less than 0.001), in spite of increased postprandial serum insulin levels. This change in insulin receptor binding occurred in the absence of changes in diet or body weight. In contrast, glibenclamide had no stimulatory effect on in vivo insulin binding to erythrocytes. The in vitro studies with monocytes revealed a dose-related insulin receptor stimulatory effect of glibenclamide (P less than 0.05), with a maximal effect of 20% above basal level. These data indicate that glibenclamide increases the insulin-binding ability of monocytes but not of erythrocytes. As the monocyte is judged a better model for studying insulin receptors on target cells than the erythrocyte, this effect may be responsible, at least in part, for the extrapancreatic effect of sulphonylureas, which seem to be of major importance for their hypoglycemic effect in noninsulin-dependent diabetic patients.

Effects of sulphonylureas on gastric inhibitory polypeptide (GIP) release in man

Effects of sulphonylureas on gastric inhibitory polypeptide (GIP) release in man

Synergistic effects of hypoglycaemic sulphonylureas and antibiotic ionophores upon calcium translocation.

1 Hypoglycaemic sulphonylureas, such as tolbutamide and gliclazide, provoke the translocation of calcium from an aqueous medium into or across a hydrophobic region. The combined effect of sulphonylureas and antibiotic ionophores upon such a process was investigated. 2 The magnitude of the sulphonylurea-induced translocation of calcium was more marked in the presence than in the absence of A23187. Gliclazide and tolbutamide also enhanced, although less markedly, X537A-mediated calcium translocation. The effect of the sulphonylureas was even less marked in the presence of both ionophores, which acted synergistically in causing calcium translocation. 3 A non-hypoglycaemic sulphonylurea and diazoxide failed to affect ionophore-mediated calcium translocation. Gliclazide failed to enhance X537A-mediated sodium translocation. 4 It is proposed that the primary site of action of hypoglycaemic sulphonylureas upon calcium-dependent physiological processes may correspond to a drug-induced facilitation of calcium transport across the plasma membrane, as mediated by native ionophores.