piperidines and glimepiride

Insulin secretagogues promote insulin release by binding to sulfonylurea receptors on pancreatic β-cells (SUR1). However, these drugs also bind to receptor isoforms on cardiac myocytes (SUR2A) and vascular smooth muscle (SUR2B). Binding to SUR2A/SUR2B may inhibit ischaemic preconditioning, an endogenous protective mechanism enabling cardiac tissue to survive periods of ischaemia. This study was designed to identify insulin secretagogues that selectively bind to SUR1 when given at therapeutic doses.. Using accepted systematic review methods, three electronic databases were searched from inception to 13 June 2011. Original studies measuring the half-maximal inhibitory concentration (IC(50)) for an insulin secretagogue on K(ATP) channels using standard electrophysiological techniques were included. Steady-state concentrations (C(SS)) were estimated from the usual oral dose and clearance values for each drug.. Data were extracted from 27 studies meeting all inclusion criteria. IC(50) values for SUR1 were below those for SUR2A/SUR2B for all insulin secretagogues and addition of C(SS) values identified three distinct patterns. The C(SS) for gliclazide, glipizide, mitiglinide and nateglinide lie between IC(50) values for SUR1 and SUR2A/SUR2B, suggesting that these drugs bind selectively to pancreatic receptors. The C(SS) for glimepiride and glyburide (glibenclamide) was above IC(50) values for all three isoforms, suggesting these drugs are non-selective. Tolbutamide and repaglinide may have partial pancreatic receptor selectivity because IC(50) values for SUR1 and SUR2A/SUR2B overlapped somewhat, with the C(SS) in the midst of these values.. Insulin secretagogues display different tissue selectivity characteristics at therapeutic doses. This may translate into different levels of cardiovascular risk.

Topics: Animals; ATP-Binding Cassette Transporters; Carbamates; Cardiovascular Diseases; Cricetinae; Cyclohexanes; Diabetes Mellitus, Type 2; Gliclazide; Glipizide; Glyburide; Humans; Hypoglycemic Agents; Ischemic Preconditioning, Myocardial; Isoindoles; Mice; Muscle, Smooth, Vascular; Myocytes, Cardiac; Nateglinide; Phenylalanine; Piperidines; Potassium Channels, Inwardly Rectifying; Rats; Receptors, Drug; Risk Factors; Sulfonylurea Compounds; Sulfonylurea Receptors; Tolbutamide

The cytochrome P4502C enzymes account for the metabolism of approximately 20% of therapeutic drugs including certain oral antidiabetic drugs (OADs).. This review focuses on the effect of CYP2C enzymes on metabolism of sulphonylureas (SUs), meglitinides, and thiazolidinediones (TZDs) discussing their impact on pharmacokinetics, drug interactions and toxicological profiles. Pharmacogenetic aspects reflecting individual gene variants and variable drug effects are also considered.. Genetic polymorphisms of CYP2C9 enzymes (*2/*2, *2/*3, *3/*3) influence the glycaemic response to SUs and impair their substrate metabolism. Restricted data from small-sized studies with heterogenous definitions of hypoglycaemia revealed no clear association between CYP2C9 genotypes and the risk of hypoglycaemia. Functional polymorphisms of CYP2C8- and CYP2C9 drug metabolizing genes affect markedly pharmacokinetics of meglitinides. Compared to wild-type carriers, patients treated with TZDs and carrying the common CYP2C8*3 and *4 variants showed a reduced glycaemic control. The strong CYP2C8 and OATP1B1 inhibitor gemfibrozil increases substantially the plasma concentrations of repaglinide and TZDs. Numerous metabolic drug interactions exist between SUs and commonly prescribed drugs, especially anti-infectives. The complex pharmacokinetic and pharmacogenetic properties and the unfavourable short and long term risk profile of glibenclamide and glimepiride raise the question whether their use can be justified any longer.

Topics: Administration, Oral; Benzamides; Blood Glucose; Carbamates; Cytochrome P-450 Enzyme System; Drug Interactions; Gemfibrozil; Humans; Hypoglycemic Agents; Inactivation, Metabolic; Pharmacogenetics; Piperidines; Polymorphism, Single Nucleotide; Sulfonylurea Compounds; Thiazolidinediones

Type 2 diabetes mellitus is a progressive disorder, and although oral monotherapy is often initially successful, it is associated with a high secondary failure rate, which contributes to the development of long-term diabetes complications resulting from persistent hyperglycemia. For patients not taking insulin, accumulating evidence suggests that combination therapy using oral antidiabetic agents with different mechanisms of action may be highly effective in achieving and maintaining target blood glucose levels. Low-dose combination therapy may be associated with fewer side effects than higher-dose monotherapy and may achieve similar or better glycemic control. The best-studied combination is that of sulfonylurea compounds plus metformin, a therapeutic approach that addresses both underlying defects in the disorder: insulin deficiency and insulin resistance. Other multidrug regimens under investigation are sulfonylurea compounds plus either alpha-glucosidase inhibitors or thiazolidinediones, and combinations of various insulin-sensitizing agents. For many patients, combination oral therapy may be used appropriately as primary management early in the course of type 2 diabetes, along with diet modification and exercise. Later in the course of the disease, the use of combinations of oral agents may delay the need for insulin while maintaining glycemic control, thus making aggressive oral treatment more acceptable for many patients.

Topics: Acarbose; Administration, Oral; Carbamates; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Glyburide; Humans; Hypoglycemic Agents; Metformin; Piperidines; Sulfonylurea Compounds

Current agents for the treatment of Type 2 diabetes mellitus improve the metabolic profile but do not reinstate normality. They also reduce chronic diabetic complications, but they do not eliminate them. Thus, new agents with novel actions are required to complement and extend the capabilities of existing treatments. Insulin resistance and beta-cell failure, which are crucial components in the pathogenesis of Type 2 diabetes, remain the underlying targets for new drugs. Recently introduced agents include a short-acting non-sulphonylurea insulin-releaser, repaglinide, which synchronizes insulin secretion with meal digestion in order to reduce post-prandial hyperglycaemia. The thiazolidinedione drugs, troglitazone, rosiglitazone and pioglitazone represent a new class of agonists for the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma). PPARgamma increases the transcription of certain insulin-sensitive genes, thereby improving insulin sensitivity. The intestinal lipase inhibitor orlistat and the satiety-inducer sibutramine are new weight-reducing agents that may benefit glycaemic control in obese Type 2 diabetes patients. Several further new insulin-releasing agents, and agents to retard carbohydrate digestion and modify lipid metabolism stand poised to enter the market. The extent to which they will benefit glycaemic control remains to be seen. However, the prospect of permanently arresting or reversing the progressive deterioration of Type 2 diabetes continues to evade therapeutic capture.

Topics: Anti-Obesity Agents; Carbamates; Chromans; Diabetes Mellitus, Type 2; Drug Design; Humans; Hypoglycemic Agents; Insulin Resistance; Piperidines; Sulfonylurea Compounds; Thiazoles; Thiazolidinediones; Troglitazone

In older patients with type 2 diabetes, life expectancy and the presence of microvascular complications determine the appropriate intensity of glucose control. The available antidiabetic agents offer many options for achieving glycemic targets, based on the needs of the individual patient. New stimulators of insulin secretion include glimepiride (a sulfonylurea) and repaglinide (a meglitinide). The biguanide metformin is especially useful in obese, insulin-resistant patients. Alpha-glucosidase inhibitors such as acarbose and miglitol act locally in the GI tract to reduce postprandial excursion in glucose levels. The insulin-sensitizing drug troglitazone enhances insulin-mediated glucose disposal. When troglitazone is used, careful monitoring of patients' liver function is required.

Topics: 1-Deoxynojirimycin; Acarbose; Age Factors; Aged; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Glucosamine; Humans; Hypoglycemic Agents; Imino Pyranoses; Metformin; Piperidines; Sulfonylurea Compounds; Trisaccharides

The choice of an optimal oral hypoglycemic agent in the initial treatment periods for type 2 diabetes mellitus (T2DM) patients remains difficult and deliberate. We compared the efficacy and safety of glimepiride (GLIM), alogliptin (ALO), and alogliptin-pioglitazone (ALO-PIO) in poorly controlled T2DM patients with drug-naïve or metformin failure.. In this three-arm, multicenter, open-label, randomized, controlled trial, poorly controlled T2DM patients were randomized to receive GLIM (n=35), ALO (n=31), or ALO-PIO (n=33) therapy for 24 weeks. The primary endpoint was change in the mean glycosylated hemoglobin (HbA1c) levels at week 24 from baseline. Secondary endpoints were changes in HbA1c level at week 12 from baseline, fasting plasma glucose (FPG) levels, lipid profiles at weeks 12 and 24, and parameters of glycemic variability, assessed by continuous glucose monitoring for 24 weeks.. At weeks 12 and 24, the ALO-PIO group showed significant reduction in HbA1c levels compared to the ALO group (-0.96%±0.17% vs. -0.37%±0.17% at week 12; -1.13%±0.19% vs. -0.18%±0.2% at week 24). The ALO-PIO therapy caused greater reduction in FPG levels and significant increase in high-density lipoprotein cholesterol levels at weeks 12 and 24 than the ALO therapy. Compared to low-dose GLIM therapy, ALO-PIO therapy showed greater improvement in glycemic variability. The adverse events were similar among the three arms.. ALO-PIO combination therapy during the early period exerts better glycemic control than ALO monotherapy and excellency in glycemic variability than low-dose sulfonylurea therapy in uncontrolled, drug-naïve or metformin failed T2DM patients.

Topics: Autoimmune Diseases; Blood Glucose; Blood Glucose Self-Monitoring; Cholesterol; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipids; Lipoproteins, HDL; Metformin; Pioglitazone; Piperidines; Sulfonylurea Compounds; Treatment Outcome; Uracil

Despite the current guideline's recommendation of a timely stepwise intensification therapy, the "clinical inertia", termed as the delayed treatment intensification, commonly exists in the real world, which may be partly due to the relatively little substantial evidence and no clear consensus regarding the efficacy and safety of triple oral agents in patients inadequately controlled with dual therapy. In this clinical trial performed in 237 centers in China, 5,535 type 2 diabetic patients inadequately controlled by previous therapies were treated with a stable metformin/sitagliptin dual therapy for 20 weeks. The patients who did not reach the glycated hemoglobin A1c (HbA1c) goal were then further randomized into glimepiride, gliclazide, repaglinide, or acarbose group for an additional 24-week triple therapy. A mean HbA1c reduction of 0.85% was observed when sitagliptin was added to the patients inadequately controlled with metformin in 16 weeks. Further HbA1c reductions in the 24-week triple therapy stage were 0.65% in glimepiride group, 0.70% in gliclazide group, 0.61% in repaglinide group, and 0.45% in acarbose group. The non-inferiority criterion for primary hypotheses was met for gliclazide and repaglinide, but not for acarbose, compared with glimepiride, when added to metformin/sitagliptin dual therapy. The incidences of adverse events (AEs) were 29.2% in the dual therapy stage and 30.3% in the triple therapy stage. Metformin/sitagliptin as baseline therapy, with the addition of a third oral antihyperglycemic agent, including glimepiride, gliclazide, repaglinide, or acarbose, was effective, safe and well-tolerated for achieving an HbA1c <7.0% goal in type 2 diabetic patients inadequately controlled with previous therapies. The timely augmentation of up to three oral antihyperglycemic agents is valid and of important clinical benefit to prevent patients from exposure to unnecessarily prolonged hyperglycemia.

Topics: Acarbose; Adult; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Gliclazide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Piperidines; Sitagliptin Phosphate; Sulfonylurea Compounds; Treatment Outcome

To compare effects of three different insulin secretagogues on early-phase insulin secretion, metabolism of glucose and lipids, and lipid peroxidation in newly diagnosed Type 2 Diabetes Mellitus (T2DM).. Totally 60 newly diagnosed T2DM outpatients were randomized to three groups with 1-month monotherapy of repaglinide (Rg), glimepiride (Gm) or gliclazide MR (Gli), respectively. Some indexes of early-phase insulin secretion, glucose, lipids, and lipid peroxidation were inspected.. Fasting plasma glucose (FPG), glycosylated hemoglobin (HbA(1c)) and fructosamine (FA) were improved in all groups similarly (p>0.05). Rg group was with the highest early-phase insulin secretion index (DeltaI30/DeltaG30) (p=0.026), lower mean amplitude of glycaemic excursion (MAGE) (p<0.05), lowest mean peak value of post-lunch glucose (p=0.043), and lowest postprandial triglyceride (TG) (p=0.039). Postprandial free fatty acid (FFA) was lower after Rg and Gli treatment (p<0.05). Serum 8-iso prostaglandin F(2alpha) (8-iso PGF(2alpha)) was improved in all groups, but the improvement showed statistically significant only in Rg group (p=0.04).. Rg, Gm and Gli can all decrease blood glucose effectively in newly diagnosed T2DM patients, while Rg performs outstandingly in the aspects of improving early-phase insulin secretion, glucose excursion, postprandial lipids and 8-iso PGF(2alpha).

Topics: Adult; Aged; Analysis of Variance; Blood Glucose; Carbamates; Chi-Square Distribution; Diabetes Mellitus, Type 2; Female; Fructosamine; Gliclazide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Lipid Peroxidation; Lipids; Male; Middle Aged; Oxidative Stress; Piperidines; Postprandial Period; Sulfonylurea Compounds; Treatment Outcome

An impaired early phase of insulin secretion in the type 2 diabetes mellitus (DM) is very important for the postprandial hyperglycemia. The aim of the study was to compare the efficacy of metformin/repaglinid and metformin/glimepirid regimes in type 2 diabetics uncontrolled with metformin monotherapy.. Totally, 60 type 2 diabetics with haemoglobin A1c > or = 7.5% and 2000 mg of metformin monotherapy for at least three months were divided in the following groups: A-30 patients with metformin+repaglinid (2 mg for each meal) and B metformin+glimepirid (3 mg in the morning). Assessment of the regimes efficacy comprised of haemoglobin A1c, fasting blood glucose (FBG) and postprandial blood glucose (PBG). Assessment of the safety was performed on the basis of recorded hypoglycemia (<4.0 mmol/l).. In both groups, FBG was significantly lower at the end of the study. In the group A it decreased from 9.03 +/- 1.00 to 7.32 +/- 0.65 (p < 0.001), in the group B from 8.94 +/- 1.01 to 7.23 +/- 0.70 (p < 0.001). There was no statistical difference between the groups. PBG was significantly lower after 12 weeks in both groups.. Metformin/repaglinid is an efficient and safe therapeutic regime in the treatment of the type 2 DM that ensure a better control of PBG levels (Tab. 4, Ref. 18).

Topics: Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Piperidines; Sulfonylurea Compounds

This study was conducted to compare the treatment efficacy between a prandial glucose regulator, repaglinide and a new sulphonylurea, glimepiride in Muslim Type 2 diabetic patients who practice Ramadan fasting. Forty-one patients, previously treated with a sulphonylurea or metformin, were divided to receive either repaglinide (n=20, preprandially three-times daily) or glimepiride (n=21, preprandially once daily) 3 months before the month of Ramadan. During Ramadan, patients modified their eating pattern to two meals daily, and the triple doses of repaglinide were redistributed to two preprandial doses. Four point blood glucose monitoring were performed weekly during the month of Ramadan and the subsequent month. Measurements of the 4-point blood glucose were significantly lower in the glimepiride group compared to the repaglinide group both during and after Ramadan. The glycaemic excursion was better in the morning for the repaglinide group and better in the afternoon and evening for the glimepiride group during the Ramadan period. There was no statistically significant difference in the incidence of hypoglycaemia between the two groups during and after Ramadan. There was no difference in the glycaemic excursion post-Ramadan. The longer duration of action of glimepiride may offer an advantage over repaglinide during the 13.5 hours of fast in Ramadan for diabetic patients.

Topics: Adult; Aged; Blood Glucose; Carbamates; Ceremonial Behavior; Diabetes Mellitus, Type 2; Fasting; Female; Humans; Hypoglycemic Agents; Islam; Male; Middle Aged; Piperidines; Sulfonylurea Compounds; Time Factors; Treatment Outcome

Aim our study is to compare the effects of repaglinide vs glimepiride administration on cardiovascular risk factors after meal test. Thus, after 2 weeks washout period, a 3-month randomised, cross-over parallel group trial of repaglinide (1 mg x 2/day) vs glimepiride (2 mg/day) in 14 patients with type 2 diabetes "naive" on diet treatment was made. Both treatments significantly declined plasma glucose, total-cholesterol, LDL-cholesterol, triglycerides, PAI-1, PAP levels and increased HDL-cholesterol. Lowering in plasma PAI-1 and PAP levels was significantly greater in repaglinide group. Furthermore, repaglinide administration resulted in a significant decrease in fasting plasma free fatty acids, fibrinogen, thrombin-antithrombin complex and reaction product of malondialdehyde with thiobarbituric acid (TBARS) levels, in absence of significant difference in fasting plasma insulin levels. Decrease in plasma TBARS levels correlated with the decrease in Plasminogen Activator Inhibitor-1 (r = 0.72; P < 0.003) and free fatty acids concentrations (r = 0.62; P < 0.01). Analysis of the insulin and glucose concentrations throughout the meal test revealed that AUC for glucose (758 +/- 19 vs 780 +/- 28 mg/Lxmin; P = 0.02) was significantly lower after repaglinide than glimepiride administration despite similar AUC for insulin (2327 +/- 269 vs 2148 +/- 292 mU/Lxmin; P = 0.105). At time 120' of meal test, repaglinide vs glimepiride administration was associated with a significant decline in plasma triglycerides, free fatty acids, fibrinogen, Plasminogen Activator Inhibitor-1, plasmin-alpha(2)-antiplasmin complex, thrombin-antithrombin complex, TBARS levels and increase in plasma HDL-cholesterol levels. In repaglinide group a negative correlation between insulin secretion during 1st phase of meal-test and plasma TBARS levels (r = -0.55; P < 0.03) at time 120' was found. Such correlation was lost after adjusting for changes in postprandial hyperglycaemia (r = -0.48; P < 0.09). In conclusion, our results support the hypothesis that repaglinide is more efficient than glimepiride on controlling for postprandial glucose excursion and may have beneficial effect on reducing cardiovascular risk factors.

Topics: Aged; Aged, 80 and over; Area Under Curve; Blood Glucose; Carbamates; Cardiovascular Diseases; Cross-Over Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diet, Diabetic; Eating; Female; Humans; Hypoglycemic Agents; Insulin; Lipids; Male; Middle Aged; Piperidines; Sulfonylurea Compounds; Thiobarbituric Acid Reactive Substances

To compare the effect of Repaglinide vs Glimepiride on glucose- and meal-induced insulin secretion and on meal-test induced postprandial glucose excursions.. After 2 weeks washout period, a 3-Month randomised, cross-over parallel group trial of R (1 mg x 2/die) vs G (2 mg/die) in 14 patients with type 2 diabetes "naive" in diet treatment was made.. Both R and G significantly but similarly lowered fasting glucose levels and improved fasting plasma insulin levels vs baseline. Hyperglycemic clamp showed that both 1st (129.15 +/- 23.6 vs 106.90 +/- 18.6 pmol/L; p=0.01) and 2nd phase (189.42 +/- 34.4 vs 144.21 +/- 37.3 pmol/L; p=0.003) B-cell response to glucose as well as area under the curve (52.07 +/- 10.86 vs 39.54 +/- 10.27 micromol/L x 120'; p=0.005) were greater in R than G groups. Insulin action (4.0 +/- 1.1 vs 3.2 +/- 0.9 mg x Kg x 60'/microU/mL; p=0.046) was also improved by R than G administration. In the meal test, R therapy produced a more rapId induction of insulin secretion during the first part. In fact, the mean rise in insulin secretion peaked at 45 min in R (p=0.001 vs G) and at 60 min in G (p=0.001 vs R). Consequently, glucose spike at 60 min was higher in G group compared to glucose spike at 45 min in R group (p=0.002).. Our study demonstrates that R is more efficient that G on improving glucose- and meal- induced insulin secretion as well as on controlling for postprandial glucose excursion.

Topics: Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Carbamates; Cholesterol; Diabetes Mellitus, Type 2; Female; Glucose Clamp Technique; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Kinetics; Male; Middle Aged; Piperidines; Postprandial Period; Sulfonylurea Compounds; Time Factors; Triglycerides

Repaglinide and glimepiride are relatively new oral hypoglycemic agents. Few data are available concerning their effects on metabolic parameters other than measures of glycemic control.. In addition to assessing the effects of repaglinide and glimepiride on glycemic control in patients with type 2 diabetes mellitus, this study also examined the effects of these agents on 3 metabolic parameters known to be cardiovascular risk factors--lipoprotein(a) (Lp[a]), plasminogen activator inhibitor-1 (PAI-1), and homocysteine (Hcy).. This randomized, placebo-controlled, double-blind trial was conducted at a single center in Italy. Eligible patients were nonsmokers; had no hypertension or coronary heart disease; were taking no hypolipidemic drugs, diuretics, beta-blockers, or thyroxin; and had normal renal function. After an initial 4-week placebo washout period, patients were randomized to receive repaglinide 1 mg/d or glimepiride 1 mg/d. The dose of study drug was optimized over an 8-week titration period, which was followed by a 12-month treatment period. Measures of glycemic control (glycated hemoglobin [HbA1c], fasting plasma glucose [FPG], postprandial plasma glucose [PPG], fasting plasma insulin [FPI], postprandial plasma insulin [PPI]) and the other metabolic parameters of interest were assessed after 6 and 12 months of treatment.. One hundred twenty-four patients (63 women, 61 men) completed the study, 62 in each treatment group. There were no significant differences in demographic characteristics between groups. After 6 and 12 months of treatment, FPG levels and HbA1c values were significantly reduced from baseline in both groups (6 months, P < 0.05; 12 months, P < 0.01). After 6 months, PPG levels were significantly decreased only in the repaglinide group (P < 0.05 vs baseline); at 12 months, however, PPG levels were significantly reduced from baseline in both groups (P < 0.01 repaglinide, P < 0.05 glimepiride). No significant changes from baseline in FPI or PPI levels were seen in either group at 6 months, although FPI levels were significantly increased in the repaglinide group at 12 months (P < 0.05). Repaglinide significantly lowered levels of Lp(a), PAI-1, and Hcy after 12 months (all, P < 0.05 vs baseline). Glimepiride significantly lowered levels of Lp(a) and Hcy after 6 months (both, P < 0.05 vs baseline) and levels of Lp(a) (P < 0.01 vs baseline), Hcy (P < 0.01 vs baseline), and PAI-1 (P < 0.05 vs baseline) after 12 months.. Repaglinide and glimepiride improved glycemic control and reduced levels of other metabolic parameters of interest in this population of patients with type 2 diabetes. It is possible that the reductions in Lp(a), PAI-1, and Hcy were the result of improved glucose metabolism; however, the possibility that repaglinide and glimepiride may have a direct effect on these parameters should not be excluded.

Topics: Blood Glucose; Blood Pressure; Carbamates; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Homocysteine; Humans; Hypoglycemic Agents; Lipoprotein(a); Male; Middle Aged; Piperidines; Plasminogen Activator Inhibitor 1; Risk Factors; Sulfonylurea Compounds; Time Factors; Treatment Outcome

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.

Topics: Administrative Claims, Healthcare; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Carbamates; Databases, Factual; Diabetes Mellitus, Type 2; Drug Interactions; Female; Glipizide; Glyburide; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Medicaid; Metformin; Middle Aged; Nateglinide; Pharmacoepidemiology; Piperidines; Secretagogues; Sulfonylurea Compounds; United States

Acanthamoeba keratitis is a sight-endangering eye infection, and causative organism Acanthamoeba presents a significant concern to public health, given escalation of contact lens wearers. Contemporary therapy is burdensome, necessitating prompt diagnosis and aggressive treatment. None of the contact lens disinfectants (local and international) can eradicate Acanthamoeba effectively. Using a range of compounds targeting cellulose, ion channels, and biochemical pathways, we employed bioassay-guided testing to determine their anti-amoebic effects. The results indicated that acarbose, indaziflam, terbuthylazine, glimepiride, inositol, vildagliptin and repaglinide showed anti-amoebic effects. Compounds showed minimal toxicity on human cells. Therefore, effects of the evaluated compounds after conjugation with nanoparticles should certainly be the subject of future studies and will likely lead to promising leads for potential applications.

Topics: Acanthamoeba castellanii; Acanthamoeba Keratitis; Acarbose; Antiprotozoal Agents; Carbamates; Cell Line; Contact Lens Solutions; Contact Lenses; HaCaT Cells; Humans; Indenes; Inositol; Nanoparticles; Piperidines; Sulfonylurea Compounds; Triazines; Vildagliptin

Topics: Acanthamoeba castellanii; Amebicides; Anti-Infective Agents; Carbamates; HeLa Cells; Humans; Hypoglycemic Agents; Metal Nanoparticles; Nanoconjugates; Piperidines; Silver; Sulfonylurea Compounds; Vildagliptin

Several insulin secretagogues are widely used to treat diabetes; however, few outcome-based comparative studies have clarified which one of these should be used when indicated. We investigated mortality and cardiovascular event risk associated with optimal forms of insulin secretagogues.. In this cohort study using real-world data from the diabetes database of Taiwan's National Health Insurance program, patients with diabetes were enrolled if their initial treatment was glimepiride, gliclazide, glipizide, glyburide, or repaglinide from 1999 to 2013. Each group was propensity score-matched to the glimepiride group before comparison. Primary outcomes were all-cause mortality and the combined cardiovascular event risk of acute myocardial infarction and ischemic stroke. Hazard ratios were calculated by Cox proportional hazard regression models.. There were 66,790, 97,426, 38,806, 92,970, and 11,468 participants in the glimepiride, gliclazide, glipizide, glyburide, and repaglinide groups, respectively. The median follow-up time was 8 years. Glimepiride was associated with the best clinical outcome, showing the lowest mortality and lowest cardiovascular event risk of the five insulin secretagogues. Using patients on glimepiride as the reference group, the adjusted hazard ratios of all-cause mortality and cardiovascular event risk were 1.52 (p < 0.001) and 1.22 (p = 0.005) for gliclazide, 1.42 (p < 0.001) and 1.19 (p = 0.073) for glipizide, 1.43 (p < 0.001) and 1.32 (p < 0.001) for glyburide, and 1.88 (p < 0.001) and 1.69 (p = 0.001) for repaglinide.. For patients with diabetes taking an insulin secretagogue, glimepiride was associated with the best clinical outcome, showing the lowest mortality and cardiovascular event risk.

Topics: Aged; Carbamates; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Follow-Up Studies; Gliclazide; Glipizide; Glyburide; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Middle Aged; Mortality; Piperidines; Secretagogues; Sulfonylurea Compounds; Taiwan

Drug-drug interactions with insulin secretagogues are associated with increased risk of serious hypoglycemia in patients with type 2 diabetes. We aimed to systematically screen for drugs that interact with the five most commonly used secretagogues-glipizide, glyburide, glimepiride, repaglinide, and nateglinide-to cause serious hypoglycemia.. We screened 400 drugs frequently coprescribed with the secretagogues as candidate interacting precipitants. We first predicted the drug-drug interaction potential based on the pharmacokinetics of each secretagogue-precipitant pair. We then performed pharmacoepidemiologic screening for each secretagogue of interest, and for metformin as a negative control, using an administrative claims database and the self-controlled case series design. The overall rate ratios (RRs) and those for four predefined risk periods were estimated using Poisson regression. The RRs were adjusted for multiple estimation using semi-Bayes method, and then adjusted for metformin results to distinguish native effects of the precipitant from a drug-drug interaction.. We predicted 34 pharmacokinetic drug-drug interactions with the secretagogues, nine moderate and 25 weak. There were 140 and 61 secretagogue-precipitant pairs associated with increased rates of serious hypoglycemia before and after the metformin adjustment, respectively. The results from pharmacokinetic prediction correlated poorly with those from pharmacoepidemiologic screening.. The self-controlled case series design has the potential to be widely applicable to screening for drug-drug interactions that lead to adverse outcomes identifiable in healthcare databases. Coupling pharmacokinetic prediction with pharmacoepidemiologic screening did not notably improve the ability to identify drug-drug interactions in this case.

Topics: Area Under Curve; Carbamates; Cyclohexanes; Databases, Factual; Diabetes Mellitus, Type 2; Drug Interactions; Glipizide; Glyburide; Humans; Hypoglycemia; Hypoglycemic Agents; Medical Informatics; Nateglinide; Pharmacoepidemiology; Phenylalanine; Piperidines; Sulfonylurea Compounds

A rapid, simple, and precise RPLC method was developed for the simultaneous determination of the widely used oral antidiabetic, metformin hydrochloride (MTF), with some commonly coadministered oral antidiabetics from different pharmacological classes-glipizide (GPZ), pioglitazone hydrochloride (PGZ), glimepiride (GLM), and repaglinide (RPG)-in bulk, laboratory-prepared mixtures and pharmaceutical formulations in the presence of metformin-reported impurity [1-cyanoguanidine (CNG)]. Chromatographic separation was achieved using isocratic elution mode with a mobile phase of acetonitrile: 0.02 M potassium dihydrogen phosphate (pH 3.17; 50-50, v/v) flowing through a CN Phenomenex column (Phenosphere Next, 250 × 4.6 mm, 5 μm) at a rate of 1.5 mL/min at ambient temperature. UV detection was carried out at 220 nm. The method was validated according to International Conference on Harmonization guidelines. Linearity, accuracy, and precision were satisfactory for concentration ranges: 0.175-350 μg/mL for MTF, 0.0525-105 μg/mL for GPZ, 0.125-250 μg/mL for PGZ, and 0.05-100 μg/mL for GLM and RPG. Correlation coefficients were >0.99 for all analytes. LOQs were 0.009 μg/mL for MTF, 0.009 μg/mL for GPZ, 0.04 μg/mL for GLM, 0.124 μg/mL for PGZ, and 0.044 μg/mL for RPG. The developed method is specific, accurate, and suitable for the QC and routine analysis of the cited drugs in their pharmaceutical products.

Topics: Carbamates; Chromatography, High Pressure Liquid; Drug Contamination; Glipizide; Guanidines; Hypoglycemic Agents; Metformin; Pioglitazone; Piperidines; Sulfonylurea Compounds; Thiazolidinediones

Metformin is the first-line treatment for most patients with type 2 diabetes but many patients need additional treatment with insulin secretagogues (IS) to achieve glycemic control. We aimed to compare mortality and cardiovascular risk among users of metformin in combination with pharmacologically different ISs.. Using nationwide administrative Danish registries, we followed all individuals without prior stroke or myocardial infarction who initiated metformin and an IS from 1997 through 2009. Rate ratios (RR) of all-cause mortality, cardiovascular death, and a composite of myocardial infarction, stroke, or cardiovascular death were compared between user groups using time-dependent multivariable Poisson regression models. The most common combination, glimepiride+metformin, was used as reference.. A total of 56,827 patients were included, 56% male, the mean age was 61 ± 12.5 years, and median duration of prior monotherapy was 2.2 (inter quartile range 0.5-4.5) years. Crude incidence rates of mortality for combinations of ISs with metformin were; 15.4 (repaglinide), 28.1 (glipizide), 23.7 (glibenclamide), 21.1 (gliclazide), 20.7 (glimepiride), 27.7 (tolbutamide) deaths per 1000 person years. In adjusted analysis, the associated mortality risk was similar for users of gliclazide+metformin (RR=1.01 [0.88-1.15]), repaglinide+metformin (RR=0.81 [0.62-1.05]), glibenclamide+metformin (RR=0.98 [0.87-1.10]), and tolbutamide+metformin (RR=1.04 [0.85-1.28]). Users of glipizide+metformin was associated with increased all-cause mortality (RR=1.16 [1.02-1.32], p=0.02), cardiovascular death (RR=1.21 [1.01-1.46], p=0.04), and the combined endpoint (RR=1.20 [1.06-1.36, p=0.005).. Most ISs in combination with metformin were associated with similar mortality and cardiovascular risk. Whether glipizide is associated with increased risk compared with other ISs when used in combinations with metformin warrants further study.

Topics: Aged; Carbamates; Cardiovascular Diseases; Denmark; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Gliclazide; Glipizide; Glyburide; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Morbidity; Myocardial Infarction; Piperidines; Registries; Retrospective Studies; Risk Factors; Stroke; Sulfonylurea Compounds; Tolbutamide

Many patients with type 2 diabetes mellitus(T2DM) do not achieve satisfactory glycemic control by monotherapy alone, and often require multiple oral hypoglycemic agents (OHAs). Combining OHAs with complementary mechanisms of action is fundamental to the management of T2DM. Fixed-dose combination therapy(FDC) offers a method of simplifying complex regimens. Efficacy and tolerability appear to be similar between FDC and treatment with individual agents. In addition, FDC can enhance adherence and improved adherence may result in improved glycemic control. Four FDC agents are available in Japan: pioglitazone-glimepiride, pioglitazone-metformin, pioglitazone-alogliptin, and voglibose-mitiglinide. In this review, the advantages and disadvantages of these four combinations are identified and discussed.

Topics: Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Inositol; Isoindoles; Metformin; Pioglitazone; Piperidines; Sulfonylurea Compounds; Thiazolidinediones; Uracil

The effect of piperine on the pharmacokinetics and pharmacodynamics of glimepiride in normal as well as diabetic rats was studied. In normal and streptozotocin induced diabetic rats the combination of glimepiride with piperine increased all the pharmacokinetic parameters, such as Cmax, AUC0-n, AUCtotal, t1/2, and MRT, and decreased the clearance, Vd, markedly as compared with the control group. In pharmacodynamic studies, the combination of glimepiride with piperine provided significant protection against the diabetes induced alterations in the biochemical parameters. In addition, the combination of glimepiride with piperine also improved the total antioxidant status significantly in diabetic rats compared with piperine and glimepiride treated groups. The results revealed that a combination of glimepiride with piperine led to the enhancement of the bioavailability of glimepiride by inhibiting the CYP2C9 enzyme, which suggested that piperine might be beneficial as an adjuvant to glimepiride in a proper dose, in diabetic patients.

Topics: Alanine Transaminase; Alkaloids; Animals; Antioxidants; Area Under Curve; Aspartate Aminotransferases; Benzodioxoles; Blood Glucose; Body Weight; Cholesterol; Chromatography, High Pressure Liquid; Diabetes Mellitus, Experimental; Hypoglycemic Agents; Male; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Sulfonylurea Compounds; Triglycerides

Topics: Carbamates; Cyclohexanes; Glipizide; Humans; Hyperglycemia; Hyperlipidemias; Hypoglycemic Agents; Nateglinide; Phenylalanine; Piperidines; Postprandial Period; Sulfonylurea Compounds

Although diabetics may be exempted from Ramadan fasting, many patients still insist on this worship. Aim of the present study is to compare the effects of glimepiride, repaglinide, and insulin glargine in type 2 diabetics during Ramadan fasting on the glucose metabolism. Patients, who were willing to fast, were treated with glimepiride (n=21), repaglinide (n=18), and insulin glargine (n=10). Sixteen non-fasting control type 2 diabetics matched for age, sex, and body mass index were also included. Fasting blood glucose (FBG), post-prandial blood glucose (PBG), HbA1c, and fructosamine as well as lipid metabolism were evaluated in pre-Ramadan, post-Ramadan, and 1-month post-Ramadan time points. There was no significant change from pre-Ramadan in FBG, PBG, and HbA1c variables in fasting diabetics at post-Ramadan and 1-month post-Ramadan. However, PBG was found higher in non-fasting control diabetics at post-Ramadan and 1-month post-Ramadan (p<0.05 and p<0.001, respectively). In fructosamine levels, a significant increase was noted both in fasting group and non-fasting group at 1-month post-Ramadan (p<0.01 for all). However, no significant difference was found in the comparison of the changes in fructosamine levels between fasting group and non-fasting group. Risk of hypoglycemia did not significantly differ between fasting and non-fasting diabetics. There was no significant difference between three drug therapies regarding glucose metabolism and rate of hypoglycemia. No adverse effects on plasma lipids were noted in fasting diabetics. In this fasting sample of patients with type 2 diabetes, glimepiride, repaglinide, and insulin glargine did not produce significant changes in glucose and lipid parameters.

Topics: Adult; Body Mass Index; Carbamates; Diabetes Mellitus, Type 2; Fasting; Female; Fructosamine; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Islam; Male; Middle Aged; Patient Selection; Piperidines; Sulfonylurea Compounds; Turkey

Pharmaceutical counterfeiting is becoming a serious problem in the world, especially in developing countries including China. Herein an isocratic reversed-phase high performance liquid chromatography (RP-HPLC) method was developed for screening counterfeit medicines and adulterated dietary supplement products. The developed method could be employed to separate and determine simultaneously six anti-diabetic drugs (glipizide, gliclazide, glibenclamide, glimepiride, gliquidone, repaglinide) on an isocratic solvent system using an Alltima C18 column (5 microm, 150 mmx4.6 mm) with an isocratic mobile phase of methanol-phosphate buffer (pH 3.0; 0.01 mol/L) (70:30, v/v), at a flow rate of 1.0 mL/min and at a wavelength of 230 nm. The proposed method was successfully applied to the analysis of medicinal and dietary supplement samples purchased from the local market in China.

Topics: Carbamates; Chromatography, High Pressure Liquid; Gliclazide; Glipizide; Glyburide; Hypoglycemic Agents; Molecular Structure; Piperidines; Reproducibility of Results; Sulfonylurea Compounds

Topics: Administration, Oral; Carbamates; Cyclohexanes; Diabetes Mellitus; Glipizide; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Nateglinide; Phenylalanine; Piperidines; Sulfonylurea Compounds

Topics: Adiponectin; Blood Glucose; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Intercellular Signaling Peptides and Proteins; Nateglinide; Phenylalanine; Piperidines; Proteins; Sulfonylurea Compounds

Nateglinide is a novel insulinotropic agent for the treatment of type 2 diabetes. It is a D-phenylalanine derivative, chemically distinct from repaglinide and sulphonylureas (glyburide or glimepiride). Although each agent is known to stimulate insulin release via the signaling cascade initiated by closure of ATP-dependent K+ (K(ATP)) channels in pancreatic beta-cells, the pharmacological effect of nateglinide is reportedly fast-acting, short-lasting, sensitive to ambient glucose and more resistant to metabolic inhibition. The aim of the present study was to elucidate the molecular mechanism(s) underlying the distinct properties of the insulinotropic action of nateglinide. By using the patch-clamp methods, we comparatively characterized the potency and kinetics of the effect of these agents on K(ATP) channels in rat beta-cells at normal vs. elevated glucose and under physiological condition vs. experimentally induced metabolic inhibition. Our results demonstrated that the mode of the action of nateglinide on K(ATP) current was unique in (a) glucose dependency; (b) increased potency and efficacy under ATP depletion and uncoupling of mitochondrial oxidative phosphorylation than physiological condition; (c) substantially more rapid onset and offset kinetics. The data provide mechanistic rationale for the unique in vivo and ex vivo activity profile of nateglinide and may contribute to reduced hypoglycemic potential associated with excessive insulin secretion.

Topics: Adenosine Triphosphate; Animals; Carbamates; Cyclohexanes; Dose-Response Relationship, Drug; Glucose; Glyburide; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Kinetics; Male; Membrane Potentials; Nateglinide; Phenylalanine; Piperidines; Potassium Channel Blockers; Potassium Channels; Rats; Rats, Sprague-Dawley; Sulfonylurea Compounds; Time Factors

The structure-activity relationships in two series of hypoglycemic benzoic acid derivatives (5, 6) were investigated. Series 5 resulted from meglitinide (3) when the 2-methoxy was replaced by an alkyleneimino residue. Maximum activity was observed with the cis-3, 5-dimethyl-piperidino (5h) and the octamethyleneimino (5l) residues. Series 6 resulted from the meglitinide analogon 4 bearing an inversed amido function when the 2-methoxy, the 5-fluoro, and the alpha-methyl residue were replaced by a 2-piperidino, a 5-hydrogen, and a larger alpha-alkyl residue, respectively. An alkoxy residue ortho to the carboxy group further increased activity and duration of action in the rat. The most active racemic compound, 6al (R4 = isobutyl; R = ethoxy), turned out to be 12 times more active than the sulfonylurea (SU) glibenclamide (1). Activity was found to reside predominantly in the (S)-enantiomers. Compared with the SUs 1 and 2 (glimepiride), the most active enantiomer, (S)-6al (AG-EE 623 ZW; repaglinide; ED50 = 10 micro/kg po), is 25 and 18 times more active. Repaglinide turned out to be a useful therapeutic for type 2 diabetic patients; approval was granted recently by the FDA and the EMEA. From investigations on the pharmacophoric groups in compounds of type 5 and 6, it was concluded that in addition to the two already known-the acidic group (COOH; SO2NH) and the amidic spacer (CONH; NHCO)-the ortho residue R1 (alkyleneimino; alkoxy; oxo) must be regarded as a third one. A general pharmacophore model suitable for hypoglycemic benzoic acid derivatives, SUs, and sulfonamides is proposed (Figure 6). Furthermore, from superpositions of low-energy conformations (LECs) of 1, 2, and (S)-6al, it was concluded that a common binding conformation (LEC II; Figure 10B) may exist and that differences in binding to the SU receptor and in the mechanism of insulin release between repaglinide and the two SUs may be due to specific hydrophobic differences.

Topics: Administration, Oral; Animals; ATP-Binding Cassette Transporters; Benzoates; Blood Glucose; Carbamates; Crystallography, X-Ray; Female; Glyburide; Hypoglycemic Agents; Models, Molecular; Molecular Conformation; Piperidines; Potassium Channels; Potassium Channels, Inwardly Rectifying; Rats; Rats, Wistar; Receptors, Drug; Stereoisomerism; Structure-Activity Relationship; Sulfonylurea Compounds; Sulfonylurea Receptors

The human ether-a-go-go-related gene (herg) encodes a K+ current (I(HERG)) which plays a fundamental role in heart excitability and in neurons by contributing to action potential repolarization and to spike-frequency adaptation, respectively. In this paper we show that I(HERG), recorded in neuroblastoma cells and guinea-pig ventricular myocytes, was reversibly inhibited by the K(ATP) channel blocker glibenclamide (IC50 = 74 microM). The voltage and use dependence of glibenclamide blockade were also evaluated. Another sulfonylurea, glimepiride, had less effective results in blocking I(HERG). The findings of this study are relevant to the interpretation of glibenclamide effects on cellular electrophysiology and suggest that oral antidiabetic therapy with sulfonylureas may contribute to iatrogenic QT prolongation and related arrhythmias.

Topics: Action Potentials; Animals; Cation Transport Proteins; Chromans; DNA-Binding Proteins; Dose-Response Relationship, Drug; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Glyburide; Guinea Pigs; Humans; Inhibitory Concentration 50; Mice; Myocardium; Neuroblastoma; Neurons; Nisoldipine; Piperidines; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Voltage-Gated; Pyridines; Rats; Sulfonamides; Sulfonylurea Compounds; Trans-Activators; Transcriptional Regulator ERG; Tumor Cells, Cultured

1. Repaglinide, a novel compound with a nonsulphonylurea structure, is currently being clinically tested as a therapeutic agent. In the present study, the hypoglycaemic effects of repaglinide in rats and dogs were investigated. 2. Whereas the R-enantiomer, AG-EE 624 ZW, showed only weak hypoglycaemic activity, the S-enantiomer, repaglinide, turned out to be a potent hypoglycaemic compound in rats after oral as well as after intravenous administration. Only 50% of the dose of repaglinide was needed to be equieffective with the racemic mixture AG-EE 388 ZW. The corresponding ED50 values calculated for the effects after 120 min p.a. (intravenous administration) were 3.4 micrograms kg-1 (repaglinide) and 6 micrograms kg-1 (AG-EE 388 ZW). 3. When compared to glimepiride or glibenclamide, repaglinide displayed a 18 to 25 times higher potency in fasted rats. The ED50 values calculated for the effects after 120 min p.a. (oral administration) were 10 micrograms kg-1 (repaglinide), 182 micrograms kg-1 (glimepiride) and 255 micrograms kg-1 (glibenclamide). 4. In glucose loaded rats (0.5, 1.0, 2.0 and 3.0 g kg-1 glucose, p.o.) repaglinide exerted a very strong antihyperglycaemic activity which was even more pronounced than under normoglycaemic conditions. So for a reduction in blood glucose of 1 mmol l-1, 10.3, 9.3, 7.0 8.4 and 7.2 micrograms kg-1 repaglinide were needed after glucose loads of 0.0, 0.5, 1.0, 2.0 and 3.0 g kg-1, respectively. 5. In beagle dogs repaglinide again showed a pronounced hypoglycaemic effect (ED50 28.3 micrograms kg-1) which lasted for up to 24 h. However, insulin levels were only transiently increased. 6. The in vivo data presented are well supported by recently published in vitro findings. From its activity profile, repaglinide appears to be a promising new therapeutic agent.

Topics: Animals; Carbamates; Dogs; Female; Glyburide; Hypoglycemic Agents; Piperidines; Rats; Rats, Wistar; Stereoisomerism; Sulfonylurea Compounds

Repaglinide (1 microg/g body wt), glibenclamide (10 microg/g) or glimepiride (10 microg/g) were administered orally to either fed or overnight fasted normal rats and hereditarily diabetic animals (GK rats). In both fed and starved normal rats, repaglinide provoked a greater and more rapid increase in plasma insulin concentration and an earlier fall in glycemia than those observed after administration of the hypoglycemic sulfonylureas. Likewise, in fed GK rats, the plasma insulin concentration was already increased by 30.0 +/- 1.6% 15 min after administration of repaglinide, whilst a sizeable insulinotropic action of the sulfonylureas was only recorded at much later times. Except for a lower glycemia at the 240th min of the test, there was little to distinguish, in starved GK rats, between control experiments including the oral administration of the solution of carboxymethylcellulose used as vehicle and the experiments conducted with the antidiabetic agents. Several converging observations indicated that glimepiride stimulated insulin release more promptly than glibenclamide. It is proposed that advantage can be taken from these vastly different time-courses of the hormonal and metabolic response to distinct hypoglycemic agents to optimize the control of glucose homeostasis in non-insulin-dependent diabetic subjects.

Topics: Administration, Oral; Animals; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Fasting; Female; Glyburide; Hypoglycemic Agents; Insulin; Male; Piperidines; Rats; Rats, Wistar; Sulfonylurea Compounds

Non-sulfonylurea hypoglycemic agents of the meglitinide family such as S3075, repaglinide, KAD-1229, and A-4166, were found to display a comparable U-shaped conformation by molecular modelling, with hydrophobic cycles placed at the extremity of each branch and a peptidic bond placed at the bottom of the U. A comparable conformation was observed with the hypoglycemic sulfonylureas glibenclamide and glimepiride. A different conformation with a greater distance between the hydrophobic cycles at the extremity of each branch was found, however, with the biologically inactive enantiomers of A-4166 and repaglinide and the poorly efficient insulinotropic agent meglitinide. The identification of a common conformation of these hypoglycemic agents may help in the design of highly active compounds and provide an imprint of their postulated target receptor on the pancreatic B-cell plasma membrane.

Topics: Benzamides; Carbamates; Cyclohexanes; Drug Design; Glyburide; Hypoglycemic Agents; Indoles; Isoindoles; Molecular Conformation; Nateglinide; Phenylalanine; Piperidines; Stereoisomerism; Structure-Activity Relationship; Sulfonylurea Compounds