Short-acting Insulin Secretagogue Research Articles

Statistically Optimized Repaglinide-loaded Floating Microspheres for the Gastric Sustained Delivery via Central Composite Design

Repaglinide (RPD) is a short-acting insulin secretagogue widely prescribed for the treatment of type 2 diabetes. In this study, RPD loaded ethyl cellulose/hydroxypropylmethylcellulose (EC/HPMC) floating microspheres (FM) have been formulated for gastric sustained release and improved bioavailability of RPD. Floating microspheres were prepared by oil in water emulsion solvent evaporation technique. A three levels Central-composite design (CCD) was applied to investigate the influence of different formulation components and process variables on the formulation responses and indicate the optimum using the numeric approach through the Minitab® software.

The Structural Basis for the Binding of Repaglinide to the Pancreatic KATP Channel

Repaglinide (RPG) is a short-acting insulin secretagogue widely prescribed for the treatment of type 2 diabetes. It boosts insulin secretion by inhibiting the pancreatic ATP-sensitive potassium channel (KATP). However, the mechanisms by which RPG binds to the KATP channel are poorly understood. Here, we describe two cryo-EM structures: the pancreatic KATP channel in complex with inhibitory RPG and adenosine-5'-(γ-thio)-triphosphate (ATPγS) at 3.3Å and a medium-resolution structure of a RPG-bound mini SUR1 protein in which the N terminus of the inward-rectifying potassium channel 6.1 (Kir6.1) is fused to the ABC transporter module of the sulfonylurea receptor 1 (SUR1). These structures reveal the binding site of RPG in the SUR1 subunit. Furthermore, the high-resolution structure reveals the complex architecture of the ATP binding site, which is formed by both Kir6.2 and SUR1 subunits, and the domain-domain interaction interfaces.

TYPE 2 DIABETES MELLITUS;

Background: Diabetic complications are related to impaired glycemic control. The UK Prospective Diabetes Study (UKPDS) showed that metformin therapy in overweight and obese patients with type 2 diabetes mellitus (T2DM) could reduce HbA1c and complications. So, metformin has been suggested to be the drug of choice after life style modifications in patients with T2DM. Repaglinide, short-acting insulin secretagogues, has excellent anti-hyperglycemic effect and a lower risk of hypoglycemia. However, whether repaglinide can be used as an initial therapy in patients with newly diagnosed T2DM is still unconfirmed. Objectives: The objective of this study was: To compare efficacy of Repaglinide and Metformin in the Treatment of New Onset Type 2 Diabetes Mellitus. Study Design: Randomized Controlled Trial. Setting: District headquarter Hospital, Faisalabad. Period: 6 Months (Jan 2018 to June 2018). Methodology: Patients were randomly divided into two groups (A & B) by using computer generated random number table. Group A was given repaglinide 0.75-1.5 mg/day while group B received metformin 750-1500mg/day. The doses of metformin and repaglinide were adjusted according to blood glucose level. For HbA1C and FBS, blood samples were sent to pathology laboratory at the start of study and after 3 months. Follow up was ensured by reaching the patients through telephonic contact. Data was collected through self-conducted interviews using a standardized Performa. Results: In our study, mean+sd was calculated as 44.54+5.92 years in Group-A and 45.31+6.13 years in Group-B, 42.86%(n=15) in Group-A and 40%(n=14) in Group-B were male whereas 57.14%(n=20) in Group-A and 60%(n=21) in Group-B were females. Baseline mean HbA1c levels of the patients were calculated as 7.51+0.50 mmol/L in Group-A and 7.54+0.52 mmol/L in Group B, p value was 0.81. After treatment, these findings were reduced to 5.57+0.65 in Group-A and 6.4+0.49 in Group-B, p value was 0.0001, At baseline mean fasting blood glucose levels of the patients were calculated as 7.43+0.56 mmol/L in Group-A and 7.46+0.50 mmol/L in Group B, p value was 0.82. After treatment, these findings were reduced to 5.83+0.71 in Group-A and 6.29+0.67 in Group-B, p value was 0.007. Conclusion: We concluded that on comparison of Metformin and Repaglinide monotherapy in the Treatment of New Onset Type 2 Diabetes Mellitus in terms of mean fasting blood glucose and mean HbA1c, both drugs reduced HbA1c and fasting blood sugar but Repaglinide was found significantly better for reduction of HbA1c and fasting blood sugar when compared to Metformin.

Drug interactions of meglitinide antidiabetics involving CYP enzymes and OATP1B1 transporter.

Meglitinides such as repaglinide and nateglinide are useful to treat type 2 diabetes patients who follow a flexible lifestyle. They are short-acting insulin secretagogues and are associated with less risk of hypoglycemia, weight gain and chronic hyperinsulinemia compared with sulfonylureas. Meglitinides are the substrates of cytochrome P450 (CYP) enzymes and organic anion transporting polypeptide 1B1 (OATP1B1 transporter) and the coadministration of the drugs affecting them will result in pharmacokinetic drug interactions. This article focuses on the drug interactions of meglitinides involving CYP enzymes and OATP1B1 transporter. To prevent the risk of hypoglycemic episodes, prescribers and pharmacists must be aware of the adverse drug interactions of meglitinides.

Diabetes medication pharmacology

Diabetes medication pharmacology

Evaluation of pharmacokinetic and pharmacodynamic interaction between repaglinide and atazanavir in healthy, diabetic and hepatic impaired rats: possible inhibition of CYP3A, OATP, and P-glycoprotein transporters

<p>The metabolic syndrome in HIV infected patients is particularly associated with the use protease inhibitors. Atazanavir is an inhibitor of the cytochrome P 450 (CYP) system, in particular CYP3A4 and CYP2C9 which can affect the metabolism of several drugs. To treat metabolic syndrome in HIV patients repaglinide is used and it is a short acting insulin secretagogues undergoing metabolism with CYP 3A4 and CYP 2C8 enzyme system. The purpose of this study was to assess the possible pharmacokinetic and pharmacodynamic drug interaction of repaglinide and atazanavir in healthy, diabetic and impaired hepatic function rats. Human oral therapeutic doses of atazanavir and repaglinide were extrapolated to rats based on the body surface area. The pharmacokinetic parameters and blood glucose concentrations of repaglinide were determined after oral administration of repaglinide alone (0.5 mg/kg) and in the presence of atazanavir (36 mg/kg) in normal, diabetic and hepatic impaired rats. The pharmacokinetics (PK) and blood glucose concentrations of repaglinide were significantly altered in the presence of atazanavir. The peak plasma concentration (C<sub>max</sub>), area under the plasma concentration time profile (AUC) and elimination half-life of repaglinide were significantly (P<0.0001) increased. The repaglinide clearance (CL) was significantly (P<0.0001) decreased in the presence of atazanavir treatment. In the presence of atazanavir, repaglinide hypoglycaemic activity was increased significantly (P<0.0001) when compared with the repaglinide control group. The present study demonstrated the significant difference in the PK/PD changes due to the enhanced bioavailability and decreased total body clearance of repaglinide may be due to the inhibition of the CYP P450 metabolic system, OATP and P-gp transporters by atazanavir.</p>

Evaluation of pharmacokinetic and pharmacodynamic interaction between repaglinide and atazanavir in healthy, diabetic and hepatic impaired rats: possible inhibition of CYP3A, OATP, and P-glycoprotein transporters

The metabolic syndrome in HIV infected patients is particularly associated with the use protease inhibitors. Atazanavir is an inhibitor of the cytochrome P 450 (CYP) system, in particular CYP3A4 and CYP2C9 which can affect the metabolism of several drugs. To treat metabolic syndrome in HIV patients repaglinide is used and it is a short acting insulin secretagogues undergoing metabolism with CYP 3A4 and CYP 2C8 enzyme system. The purpose of this study was to assess the possible pharmacokinetic and pharmacodynamic drug interaction of repaglinide and atazanavir in healthy, diabetic and impaired hepatic function rats. Human oral therapeutic doses of atazanavir and repaglinide were extrapolated to rats based on the body surface area. The pharmacokinetic parameters and blood glucose concentrations of repaglinide were determined after oral administration of repaglinide alone (0.5 mg/kg) and in the presence of atazanavir (36 mg/kg) in normal, diabetic and hepatic impaired rats. The pharmacokinetics (PK) and blood glucose concentrations of repaglinide were significantly altered in the presence of atazanavir. The peak plasma concentration (C max ), area under the plasma concentration time profile (AUC) and elimination half-life of repaglinide were significantly (P<0.0001) increased. The repaglinide clearance (CL) was significantly (P<0.0001) decreased in the presence of atazanavir treatment. In the presence of atazanavir, repaglinide hypoglycaemic activity was increased significantly (P<0.0001) when compared with the repaglinide control group. The present study demonstrated the significant difference in the PK/PD changes due to the enhanced bioavailability and decreased total body clearance of repaglinide may be due to the inhibition of the CYP P450 metabolic system, OATP and P-gp transporters by atazanavir.

Prolonged hypoglycemia after a suicidal ingestion of repaglinide with unexpected slow plasma elimination

Context: Repaglinide is a short-acting insulin secretagogue with high interindividual variability in pharmacokinetics due to genetic polymorphisms. Little is known about repaglinide overdoses, both with respect to pharmacokinetics and appropriate management. Given its short serum half-life of less than 1 h, hypoglycemic effects of repaglinide are expected to cease within a few hours post-ingestion. Case details: A 15-year-old girl ingested 10.5 mg of repaglinide in a suicide attempt. Few hours later, she developed a strong food craving, nausea, abdominal pain, and a headache. The lowest recorded serum glucose was 44 mg/dl (2.4 mmol/l) 14 h post-ingestion. Using liquid chromatography–mass spectrometry, we detected repaglinide serum levels of 5.3, 2.6, and 1.0 ng/ml at 14, 20, and 26 h post-ingestion, respectively. Discussion: This case illustrates that in the context of overdose, repaglinide can lead to prolonged hypoglycemia. We therefore recommend glucose monitoring and observation for 24 h in all patients who remain hypoglycemic or show symptoms of hypoglycemia for an unusually long period of time.

PPARD rs2016520 polymorphism affects repaglinide response in Chinese Han patients with type2 diabetes mellitus.

Repaglinide is a short-acting insulin secretagogue, which often results in considerable interindividual variability in therapeutic efficacy when widely used in a clinical setting. Among various reasons under discussion is genetic polymorphism, especially the genes related to insulin secretion and resistance. Recent studies have described the importance of PPARD in regulating the secretion and resistance of insulin. However, little is known about the impacts of PPARD genetic polymorphism on the efficacy of repaglinide. Therefore, the current study was designed to investigate the associations of PPARD rs2016520 polymorphism with type2 diabetes mellitus (T2DM) susceptibility and repaglinide therapeutic efficacy in Chinese Han T2DM patients. A total of 338 T2DM patients and 200 healthy subjects were genotyped for PPARD rs2016520 polymorphism by polymerase chain reaction-restriction fragment length polymorphism assay. A total of 84 patients with the same genotypes of CYP2C8*3 139Arg and OATP1B1 521TT were randomized to orally take repaglinide for 8weeks. Then the pharmacodynamic parameters of repaglinide and biochemical indicators were determined before and after repaglinide treatment. No significant difference was found in either allelic frequency (P=0.298) or genotype distribution (P=0.151) of PPARD rs2016520 between T2DM patients and healthy subjects. However, T2DM patients carrying genotype TC showed a significantly lower increase in postprandial serum insulin (mU/L) than those with wild-type TT (P<0.05). These findings suggest that PPARD rs2016520 polymorphism might influence the therapeutic effect of repaglinide rather than T2DM susceptibility in Chinese Han T2DM patients.

Effects of combination therapy with mitiglinide and voglibose on postprandial plasma glucose in patients with type 2 diabetes mellitus

Patients with diabetes mellitus are at increased risk from cardiovascular-related morbidity and mortality as compared with healthy individuals. An association between the postprandial metabolic state and atherogenesis has been observed in patients with diabetes mellitus. In the Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM), treatment with an α-glucosidase inhibitor (α-GI) in patients with impaired glucose tolerance not only reduced the rate of conversion from impaired glucose tolerance to type 2 diabetes mellitus (T2DM), but was also associated with a reduction in the risk of cardiovascular events. These results suggested the importance of treating postprandial hyperglycemia in the early stages of T2DM. Glinides are rapid and short-acting insulin secretagogues that bind to the sulfonylurea receptors on pancreatic β-cells to facilitate rapid insulin secretion, restore postprandial early insulin secretion, and reduce the postprandial glucose spike. Moreover, α-GIs reduce postprandial hyperglycemia and insulin secretion by delaying the digestion of carbohydrates and polysaccharides in the small intestine. Then, both glinides and α-GI have beneficial effects for treating patients with T2DM and impaired glucose tolerance. Considering the ameliorating effects of these drugs on postprandial metabolic disorders, combinations of glinides and α-GI might constitute a promising therapeutic strategy for managing patients with T2DM, and also appear to be suitable for Japanese people, who consume more carbohydrates, such as polished rice, than Caucasians. It has recently been reported that combined use of mitiglinide and voglibose reduces postprandial insulin secretion and blunts diurnal glycemic changes in T2DM patients. This therapy can thus be regarded as being suitable for achieving strict postprandial glycemic control. In this report, we outline the effects of this combination therapy on postprandial plasma glucose and assess its safety.

Effects of Mitiglinide, a Short-Acting Insulin Secretagogue, on Daily Glycemic Variability and Oxidative Stress Markers in Japanese Patients with Type 2 Diabetes Mellitus

The objective of this study was to clarify the effects of mitiglinide on daily glycemic variability and oxidative stress markers in outpatients with type 2 diabetes mellitus that is insufficiently controlled by diet and/or non-insulin secretagogues. We enrolled 24 patients with type 2 diabetes whose glycemic control had been suboptimal [i.e. glycosylated hemoglobin (HbA(1c)) ≥ 6.9 %]. The patients were treated with mitiglinide 10 mg three times daily for 16 weeks. If their glycemic control was not improved at week 8, the dose of mitiglinide was increased to 20 mg three times daily. Daily glycemic variability was assessed by 7-point self-monitoring of blood glucose for 2 days, and standard deviation (SD), M value, and mean of daily differences(MODD) were calculated. Oxidative stress was assessed by oxidized low-density lipoprotein, pentosidine,urinary 8-iso-prostaglandin F2 alpha, and urinary 8-hydroxydeoxy guanosine. After 16 weeks of mitiglinide treatment, the HbA(1c) level was significantly decreased (mean ± SD,7.4 ± 0.7 to 6.8 ± 0.5 %, P < 0.0001). Postprandial glucose excursion and glycemic variability were also significantly improved after mitiglinide treatment (all P < 0.05). The reductions in SD, M value, and MODD were 17, 50,and 48 %, respectively. There was a significant positive correlation between the change in HbA(1c) and change in SD during the study (r = 0.454, P = 0.03). There were no significant changes in oxidative stress markers. The present study supports the notion that mitiglinide improves postprandial glucose excursion and HbA(1c) level in patients with type 2 diabetes. In addition,we demonstrated that mitiglinide also effectively improves daily glycemic variability. The effect of mitiglinide on oxidative stress needs further investigation.

Dynamic Metabolic Profiling of Urine From Type 2 Diabetic KK-Ay Mice Treated with Repaglinide by GC-MS

Repaglinide is a short-acting insulin secretagogue, commonly used for the treatment of type 2 diabetes. In this paper, metabolomics were first applied to research of dynamic urine metabolic profiling and biomarkers of type 2 diabetic KK-Ay mice treated with repaglinide based on GC-MS. Twenty diabetic KK-Ay mice were randomly assigned to four groups and fed with repaglinide for 6, 9, 12, and 14 weeks, respectively. Five C57BL/6 J mice were used as the healthy control group and fed with water as contrast. The PCA scores plot of the identified 41 metabolites showed that as treating time went on, the diabetic groups got closer to the healthy group. Furthermore, five marker metabolites, d-Glucose, d-Galactose, 1,5-Anhydro-d-glucitol, myo-inositol and tartaric acid were screened out, which have similar change footprints of the whole metabolic profiles. The results demonstrated that repaglinide not only regulates the sugars and polyalcohol but also the organic acid in the organism. This work has illustrated the potential of metabolomics to disease diagnosis, pharmacology, and pharmacodynamics research.

Role of oral hypoglycemic agents in the management of type 2 diabetes mellitus during Ramadan

It is obligatory for all adult Muslims to observe fast during the holy month of Ramadan, but sick individuals including those with diabetes mellitus are exempted from the duty of fasting. Specific medical advice must be provided to individual patients concerning the potential risks they must accept if they decide to fast. Any alteration in medications deemed necessary to provide an effective and safe antidiabetic regimen should be instituted well before the start of Ramadan. Diet-controlled patients and those well controlled on insulin sensitizers have low risk of hypoglycemia and may safely fast with some modification in the timing of the doses. Newer generation sulfonylureas (gliclazide MR and glimepiride) have reasonable safety profile during Ramadan fasting and are economical options for a large number of diabetics worldwide, especially in the developing countries; older, long acting sulfonylureas like glibenclamide and chlorpropamide should be avoided during fasting. Oral DPP-IV inhibitors are important substitutes to sulfonylureas for patients with diabetes mellitus during fasting owing to their glucose-dependent mechanism of action, efficacy, and tolerability. This group of drugs causes a moderate A1c reduction, are weight neutral, and have a very low risk of hypoglycemia. Short-acting insulin secretagogues are an option in the subset of fasting diabetic patients who have predominantly post-prandial hyperglycemia.

Efficacy and safety of repaglinide vs nateglinide for treatment of Japanese patients with type 2 diabetes mellitus.

Aims/Introduction: Repaglinide is a short-acting insulin secretagogue. We assessed the efficacy and safety of repaglinide in comparison with nateglinide in Japanese patients with type 2 diabetes previously treated with diet and exercise. In this 16-week randomized, multicenter, double-blind, parallel-group, active-controlled superiority trial, Japanese patients with type 2 diabetes and glycated hemoglobin (HbA1c) of ≥6.9 and ≤9.4% were enrolled. Patients were randomly assigned to receive 0.5 mg repaglinide (n = 64) or 90 mg nateglinide (n = 66) three times a day. The primary end-point was changes in HbA1c from baseline to the end of treatment. Mean reductions of HbA1c were significantly greater for the repaglinide group than the nateglinide group (-1.17 ± 0.62 vs -0.81 ± 0.39%, P < 0.001). The target HbA1c values of <6.9% were achieved by 75.0% of the repaglinide group vs 59.1% for nateglinide. Mean changes in fasting plasma glucose also showed significantly greater efficacy for repaglinide than nateglinide (-26.0 ± 20.9 vs -18.3 ± 17.8 mg/dL, P < 0.001). There were no differences in the adverse event rates between the repaglinide and the nateglinide group, by 57.8% (37/64) and 60.6% (40/66), respectively. Incidences of hypoglycemic symptoms were 17.2% (11/64, 28 events) in the repaglinide group and 6.1% (4/66, 20 events) in the nateglinide group, respectively. In type 2 diabetic patients treated with diet and exercise, repaglinide monotherapy gives greater glycemic improvement than nateglinide monotherapy in reducing HbA1c and fasting plasma glucose values after 16 weeks. This trial was registered with JapicCTI (no. JapicCTI-080521). (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00188.x, 2011).

Quo vadis nateglinide? Ten-year perspective

Introduction:It has been hypothesized that reducing postprandial glucose spikes would result both in improved overall glycemic control and long-term (especially cardiovascular) outcomes in patients with type 2 diabetes. Nateglinide, a short-acting insulin secretagogue of the meglitinide class of antidiabetic agents, has been marketed for the past decade specifically to address the diminished postprandial insulin secretion. It is thus timely to review our experience with this agent.Areas covered:This review summarizes findings from the key preclinical and pivotal clinical research studies that eventually led to drug approval. The literature search involved both original experimental studies and subsequent comprehensive reviews of the subject. The search included the databases (in English language) in the PubMed (maintained by the US Library of Medicine) domain as well as review of the articles in the author's files spanning the years 1995 – 2011.Expert opinion:The author's subjective feelings about our understanding of the importance of controlling postprandial glucose excursions and what, if any, effect nateglinide has had in that respect since its introduction are given. Despite promising animal and human research data, no evidence has accumulated to date to suggest that addressing postprandial hyperglycemia with nateglinide (or any other antidiabetic medication for that matter) leads to improved outcomes in patients with type 2 diabetes mellitus.

Biphasic insulin-releasing effect of BTS 67 582 in rats.

BTS 67 582 (1,1-dimethyl-2(2-morpholinophenyl)guanidine fumarate) is being developed as a short-acting anti-diabetic insulin secretagogue. The effect of BTS 67 582 on the phasic pattern of insulin release was assessed in anaesthetized normal rats by measuring arterial plasma insulin concentrations while arterial glucose concentrations were fixed at 6, 8.5 and 12.5 mM. Intravenous BTS 67 582 (10 mg kg(-1)) induced an immediate but transient increase in insulin concentrations which declined by 10 min (first phase). This was followed by a smaller but sustained increase in insulin concentrations (second phase). The increment from basal to peak insulin release (0-2 min) was independent of glucose, but the first phase was maintained for longer and the second phase was greater at the highest concentration of glucose (12.5 mM). BTS 67 582 also extended the first-phase insulin response to a standard intravenous glucose challenge and enhanced the rate of glucose disappearance by approximately 12%. Thus BTS 67 582 causes biphasic stimulation of insulin release and augments the insulin-releasing effect of glucose.

Effects of two oral antidiabetics, pioglitazone and repaglinide, on aconitase inactivation, inflammation and oxidative/nitrosative stress in tissues under alloxan-induced hyperglycemia

Pathological changes identified in different tissues in hyperglycemic state are undoubtedly connected with increased oxidative/nitrosative stress and inflammation. In our study myeloperoxidase (MPO), nitrotyrosine and lipid peroxidation were enhanced in the heart and lung of alloxan-treated hyperglycemic animals. Additionally, pulmonary aconitase was inhibited. In the testis the changes occurred as an increase of MPO and lipid peroxidation, and as a decrease of aconitase. The effects of two different antidiabetics, the peroxisome proliferator activated receptor gamma (PPARγ) agonist, pioglitazone, and a short acting insulin secretagogue, repaglinide, on the mentioned parameters, were investigated and compared. The insulin deficient alloxan-induced hyperglycemic animals were used to differentiate a direct anti-oxidative effect of the drugs from secondary effects mediated via increased insulin sensitivity or secretion. Pioglitazone acted by normalization of pulmonary and testicular aconitase, normalization of pulmonary and cardiac nitrotyrosine, reduction of pulmonary and testicular MPO, and by reduction of lipid peroxidation in all tissues examined. Repaglinide prevented oxidative changes by normalization of aconitase activity in the lung and testis, and by reduction of lipid peroxidation and nitrotyrosine in the heart and lung. At the same time, no effect of this drug on MPO was observed. Finally, principal component analysis was performed to explore and visualize similarities and differences of the results obtained for the both drugs.

Repaglinide/metformin fixed-dose combination to improve glycemic control in patients with type 2 diabetes: an update

Type 2 diabetes is a progressive disease associated with high levels of morbidity and mortality and for which there is both a large and growing prevalence worldwide. Lifestyle advice plus metformin is commonly recommended initially to manage hyperglycemia and to minimize the risk of vascular complications. However, additional agents are required when glycemic targets cannot be achieved or maintained due to the progressive nature of the disease. Repaglinide/metformin fixed-dose combination (FDC) therapy (PrandiMet(®); Novo Nordisk, Bagsværd, Denmark) has been approved for use in the USA. This FDC is a rational second-line therapy given the complementary mechanisms of action of the components. Repaglinide is a rapidly absorbed, short-acting insulin secretagogue targeting postprandial glucose excursions; metformin is an insulin sensitizer with a longer duration of action that principally regulates basal glucose levels. A pivotal, 26-week, randomized study with repaglinide/metformin FDC therapy has been conducted in patients experiencing suboptimal control with previous oral antidiabetes therapy. Repaglinide/metformin FDC improved glycemic control and weight neutrality without adverse effects on lipid profiles. There were no major hypoglycemic episodes and patients expressed greater satisfaction with repaglinide/metformin FDC than previous treatments. Repaglinide/metformin FDC is expected to be more convenient than individual tablets for patients taking repaglinide and metformin in loose combination, and it is expected to improve glycemic control in patients for whom meglitinide or metformin monotherapies provide inadequate control.

Effect of Nateglinide on the Incidence of Diabetes and Cardiovascular Events

The ability of short-acting insulin secretagogues to reduce the risk of diabetes or cardiovascular events in people with impaired glucose tolerance is unknown. In a double-blind, randomized clinical trial, we assigned 9306 participants with impaired glucose tolerance and either cardiovascular disease or cardiovascular risk factors to receive nateglinide (up to 60 mg three times daily) or placebo, in a 2-by-2 factorial design with valsartan or placebo, in addition to participation in a lifestyle modification program. We followed the participants for a median of 5.0 years for incident diabetes (and a median of 6.5 years for vital status). We evaluated the effect of nateglinide on the occurrence of three coprimary outcomes: the development of diabetes; a core cardiovascular outcome that was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure; and an extended cardiovascular outcome that was a composite of the individual components of the core composite cardiovascular outcome, hospitalization for unstable angina, or arterial revascularization. After adjustment for multiple testing, nateglinide, as compared with placebo, did not significantly reduce the cumulative incidence of diabetes (36% and 34%, respectively; hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15; P=0.05), the core composite cardiovascular outcome (7.9% and 8.3%, respectively; hazard ratio, 0.94, 95% CI, 0.82 to 1.09; P=0.43), or the extended composite cardiovascular outcome (14.2% and 15.2%, respectively; hazard ratio, 0.93, 95% CI, 0.83 to 1.03; P=0.16). Nateglinide did, however, increase the risk of hypoglycemia. Among persons with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors, assignment to nateglinide for 5 years did not reduce the incidence of diabetes or the coprimary composite cardiovascular outcomes. (ClinicalTrials.gov number, NCT00097786.)

Comparison of insulin sensitivity, glucose sensitivity, and first phase insulin secretion in patients treated with repaglinide or gliclazide

The traditional sulfonylureas with long half-lives have sustained stimulatory effects on insulin secretion compared to the short-acting insulin secretagogue. In this study, we used the frequently sampled intravenous glucose tolerance test (FSIGT) to evaluate the insulin sensitivity (IS), glucose sensitivity (SG), and acute insulin response after glucose load (AIRg) after 4 months treatment with either gliclazide or repaglinide. The design of study was randomizedcrossover. We enrolled 20 patients with new-onset type 2 diabetes (mean age, 49.3 years). Totally three FSIGTs were performed, one before and one after each of the two treatment periods as aforementioned. No significant differences in fasting plasma glucose, insulin, body mass index, blood pressure, glycated hemoglobin, or lipids were noted between the two treatments. After the repaglinide treatment, higher AIRg, lower IS, and lower SG were noted, but they did not reach statistical significance. The disposal index (DI) was also not significantly different between the two treatments. In conclusion, since non-significantly higher DI, AIRg, lower IS and SG were noted after repaglinide treatment, it might be a better treatment for diabetes, relative to gliclazide.