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Background Permanent neonatal diabetes mellitus (PNDM) presents with dehydration and hyperglycemia, which usually occurs during the first 12 months of life. Activating mutations of beta-cell adenosine triphosphate-sensitive potassium [KATP] channel subunits that cause opening of the channel are associated with PNDM. Some patients with PNDM respond to administration of a sulfonylurea derivative, which has long action on blood glucose even during hypoglycemia and has an apoptotic effect on beta cells. However, there have been no reports regarding treatment with meglitinide (repaglinide), which has rapid and short duration of action during the rise in blood glucose after meals that is more similar to beta cell function. It has no effects during hypoglycemia, so it does not cause neurological damage, and has no apoptotic effect on beta cells. We report herein the effects of repaglinide administration in the management and clinical outcome of two patients with PNDM during 9 and 10 years of follow-up. Case presentation Two Iranian infants were brought to our institution with poor general condition, dehydration, lethargy, and poor feeding. They had diabetic ketoacidosis at 52 days and 3.5 months of age, respectively. Their genetic analysis revealed mutations in the KCNJ11 gene encoding KIR6.2, so they both had PNDM. After treatment of diabetic ketoacidosis with insulin, they responded to sulfonylurea (glibenclamide) treatment, but were switched to repaglinide because of blood sugar fluctuations in terms of hyper- and hypoglycemia. Repaglinide was administered with the dosage of 0.04 mg/kg/day divided before every meal. Results The patients were 10 and 9 years old at the last visit, with normal growth parameters. The values of self-monitored blood glucose were well-controlled, and the hemoglobin A1C (HbA1C) levels ranged from 3.6 to 6.4% during the follow-up period. There was no complication of diabetes, neurological disorder, or adverse effects related to repaglinide. Conclusion In every neonate or infant < 6 months of age with diabetes mellitus, PNDM should be considered. A trial of oral repaglinide can be performed and substituted for glibenclamide for prevention of hypoglycemia, neurological damage, and apoptosis of beta cells during long-term administration.

Objective: Repaglinide is a well-known FDA approved drug from category of meglitinide; used for the treatment of diabetes. However, its use is limited because of its poor water solubility which lea...

OBJECTIVE To estimate trends in total payment and patients’ out-of-pocket (OOP) payments of noninsulin glucose-lowering drugs by class from 2005 to 2018. RESEARCH DESIGN AND METHODS We analyzed data for 53 million prescriptions from adults aged >18 years with type 2 diabetes under fee-for-service plans from the 2005–2018 IBM MarketScan Commercial Databases. The total payment was measured as the amount that the pharmacy received, and the OOP payment was the sum of copay, coinsurance, and deductible paid by the beneficiaries. We applied a joinpoint regression to evaluate nonlinear trends in cost between 2005 and 2018. We further conducted a decomposition analysis to explore the drivers for total payment change. RESULTS Total annual payments for older drug classes, including metformin, sulfonylurea, meglitinide, α-glucosidase inhibitors, and thiazolidinedione, declined during 2005–2018, ranging from −$271 (−53.8%) for metformin to −$2,406 (−92.2%) for thiazolidinedione. OOP payments for these drug classes also reduced. In the same period, the total annual payments for the newer drug classes, including dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists, and sodium–glucose cotransporter 2 inhibitors, increased by $2,181 (88.4%), $3,721 (77.6%), and $1,374 (37.0%), respectively. OOP payment for these newer classes remained relatively unchanged. Our study findings indicate that switching toward the newer classes for noninsulin glucose-lowering drugs was the main driver that explained the total payment increase. CONCLUSIONS Average annual payments and OOP payment for noninsulin glucose-lowering drugs increased significantly from 2005 to 2018. The uptake of newer drug classes was the main driver.

Most patients with type 2 diabetes (T2D) are treated in primary care, but data to guide evidence-based, shared decision making in this setting are scarce. LIRA-PRIME (NCT02730377) was a randomized, open-label, active-controlled trial in a primary care setting, comparing efficacy and safety of liraglutide vs. an oral antidiabetic drug (OAD) in patients with T2D inadequately controlled with metformin. Patients aged ≥18 years, with A1C 7.5-9.0%, recruited from nine countries (219 sites), were randomized 1:1 using an interactive web response system to liraglutide or an OAD (α-glucosidase inhibitor, DPP-4i, meglitinide, SGLT2i, SU or TZD, chosen by their physician) on top of metformin, for up to 104 weeks. Primary endpoint: time to inadequate glycemic control, defined as A1C >7.0% at two consecutive visits after the first 26 weeks of treatment. Key secondary endpoints: time to premature treatment discontinuation, including for inadequate glycemic control, and occurrence of adverse events (AEs). From Mar 2016 to Aug 2017, patients were randomized to liraglutide (N=996) or OAD (N=995; 48% SGLT2i, 40% DPP-4i, 11% SU). Liraglutide significantly reduced the risk of inadequate glycemic control vs. OAD (416/996 [42%] vs. 547/995 [55%] patients, respectively; hazard ratio [95% CI] 0.58 [0.51;0.66]; p Disclosure J. Unger: Consultant; Self; Bayer. Research Support; Self; GlaxoSmithKline, Merck, Pfizer, Sanofi, Lilly, Janssen. Stock/Shareholder; Self; Tandem Diabetes. Other Relationship; Self; Abbott, Abbott Diabetes, Novo Nordisk. M. Kaltoft: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. D. Kolhe: Employee; Self; Novo Nordisk. J. Panda: None. M. Sargın: Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc., Pfizer Inc. B. Wolthers: Other Relationship; Self; Novo Nordisk. M. Zoghbi: Advisory Panel; Spouse/Partner; Janssen Pharmaceuticals, Inc., New Bridge. Advisory Panel; Self; Novartis AG. Advisory Panel; Spouse/Partner; Novartis AG. Advisory Panel; Self; Novo Nordisk A/S. Advisory Panel; Spouse/Partner; Pfizer Inc., Roche Pharma. Advisory Panel; Self; Sanofi. Funding Novo Nordisk A/S

Abstract:: Meglitinides are a group of oral hypoglycemic medications currently approved for the treatment of type 2 diabetes mellitus (T2DM). Two meglitinide molecules, Repaglinide and Nateglinide, are presently in use. Repaglinide is preferred because of its superior glycemic efficacy. They have modest efficacy with a mean decrement of glycosylated haemoglobin (HbA1c) ranging between -0.2 to -1.50% with individual therapy. Additional HbA1c reduction can occur with combination therapy with other oral hypoglycemics. This class of drugs is effective in controlling postprandial hyperglycemia with minimal risk of hypoglycemia. It is also useful in patients with variable meal timings, especially in the elderly, and in patients with renal failure. There are a dearth of long-term studies on meglitinides to assess cardiovascular outcomes or mortality in T2DM, although the Nateglinide and Valsartan in Impaired Glucose ToleranceOutcomes Research (NAVIGATOR) study showed no difference between Nateglinide and placebo with regard to the core composite cardiovascular outcomes. Based on a PubMed literature search using key words: ‘meglitinides’, ‘repaglinide’, ‘nateglinide’, ‘HbA1c’, ‘glycated haemoglobin’, ‘cardiovascular safety’, ‘cardiovascular events’, ‘cardiovascular outcome trials’, ‘type 2 diabetes mellitus’ and heart failure, and combining the search terms using Boolean operators ‘AND’, ‘OR’ and ‘NOT’ as needed we compiled current evidence for use of these oral hypoglycemic agents in clinical use. This article is an attempt to review the efficacy and cardiovascular (CV) safety of Meglitinides to help clinicians to use this class of oral hypoglycaemic agents prudently.

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.

Aims/Introduction We investigated the failure of monotherapy in patients with type 2 diabetes mellitus in real practice settings. Materials and Methods The Korean National Diabetes Program was a prospective, multicenter observational cohort study of type 2 diabetes mellitus patients in Korea. Of the 3,950 patients enrolled in the study, we studied 998 who were continuously maintained on monotherapy for at least 90 days at six participating centers. To balance the baseline characteristics of patients in each group, we used propensity matching at a 1:1 ratio (metformin vs sulfonylureas) and 4:1 ratio (metformin vs meglitinides and metformin vs alpha‐glucosidase inhibitors [aGIs]). The hazard ratios (HRs) of treatments (compared with metformin) were determined by Cox's proportional hazards regression modeling. Results The median follow‐up time was 56 months, and monotherapy failed in 45% of all patients. The annual incidences of failure were 15.6%, 21.3%, 27% and 9.6% in the metformin, sulfonylurea, meglitinide and aGI groups. Compared with metformin, sulfonylureas and meglitinides were associated with higher risks of monotherapy failure (HR 1.39, 95% confidence interval [CI] 1.08–1.80; HR 1.92, 95% CI 1.13–3.27), and aGIs with risks similar to that of metformin (HR 0.80, 95% CI 0.44–1.45). When analyzed by failure type, sulfonylureas, meglitinides and aGIs were associated with a higher risk of a switch to other agents (HR 4.43, 95% CI 2.14–9.17; HR 18.80, 95% CI 6.21–56.93; HR 4.25, 95% CI 1.49–12.13), and aGIs with a lower risk of prescription of add‐on second agents (HR 0.16, 95% CI 0.04–0.64). Conclusions Metformin was associated with a lower failure risk than were sulfonylureas and meglitinides, but a comparable aGI failure rate.

Aim People with young-onset diabetes (YOD) exhibit a higher risk of morbidity and mortality than those with late-onset diabetes. Few studies have explored the preferred management of diabetes in such patients. We compared the risks of hospitalization and mortality among people with YOD to whom second-line oral antidiabetic drugs (OADs) were administered. Methods 7257 people taking second-line OADs after initial metformin therapy were enrolled during 2009–2014. Using add-on sulfonylureas (SUs) as a reference, the multivariable Cox regression model was used to compare the hospitalization and mortality risks among 5 categories of second-line OADs: alpha-glucosidase inhibitors, meglitinide, dipeptidyl peptidase-4 (DPP-4) inhibitors, SUs, and thiazolidinediones. Results After baseline characteristics, comorbidities, duration of diabetes, and drug use were controlled, the adjusted hazard ratios and 95% confidence interval for all-cause, cardiovascular, and non-infection hospitalization and all-cause mortality for metformin plus DPP-4 inhibitors were 0.62 (0.52–0.73), 0.49 (0.29–0.85), 0.64 (0.54–0.76), and 0.50 (0.27–0.92), respectively, when compared with the data for metformin plus SUs. Conclusions Among people with YOD, taking add-on DPP-4 inhibitors was associated with lower risks of all-cause hospitalization and mortality than taking add-on SUs. DPP-4 inhibitors thus seem to be a suitable second-line OAD for such patients.

// Pei-Chen Wu 1,2,* , Vin-Cent Wu 3,* , Cheng-Jui Lin 1,4,5 , Chi-Feng Pan 1 , Chih-Yang Chen 1 , Tao-Min Huang 6 , Che-Hsiung Wu 7 , Likwang Chen 8 , Chih-Jen Wu 1,4,9,10 and The NRPB Kidney Consortium 11 1 Division of Nephrology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan 2 Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan 3 Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan 4 Department of Medicine, Mackay Medical College, Taipei, Taiwan 5 Mackay Junior College of Medicine, Nursing and Management, Taipei, Taiwan 6 Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Douliou, Taiwan 7 Division of Nephrology, Taipei Buddhist Tzu Chi General Hospital, Buddhist Tzu Chi University, Taipei, Taiwan 8 Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan 9 Graduate Institute of Medical Sciences and Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei, Taiwan 10 Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan 11 NRPB, National Research Program for Biopharmaceuticals, ROC, Taiwan * These authors have contributed equally to this work Correspondence to: Chih-Jen Wu, email: // Keywords : meglitinide, diabetes mellitus, hypoglycemia, chronic kidney disease, mortality Received : January 21, 2017 Accepted : April 14, 2017 Published : April 27, 2017 Abstract The safety of short-acting meglitinides in diabetic patients with advanced chronic kidney disease (CKD) has not been widely reported. Diabetic patients with advanced CKD who had a serum creatinine level of > 6 mg/dL a hematocrit level of ≦ 28% and received erythropoiesis-stimulating agent treatment between 2000 and 2010, were included in this nationwide study in Taiwan. The outcomes of interest were defined as hypoglycemia and long-term mortality. The risks of hypoglycemia and death were analyzed using Cox proportional hazards models, with end-stage renal disease and anti-diabetic drugs as time-dependent variables. Fresh users and matched non-users of meglitinides (both n = 2,793) were analyzed. The use of meglitinides increased the risk of hypoglycemia (HR, 1.94, p 62 and ≤ 33 years from the generalized additive model. This study suggests that the use of short-acting meglitinides could be associated with increased risk of hypoglycemia in diabetic patients with advanced CKD, especially in patients aged > 62 and ≤ 33 years. Meglitinide combined with insulin will increase hypoglycemia in patients with advanced CKD.

Type 2 diabetes mellitus (T2DM) is one of the most prevalent diseases in the world. An important difference in effectiveness and toxicity of hypoglycemic agents has been associated with the presence of genetic variants in people with T2DM. We conducted a literature review up November 2015 by combining keywords type 2 diabetes mellitus, hypoglycemic agents and pharmacogenetics (PKG). Metformin, sulfonylureas, and meglitinide drugs are widely used for the T2DM treatment, although new drugs in combination with metformin are administered. Genetic variants in proteins that function as carriers, channels, or metabolizing enzymes affect both the pharmacokinetics and pharmacodynamics of these agents. Significant progress in T2DM’s pharmacogenetics has been made; however, more studies involving a larger number of patients from different ethnic groups must be done. Furthermore, patients with T2DM generally are complex patients receiving hypolipidemic and hypotensive medications. Drug-drug interaction studies between these drugs must be done to really know the contribution of each polymorphism in drug effectiveness and/or toxicity.

ObjectiveWe constructed a predictive model of long-term risk for severe hypoglycemia (SH: hypoglycemia requiring assistance) in patients with type 2 diabetes (T2DM).Research design and methodsData from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study (original n=10 251, n=5135 used in the current analysis), a randomized, multicenter, double 2×2 factorial design study examining the effect of glycemic, blood pressure, and lipid control on cardiovascular outcomes in patients with diagnosed T2DM, were used. Over the follow-up (3.76±1.12 years), the ACCORD participants experienced 607 incident SH events. Cox regression was used to identify the SH risk prediction model.ResultsWe identified 17 predictors—glycemic management, age, race, education, waist circumference, medications (insulin, antihypertensive, HMG-CoA reductase inhibitors, sulfonylurea, biguanide and meglitinide), years since diabetes diagnosis, history of hypoglycemia in the last week, systolic blood pressure, diastolic blood pressure, serum creatinine, and urinary albumin creatinine ratio—to construct a prediction model for SH (c-statistic=0.782). Using this information, we derived point scores to estimate the 5-year risk for SH in individual patients with T2DM. After adjusting for other variables in the model, the three strongest predictors for SH over 5 years were intensive glycemic management (HR=2.37, 95% CI 1.99 to 2.83), insulin use (HR=2.14, 95% CI 1.77 to 2.59), and antihypertensive medication use (HR=1.90, 95% CI 1.26 to 2.86).ConclusionUsing the ACCORD data, we identified attributes to predict 5-year risk of SH in patients with T2DM, which warrant evaluation in broader populations to determine applicability.

Diabetes mellitus is a chronic disease that is associated with long-term complications and requires life-long pharmacological and nonpharmacological management. Several new agents have been approved for diabetes mellitus management in recent years. It is important to understand the efficacy and safety of these medications to properly use these drug therapies for diabetes. This review will provide an overview of the currently availability antidiabetic agents. Among the available antihyperglycemic agents, the dipeptidyl peptidase-4 inhibitors are efficacious alone and in combination with other agents, and have low side effects compared with metformin. They are a recommended alternative when metformin use is limited by gastrointestinal (GI) side effects or when sulfonylurea treatment results in significant hypoglycemia or weight gain. Meglitinide analogs are limited by their frequent dosing, expense, and hypoglycemia, while alpha-glucosidase inhibitors are also limited by their dosing schedule and GI side-effect profile.

Background Repaglinide, an oral insulin secretagogue, was the first meglitinide analogue to be approved for use in patients with type 2 diabetes mellitus. Objective In our study, the bioavailability and tolerability of the proposed generic formulation with the established reference formulation of repaglinide 2 mg were compared in a fasting, healthy Chinese male population. Methods This 2-week, open-label, randomized-sequence, single-dose, 2-period crossover study was conducted in 22 healthy native Han Chinese male volunteers. Eligible subjects were randomly assigned in a 1:1 ratio to receive a single 2-mg dose of the test or reference formulation, followed by a 7-day washout period and administration of the alternate formulation. After an overnight fast, subjects received a single oral dose of repaglinide (2 mg). Blood samples were drawn at predetermined time points (0, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, and 6.0 hours). All plasma concentrations of repaglinide were measured by LC-MS/MS. The observed Cmax, Tmax, t1/2, and AUC were assessed. The formulations were to be considered bioequivalent if the ln-transformed ratios of Cmax and AUC were within the predetermined bioequivalence range of 80% to 125% established by the State Food and Drug Administration of the People’s Republic of China. Tolerability was assessed throughout the study via subject interview, vital signs, and blood sampling. Results The mean (SD) age of the subjects was 24.2 (2.3) years; their mean (SD) weight was 62.6 (5.8) kg, their mean (SD) height was 172 (5.7) cm, and their mean (SD) body mass index was 21.0 (1.1). The mean (SD) Cmax for repaglinide with the test and reference formulations were 20.0 (5.1) and 18.7 (8.7) ng/mL. The AUC0–t for the test formulation was 46.3 (15.1) and AUC0–∞ was 47.9 (16.5) ng•h/mL. With the reference formulation, the corresponding values were 46.4 (26.1) and 49.0 (31.3) ng•h/mL. The mean (SD) Tmax values with the test and reference formulations were 1.2 (0.7) hours and 1.5 (0.8) hours and the mean (SD) values t1/2 values were 1.0 (0.3), and 0.9 (0.3) hours, respectively. The ln-transformed ratios of Cmax, AUC0–t, and AUC0–∞ were 113.6:1, 105.6:1, and 104.7:1. The corresponding 90% CIs were 99.8 to 129.2, 93.4 to 119.5, and 91.8 to 119.5, respectively. Conclusions This single-dose study found that the test and reference formulations of repaglinide met the regulatory criteria for bioequivalence in these fasting, healthy Chinese male volunteers. Both formulations appeared to be well tolerated. ClinicalTrials.gov identifier: 2012L01684.

Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases worldwide, presenting a great challenge to the public health systems due to high morbidity and mortality, because of frequent micro-/macro-vascular complications. Many treatment options are now available, with different efficacy as well as mechanisms of action to improve deranged glucose metabolism. We review some of the available data on derivatives of meglitinide, namely nateglinide and repaglinide. These two compounds increase insulin secretion by a mechanism similar to the one of sulfonylureas, but with a shorter half-life. Nateglinide and repaglinide, derivatives of meglitinides, have characteristic pharmacodynamic and pharmacokinetic properties that, together with their proposed mechanism of action, make them useful for type 2 diabetes mellitus, especially when used in combination therapy.

Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases worldwide, presenting a great challenge to the public health systems due to high morbidity and mortality, because of frequent micro-/macro-vascular complications. Many treatment options are now available, with different efficacy as well as mechanisms of action to improve deranged glucose metabolism. We review some of the available data on derivatives of meglitinide, namely nateglinide and repaglinide. These two compounds increase insulin secretion by a mechanism similar to the one of sulfonylureas, but with a shorter half-life. Nateglinide and repaglinide, derivatives of meglitinides, have characteristic pharmacodynamic and pharmacokinetic properties that, together with their proposed mechanism of action, make them useful for type 2 diabetes mellitus, especially when used in combination therapy.

Purpose To examine and compare risks of serious hypoglycemia among antidiabetic monotherapy-treated adults receiving metformin, a sulfonylurea, a meglitinide, or a thiazolidinedione. Methods We performed a retrospective cohort study of apparently new users of monotherapy with metformin, glimepiride, glipizide, glyburide, pioglitazone, rosiglitazone, nateglinide, or repaglinide within a dataset of Medicaid beneficiaries from California, Florida, New York, Ohio, and Pennsylvania. We did not include users of dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 agonists, or sodium-glucose co-transporter 2 inhibitors. We identified serious hypoglycemia outcomes within 180 days following new use using a validated, diagnosis-based algorithm. We calculated age- and sex-standardized outcome occurrence rates for each drug and generated propensity score–adjusted hazard ratios vs metformin using Cox proportional hazards regression. Results The ranking of standardized occurrence rates of serious hypoglycemia was glyburide > glimepiride > glipizide > repaglinide > nateglinide > rosiglitazone > pioglitazone > metformin. Rates were increased for all study drugs at higher average daily doses. Adjusted hazard ratios (95% confidence intervals) vs metformin were 3.95 (3.66-4.26) for glyburide, 3.28 (2.98-3.62) for glimepiride, 2.57 (2.38-2.78) for glipizide, 2.03 (1.64-2.52) for repaglinide, 1.21 (0.89-1.66) for nateglinide, 0.90 (0.75-1.07) for rosiglitazone, and 0.80 (0.68-0.93) for pioglitazone. Conclusions Sulfonylureas were associated with the highest rates of serious hypoglycemia. Among all study drugs, the highest rate was seen with glyburide. Pioglitazone was associated with a lower adjusted hazard for serious hypoglycemia vs metformin, while rosiglitazone and nateglinide had hazards similar to that of metformin.

Because management of type 2 diabetes mellitus usually involves combined pharmacological therapy to obtain adequate glucose control and treatment of concurrent pathologies (especially dyslipidaemia and arterial hypertension), drug-drug interactions must be carefully considered with antihyperglycaemic drugs. Additive glucose-lowering effects have been extensively reported when combining sulphonylureas (or the new insulin secretagogues, meglitinide derivatives, i.e. nateglinide and repaglinide) with metformin, sulphonylureas (or meglitinide derivatives) with thiazolidinediones (also called glitazones) and the biguanide compound metformin with thiazolidinediones. Interest in combining alpha-glucosidase inhibitors with either sulphonylureas (or meglitinide derivatives), metformin or thiazolidinediones has also been demonstrated. These combinations result in lower glycosylated haemoglobin (HbA(1c)), fasting glucose and postprandial glucose levels than with either monotherapy. Even if modest pharmacokinetic interferences have been reported with some combinations, they do not appear to have important clinical consequences. No significant adverse effects, except a higher risk of hypoglycaemic episodes that may be attributed to better glycaemic control, occur with any combination. Challenging the classical dual therapy with sulphonylurea plus metformin, there is a recent trend to use alternative dual combinations (sulphonylurea plus thiazolidinedione or metformin plus thiazolidinedione). In addition, triple therapy with the addition of a thiazolidinedione to the metformin-sulphonylurea combination has been recently evaluated and allows glucose targets to be reached before insulin therapy is considered. This triple therapy appears to be safe, with no deleterious drug-drug interactions being reported so far.Potential interferences may also occur between glucose-lowering agents and other drugs, and such drug-drug interactions may have important clinical implications. Relevant pharmacological agents are those that are widely coadministered in diabetic patients (e.g. lipid-lowering agents, antihypertensive agents); those that have a narrow efficacy/toxicity ratio (e.g. digoxin, warfarin); or those that are known to induce (rifampicin [rifampin]) or inhibit (fluconazole) the cytochrome P450 (CYP) system. Metformin is currently a key compound in the pharmacological management of type 2 diabetes, used either alone or in combination with other antihyperglycaemics. There are no clinically relevant metabolic interactions with metformin, because this compound is not metabolised and does not inhibit the metabolism of other drugs. In contrast, sulphonylureas, meglitinide derivatives and thiazolidinediones are extensively metabolised in the liver via the CYP system and thus, may be subject to drug-drug metabolic interactions. Many HMG-CoA reductase inhibitors (statins) are also metabolised via the CYP system. Even if modest pharmacokinetic interactions may occur, it is not clear whether drug-drug interactions between oral antihyperglycaemic agents and statins may have clinical consequences regarding both efficacy and safety. In contrast, a marked pharmacokinetic interference has been reported between gemfibrozil and repaglinide and, to a lesser extent, between gemfibrozil and rosiglitazone. This leads to a drastic increase in plasma concentrations of each antihyperglycaemic agent when they are coadministered with the fibric acid derivative, and an increased risk of adverse effects. Some antihypertensive agents may favour hypoglycaemic episodes when co-prescribed with sulphonylureas or meglitinide derivatives, especially ACE inhibitors, but this effect seems to result from a pharmacodynamic drug-drug interaction rather than from a pharmacokinetic drug-drug interaction. No, or only modest, interferences have been described with glucose-lowering agents and other pharmacological compounds such as digoxin or warfarin. The effects of inducers or inhibitors of CYP isoenzymes on the metabolism and pharmacokinetics of the glucose-lowering agents of each pharmacological class has been tested. Significantly increased (with CYP inhibitors) or decreased (with CYP inducers) plasma levels of sulphonylureas, meglitinide derivatives and thiazolidinediones have been reported in healthy volunteers, and these pharmacokinetic changes may lead to enhanced or reduced glucose-lowering action, and thus hypoglycaemia or worsening of metabolic control, respectively. In addition, some case reports have evidenced potential drug-drug interactions with various antihyperglycaemic agents that are usually associated with a higher risk of hypoglycaemia.

Type 2 Diabetes Mellitus, a chronic metabolic disorder which results from a high blood glucose level, is one of the most prevalent and costly diseases of our time. Considering increasing rates of obesity and the aging population in Korea, the number of diabetic patients is likely to rise rapidly in the future. There are five conventional diabetic drugs which work through different mechanisms; sulfonylureas, biguanide, meglitinide, alpha-glucosidase inhibitors, and thiazolidinedione. Although they all have antidiabetic effects, some side effects such as hypoglycemia, weight gain and gastrointestinal intolerance are associated with them. Incretin based therapies, utilizing glucagon-like peptide-1 (GLP-1) and dipeptidyl peptidase-4 (DPP-4) inhibitors, which have a lower risk of adverse side effects, have recently been introduced. At present PPAR-targeting drugs are being actively developed. In this research review, particular emphasis has been placed on the current trends and possible biological targets for the new generation of antidiabetic drugs.

Oral repaglinide (GlucoNorm®; NovoNorm®; Prandin®; Surepost®) is a rapid-acting insulin secretagogue that lowers postprandial glucose (PPG) excursions by targeting early-phase insulin release, with reductions in PPG considered to be important in reducing long-term cardiovascular complications of diabetes mellitus. Repaglinide, a carbamoylbenzoic acid derivative, is chemically related to the meglitinide class of insulin secretagogues, but unrelated to the sulfonylurea insulin secretagogues. Meglitinides, including repaglinide, have a distinct binding site at the β-cell membrane, which differs from that of sulfonylureas, and corresponds to greater insulinotropic effects with repaglinide than with glibenclamide and/or glimepiride and a more rapid onset of action in in vitro and in vivo studies. This article reviews the clinical efficacy and tolerability of oral repaglinide in the treatment of patients with type 2 diabetes and provides an overview of its pharmacological properties. In well designed clinical trials of up to 52 weeks' duration and in the clinical practice setting, recommended dosages of repaglinide (0.5-4 mg three times daily up to 30 minutes prior to a meal) provided effective glycaemic control and were generally well tolerated in treatment-naive or -experienced adult patients with type 2 diabetes, including elderly patients and those with renal impairment. Furthermore, as monotherapy or in combination with other oral antihyperglycaemic drugs, repaglinide was at least as effective as other oral antihyperglycaemic drugs at improving or maintaining glycaemic control, with a tolerability profile that was generally similar to that of sulfonylurea drugs and nateglinide. Thus, repaglinide remains an effective option for the management of patients with type 2 diabetes.

Diabetes mellitus, an epidemic metabolic disorders characterized by high blood glucose level associated with various macrovascular and microvascular complications, is one of the main causes of human suffering across the globe. Researchers around the world mainly focused on insulin, insulin analogues, oral hypoglycemic agents and various other complementary and alternate medicines to control the blood glucose levels in diabetes. The present review summarizes the disorders associated with elevation of blood glucose level, biochemical & endocrinological aspects and the current strategies to control. The emphasis has been laid in particular on the new potential biological targets and the possible treatment as well as the current ongoing research status on new generation hypoglycemic agents.

Objective: To review the pharmacology, pharmacokinetics, efficacy, and safety of mitiglinide, a rapid-acting insulin secretion-stimulating agent to determine its potential role in therapy for the treatment of type 2 diabetes mellitus. Data Sources: A MEDLINE search (1966–May 2010) was conducted for English-language, human studies using the terms mitiglinide, KAD 1229, S 21403, and meglitinide analogs. Abstracts presented at the American Association and European Association for the Study of Diabetes annual meetings from 2005 to 2009 were also evaluated for relevant data. Study Selection and Data Extraction: Articles pertinent to the pharmacology, pharmacokinetics, efficacy, and safety of mitiglinide were reviewed. Data Synthesis: Mitiglinide has been shown through small clinical studies (N 1c, postprandial hyperglycemia, and oxidative stress and inflammatory markers associated with postprandial hyperglycemia. Mitiglinide exerts its hypoglycemic activity by closing adenosine triphosphate (ATP)–sensitive potassium channels in the β-islet cells of the pancreas. This agent has a rapid onset and short duration of action, mimicking a physiologic pattern of insulin release in nondiabetic people. Studies suggest a starting dose of 5 mg 3 times daily with meals and a maximum dose of 20 mg 3 times daily. Overall, mitiglinide is well tolerated, with the most common adverse effect being hypoglycemia. Conclusions: Mitiglinide is the third agent in the class of meglitinides that targets postprandial hyperglycemia. Because of a more intensive dosing regimen, potential cost, and lack of studies assessing the clinical impact of mitiglinide therapy on oxidative stress and inflammatory markers secondary to postprandial hyperglycemia, we cannot recommend this therapy over currently approved therapies.

In patients with Type 2 diabetes mellitus (T2DM), adequate glycemic control is a critical factor in reducing long-term micro- and macro-vascular complications. Traditionally, the approach is to initiate monotherapy first, followed by combination therapy that targets two main defects in T2DM. Repaglinide, a rapidly acting insulin secretagog, stimulates insulin secretion via closure of ATP-dependent potassium channels on the cell membrane of β-cells. Repaglinide is ideally used at mealtime to reduce postprandial glucose levels, thus lowering the 24-h blood glucose profile and improving HbA1c levels. Metformin is an insulin sensitizer that effectively acts against insulin resistance, one of the predominant metabolic defects in T2DM. A combination of repaglinide and metformin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. When monotherapy with oral antidiabetic agents fails, combination therapy with repaglinide plus metformin has been demonstrated to be safe and effective in the treatment of T2DM.

Hypoglycemia is a common clinical problem in elderly patients with diabetes. Aging modifies the counterregulatory and symptomatic responses to hypoglycemia. Hypoglycemia in the elderly is not only due to tight blood sugar control, but also due to a multitude of other factors. Hypoglycemia often occurs with insulin, sulfonylureas, or meglitinide therapy. However, other causes may also contribute to hypoglycemia, such as decreased cognition, renal impairment, or polypharmacy. The presenting features of hypoglycemia may be atypical and misinterpreted, resulting in delayed treatment. Morbidity is greater in elderly patients, and the risk of progression to severe hypoglycemia is high because of their altered symptom profile, diminished symptom intensity, and altered glycemic thresholds. Hypoglycemia seems to be the main limiting factor in their glycemic control. In this article we discuss strategies to prevent hypoglycemic episodes.

Purpose Data on cardiovascular outcomes among treated diabetics have been inconsistent. Our goal was to compare cardiovascular outcomes associated with different treatments for diabetes. Methods This is a retrospective cohort study of diabetic patients at least 40 years of age treated in general practices participating in The Health Information Network (THIN) data system between 2002 and 2006. Our primary outcome was serious atherosclerotic vascular disease of the heart. Results Among all diabetics (N = 63 579), the fully adjusted hazard ratios of association with our outcome were 1.2 (1.1, 1.3) for insulin, 1.03 (0.97, 1.09) for sulfonylureas, 0.8 (0.7, 0.8) for biguanide, 1.2 (0.99, 1.5) for meglitinide, 0.5 (0.5, 0.6) for thiazolidinediones, and individually 0.6 (0.5, 0.6) for rosiglitazone, and 0.5 (0.4, 0.7) for pioglitazone. Among those individuals newly diagnosed and treated for diabetes after 2002 (N = 13 576), the adjusted hazard ratios of association with our outcome were 2.4 (2.0, 2.9) for insulin, 1.4 (1.2, 1.7) for sulfonylureas, 0.5 (0.4, 0.5) for biguanide, 0.9 (0.4, 2.1) for meglitinide, 0.8 (0.7, 1.0) for thiazolidinediones, and individually 0.8 (0.6, 1.0) for rosiglitazone, and 0.9 (0.6, 1.4) for pioglitazone. Risk increased as total duration of therapy increased for insulin, sulfonylureas, and biguanide, but decreased with duration for rosiglitazone and pioglitazone. Conclusions Overall, insulin was associated with an increased risk of myocardial infarction. Its risk increased with longer use, and risk emerged with longer use of sulfonylureas and biguanide. Conversely, a protective effect emerged with longer use of rosiglitazone or pioglitazone. Copyright © 2008 John Wiley & Sons, Ltd.

Intrasperm calcium concentration ([Ca2+]is) is known to play a vital role in regulating motility and viability of ejaculated spermatozoa. KATP channel blockers are reported to block KATP channels, leading to depolarization of the cell membrane. This activates the voltage-gated calcium channels, resulting in enhanced Ca2+ influx, which eventually elevates the intracellular [Ca2+] level. Hence, it can be hypothesized that drugs acting on KATP channels could possess the ability to elevate [Ca2+]is. Sulfonylureas such as glibenclamide or gliclazide, as well as meglitinide analogues such as repaglinide, produced a dose- and time-dependent decrease in viability, each requiring 7.5 mm, 10 mm and 6.5 mm, respectively, to produce death of all sperm cells immediately upon addition to ejaculated human semen samples. The reduction in sperm viability was accompanied by an elevation of [Ca2+]is and was affected by removal of extracellular Ca2+. Significantly (P < 0.05) less time was required to elevate [Ca2+]is and produce complete loss of sperm viability when any of these drugs were added to sperm cells simultaneously with selected agents affecting Ca2+ homeostasis. Thus, the spermicidal activity of these drugs attributed to elevation of [Ca2+]is and their synergism can be potentially exploited for developing contact spermicidal formulations.

Background: Diabetes mellitus (DM) is of epidemic proportions worldwide, and its microvascular and macrovascular complications have been well described. Achieving glycemic control has been demonstrated to reduce patients' risk of developing these complications. Objective: The objective of this article was to examine how prandial hyperglycemia-especially postprandial hyperglycemia (PPHG)-affects overall glycemic control and the complications of DM and to discuss the pharmacologic agents available to reduce PPHG. Methods: Materials used for this article were identified through a MEDLINE search of the literature (1975–2006). English-language randomized, controlled, prospective, cohort, and observational studies were chosen using the search terms postprandial hyperglycemia, oxidative stress, cardiovascular disease, macrovascular disease, microvascular disease, lipidemia, and coagulation. Results: Data show that controlling prandial hyperglycemia reduces the risk of cardiovascular disease (CVD) andmicrovascular complications, lowers glycosylated hemoglobin levels, causes less oxidative stress, and leads to a more favorable coagulation and postprandial lipidemia profile. Guidelines for targeting PPHG are becoming standard, and various pharmacologic agents (eg, a-glucosidase inhibitors, amylin analogues, incretin mimetics, rapid-acting insulins and insulin analogues, meglitinide analogues) that target PPHG may also improve overall glycemic control and reduce CVD risk. Conclusions: Although the level of hyperglycemia that leads to microvascular and macrovascular complications inpatients with DM remains to be elucidated, it appears prudent to address prandial hyperglycemia, especially PPHG, rather than focus solely on fasting glucose levels. Clinicians should consider incorporating agents that lower PPHG in their treatment of patients with DM.

Objective To analyze the durability of monotherapy with different classes of oral hypoglycemic agents (OHAs) in drug naive patients with type 2 diabetes mellitus (T2DM) in real life. Methods Men and women with T2DM, who were new users of OHA monotherapy and registered in the Swedish National Diabetes Register July 2005–December 2011, were available (n=17 309) and followed for up to 5.5 years. Time to monotherapy failure, defined as discontinuation of continuous use with the initial agent, switch to a new agent, or add-on treatment of a second agent, was analyzed as a measure of durability. Baseline characteristics were balanced by propensity score matching 1:5 between groups of sulfonylurea (SU) versus metformin (n=4303) and meglitinide versus metformin (n=1308). HRs with 95% CIs were calculated using Cox regression models. Results SU and meglitinide, as compared with metformin, were associated with increased risk of monotherapy failure (HR 1.74; 95% CI 1.56 to 1.94 and 1.66; 1.37 to 2.00 for SU and meglitinide, respectively). When broken down by type of monotherapy failure, SU and meglitinide were associated with an increased risk of add-on treatment of a second agent (HR 3.14; 95% CI 2.66 to 3.69 and 2.52; 1.89 to 3.37 for SU and meglitinide, respectively) and of switch to a new agent (HR 2.81; 95% CI 2.01 to 3.92 and 3.78; 2.25 to 6.32 for SU and meglitinide, respectively). The risk of discontinuation did not differ significantly between the groups. Conclusions In this nationwide observational study reflecting clinical practice, SU and meglitinide showed substantially increased risk of switch to a new agent or add on of a second agent compared with metformin. These results indicate superior glycemic durability with metformin compared with SU and also meglitinide in real life.

Aims Nateglinide is a meglitinide analogue with antidiabetic action. A recent study showed that SLCO1B1 (which codes the OATP1B1 gene, also known as OATP-C, OATP2) is a major determinant which markedly affects the pharmacokinetics of repaglinide. Our objective was to assess the association between single nucleotide polymorphisms (SNPs) of SLCO1B1 and the pharmacokinetics of nateglinide. Methods Seventeen healthy volunteers with different SLCO1B1 genotypes (11 with 521TT, four with 521TC and two with 521CC) were enrolled in this study. Each was given a single oral dose of 90 mg nateglinide. Plasma concentrations of nateglinide were measured up to 8 h by HPLC. Results The Cmax and AUC(0,∞) of nateglinide were 83% (P = 0.002) and 82% (P = 0.001) higher in the SLCO1B1521TC subjects (n = 4), and 76% (P = 0.016) and 108% (P = 0.001) higher in the SLCO1B1521CC subjects (n = 2) than in the SLCO1B1521TT subjects (n = 11), respectively. The t1/2 of nateglinide in SLCO1B1521CC subjects was 78% longer than that in 521TT subjects (P = 0.036). The difference in tmax values among the three genotypic groups was not statistically significant. Conclusions Our results suggest that OATP1B1-mediated hepatic uptake of nateglinide may be the prior step for its metabolism and elimination. SLCO1B1521T > C SNP might play an important role in the pharmacokinetics of nateglinide.

Summary Glinides represent a chemically heterogeneous new class of insulinsecreting agents characterized by a rapid onset and short duration of action. They act by closure of the ATP-dependant K channel. Repaglinide, the only glinide available in France, has an equivalent HbA 1c lowering effect to conventional sulfonylureas but reduces predominantly postprandial glucose levels. Several studies indicate a decreased risk of hypoglycaemias, particularly nocturnal or in case of a shift or omission of a meal. This drug appears particularly useful in early stage type 2 diabetes or in combination with metformin. The only significant drug-drug interaction concerns gemfibrozil. Due to its hepatic metabolism and biliary elimination, repaglinide can be used in patients with renal insufficiency. Nateglinide has a even shorter duration of action and has almost no effect on fasting plasma glucose levels. For this reason, this drug is only indicated in combination with metformin in the countries where it is licensed. Several experimental data suggest that glinides could preserve β cell function over time better than hypoglycaemic sulfonylureas, and that the improvement of post-prandial glucose levels could exert a long term protective cardiovascular effect.

Repaglinide (Prandin), NovoNorm, GlucoNorm, an oral insulin secretagogue, was the first meglitinide analogue to become available for use in patients with type 2 diabetes mellitus. The drug lowers postprandial glucose excursions by targeting early-phase insulin release, an effect thought to be important in reducing long-term cardiovascular complications of diabetes. Repaglinide provided similar overall glycaemic control to that achieved with glibenclamide (glyburide), as assessed by glycosylated haemoglobin (HbA(1c)) and fasting blood glucose levels, and was generally well tolerated in well designed clinical trials. Its rapid onset and relatively short duration of action allow for flexible meal schedules. Two modelled US cost-effectiveness analyses projected lifetime costs and outcomes for a hypothetical cohort of patients with type 2 diabetes. Both analyses projected long-term complications using data on HbA(1c) level changes from short-term clinical trials. Repaglinide plus rosiglitazone was dominant over rosiglitazone in one analysis, and repaglinide plus metformin was dominant over nateglinide plus metformin in the other. A similar Canadian analysis showed a favourable incremental cost-effectiveness ratio (