Stability Development, Optimization and Evaluation of Gastro-Retentive Microspheres of Antidiabetic Agent by Full Factorial Design.

OBJECTIVE: This work is aimed to Formulate, Optimize and Evaluate Gastro-Retentive Microspheres of Antidiabetic Agent by Full Factorial Design. METHODS: Microspheres were prepared using Emulsification-cross linking technique. To this HPMC-K4M and Carbopol was dissolved in 250 ml of water and allowed to swell for 24 hr at room temperature. And separately chitosan was dissolved in 3% (v/v) glacial acetic acid and this also kept for 24 h to swell or dissolve properly. After 24hr this swelled mixture was mixed under magnetic stirrer (Remi, India) at specific stirring rate for 1hr in order to find homogeneous mass of both the gum. Then slurry of chitosan also was homogenized for half an hour. The drug, Glipizide (1g) was then added to the chitosan solution and mixed homogenesously. RESULTS: The aim of the study was to formulate and evaluate microspheres, for Gastro-Retentive Microspheres of the chosen drug. The EE of microspheres was found to be 91.52%, maximum . Buoyancy property observed was 93.82% for Optimized formulation F-9, Drug release 57.34% till 8 h. The work also aims to study various parameters affecting the behaviour of microspheres in oral dosage form. CONCLUSION: Drugs with short half-life that are absorbed from the gastrointestinal tract (GIT) are eliminated rapidly from the blood flow. To avoid this, the oral SR Gastro-retentive was developed as this formulation released the drug slowly into the GIT and maintained a stable drug concentration in the serum for a longer duration of time.

Using Data From Routine Care to Estimate the Effectiveness and Potential Limitations of Outcomes-Based Contracts for Diabetes Medications.

OBJECTIVES: Outcomes-based contracts tie rebates and discounts for expensive drugs to outcomes. The objective was to estimate the utility of outcomes-based contracts for diabetes medications using real-world data and to identify methodologic limitations of this approach. METHODS: A population-based cohort study of adults newly prescribed a medication for diabetes with a publicly announced outcomes-based contract (ie, exenatide microspheres ["exenatide"], dulaglutide, or sitagliptin) was conducted. The comparison group included patients receiving canagliflozin or glipizide. The primary outcome was announced in the outcomes-based contract: the percentage of adults with a follow-up hemoglobin A1C <8% up to 1 year later. Secondary outcomes included the percentage of patients diagnosed with hypoglycemia and the cost of a 1-month supply. RESULTS: Thousands of adults newly filled prescriptions for exenatide (n = 5079), dulaglutide (n = 6966), sitagliptin (n = 40 752), canagliflozin (n = 16 404), or glipizide (n = 59 985). The percentage of adults subsequently achieving a hemoglobin A1C below 8% ranged from 83% (dulaglutide, sitagliptin) to 71% (canagliflozin). The rate of hypoglycemia was 25 per 1000 person-years for exenatide, 37 per 1000 person-years for dulaglutide, 28 per 1000 person-years for sitagliptin, 18 per 1000 person-years for canagliflozin, and 34 per 1000 person-years for glipizide. The cash price for a 1-month supply was $847 for exenatide, $859 for dulaglutide, $550 for sitagliptin, $608 for canagliflozin, and $14 for glipizide. CONCLUSION: Outcomes-based pricing of diabetes medications has the potential to lower the cost of medications, but using outcomes such as hemoglobin A1C may not be clinically meaningful because similar changes in A1C can be achieved with generic medications at a far lower cost.

pH Sensitive Interpenetrating Network Bio Containers of Gum Ghatti for Sustained Release of Glipizide.

OBJECTIVE: A novel natural polymer, Gum Ghatti (GG) was explored to develop a new polymeric system that will combine the biodegradable and biocompatible properties of GG and mechanical properties of poly vinyl alcohol (PVA) for drug delivery application. METHODS: Smart pH sensitive, porous, glutaraldehyde (GA) crosslinked interpenetrating network (IPN) microspheres loaded with glipizide were developed by the emulsion crosslinking method. The drug entrapment efficiency was 92.85±1.5%. FTIR confirmed the formation of IPN structure. Drug release can be extended upto 7 hours by modulating the concentration of crosslinking agent. Swelling study and diffusion co-efficient (D) of water transport were performed in order to understand the phenomenon of water penetration through the microsphere. In vivo antidiabetic activity performed on alloxane induced diabetic rats indicated that in case of pure glipizide sudden reduction of elevated blood glucose was observed after 3 hours. RESULTS: In case of rats treated with glipizide loaded IPN microparticles, the initial percentage reduction of blood glucose level was slow within the first 3 hours of administration, as compared to pure glipizide but after 6 hours 90% reduction was observed which confirmed sustained release nature of microspheres. CONCLUSION: Thus IPN microparticles were found suitable for sustained delivery of BCS class II drug glipizide.

Digitizing Medicines for Remote Capture of Oral Medication Adherence Using Co-encapsulation.

High-resolution measurement of medication adherence is essential to personalized drug therapy. A US Food and Drug Administration (FDA)-cleared device, using an edible ingestion sensor (IS), external wearable patch, and paired mobile device can detect and record ingestion events. Oral medications must be combined with an IS to generate precise "digitized-medication" ingestion records. We developed a Good Manufacturing Practice protocol to repackage oral medications with the IS within certified Capsugel capsules, termed co-encapsulation (CoE). A randomized bioequivalence study of CoE-IS-Rifamate (Isoniazid/Rifampin 150/300 mg) vs. native-Rifamate was conducted in 12 patients with active Mycobacterium tuberculosis and demonstrated bioequivalence using the population method ratio test (95% confidence interval). Subsequently, CoE-IS-medications across all biopharmaceutical classes underwent in vitro dissolution testing utilizing USP and FDA guidelines. CoE-IS medications tested met USP dissolution specifications and were equivalent to their native formulations. CoE combines oral medications with the IS without altering the quality of the native formulation, generating "digitized" medications for remote capture of dosing histories.

Pharmacologic Differences of Sulfonylureas and the Risk of Adverse Cardiovascular and Hypoglycemic Events.

OBJECTIVE: Sulfonylureas have been associated with an increased risk of cardiovascular adverse events and hypoglycemia, but it is unclear if these risks vary with different agents. We assessed whether the risks of acute myocardial infarction, ischemic stroke, cardiovascular death, all-cause mortality, and severe hypoglycemia differ between sulfonylureas grouped according to pancreas specificity and duration of action. RESEARCH DESIGN AND METHODS: Using the U.K. Clinical Practice Research Datalink, linked with the Hospital Episodes Statistics and the Office for National Statistics databases, we conducted a cohort study among patients with type 2 diabetes initiating monotherapy with sulfonylureas between 1998 and 2013. Adjusted hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models, comparing use of pancreas-nonspecific, long-acting sulfonylureas (glyburide/glimepiride) to pancreas-specific, short-acting sulfonylureas (gliclazide/glipizide/tolbutamide). RESULTS: The cohort included 17,604 sulfonylurea initiators (mean [SD] follow-up 1.2 [1.5] years). Compared with specific, short-acting sulfonylureas (15,741 initiators), nonspecific, long-acting sulfonylureas (1,863 initiators) were not associated with an increased risk of acute myocardial infarction (HR 0.86; CI 0.55-1.34), ischemic stroke (HR 0.92; CI 0.59-1.45), cardiovascular death (HR 1.01; CI 0.72-1.40), or all-cause mortality (HR 0.81; CI 0.66-1.003), but with an increased risk of severe hypoglycemia (HR 2.83; CI 1.64-4.88). CONCLUSIONS: The nonspecific, long-acting sulfonylureas glyburide and glimepiride do not have an increased risk of cardiovascular adverse events compared with the specific, short-acting sulfonylureas gliclazide, glipizide, and tolbutamide. However, nonspecific, long-acting sulfonylureas glyburide and glimepiride have an increased risk of severe hypoglycemia.

Computational Modeling of Polymeric Physicochemical Properties for Formulation Development of a Drug Containing Basic Functionality.

In the present research, predictive models were developed by correlating polymeric properties with characteristics of a formulation containing a drug with basic heterocycle (glipizide). Glipizide tablets containing different polymers from 3 categories (immediate, moderate, and extended release) were prepared and evaluated. Dissolution kinetics indicated Korsmeyer-Peppas as the best-fit model, whereas transportability was influenced by release rate and hydrophobicity of the drug. Calculated polymeric descriptors were correlated with formulation properties for the development of predictive quantitative structure-property relationship models. Regression coefficients and subsequent validation of developed models indicated potential predictability of the model for formulation properties containing any drug with basic heterocycle. Such models could also help to decide the formulation composition for desired characteristics with saving of time and formulation cost.

Preparation and investigation of controlled-release glipizide novel oral device with three-dimensional printing.

The purpose of this study was to explore the feasibility of combining fused deposition modeling (FDM) 3D printing technology with hot melt extrusion (HME) to fabricate a novel controlled-release drug delivery device. Glipizide used in the treatment of diabetes was selected as model drug, and was successfully loaded into commercial polyvinyl alcohol (PVA) filaments by HME method. The drug-loaded filaments were printed through a dual-nozzle 3D printer, and finally formed a double-chamber device composed by a tablet embedded within a larger tablet (DuoTablet), each chamber contains different contents of glipizide. The drug-loaded 3D printed device was evaluated for drug release under in vitro dissolution condition, and we found the release profile fit Korsmeyer-Peppas release kinetics. With the double-chamber design, it is feasible to design either controlled drug release or delayed drug release behavior by reasonably arranging the concentration distribution of the drug in the device. The characteristics of the external layer performed main influence on the release profile of the internal compartment such as lag-time or rate of release. The results of this study suggest the potential of 3D printing to fabricate controlled-release drug delivery system containing multiple drug concentration distributions via hot melt extrusion method and specialized design configurations.

Influence of Single and Multi Dose Treatment of Glipizide on Pharmacokinetics and Pharmacodynamics of Irbesartan in Normal and Hypertensive Rats.

PURPOSE: The present study was carried out to investigate the pharmacokinetic and pharmacodynamic drug interaction of irbesartan with glipizide after single and multi dose treatment in normal and hypertensive rat models to evaluate the safety and effectiveness of the combination. METHODS: The study was conducted on normal and 10% fructose solution induced hypertensive rats. Irbesartan and glipizide were administered orally for 7 days and on 8th day blood samples were collected for 12 h at regular time intervals from irbesartan alone and in combination with glipizide treated groups. The blood samples were analyzed for various pharmacokinetic and pharmacodynamic parameters. RESULTS: Irbesartan caused marked reduction in blood pressure in hypertensive rats. The combination of irbesartan and glipizide in hypertensive rats produce significant change in blood pressure (pharmacodynamic) and also significance in pharmacokinetic parameters of irbesartan with glipizide in single dose and multiple doses. CONCLUSION: The results of present study demonstrated that the synergistic activity of irbesartan with glipizide was observed.

Stable amorphous binary systems of glipizide and atorvastatin powders with enhanced dissolution profiles: formulation and characterization.

The aim of this study was to enhance the dissolution profile of the combination of glipizide and atorvastatin used for simultaneous treatment of hyperglycemia and hyperlipidemia. The strategy to formulate coamorphous glipizide-atorvastatin binary mixture was explored to achieve enhancement in dissolution. The coamorphous glipizide-atorvastatin mixtures (1:1, 1:2 and 2:1) were prepared by cryomilling and characterized with respect to their dissolution profiles, preformulation parameters and physical stability. Amorphization was found to be possible by cryomilling at various tried ratios of the two drugs. The data obtained from glass transition temperatures and from Raman spectroscopy point toward practically no interaction between the two drugs. The dissolution studies revealed the highest enhancement in dissolution profiles of cryomilled coamorphous mixtures containing GPZ:ATV in ratios 1:1 (B-5) and 2:1 (B-7). These two mixtures were, therefore, subjected to studies for the evaluation of precompression parameters in order to find their amenability to satisfactory compression into tablet dosage form. The selected formulation was found to be stable when subjected to accelerated stability testing at 40°. C/75% RH for six months as per ICH guidelines. Based on all these studies, it was concluded that GPZ:ATV (1:1) combination may be able to provide an effective therapy for the comorbidities of hyperglycemia and hyperlipidemia.

Comparison of alogliptin and glipizide for composite endpoint of glycated haemoglobin reduction, no hypoglycaemia and no weight gain in type 2 diabetes mellitus.

This was a post hoc analysis of a 2-year, double-blind study of 2639 patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin monotherapy, which assessed achievement of a composite endpoint of sustained glycated haemoglobin (HbA1c) reduction (≤7.0% at week 104 or ≥0.5% decrease from baseline) with no weight gain and no hypoglycaemic events with alogliptin 12.5 and 25 mg daily or glipizide (≤20 mg daily), each added to metformin. With an HbA1c target of ≤7.0%, 24.2 and 26.9% of patients treated with alogliptin 12.5 and 25 mg, respectively, achieved the composite endpoint versus 10.7% of patients treated with glipizide (both p < 0.001). With a criterion of ≥0.5% decrease in HbA1c, the composite endpoint was reached in 22.5, 25.2 and 10.4% of patients treated with alogliptin 12.5 mg, alogliptin 25 mg and glipizide, respectively. Odds ratios for achieving the composite endpoint favoured alogliptin in the primary analysis set and in all subgroups of patients. Patients with T2DM failing metformin monotherapy were more likely to achieve sustained glycaemic control with no hypoglycaemia or weight gain at 2 years with alogliptin than with glipizide.

Severe hypoglycemia in users of sulfonylurea antidiabetic agents and antihyperlipidemics.

Drug-drug interactions causing severe hypoglycemia due to antidiabetic drugs is a major clinical and public health problem. We assessed whether sulfonylurea use with a statin or fibrate was associated with severe hypoglycemia. We conducted cohort studies of users of glyburide, glipizide, and glimepiride plus a statin or fibrate within a Medicaid population. The outcome was a validated, diagnosis-based algorithm for severe hypoglycemia. Among 592,872 persons newly exposed to a sulfonylurea+antihyperlipidemic, the incidence of severe hypoglycemia was 5.8/100 person-years. Adjusted hazard ratios (HRs) for sulfonylurea+statins were consistent with no association. Most overall HRs for sulfonylurea+fibrate were elevated, with sulfonylurea-specific adjusted HRs as large as 1.50 (95% confidence interval (CI): 1.24-1.81) for glyburide+gemfibrozil, 1.37 (95% CI: 1.11-1.69) for glipizide+gemfibrozil, and 1.63 (95% CI: 1.29-2.06) for glimepiride+fenofibrate. Concomitant therapy with a sulfonylurea and fibrate is associated with an often delayed increased rate of severe hypoglycemia.

3D printing of tablets containing multiple drugs with defined release profiles.

We have employed three-dimensional (3D) extrusion-based printing as a medicine manufacturing technique for the production of multi-active tablets with well-defined and separate controlled release profiles for three different drugs. This 'polypill' made by a 3D additive manufacture technique demonstrates that complex medication regimes can be combined in a single tablet and that it is viable to formulate and 'dial up' this single tablet for the particular needs of an individual. The tablets used to illustrate this concept incorporate an osmotic pump with the drug captopril and sustained release compartments with the drugs nifedipine and glipizide. This combination of medicines could potentially be used to treat diabetics suffering from hypertension. The room temperature extrusion process used to print the formulations used excipients commonly employed in the pharmaceutical industry. Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR-FTIR) and X-ray powder diffraction (XRPD) were used to assess drug-excipient interaction. The printed formulations were evaluated for drug release using USP dissolution testing. We found that the captopril portion showed the intended zero order drug release of an osmotic pump and noted that the nifedipine and glipizide portions showed either first order release or Korsmeyer-Peppas release kinetics dependent upon the active/excipient ratio used.

Utility of capillary microsampling for rat pharmacokinetic studies: Comparison of tail-vein bleed to jugular vein cannula sampling.

INTRODUCTION: Serial sampling methods have been used for rat pharmacokinetic (PK) studies for over 20 years. Currently, it is still common to take 200-250 µL of blood at each timepoint when performing a PK study in rats and using serial sampling. While several techniques have been employed for collecting blood samples from rats, there is only limited published data to compare these methods. Recently, microsampling (≤ 50 µL) techniques have been reported as an alternative process for collecting blood samples from rats. METHODS: In this report, five compounds were dosed orally into rats. For three proprietary compounds, jugular vein cannula (JVC) sampling was used to collect whole blood and plasma samples and capillary microsampling (CMS) was used to collect blood samples from the tail vein of the same animal. For the two other compounds, marketed drugs fluoxetine and glipizide, JVC sampling was used to collect both whole blood and blood CMS samples while tail-vein sampling from the same rats was also used to collect both whole blood and blood CMS samples. RESULTS: For the three proprietary compounds, the blood AUC as well as the blood concentration-time profile that were obtained from the tail vein were different from those obtained via JVC sampling. For fluoxetine, the blood total exposure (AUC) was not statistically different when comparing tail-vein sampling to JVC sampling, however the blood concentration-time profile that was obtained from the tail vein was different than the one obtained from JVC sampling. For glipizide, the blood AUC and concentration-time profile were not statistically different when comparing the tail-vein sampling to the JVC sampling. For both fluoxetine and glipizide, the blood concentration profiles obtained from CMS were equivalent to the blood concentration profiles obtained from the standard whole blood sampling, collected at the same sampling site. DISCUSSION: The data in this report provide strong evidence that blood CMS is a valuable small volume blood sampling approach for rats and that it provides results for test compound concentrations that are equivalent to those obtained from traditional whole blood sampling. The data also suggest that for some compounds, the concentration-time profile that is obtained for a test compound based on sampling from a rat tail vein may be different from that obtained from rat JVC sampling. In some cases, this shift in the concentration-time profile will result in different PK parameters for the test compound. Based on these observations, it is recommended that a consistent blood sampling method should be used for serial microsampling in discovery rat PK studies when testing multiple new chemical entities. If the rat tail vein sampling method is selected for PK screening, then conducting a bridging study on the lead compound is recommended to confirm that the rat PK obtained from JVC sampling is comparable to the tail-vein sampling.

The biopharmaceutics of successful controlled release drug product: Segmental-dependent permeability of glipizide vs. metoprolol throughout the intestinal tract.

The purpose of this work was to study the challenges and prospects of regional-dependent absorption in a controlled-release scenario, through the oral biopharmaceutics of the sulfonylurea antidiabetic drug glipizide. The BCS solubility class of glipizide was determined, and its physicochemical properties and intestinal permeability were thoroughly investigated, both in-vitro (PAMPA and Caco-2) and in-vivo in rats. Metoprolol was used as the low/high permeability class boundary marker. Glipizide was found to be a low-solubility compound. All intestinal permeability experimental methods revealed similar trend; a mirror image small intestinal permeability with opposite regional/pH-dependency was obtained, a downward trend for glipizide, and an upward trend for metoprolol. Yet the lowest permeability of glipizide (terminal Ileum) was comparable to the lowest permeability of metoprolol (proximal jejunum). At the colon, similar permeability was evident for glipizide and metoprolol, that was higher than metoprolol's jejunal permeability. We present an analysis that identifies metoprolol's jejunal permeability as the low/high permeability class benchmark anywhere throughout the intestinal tract; we show that the permeability of both glipizide and metoprolol matches/exceeds this threshold throughout the entire intestinal tract, accounting for their success as controlled-release dosage form. This represents a key biopharmaceutical characteristic for a successful controlled-release dosage form.

Effects of pioglitazone and glipizide on platelet function in patients with type 2 diabetes.

OBJECTIVE: Platelet hyper-reactivity is one of the most important causes of accelerated atherosclerosis and increased risk of thrombotic vascular events associated with type 2 diabetes mellitus (T2DM). This study aimed to investigate the effects of different add-on anti-diabetic therapies on platelet function in T2DM patients. PATIENTS AND METHODS: A three-group parallel study was conducted in 120 patients with T2DM (HbA1c > 7%) undergoing treatment with metformin. Patients were randomly assigned to receive add-on therapy with glipizide or pioglitazone. Markers of PF (platelet PAC-1 binding, p-selectin expression and adenosine diphosphate-induced platelet aggregation) were measured at weeks 0, 4 and 24. Primary outcome was effects of pioglitazone and glipizide on platelet aggregation. Secondary outcome was the related influencing factors of platelet aggregation. RESULTS: There were no significant differences in baseline characteristics between glipizide and pioglitazone groups. After 24 weeks, fasting blood glucose (p < 0.01) and HbA1c (p < 0.01) were higher in pioglitazone group than those in glipizide group. Fasting insulin (p < 0.01) and HOMA-IR (p < 0.01) were lower in pioglitazone group than that in glipizide group. Markers of platelet function were significantly decreased in both groups at 24 weeks (PAC-1: pioglitazone: -63.3%; glipizide: -45.9%; p-selectin: pioglitazone: -73.9%; glipizide: -54.9%; platelet aggregation: pioglitazone: -24.1%; glipizide: -13.4%; all p < 0.01 vs. baseline), but the decrease in platelet function was more significant in pioglitazone group (p < 0.05). Multiple linear regression analyses showed that platelet aggregation was independently associated with treatment groups (p < 0.001), Triglyceride (p = 0.009) and HDL-C (p = 0.015). CONCLUSIONS: Add-on therapy with pioglitazone may be more effective than glipizide for inhibiting platelet activation in T2DM.

Impact of gelation period on modified locust bean-alginate interpenetrating beads for oral glipizide delivery.

In this work, the effect of hydrogelation period in the design of glipizide-loaded biopolymer-based interpenetrating network (IPN) beads was investigated. Carboxymethyl locust bean gum and sodium alginate IPN beads were prepared by ionic crosslinking method using aqueous aluminium chloride salt solution as gelation medium. The longer exposure of the IPN beads in the gelation medium caused a considerable loss of the drug (∼ 8%), and also affected their surface morphology and drug release performance. Spherical shape of the IPN beads was observed under scanning electron microscope (SEM). The diameter of IPN beads increased with increasing gelation time. The IPNs cured for 0.5h exhibited slower drug release kinetics in HCl (pH 1.2) and phosphate buffer (pH 7.4) solution than those incubated for 1-2h. The drug release occurred at a faster rate in phosphate buffer solution and continued for a minimum period of 8h. The IPNs cured for the lowest period obeyed polymer chain-relaxation phenomenon as dominating mechanism for drug release. However, all the IPNs followed anomalous mechanism of drug transport. The drug release corroborated well with pH-dependent swelling behaviors of the IPNs. Thus, IPN beads cured for 0.5h were found most suitable for controlled delivery of BCS class II anti-diabetic drug glipizide.

Metformin in combination with various insulin secretagogues in type 2 diabetes and associated risk of cardiovascular morbidity and mortality--a retrospective nationwide study.

AIMS: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Coadministration of co-trimoxazole with sulfonylureas: hypoglycemia events and pattern of use.

BACKGROUND: Coadministration of co-trimoxazole with sulfonylureas is reported to increase the risk of hypoglycemia. METHODS: We identified a cohort of Medicare beneficiaries aged 66 years or older who took glyburide or glipizide for diabetes from a 5% national sample of Medicare Part D claims data in 2008 (n = 34,239). We tracked each participant's claims during 2008-2010 for a co-trimoxazole prescription and subsequent emergency room visits for hypoglycemia. Descriptive statistics and logistic regression modeling were used to evaluate hypoglycemia-related emergency room visits after coadministration of co-trimoxazole with sulfonylureas and its utilization patterns in older adults with diabetes. RESULTS: Sulfonylureas users prescribed co-trimoxazole had a significant higher risk of emergency room visits for hypoglycemia, compared with those prescribed noninteracting antibiotics (odds ratio = 3.89, 95% confidence interval = 2.29-6.60 for glipizide and odds ratio = 3.78, 95% confidence interval = 1.81-7.90 for glyburide with co-trimoxazole, using amoxicillin as the reference). Co-trimoxazole was prescribed to 16.9% of those taking glyburide or glipizide during 2008-2010, varying from 4.0% to 35.9% across U.S. hospital referral regions. Patients with polypharmacy and with more prescribers were more likely to receive co-trimoxazole. Patients with an identifiable primary care physician had 20% lower odds of receiving a co-trimoxazole prescription. Hospital referral regions with more PCPs had lower rates of coadministration of the two drugs (r = -.26, p < 0.001). CONCLUSIONS: Coadministration of co-trimoxazole with sulfonylureas is associated with increased risk of hypoglycemia, compared with noninteracting antibiotics. Such coadministration is prevalent among older diabetic patients in the United States, especially in patients without an identifiable primary care physician.

Durability of the efficacy and safety of alogliptin compared with glipizide in type 2 diabetes mellitus: a 2-year study.

AIMS: To evaluate the long-term durability of the efficacy of alogliptin compared with glipizide in combination with metformin in people with type 2 diabetes inadequately controlled on stable-dose metformin. METHODS: This multicentre, double-blind, active-controlled study randomized 2639 patients aged 18-80 years to 104 weeks of treatment with metformin in addition to alogliptin 12.5 mg once daily (n = 880), alogliptin 25 mg once daily (n = 885) or glipizide 5 mg once daily, titrated to a maximum of 20 mg (n = 874). The primary endpoint was least square mean change from baseline in HbA1c level at 104 weeks. RESULTS: The mean patient age was 55.4 years, the mean diabetes duration was 5.5 years and the mean baseline HbA1c was 7.6%. HbA1c reductions at week 104 were -0.68%, -0.72% and -0.59% for alogliptin 12.5 and 25 mg and glipizide, respectively [both doses met the criteria for non-inferiority to glipizide (p<0.001); alogliptin 25 mg met superiority criteria (p=0.010)]. Fasting plasma glucose concentration decreased by 0.05 and 0.18 mmol/l for alogliptin 12.5 and 25 mg, respectively, and increased by 0.30 mmol/l for glipizide (p < 0.001 for both comparisons with glipizide). Mean weight changes were -0.68, -0.89 and 0.95 kg for alogliptin 12.5 and 25 mg and glipizide, respectively (p < 0.001 for both comparisons with glipizide). Hypoglycaemia occurred in 23.2% of patients in the glipizide group vs. 2.5 and 1.4% of patients in the alogliptin 12.5 and 25 mg groups, respectively. Pancreatitis occurred in one patient in the alogliptin 25 mg group and three in the glipizide group. CONCLUSIONS: Alogliptin efficacy was sustained over 2 years in patients with inadequate glycaemic control on metformin alone.

Effect of tolbutamide, glyburide and glipizide administered supraspinally on CA3 hippocampal neuronal cell death and hyperglycemia induced by kainic acid in mice.

Sulfonylureas are widely used oral drugs for the treatment of type II diabetes mellitus. In the present study, the effects of sulfonylureas administered supraspinally on kainic acid (KA)-induced hippocampal neuronal cell death and hyperglycemia were studied in ICR mice. Mice were pretreated intracerebroventricularly (i.c.v.) with 30µg of tolbutamide, glyburide or glipizide for 10min and then, mice were administered i.c.v. with KA (0.1µg). The neuronal cell death in the CA3 region in the hippocampus was assessed 24h after KA administration and the blood glucose level was measured 30, 60, and 120min after KA administration. We found that i.c.v. pretreatment with tolbutamide, glyburide or glipizide attenuated the KA-induced neuronal cell death in CA3 region of the hippocampus and hyperglycemia. In addition, KA administered i.c.v. caused an elevation of plasma corticosterone level and a reduction of the plasma insulin level. The i.c.v. pretreatment with tolbutamide, glyburide or glipizide attenuated KA-induced increase of plasma corticosterone level. Furthermore, i.c.v. pretreatment with tolbutamide, glyburide or glipizide causes an elevation of plasma insulin level. Glipizide, but not tolbutamide or glyburide, pretreated i.c.v. caused a reversal of KA-induced hypoinsulinemic effect. Our results suggest that supraspinally administered tolbutamide, glyburide and glipizide exert a protective effect against KA-induced neuronal cells death in CA3 region of the hippocampus. The neuroprotective effect of tolbutamide, glyburide and glipizide appears to be mediated by lowering the blood glucose level induced by KA.