Glibenclamide nanosuspension inhaler: development, in vitro and in vivo assessment.

Objective: The development of nanosuspension for targeted delivery of glibenclamide as hypoglycemic agent to the lung in an inhaler dosage form.Method: Glibenclamide nanosuspension formulations were prepared using Box-Behnken design to investigate the effect of independent factors on the dependent variables, Fourier-transform Infrared spectroscopy, Differential Scanning Calorimetry, evaluation of glibenclamide nanosuspension inhaler and in vivo hypoglycemic efficacy were performed to determine glibenclamide nanosuspension inhaler effect.Results: The results revealed that the mean particle sizes of the prepared nanosuspension ranged from 0.216 to 0.856 µm, zeta potential from +9 to +16 mV, the solubility ranged from 43% to 75%, the mass median aerodynamic diameter was 2.34 µm and the glucose level in rat was significantly reduced by about 60%.Conclusion: These results confirmed that glibenclamide nanosuspension inhaler enhance hypoglycemic effectiveness and reduce adverse effect of glibenclamide, opening up new dosage form in Diabetes mellitus treatment.

Prevalence of hypoglycemia among a sample of sulfonylurea-treated patients with Type 2 diabetes mellitus in Argentina: The real-life effectiveness and care patterns of diabetes management (RECAP-DM) study.

AIM: Strict blood glucose control in the treatment of diabetes can sometimes lead to hypoglycemia. The main aim of this study was to assess the prevalence of hypoglycemia among patients receiving sulfonylureas alone, or in combination with metformin, for the treatment of Type 2 Diabetes Mellitus (T2DM) in Argentina. METHODS: This is a real life, multi-center, retrospective, and cross-sectional study based on clinical chart reviews including cross-sectional data, and evaluation of patient questionnaires of T2DM patients (>30 years), treated with sulfonylureas alone or in combination with metformin, during a routine clinic visit in 16 medical centers across Argentina. Socio-demographic and clinical parameters were collected from medical records, as well as hypoglycemic events from both the medical records and the patient questionnaires. The glycated hemoglobin (HbA1c) levels were obtained from medical records as well as a blood test. RESULTS: The study included a total of 397 patients with a mean age of 62.5 years, diagnosed for 9.9 years, and 54.2% male. Mean HbA1c levels were 8.1%, (65mmol/mol) at enrolment, with 36.4% being in control (HbA1c<7%, (53mmol/mol). Patients with HbA1c<7%, (53mmol/mol) were significantly older, diagnosed at older age, and had lower triglyceride levels. Almost 50% reported hypoglycemic episodes that were mostly mild, and with women more likely to report them. The large majority (86%) were on combined metformin and sulfonylureas, most commonly Glibenclamide (48.6%). Patients on combined therapy were significantly younger and more likely to have uncontrolled diabetes. CONCLUSIONS: This study demonstrated that out of a sample of 397 patients with T2DM treated with sulfonylureas alone or in combination with metformin in Argentina, around 50% of them reported symptoms of hypoglycemia induced by sulfonylureas, and one third of them achieved target HbA1c<7% levels.

Implementation and Assessment of an Ambulatory Prescribing Guidance Tool to Improve Patient Safety in the Geriatric Population.

OBJECTIVE: The purpose of this study was to assess the effects of a clinical decision support (CDS) tool aimed at decreasing the prescribing of glyburide, a potentially inappropriate medication (PIM), in patients 65 years of age and older. DESIGN: Quasi-experimental, pre-post intervention study. SETTING: Ambulatory care clinics of an academic medical center. INTERVENTION: The tool appeared to providers when entering new prescriptions or refills for glyburide. Glimepiride, which is a more appropriate sulfonylurea, was suggested as an alternative at order entry. MAIN OUTCOME MEASURE(S): The primary outcome was the prescribing of glyburide orders, measured as a percentage of the total oral diabetic medications ordered in patients 65 years of age and older, during the study period. The secondary outcome measured was the response to the CDS tool (accept versus reject). RESULTS: The CDS tool alerted providers 101 times during the 90-day postimplementation period. When the tool appeared, patients were transitioned off of glyburide 17.8% of the time. Subanalysis found that when physicians viewed the alert, patients were transitioned off of glyburide 46.2% of the time. As a percentage of the total number of oral diabetic medications, glyburide prescribing was significantly decreased from pre- to postimplementation study period (3.3% vs. 1.2%; P < 0.001). CONCLUSIONS: A CDS tool can be used in the ambulatory care setting to influence prescribing and provide a safer alternative medication. Additional information is needed to test the use of a CDS tool in conjunction with education to ensure providers are comfortable with and understand implications of a CDS tool.

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.

Glycaemic control and cost analysis when changing from gliclazide co-administered with metformin to pre-combined glibenclamide-metformin tablets in type 2 diabetes mellitus.

Type-2 diabetes mellitus (T2DM) patients who were on gliclazide co-administered with metformin were changed to pre-combined glibenclamide-metformin tablets in the Endocrine Clinic, Penang Hospital. We conducted a retrospective study to evaluate the differences in glycaemic control and treatment cost following the change. Eighty patients (60% females) with a mean age of 55 years old were studied. Mean glycosylated haemoglobin (HbAlc) reduction was -0.92% (p<0.01) and -0.83% (p<0.01) after three and six months respectively. Patients with baseline HbA1c > or =8% had greater reduction in mean HbA1c (-1.36%) after six months. The treatment cost per month was reduced by 45% at 3 months (p<0.01)) and 44% at 6 months (p<0.01). The change to pre-combined glibenclamide-metformin tablets resulted in significant improvement in glycaemia and reduction in treatment cost

Coadministration of pioglitazone or glyburide and alogliptin: pharmacokinetic drug interaction assessment in healthy participants.

Alogliptin is a dipeptidyl peptidase-4 inhibitor under investigation for treatment of patients with type 2 diabetes mellitus. Potential pharmacokinetic (PK) drug-drug interactions of alogliptin with pioglitazone or glyburide were evaluated in healthy adults. In a randomized, 6-sequence, 3-period crossover study (study I), participants (n = 30 enrolled; n = 27 completed) received monotherapy with pioglitazone 45 mg once daily (qd), alogliptin 25 mg qd, or coadministration of the 2 agents. The 12-day treatment periods were separated by a > or =10-day washout interval. In a nonrandomized, single-sequence study (study II), participants (n = 24 completed) received a single 5-mg dose of the sulfonylurea glyburide, alone and after 8 days of dosing with alogliptin 25 mg qd. Sequential samples of blood (both studies) and urine (first study) were obtained for determination of PK parameters for alogliptin, pioglitazone, their metabolites, and glyburide. Minor changes in PK parameters between combination therapy and monotherapy were obtained but not judged to be clinically relevant. The combination treatments were well tolerated, although glyburide frequently caused hypoglycemia. Most adverse events were of mild intensity and occurred with a frequency similar to that with monotherapy. It is concluded that pioglitazone or glyburide can be administered with alogliptin without dose adjustment to any component of the combination therapy.

Willingness to pay for inhaled insulin: a contingent valuation approach.

PURPOSE: To determine the willingness to pay (WTP) of patients with diabetes mellitus for inhaled insulin. METHODS: A contingent valuation survey was administered to 96 diabetic outpatients at St. Michael's Hospital, Toronto, Canada. Standardised information about inhaled insulin and subcutaneous rapid-acting insulin was provided via video. Participants' WTP for their preferred product was elicited in Canadian dollars (Can dollars) using a 'payment-scale' method. RESULTS: The mean age of participants was 51.8 years (SD 13.4). Seventy-seven patients had type 2 and 19 had type 1 diabetes. Significantly more participants preferred inhaled insulin over subcutaneous insulin (85 vs 11; p < 0.01). Mean monthly WTP for inhaled insulin (153.70 Can dollars, SD 99.90) was significantly more than the typical 50 Can dollars per month for subcutaneous insulin (p < 0.01). Significantly more participants with type 2 diabetes using oral drugs than those with type 1 diabetes and using insulin preferred inhaled insulin (98.5% vs 69%, p < 0.001). Diabetic patients who did not use insulin were willing to pay significantly more than were insulin users (p < 0.001). Multiple regression analysis showed that income was significantly associated with WTP for inhaled insulin. CONCLUSION: Diabetic patients, particularly those who are not using insulin, indicated that they would prefer inhaled insulin over insulin injection and would be willing to pay a substantial amount per month to use it. An economic evaluation of inhaled insulin would provide important information to healthcare policy decision makers and private payers about its economic value.

[Use of oral lipid-lowering drugs in patients with type-2 diabetes mellitus]. / Uso de hipoglucemiantes orales en pacientes con diabetes mellitus tipo 2.

OBJECTIVE: To investigate whether oral lipid-lowering drugs (OLL) are used in line with the Mexican Official Regulation (NOM)-015-SSA-1994 for preventing, treating, and monitoring diabetes mellitus 2 (DM2) patients. DESIGN: Observational, descriptive study. SETTING: Primary care. Unit of Family Medicine (UMF) No. 80 of the Mexican Social Security Institute. PARTICIPANTS: 332 patients diagnosed with DM2, taking pharmacological treatment and with recent laboratory studies. MAIN MEASUREMENTS: Age, body mass index (BMI), years of evolution of diabetes, type of medication and OLL dose, time taking OLL, glucose, total cholesterol, and triglycerides. The patients were divided into 2 groups on the basis of the BMI: group 1 with BMI<27; group 2 >=27. In addition, each group was sub-divided by the type of medication. RESULTS: Glibenclamide was the OLL most prescribed (52% in both groups). In group 1 there were significant intra-group differences between patient's age and years of evolution of diabetes, whereas in group 2 only the metformin sub-group was associated with lower glucose concentrations and higher concentrations of triglycerides than in the other sub-groups. All patients had deficient glucaemia control. CONCLUSIONS: The data show that OLL treatment for DM2 patients varied from the NOM. Unification of criteria in primary care for the prescription pattern and the use of OLL for better metabolic control of this kind of patient were recommended.

A comparison of costs for four oral antidiabetic regimens within a managed care population.

A retrospective database analysis compared costs among patients with type 2 diabetes receiving four antidiabetic regimens: (1) repaglinide monotherapy, (2) metformin monotherapy, (3) repaglinide and metformin in combination, or (4) metformin and glyburide in combination. Pharmacy, medical, and total costs were measured for each cohort over a nine-month period. Although not statistically significant, total adjusted costs were lowest for the repaglinide-metformin combination ($8,924), followed by metformin monotherapy ($9,448), metformin and glyburide ($9,576), and repaglinide monotherapy ($11,910). These results must be confirmed in larger populations, but they imply that differences in pharmacy costs of repaglinide-metformin therapy are offset by measurable medical cost savings.

Glyburide/metformin tablets: a new therapeutic option for the management of Type 2 diabetes.

Oral antidiabetic combination therapy is a proven means of establishing glycaemic control in the hyperglycaemic, Type 2 diabetic patient, but co-administering two oral antidiabetic agents separately may hinder compliance with therapy. A new single-tablet of glyburide/metformin combination therapy (Glucovance), Bristol-Myers Squibb, Inc.) has recently been developed, which addresses the primary defects of Type 2 diabetes: beta-cell dysfunction and insulin resistance. The glyburide/metformin tablet, taken with meals, is designed to optimise the absorption of glyburide and to address the postprandial glucose rise. Glyburide/metformin tablets are more effective in controlling fasting and postprandial glycaemia than its component monotherapies, at lower doses of metformin and glyburide compared with monotherapy because of the synergy between its glyburide and metformin components. Moreover, a double-blind study showed that glyburide/metformin tablets are more effective than a free combination of glyburide co-administered with metformin in controlling postprandial glucose. Retrospective analyses suggested that glyburide/metformin tablets control glycated haemoglobin (A1C) more effectively than a free combination of glyburide co-administered with metformin, at lower mean doses of glyburide and metformin. The incidence of side effects is lower than separate component therapy for any given A1C. Glyburide/metformin tablets are an effective option for optimising the control of blood glucose in Type 2 diabetic patients and appear to enhance adherence to therapy.

Adherence to oral antidiabetic therapy in a managed care organization: a comparison of monotherapy, combination therapy, and fixed-dose combination therapy.

BACKGROUND: Although medication adherence is one of the most important aspects of the management of diabetes mellitus, low rates of adherence have been documented. OBJECTIVE: This study sought to examine medication adherence among patients with diabetes mellitus in a managed care organization who were receiving antidiabetic monotherapy (metformin or glyburide), combination therapy (metformin and glyburide), or fixed-dose combination therapy (glyburide/metformin). METHODS: Medication adherence was evaluated through a retrospective database analysis of pharmacy claims. The adherence rate was defined as the sum of the days' supply of oral antidiabetic medication obtained by the patient during the follow-up period divided by the total number of days in the designated follow-up period (180 days). Health plan members were included in the analysis if they had an index pharmacy claim for an oral antidiabetic medication between August 1 and December 31, 2000, were continuously enrolled in the health plan, and were aged > or =18 years. A 6-month pre-index period was used to classify patients as newly treated or previously treated. Patients were grouped according to their medication-use patterns. RESULTS: After adjustment for potential confounding factors, including overall medication burden at index, there were no significant differences in adherence rates among 6502 newly treated patients receiving monotherapy, combination therapy, or fixed-dose combination therapy. Among the 1815 previously treated patients receiving glyburide or metformin monotherapy who required the addition of the alternative agent, resulting in combination therapy, adherence rates were significantly lower (54.0%; 95% CI, 0.52-0.55) than in the 105 patients receiving monotherapy who were switched to fixed-dose combination therapy (77.0%; 95% CI, 0.72-0.82). The 59 previously treated patients receiving combination therapy who were switched to fixed-dose combination therapy had a significant improvement in adherence after the switch (71.0% vs 87.0%; P < 0.001). CONCLUSIONS: In a managed care organization, previously treated patients receiving monotherapy with an oral antidiabetic medication who required additional therapy exhibited significantly greater adherence when they were switched to fixed-dose combination therapy compared with combination therapy. Patients receiving combination therapy who were switched to fixed-dose combination therapy exhibited significantly greater adherence after the switch.

[Free radical scavenging activity of sulfonylureas: a clinical assessment of the effectiveness of gliclazide]. / Sposobnost' proizvodnykh sul'fanilmocheviny neitralizovat' sposobnye radikali: klinicheskaia otsenka éffektivnosti gliklazida.

In long-term clinical studies the beneficial effects of gliclazide on platelets have been related to a reduction in oxidative stress. This property is because of gliclazide's free radical scavenging ability that relates to the unique amino azabicyclo-octane ring, which is grafted on to the sulfonylurea. During a blinded clinical trial, the possible effects of gliclazide were assessed in 30 non-insulin-dependent diabetic patients. All patients had been treated for diabetes for more than 2 years (mean 8 years) and had been established on glibenclamide for over 2 years with or without adjunctive metformin therapy. Patients were studied for 6 months and randomized to continue either their present dose of glibenclamide or to be converted to an equipotent dose of gliclazide. Measurements were taken of hemostatic variables, the oxidative status of the plasma, and the redox status, both extracellularly as plasma albuminthiols (PSH) and lipid peroxides, and intracellularly as red blood cell superoxide dismutase activity (SOD). At 3 months, diabetic control was unaltered, but there were significant improvements in the oxidative status of the gliclazide-treated patients. Lipid peroxides decreased (8.3 +/- 1.1 to 7.0 +/- 0.06 mumol/l, P < 0.01) and red blood cell SOD increased (135 +/- 21 to 152 +/- 36 micrograms/ml, P < 0.05). PSH levels were unaltered at 453 +/- 38 mumol/l, whereas they had decreased significantly in the glibenclamide patients (414 +/- 34 mumol/l, P < 0.05), resulting in a significant difference between the 2 treatment groups (P < 0.004). Platelet reactivity to collagen also improved in the gliclazide-treated patients, decreasing from 65.1% +/- 14% to 50.8 +/- 24% (p < 0.01). The reactivity of the platelets remained unaltered in the glibenclamide patients. At 6 months, the significant differences between the 2 treatment groups remained. Hence, gliclazide was shown in a clinical study to have free radical scavenging activity independent of glycemic control.

Polypharmacy: a case report and new protocol for management.

BACKGROUND: Polypharmacy is an important issue in primary care, yet few data are available concerning its prevalence, complications, and management in clinical medicine. The following case illustrates the clinical perils of polypharmacy and serves as a point for critical discussion. METHODS: MEDLINE was searched, using the key word "polypharmacy," from 1994 to the present. A case report of polypharmacy is described, and a novel protocol for the management of polypharmacy is proposed. RESULTS: Polypharmacy can lead to unnecessary expense, wasted time, and embarrassment on the part of the patient and confusion and mismanagement on the part of the physician. The literature reveals controversy surrounding the definition of polypharmacy and reflects the considerable morbidity and expense associated with polypharmacy. Finally, the SAIL protocol shows that physicians need to keep in mind simplicity, adverse effects, indications, and a precise list of all medications to manage appropriately a patient's drug regimen. CONCLUSIONS: Polypharmacy is associated with morbidity and iatrogenic complications. The SAIL protocol can be a useful tool in the management of this entity. More research needs to be done on the prevalence, complications, and management of polypharmacy.

Evaluation of glipizide and glyburide in a health maintenance organization.

OBJECTIVE: To determine if there was a difference in the long-term glycemic control, average daily dose, and cost of therapy in patients with noninsulin-dependent diabetes mellitus (NIDDM) treated with glyburide and glipizide in a health maintenance organization (HMO). DESIGN: Retrospective evaluation of medical and pharmacy records. SETTING: Multispecialty group practice HMO. PATIENTS: 140 NIDDM patients being treated with either glyburide (n = 70) or glipizide (n = 70) were randomly selected from the populations of patients receiving either drug using computerized pharmacy records. MAIN OUTCOME MEASURE: Mean daily doses and blood glucose measurements (fasting blood glucose, random blood glucose, hemoglobin A1C) were stratified in 3-month periods from the time the drug therapy was started or the patient first presented to the clinic for a total of 18 months. Long-term glycemic control was defined as fasting blood glucose less than 8.33 mmol/L (150 mg/dL). RESULTS: The groups were comparable with regard to age (53.4 y glyburide, 56.7 y glipizide), gender (43 M:27 F glyburide, 47 M:23 F glipizide), race (38 W/16 B/16 H glyburide, 45 W/16 B/9 H glipizide), concurrent medical conditions, adverse effects, and compliance. Long-term glycemic control was similar in both groups. Although the number of subjects who were controlled (by definition) tended to be greater in the glyburide group, no clinical or statistical difference was found. There was no statistical difference in mean daily dose between the ethnic groups, but the small numbers preclude further analysis. The glipizide group had a larger percentage increase in dose within the first year than did the glyburide group; however, the percentage increase from the 3-month dose was similar after 18 months (22.7 percent glyburide, 27.5 percent glipizide.) Average daily cost of therapy, based on mean daily dose, was slightly lower for glyburide-treated patients. CONCLUSIONS: If glycemic control is similar with glyburide and glipizide, as seen in this study, economic considerations regarding choice of therapy and formulary inclusion may be appropriate.

Conversion from glipizide to glyburide: a prospective cost-impact survey.

Despite extensive clinical experience with second-generation oral hypoglycemic agents, the relative dosing equivalence of glyburide and glipizide remains controversial. A prospective survey was conducted to determine the feasibility and cost of converting noninsulin-dependent diabetic patients from glipizide to glyburide. A total of 211 patients previously stabilized on glipizide were converted to glyburide and returned to their respective clinics at least once during the following six months. The mean daily dose (+/- SD) of glipizide before conversion was 18.7 +/- 12.32 mg; the mean daily dose of glyburide after seven months was 9.9 +/- 6.52 mg (P less than 0.001, paired t test). Glyburide was well tolerated. The conversion program appeared to be successful and resulted in a 47% reduction in the mean daily dose after conversion from glipizide to glyburide, which, in turn, conferred a 43% savings in the projected yearly expenditures for second-generation oral hypoglycemics.