Modified Release Research Articles

PQRI Workshop Report: Application of IVIVC in Formulation Development

This article summarizes the proceeding of the September 2012 Workshop on Application of In vitro–In vivo correlation (IVIVC) in Formulation Development. The workshop brought together international experts with the goal of establishing common concepts that could be utilized to facilitate the development and validation of IVIVCs in the registration of and post-approval changes to oral solid dosage forms. The workshop was organized by the Product Quality Research Institute (PQRI) and cosponsored by AAPS, FDA, FIP, and USP. Open access of this information is available to all interested parties. INTRODUCTION IVIVC is an important concept and a tool in the development and evaluation of pharmaceutical dosage forms. A properly conducted IVIVC provides assurance of the robustness of a dosage form and provides justification of manufacturing changes during drug product development. A filed IVIVC can accelerate internal decision making of proposed SUPAC changes by providing linkage back to preapproval formulations. As such, a well-conducted IVIVC may have substantial value to pharmaceutical manufacturers, regulatory bodies, and ultimately, consumers of the product. Early history (1982–1992) suggests that few IVIVCs were filed. Since the advent of the FDA guidance (1) approximately fifteen years ago, the number of NDAs containing IVIVC studies has increased, and it is anticipated that exploration of IVIVCs and IVIVRs will continue to grow. FDA scientists confirmed that most IVIVCs filed are for modified-release (MR) products with fewer for immediaterelease (IR) dosage forms. Many of the latter were identified as insufficient and not approvable. Early statistics immediately following the issuance of the FDA Guidance *Corresponding author. e-mail: vanbuskirk@drugdevconsult.com dx.doi.org/10.14227/DT210214P51

The Relative and Combined Ability of High-Sensitivity Cardiac Troponin T and N-Terminal Pro-B-Type Natriuretic Peptide to Predict Cardiovascular Events and Death in Patients With Type 2 Diabetes

OBJECTIVE Current methods of risk stratification in patients with type 2 diabetes are suboptimal. The current study assesses the ability of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) to improve the prediction of cardiovascular events and death in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS A nested case-cohort study was performed in 3,862 patients who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. RESULTS Seven hundred nine (18%) patients experienced a major cardiovascular event (composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) and 706 (18%) died during a median of 5 years of follow-up. In Cox regression models, adjusting for all established risk predictors, the hazard ratio for cardiovascular events for NT-proBNP was 1.95 per 1 SD increase (95% CI 1.72, 2.20) and the hazard ratio for hs-cTnT was 1.50 per 1 SD increase (95% CI 1.36, 1.65). The hazard ratios for death were 1.97 (95% CI 1.73, 2.24) and 1.52 (95% CI 1.37, 1.67), respectively. The addition of either marker improved 5-year risk classification for cardiovascular events (net reclassification index in continuous model, 39% for NT-proBNP and 46% for hs-cTnT). Likewise, both markers greatly improved the accuracy with which the 5-year risk of death was predicted. The combination of both markers provided optimal risk discrimination. CONCLUSIONS NT-proBNP and hs-cTnT appear to greatly improve the accuracy with which the risk of cardiovascular events or death can be estimated in patients with type 2 diabetes.

Modified-Release Prednisone: in Patients with Rheumatoid Arthritis

Prednisone is a well-established treatment option in rheumatoid arthritis. Low-dose glucocorticoid therapy alleviates disease signs and symptoms, is better tolerated than high-dose therapy, and its addition to disease-modifying anti-rheumatic drugs (DMARDs) inhibits radiographic disease progression. A low-dose, modified-release (MR) formulation of prednisone, administered in the evening, was developed to counter the circadian rise in pro-inflammatory cytokine levels that contributes to disease activity. In a 12-week, randomized trial (CAPRA-2) in adult patients with rheumatoid arthritis who were receiving stable DMARD therapy, the addition of MR prednisone reduced disease signs and symptoms by ≥20% according to the American College of Rheumatology criteria (in 48% of patients vs. 29% with placebo; p<0.002 [primary endpoint]). In another 12-week trial (CAPRA-1), addition of evening MR prednisone to stable DMARD therapy reduced the mean duration of morning stiffness to a greater extent than addition of morning immediate-release (IR) prednisone (22.7 vs. 0.4%; p=0.045 [primary endpoint]). The improvement in morning stiffness with MR prednisone was maintained for 9-12months during the open-label extension of CAPRA-1. These findings were supported by data from observational studies in various adult populations with rheumatoid arthritis. Treatment with evening MR prednisone for up to 12months was generally well tolerated, with an overall similar tolerability profile compared with evening placebo or morning IR prednisone, and no new safety concerns. MR prednisone was estimated to be cost effective relative to IR prednisone in patients with rheumatoid arthritis in a UK pharmacoeconomic model.

Stability of Dexlansoprazole MR Granules in Soft Foods and Liquids Appropriate for Alternative Methods of Administration

Purpose: The proton pump inhibitor dexlansoprazole (DEX) is a pH-dependent modified release (MR) formulation consisting of 2 types of granules within a single capsule. DEX MR is approved for use in adults for treatment of heartburn associated with symptomatic nonerosive gastroesophageal reflux disease (GERD), healing of erosive esophagitis (EE), maintenance of healed EE and relief of heartburn. The option to administer DEX MR granules mixed with liquids or soft foods is desirable for patients unable to take capsules. The objectives were to assess the in vitro stability of DEX MR granules when mixed with liquids or soft foods and assess the bioavailability (BA) of DEX MR granules mixed with applesauce or water. Methods: The stability of DEX MR granules in soft foods and liquids was determined by an in use stability study. DEX MR capsules were opened and granules were sprinkled on foods or mixed with liquids. After exposing the granules to foods or liquids under ambient conditions, the granules were analyzed for assay and dissolution to determine the DEX potency and the granule enteric coating integrity. Two phase 1, randomized, single-dose, crossover studies were conducted in healthy subjects 18-55 years old. In Study 1, subjects received a single oral dose of DEX MR 90 mg as a capsule or as granules sprinkled on applesauce. In Study 2, subjects received a single oral dose of DEX MR 60 mg as a capsule or an aqueous mixture of granules administered via oral syringe or NG tube. Blood samples for determination of DEX in plasma were collected for 24 hours post-dose. Analyses of variance models were performed, and bioequivalence (BE) between an administration option and the capsule was declared if 90% confidence intervals (CIs) of central value ratios between two regimens for maximum plasma concentration (Cmax) and area under the curve (AUC) were contained within the 0.80-1.25 BE limits. Results: Stability of DEX MR granules was established for at least 1 hour in liquids and soft foods ranging in pH from acidic to near neutral. DEX potency in the granules was not affected by exposing to the soft foods or liquids. The granule enteric coating integrity was well maintained. The 90% CIs for the relative BA of DEX MR 90 mg from granules sprinkled on applesauce to that of the capsule, and the 90% CIs for the relative BA of DEX MR 60 mg from an aqueous mixture of granules to that of the capsule for Cmax and AUCs were within the 0.80-1.25 BE range. Conclusion: Stability of DEX MR granules for 1 hour in liquids and soft foods was established. Administration of DEX MR granules mixed with applesauce or water was BE to the intact capsule. DEX MR granules in liquids or soft foods is expected to provide BA similar to the intact capsule. Disclosure - Michael Kukulka - Employee: Takeda Pharmaceuticals America, Inc. Haiyan Grady - Employee: Takeda Pharmaceuticals America, Inc. Richard Czerniak - Employee: Takeda Pharmaceuticals America, Inc. Jing-tau Wu - Employee: Takeda Pharmaceuticals America, Inc. Claudia Perez - Employee: Takeda Pharmaceuticals America, Inc.

Cost-effectiveness of modified-release prednisone in the treatment of moderate to severe rheumatoid arthritis with morning stiffness based on directly elicited public preference values

BackgroundAssessing the cost-effectiveness of treatments in rheumatoid arthritis (RA) is of growing importance due to the chronic nature of the disease, rising treatment costs, and budget-constrained health care systems. This analysis assesses the cost-effectiveness of modified-release (MR) prednisone compared with immediate-release (IR) prednisone for the treatment of morning stiffness due to RA.MethodsA health state transition model was used to categorize RA patients into four health states, defined by duration of morning stiffness. The model applied a 1-year time horizon and adopted a UK National Health Service (NHS) perspective. Health benefits were measured in quality-adjusted life years (QALYs) and the final output was the incremental cost-effectiveness ratio (ICER). Efficacy data were derived from the CAPRA-1 (Circadian Administration of Prednisone in Rheumatoid Arthritis) study, drug costs from the British National Formulary (BNF), and utility data from a direct elicitation time-trade-off (TTO) study in the general population. Sensitivity analyses were conducted.ResultsMean treatment costs per patient were higher for MR-prednisone (£649.70) than for IR-prednisone (£46.54) for the duration of the model. However, the model generated an incremental QALY of 0.044 in favor of MR-prednisone which resulted in an ICER of £13,577. Deterministic sensitivity analyses did not lead to significant changes in the ICER. Probabilistic sensitivity analysis reported that MR-prednisone had an 84% probability of being cost-effective at a willingness-to-pay threshold of £30,000 per QALY. The model only considers drug costs and there was a lack of comparative long-term data for IR-prednisone. Furthermore, utility benefits were not captured in the clinical setting.ConclusionThis analysis demonstrates that, based on the CAPRA-1 trial and directly elicited public preference values, MR-prednisone is a cost-effective treatment option when compared with IR-prednisone for RA patients with morning stiffness over one year, according to commonly applied UK thresholds (£20,000–£30,000 per QALY). Further research into the costs of morning stiffness in RA is required.

Adsorption and Release of Active Species into and from Multifunctional Ionic Microgel Particles

We synthesize monodisperse ionic microgel particles which undergo a large change in volume in response to environmental stimuli such as pH and temperature. In addition, the study elucidates the effective uptake and release of rheology modifiers from these microgel particles to alter the bulk viscosity of a surrounding fluid. Moreover, we found that the prepared ionic microgel particles can demonstrate abilities to adsorb and repel iron oxide nanoparticles (Fe3O4-NPs) upon pH variation. The extent of the loading of Fe3O4-NPs within the colloidal particles and morphology can be manipulated by tunable interactions between the Fe3O4-NPs and ionic microgel particles.

Effects of Visit-to-Visit Variability in Systolic Blood Pressure on Macrovascular and Microvascular Complications in Patients With Type 2 Diabetes Mellitus

Recent evidence suggests that visit-to-visit variability in systolic blood pressure (SBP) and maximum SBP are predictors of cardiovascular disease. However, it remains uncertain whether these parameters predict the risks of macrovascular and microvascular complications in patients with type 2 diabetes mellitus. The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) was a factorial randomized controlled trial of blood pressure lowering and blood glucose control in patients with type 2 diabetes mellitus. The present analysis included 8811 patients without major macrovascular and microvascular events or death during the first 24 months after randomization. SBP variability (defined as standard deviation) and maximum SBP were determined during the first 24 months after randomization. During a median 2.4 years of follow-up from the 24-month visit, 407 major macrovascular (myocardial infarction, stroke, or cardiovascular death) and 476 microvascular (new or worsening nephropathy or retinopathy) events were observed. The association of major macrovascular and microvascular events with SBP variability was continuous even after adjustment for mean SBP and other confounding factors (both P<0.05 for trend). Hazard ratios (95% confidence intervals) for the highest tenth of SBP variability were 1.54 (0.99-2.39) for macrovascular events and 1.84 (1.19-2.84) for microvascular events in comparison with the lowest tenth. For maximum SBP, hazard ratios (95% confidence intervals) for the highest tenth were 3.64 (1.73-7.66) and 2.18 (1.04-4.58), respectively. Visit-to-visit variability in SBP and maximum SBP were independent risk factors for macrovascular and microvascular complications in type 2 diabetes mellitus. http://www.clinicaltrials.gov.

High sensitivity cardiac troponin T and N-terminal pro-BNP predict cardiovascular events and death in patients with type 2 diabetes mellitus

Purpose: Current methods of risk-stratification in patients with type 2 diabetes mellitus (T2DM) are suboptimal. The current study assesses the ability of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high sensitivity cardiac troponin T (hs-cTnT) to improve the prediction of cardiovascular events and death in patients with T2DM. Methods: A nested case-cohort study was performed in patients with T2DM who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Results: In 3,862 patients with available samples, 709 (18%) experienced a major cardiovascular event (composite of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke) and 706 (18%) died during a median of 5 years follow-up. In Cox regression models, adjusting for all established risk predictors, the hazard ratio [HR] for cardiovascular events for NT-proBNP was 1.94 per 1 standard deviation [SD] increase (95% confidence interval [CI] 1.72-2.19) and the HR for hs-cTnT was 1.52 per 1 SD increase (95% CI 1.38-1.67). The HRs for death were 1.97 (95% CI 1.74-2.23) and 1.54 (95% CI 1.39-1.70), respectively. The addition of either marker improved 5-year risk classification for cardiovascular events (net reclassification improvement in continuous model, 39% for NT-proBNP and 45% for hs-cTnT). Likewise, both markers greatly improved the accuracy with which the 5-year risk of death was predicted (table). The combination of both markers provided the best risk discrimination. View this table: Table 1. NT-proBNP and/or cTnT and 5 yr mortality Conclusion: NT-proBNP and hs-cTnT appear to remarkably improve the accuracy with which the risk of cardiovascular events or death can be estimated in patients with T2DM.

Inflammatory markers and the risk of vascular complications and mortality in type 2 diabetes mellitus

Purpose: There are few data assessing the relationship between circulating levels of C-reactive protein (CRP), fibrinogen, and interleukin-6 (IL-6) and the risk of vascular complications in individuals with type 2 diabetes mellitus (T2DM). We studied the associations between these inflammatory markers and the risk of major CV events (CV death, myocardial infarction or stroke), microvascular complications and death in patients T2DM who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Methods: Baseline high sensitivity CRP, fibrinogen and IL-6 levels were determined in a case-cohort study (n=3,865), nested within the ADVANCE trial. Results: During 5 years of follow-up, 709 patients suffered a major CV event, 439 a microvascular complication and 706 died. All 3 markers were associated with an increased risk of CV events and death in analyses adjusting for age, sex and treatment groups. After further adjustment, for other potential confounders and for each other, only IL-6 was an independent predictor of these outcomes (hazard ratio [HR] for CV events 1.37 per 1 standard deviation [SD] increase in log IL-6, 95% confidence interval [CI] 1.24-1.51; HR for death 1.35, 95% CI 1.23-1.49). This increased hazard was seen in patients with and without prior CV disease (figure, HR per 1 SD increase in log IL-6). IL-6 significantly improved the prediction of CV events and death using reclassification statistics (net reclassification improvement in continuous models 23% for CV events and 30% for death). After adjustment, none of the markers predicted microvascular complications. ![Figure][1] Death stratified by prior CV disease Conclusions: IL-6, but not CRP or fibrinogen, levels add significantly to the prediction of CV events and mortality in individuals with T2DM. [1]: pending:yes

Computer Modeling of Diabetes and Its Complications: A Report on the Fifth Mount Hood Challenge Meeting

ObjectivesThe Mount Hood Challenge meetings provide a forum for computer modelers of diabetes to discuss and compare models, to assess predictions against data from clinical trials and other studies, and to identify key future developments in the field. This article reports the proceedings of the Fifth Mount Hood Challenge in 2010. MethodsEight modeling groups participated. Each group was given four modeling challenges to perform (in type 2 diabetes): to simulate a trial of a lipid-lowering intervention (The Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus [ASPEN]), to simulate a trial of a blood glucose–lowering intervention (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation [ADVANCE]), to simulate a trial of a blood pressure–lowering intervention (Cardiovascular Risk in Diabetes [ACCORD]), and (optional) to simulate a second trial of blood glucose–lowering therapy (ACCORD). Model outcomes for each challenge were compared with the published findings of the respective trials. ResultsThe results of the models varied from each other and, in some cases, from the published trial data in important ways. In general, the models performed well in terms of predicting the relative benefit of interventions, but performed less well in terms of quantifying the absolute risk of complications in patients with type 2 diabetes. Methodological challenges were highlighted including matching trial end-point definitions, the importance of assumptions concerning the progression of risk factors over time, and accurately matching the patient characteristics from each trial. ConclusionsThe Fifth Mount Hood Challenge allowed modelers, through systematic comparison and validation exercises, to identify important differences between models, address key methodological challenges, and discuss avenues of research to improve future diabetes models.

Bioequivalence of Trimetazidine Modified Release Tablet Formulations Assessed in Indonesian Subjects

This study was conducted in order to compare the bioavailability of two modified release tablets containing 35 mg of trimetazidine. Twenty-four subjects were enrolled in a single center, randomized, single dose, open label, two-way crossover study with a one-week washout period. Plasma samples were collected up 48 hours following drug administration and trimetazidine was determined by liquid chromatography-tandem mass spectrometry (LC- MS/MS) method with turboionspray mode. Pharmacokinetic parameters used for bioequivalence assessment were AUC 0-t , AUC 0- ∞ and C max . The 90% confidence intervals obtained by analysis of variance for AUC 0-t , AUC 0- ∞ and C max were 94.89-105.15%, 94.85-105.23%, 93.31-107.36%, respectively. These results were all within the range of 80.00-125.00%. Bioequivalence between formulations was concluded both in terms of rate and extent of absorption.

Targeting risk factors: a feasible way for prevention of vascular complications in type 2 diabetes mellitus

The article addresses challenges in the prevention of microvascular complications in type 2 diabetes mellitus (T2DM) and discusses necessity of multifactorial approach to management of these conditions. We present results of a large-scale ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial that elucidates the combined influence of antihypertensive and of intensive glucose-lowering therapy on the risk of development of micro- and macrovascular complications of T2DM

In Vitro-In Vivo Correlation Evaluation of Generic Alfuzosin Modified Release Tablets

Alfuzosin, a selective alpha-1a antagonistis is the most recently approved AARAS, with limited cardiac toxicity and exclusively used for lower urinary tract syndromes (LUTS). In order to reduce pill burden and better patient compliance modified release (MR) formulations have been developed. Alfuzosin MR tablet was developed by the use of hot-melt granulation techniques using mono- and diglycerides as rate controlling membranes to minimize health care cost and uses of costly excipients. The other purpose of the study was to evaluate in vitro-in vivo performance of the scale up batch in healthy human subjects for commercialization. The blend uniformity (mean ± RSD%), assay, cumulative percent dissolution at 24 h, hardness, and friability of the biobatch were 100.2 ± 0.05%, 100.43 ± 0.023%, 93.98%, 4.5 kg, 5 min, and 0.08%, respectively. The in vivo pharmacokinetic parameters under fasting conditions between test and reference formulations (Uroxatral 10 mg extended release tablets) were comparable. The 90% CI, geometric mean ratio (%) and power of C max, AUCT, and AUCI of the fasting study for the test and reference formulation were 99.03% to 122.78%, 109%, 0.998; 92.94% to 116.71%, 104%, 1; 98.17% to 124.01%, 110% 1, respectively. The scale up biobatch showed negligible difference in in vitro properties with respect to the pilot batch. The formulation developed with these agents was safe to use as there were no serious adverse events developed during the conduction of the clinical trial on the healthy subjects. Furthermore, the developed formulation was bioequivalent with respect to rate and extends of absorption to the reference formulation.

Comparative Pharmacokinetics Studies of Immediate- and Modified-Release Formulations of Glipizide in Pigs and Dogs

The utility of pigs as preclinical animals for pharmaceutical development was assessed by evaluating the pharmacokinetics and pharmacodynamics of glipizide (Glucotrol®) following oral administration of immediate-release (IR) and modified-release (MR) formulations. Doses of 10 and 30 mg were administered to six male pigs in a crossover design. Blood samples were collected at selected time-points up to 48 h after dose. Relative to the IR formulation, the time to reach the maximum concentration (t(max) ) was delayed with the MR formulation from 1.3 to 8.7 h with the 10 mg dose and to 6.2 h with the 30 mg dose. The relative bioavailability (BA) was approximately 92% at 10 mg and 79% at 30 mg dose. The area under the curve of the plasma concentration versus time curve (AUC) increased nearly proportionally with the dose. Interanimal coefficient of variation (CV) in AUC ranged from approximately 40% to 60%. Blood glucose results suggest that pigs demonstrate formulation-dependent response to glipizide. Compared with the pigs, the 10 mg MR formulation in dogs showed a higher AUC CV of approximately 80%, a t(max) of 5.5 h, and a lower relative BA of 18%. These data indicate that the MR formulation performed less consistently in dogs as compared with humans, whereas the porcine absorption kinetics and BA were consistent with published clinical data.

Drug Delivery Systems with Modified Release for Systemic and Biophase Bioavailability

This review describes the most important new generations of pharmaceutical systems: medicines with extended release, controlled release pharmaceutical systems, pharmaceutical systems for the targeted delivery of drug substances. The latest advances and approaches for delivering small molecular weight drugs and other biologically active agents such as proteins and nucleic acids require novel delivery technologies, the success of a drug being many times dependent on the delivery method. All these dosage forms are qualitatively superior to medicines with immediate release, in that they ensure optimal drug concentrations depending on specific demands of different disease particularities of the body. Drug delivery of these pharmaceutical formulations has the benefit of improving product efficacy and safety, as well as patient convenience and compliance. This paper describes the biopharmaceutical, pharmacokinetic, pharmacologic and technological principles in the design of drug delivery systems with modified release as well as the formulation criteria of prolonged and controlled release drug delivery systems. The paper presents pharmaceutical prolonged and controlled release dosage forms intended for different routes of administration: oral, ocular, transdermal, parenteral, pulmonary, mucoadhesive, but also orally fast dissolving tablets, gastroretentive drug delivery systems, colon-specific drug delivery systems, pulsatile drug delivery systems and carrier or ligand mediated transport for site specific or receptor drug targeting. Specific technologies are given on the dosage forms with modified release as well as examples of marketed products, and current research in these areas.

Food Effect on Bioavailability of Modified‐Release Trimetazidine Tablets

This study aimed to investigate a food effect on the bio-availability of modified-release (MR) trimetazidine tablets in 36 healthy volunteers. Trimetazidine, an anti-ischemic drug, protects the myocardial cell from the harmful effects of ischemia. The authors investigated the effect of being under a fasting or fed state at the time of drug intake on the bioavailability of trimetazidine 35-mg MR tablets in a randomized, open-label, crossover, 2-arm, 4-period, 2-sequence bioequivalence study design with a 14-day washout period. Plasma concentration of trimetazidine was assayed in timed samples with a validated high- performance liquid chromatography/mass selective detector that had a lower limit of quantification of 2.5 ng/mL. Test and reference formulations gave a mean trimetazidine C(max) of 63.26 ng/mL and 69.18 ng/mL for the fasting state and 64.19 ng/mL and 63.11 ng/mL for the fed state, respectively. The AUC(0-tlast) mean of trimetazidine was 726.31 ng·h/mL and 733.01 ng·h/mL for the fasting state and 706.40 ng·h/mL and 691.40 ng·h/mL for the fed state for test/reference formulations. There were no significant differences in pharmacokinetic parameters between the 2 formulations and the fasting/fed states. The authors showed that there is no food effect and no need for a 4-period study to evaluate the bioequivalence of trimetazidine MR tablets.

Resting Heart Rate and the Risk of Microvascular Complications in Patients With Type 2 Diabetes Mellitus

BackgroundA higher resting heart rate is associated with an increased probability of cardiovascular complications and premature death in patients with type 2 diabetes mellitus. The impact of heart rate on the risk of developing microvascular complications, such as diabetic retinopathy and nephropathy, is, however, unknown. The present study tests the hypothesis that a higher resting heart rate is associated with an increased incidence and a greater progression of microvascular complications in patients with type 2 diabetes mellitus.Methods and ResultsThe relation between baseline resting heart rate and the development of a major microvascular event was examined in 11 140 patients who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study. Major microvascular events were defined as a composite of new or worsening nephropathy or new or worsening retinopathy. Patients with a higher baseline heart rate were at increased risk of a new major microvascular complication during follow-up (adjusted hazard ratio: 1.13 per 10 beats per minute; 95% confidence interval: 1.07–1.20; P<0.001). The excess hazard was evident for both nephropathy (adjusted hazard ratio: 1.16 per 10 beats per minute; 95% confidence interval: 1.08–1.25) and retinopathy (adjusted hazard ratio: 1.11 per 10 beats per minute; 95% confidence interval: 1.02–1.21).ConclusionPatients with type 2 diabetes mellitus who have a higher resting heart rate experience a greater incidence of new-onset or progressive nephropathy and retinopathy.Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00145925. http://www.advance-trial.com/static/html/prehome/prehome.asp

In search of the ideal basal insulin: Does the new-generation ultra-long-acting insulin, degludec, provide the answer?

In search of the ideal basal insulin: Does the new-generation ultra-long-acting insulin, degludec, provide the answer?

Influence of intensive glycemic control on development and progression of diabetic nephropathy in patients with type 2 diabetes mellitus (based on results from ADVANCE study)

Current article presents data on effects of intensive glycemic control with Diabeton MR on development and progression of diabeticnephropathy in patients with type 2 diabetes mellitus (T2DM), accumulated from ADVANCE (Action in Diabetes and Vascular Disease:Preterax and DiamicroN Modified Release Controlled Evaluation study). Influence of intensive therapy with Diabeton MR wasassessed in that study separately and in conjunction with active antihypertensive treatment with perindopril and indapamide.

Use of Partial Area under the Curve Metrics to Assess Bioequivalence of Methylphenidate Multiphasic Modified Release Formulations

Use of Partial Area under the Curve Metrics to Assess Bioequivalence of Methylphenidate Multiphasic Modified Release Formulations