Spotlight on rivastigmine transdermal patch: in dementia of the Alzheimer's type

Rivastigmine, a cholinesterase inhibitor, is available as a transdermal patch (Exelon? patch, Rivastach? patch, Prometax? patch) for the treatment of mild to moderate Alzheimer's disease. Rivastigmine transdermal patch was effective, in terms of improving cognitive and global function, and generally well tolerated in patients with mild to moderate dementia of the Alzheimer's type in a large, well designed trial. Most adverse events associated with rivastigmine patch were mild to moderate in severity, with the patch generally better tolerated than oral rivastigmine, especially in terms of cholinergic gastrointestinal adverse events. The patch also had good skin adhesion and a favourable skin tolerability profile in this study, with most application-site reactions being mild in severity. Additionally, in a safety and tolerability study, rivastigmine patch, regardless of concomitant memantine therapy, was generally well tolerated in patients switching from oral donepezil therapy. Thus, current evidence suggests that rivastigmine transdermal patch is an effective treatment option for patients with Alzheimer's disease, with the potential for improving compliance and providing sustained clinical benefit because of its ease of use and generally favourable tolerability profile.     

Rotigotine transdermal patch: a review of its use in the management of Parkinson's disease

A transdermal patch formulation of the non-ergolinic dopamine agonist rotigotine (Neupro) is indicated for use as monotherapy in the treatment of early-stage Parkinson's disease or, in the EU, as an adjunct to levodopa across all disease stages. Transdermal rotigotine is an effective and generally well tolerated addition to the armamentarium for the control of Parkinson's disease, with the once-daily transdermal patch system offering several practical advantages and the possible benefits of avoiding pulsatile dopaminergic stimulation. Transdermal rotigotine was superior to placebo in patients with early-stage and advanced Parkinson's disease, although noninferiority to the oral dopamine agonists ropinirole or pramipexole was not consistently demonstrated. Additional active comparator trials would be of interest. In the meantime, transdermal rotigotine offers a convenient new treatment option for patients with Parkinson's disease.     

Rivastigmine. A pharmacoeconomic review of its use in Alzheimer's disease

Alzheimer's disease is associated with a large cost burden, of which institutionalised care constitutes a major component. Therefore, the decision to move a patient from the community to institutionalised care is associated with a significant increase in direct costs. About three-quarters of patients with Alzheimer's disease are admitted to a nursing home within 5 years of diagnosis. Unpaid or informal caregiver time is another large cost in Alzheimer's disease, especially for patients cared for in the community; informal care can account for up to three-quarters of healthcare costs in non-institutionalised patients. Several cholinesterase inhibitors, of which rivastigmine is one, are available for the treatment of patients with mild to moderate Alzheimer's disease. By improving cognitive function and slowing the rate of cognitive decline, cholinesterase inhibitor therapy may reduce a significant part of the economic burden of the disease by delaying the move to institutionalised care. In the absence of prospective long term data which focus on pharmacoeconomic end-points, modelling techniques have been used to extrapolate clinical data available for some cholinesterase inhibitors, including rivastigmine. Four economic analyses, based on a single model of cognitive decline, have been performed with rivastigmine from the perspective of the provider or society. All show that rivastigmine therapy (excluding drug-related costs) is associated with cost savings in patients with mild to moderate Alzheimer's disease by delaying the time to institutionalisation. If the acquisition cost of the drug was factored in, the cost savings completely or partially offset treatment costs. The magnitude of the cost savings increased as the time horizon increased (up to 2 years). The largest savings were realised in patients with mild disease over a 2-year time-frame, suggesting that treatment should be initiated early from an economic viewpoint. Pharmacoeonomic data comparing different cholinesterase inhibitors are, as yet, unavailable. CONCLUSION: Pharmacoeconomic analyses, based on modelled data excluding drug costs, indicate that rivastigmine completely or partially offsets the costs of treatment by delaying cognitive decline and the time to institutionalisation in patients with mild to moderate Alzheimer's disease. From a societal perspective, cost savings are realised if the drug is introduced early in the disease. Additional benefits offered by rivastigmine on behavioural symptoms, which may reduce caregiver burden, have yet to be investigated from a pharmacoeconomic perspective.     

Rivastigmine exposure provided by a transdermal patch versus capsules

ABSTRACT

Objectives: The rivastigmine transdermal patch is the first transdermal treatment for Alzheimer's disease (AD) and dementia associated with Parkinson's disease. The objective of this study was to evaluate the pharmacokinetics of rivastigmine following transdermal delivery by a patch versus oral delivery with conventional capsules in a population of AD patients.

Methods: Both non-compartmental and compartmental analyses were performed on the same database showing relatively large inter-patient variations in pharmacokinetic parameters (up to 73% for the capsule group). The compartmental analysis provided model-based predictions of pharmacokinetic parameters, with the aim of comparing the two modes of administration when adjusting for confounding factors such as patient body weight and gender.

Results: According to both non-compartmental and compartmental analyses, the patch provided significantly lower peak rivastigmine plasma concentrations (C_max) and slower times to C_max (t_max), compared with capsules. However, drug exposure (area under the curve; AUC) was not significantly different between the 4.6?mg/24 hour (5?cm²) patch and 3?mg BID (6?mg/day) capsule doses, or between the 9.5?mg/24 hour (10?cm²) patch and 6?mg BID (12?mg/day) capsule doses, according to both analyses. This suggests comparable exposure from these two rivastigmine delivery systems.

Conclusion: The analyses were consistent with previous reports of a markedly less fluctuating, more continuous drug delivery with the rivastigmine patch. This characteristic delivery profile is associated with similar efficacy yet improved tolerability, compared with capsules.     

Rotigotine transdermal patch: a review of its use in the treatment of Parkinson's disease

A transdermal patch formulation of the non-ergolinic dopamine agonist rotigotine (Neupro?) is indicated as monotherapy for the treatment of early Parkinson's disease and as combination therapy with levodopa throughout the course of the disease. Daily application of the rotigotine transdermal patch (referred to here as rotigotine) provided predictable release and absorption of rotigotine, with steady-state rotigotine concentrations reached within 1-2 days. In six large, well designed clinical trials, rotigotine was an efficacious treatment for Parkinson's disease. In early Parkinson's disease, rotigotine initiated without levodopa produced significantly greater improvements than placebo in the Unified Parkinson's Disease Rating Scale (UPDRS) summed motor and activities of daily living (ADL) scores, as well as significantly higher response rates. In a comparison with oral ropinirole, rotigotine did not meet a prespecified response-rate noninferiority criterion, although this may reflect the dosages used, which may not have been directly comparable. In advanced Parkinson's disease, rotigotine in combination with levodopa reduced 'off' time and improved motor functioning and ADL significantly more than levodopa plus placebo. Rotigotine was noninferior to oral pramipexole in reducing 'off' time, although it did not meet a response-rate noninferiority criterion. A recent trial focused on both motor and non-motor endpoints in patients with inadequate early morning motor control despite antiparkinsonian treatment (most received levodopa). Rotigotine improved morning motor functioning and reduced sleep disturbances, night-time motor symptoms, depressive symptoms, pain and functioning, and quality of life to a significantly greater extent than placebo. Rotigotine was generally well tolerated across the trials and in longer-term extension studies, with the most common treatment-emergent adverse events being application-site reactions, gastrointestinal disturbances, somnolence and headache. Application-site reactions were generally mild to moderate in severity; where reported, up to 3% of patients had severe skin reactions. Thus, rotigotine offers a novel approach to the treatment of Parkinson's disease and, given its ease of administration, efficacy in reducing disabling motor and non-motor symptoms, and acceptable tolerability profile, it has the potential to be an attractive treatment option for this highly debilitating disease.     

A review of compliance to treatment in Alzheimer's disease: potential benefits of a transdermal patch

ABSTRACT

Background: Following prescribed medication regimens is essential for the effective treatment of any medical condition. Unfortunately, patients often fail to follow recommendations, and treatment non-compliance represents a widespread, often underestimated problem, placing tremendous burden on the healthcare system. Compliance in Alzheimer's disease (AD), a chronic neurodegenerative disease typically afflicting older adults, is especially challenging.

Scope: To review factors contributing to poor treatment compliance in AD, considering the prominent role care­givers often play in treatment management; and acknowledging strategic approaches, particularly modern transdermal patches, to improve compliance in this particularly susceptible population. Articles were identified by searching MEDLINE in November 2006 (search limits: 1987–2007) using the terms: compliance; Alzheimer's; treatment; and transdermal. Additional resources included bibliographies of identified articles.

Findings: Strategic approaches to improving treatment compliance include: simplifying treatment regimens, using reminder packaging, and developing more patient- or caregiver-friendly modes of administration. To date, AD therapies have been administered orally. However, recent developments in alternative modes of drug delivery, such as transdermal patches, may offer effective, well-tolerated treatment options with the potential to enhance compliance. A patch containing rivastigmine (Exelon*), an established cholinesterase inhibitor, has been developed and demonstrated to have good efficacy and tolerability in patients with AD. In addition, initial caregiver experience suggests preference for the patch over oral administration.

Conclusion: Transdermal patches may be an effective way to optimize treatment compliance for AD, as well as an increasing number of other chronic conditions that typically afflict the older population, offering the possibility of more sustained clinical benefits.     

芬太尼透皮贴剂的安全性及其合理使用

芬太尼透皮贴剂是一种新型强效镇痛透皮缓释给药剂型,使用方法简便,不良反应较低,止痛效果好,广泛用于癌性疼痛(CP)和非癌性疼痛(NCP)的治疗。常见的不良反应有便秘、恶心、呕吐和嗜睡等。但如果使用不当或过量,可造成呼吸抑制甚至死亡。因此,使用芬太尼透皮贴剂时应正确选择适应证,掌握个体用药剂量,避免严重不良反应的发生。     

Galantamine: a review of its use in Alzheimer's disease

Currently, acetylcholinesterase (AChE) inhibitors are the most promising class of drugs for the treatment of Alzheimer's disease (AD). Galantamine is a reversible, competitive, tertiary alkaloid AChE inhibitor. The drug is selective for AChE rather than butyrylcholinesterase. In addition to inhibition of AChE galantamine interacts allosterically with nicotinic acetylcholine receptors to potentiate the action of agonists at these receptors. Recipients of galantamine 16 or 24 mg/day achieved significant improvements in cognitive and global symptoms relative to placebo recipients in large (n = 285 to 978 patients with mild to moderate AD) well-designed trials of 3 to 6 months' duration. Galantamine also improved activities of daily living in these patients and significantly reduced the requirement for caregiver assistance with activities of daily living. Moreover, galantamine recipients achieved significantly better outcomes on behavioural symptoms than placebo recipients. In a long term study (12 months), galantamine 24 mg/day slowed the progression of symptoms of the disease and maintained cognitive function and activities of daily living in patients with mild to moderate AD. Galantamine was generally well tolerated with the majority of adverse events being mild to moderate in intensity and transient. Predictably, adverse events were cholinergic in nature and generally related to the gastrointestinal system. These effects were reduced in patients receiving the recommended dose escalation regimen. Galantamine had no clinically relevant effects on vital signs, haematological or biochemical laboratory parameters and, importantly, there were no reports of hepatotoxicity. The incidence of serious adverse events was similar between galantamine (8 to 32 mg/day) and placebo groups (6 to 16% of patients across all treatment groups). CONCLUSIONS: Galantamine is an effective well tolerated symptomatic treatment for AD which improves cognition, function and activities of daily living in the short term (up to 6 months) in patients with mild to moderate AD. In addition, it delays the development of behavioural disturbances and psychiatric symptoms, and reduces caregiver burden (as measured by caregiver time). In the long term (up to 1 year), galantamine maintains cognition and activities of daily living. Adverse events associated with galantamine are mainly cholinergic, usually mild to moderate in intensity and transient. Galantamine has been evaluated in several large well-designed studies and, given the relative lack of established treatment options, it may be considered as one of the first-line pharmacological treatments in patients with mild to moderate AD.     

Donepezil: a review of its use in Alzheimer's disease

Donepezil (E-2020) is a reversible, noncompetitive, piperidine-type cholinesterase inhibitor. It is selective for acetylcholinesterase rather than butyrylcholinesterase. Donepezil 5 and 10 mg/day significantly improved cognition and global clinical function compared with placebo in well designed short term trials (14 to 30 weeks) in 161 to 818 patients with mild to moderate Alzheimer's disease. Beneficial effects on cognition were observed from week 3 of treatment. Donepezil 10 mg/day significantly delayed the deterioration in activities of daily living (ADL) [by 55 weeks] compared with placebo in a retrospective analysis of 1 trial, and in the largest trial significantly improved patients' abilities to perform complex tasks. However, no significant improvement in function was observed with donepezil 5 mg/day in another trial. In the 2 trials of longest duration donepezil (5 and 10 mg) significantly delayed symptomatic progression of the disease. While there was no evidence for a positive effect of donepezil on patients' quality of life, there are no validated measures of this parameter specific to patients with Alzheimer's disease. Donepezil (5 and 10 mg) significantly reduced caregiver burden. Long term efficacy data suggest that improvements in cognition, global function or ADL are maintained for about 21 to 81 weeks with donepezil (10 mg/day in most patients). Donepezil is generally well tolerated with the majority of adverse events being mild and transient. Predictably, most events were cholinergic in nature and generally related to the gastrointestinal and nervous systems. The incidence of these events was significantly higher with donepezil 10 mg than with placebo in short term clinical trials; however, this may have been due to the 7-day dose increase schedule used in these studies and can be minimised by increasing the dose after a longer (6-week) period. The incidence of serious adverse events was generally similar between donepezil 5 and 10 mg (4 to 10%) and placebo (5 to 9%) in short term trials. 26% of patients receiving donepezil (5 and 10 mg) reported serious events over a 98-week period in a long term trial. Importantly, there was no evidence of hepatotoxicity with this drug. Conclusions. Donepezil (5 and 10 mg) is an agent with a simple once-daily dosage schedule which improves cognition and global clinical function in the short (up to 24 weeks) and long term (up to about 1 year) in patients with mild to moderate Alzheimer's disease. Improvements in ADL were also observed with donepezil 10 mg/day. Adverse events associated with donepezil are mainly cholinergic. Donepezil has been extensively studied and should be considered as a first-line treatment in patients with mild to moderate Alzheimer's disease.     

Memantine: a review of its use in Alzheimer's disease

Memantine (Ebixa, Axura, Namenda, Akatinol) is a moderate-affinity, uncompetitive, voltage-dependent, NMDA-receptor antagonist with fast on/off kinetics that inhibits excessive calcium influx induced by chronic overstimulation of the NMDA receptor. Memantine is approved in the US and the EU for the treatment of patients with moderate to severe dementia of the Alzheimer's type. In well designed clinical trials, oral memantine, as monotherapy or in addition to a stable dose of acetylcholinesterase inhibitors, was well tolerated during the treatment of mild to severe Alzheimer's disease for up to 52 weeks. Memantine generally modified the progressive symptomatic decline in global status, cognition, function and behaviour exhibited by patients with moderate to severe Alzheimer's disease in four 12- to 28-week trials. In patients with mild to moderate Alzheimer's disease, data from three 24-week trials are equivocal, although meta-analyses indicate beneficial effects on global status and cognition. Memantine is an effective pharmacotherapeutic agent, and currently the only approved option, for the treatment of moderate to severe Alzheimer's disease.     

Risperidone: a review of its use in the management of the behavioural and psychological symptoms of dementia

Risperidone is a benzisoxazole derivative which has proven efficacy against the positive and negative symptoms of schizophrenia. It has more recently been investigated and shown efficacy as a treatment for the behavioural and psychological symptoms associated with dementia in the elderly. Risperidone has pharmacological properties resembling those of the atypical antipsychotic clozapine and an improved tolerability profile compared with the conventional antipsychotic haloperidol. Risperidone has antagonistic activity primarily at serotonin 5-HT2A and dopamine D2 receptors. In the first 2 large, well controlled trials of an antipsychotic agent used in the treatment of elderly patients with Alzheimer's dementia, vascular dementia or mixed dementia, risperidone 1 mg/day was at least as effective as haloperidol and superior to placebo, as assessed by the rating scales for global behaviour, aggression and psychosis. In extension phases of the 2 trials, clinical benefits were maintained for treatment periods of up to 1 year, with an incidence rate of tardive dyskinesia (2.6%) one-tenth of that seen with conventional antipsychotics. Risperidone, administered at a low dosage of 1 mg/day was associated with fewer extrapyramidal symptoms compared with haloperidol in elderly patients. Risperidone was well tolerated with no clinically relevant abnormalities in laboratory tests, vital signs or electrocardiogram results. Conclusion: The efficacy of risperidone has been demonstrated in the treatment of the behavioural and psychological symptoms associated with dementia in the elderly. Preliminary results from 1-year extension studies confirm the favourable efficacy and tolerability profile of risperidone 1 mg/day. Although head to head studies with other atypical antipsychotic agents are required and the long term use of the drug requires clarification, risperidone represents a generally well tolerated and effective treatment in the management of dementia-associated behavioural and psychological symptoms in the elderly.     

Liraglutide: a review of its use in the management of type 2 diabetes mellitus

Liraglutide (Victoza?) is a subcutaneously administered glucagon-like peptide-1 (GLP-1) receptor agonist produced by recombinant DNA technology and used as an adjunct to diet and exercise in the treatment of adults with type 2 diabetes mellitus. This article reviews the clinical efficacy and tolerability of liraglutide in adults with type 2 diabetes, and provides a summary of its pharmacological properties. Recently published pharmacoeconomic studies of liraglutide are also reviewed. Administered subcutaneously, liraglutide (usually 1.2 or 1.8?mg once daily) generally produced greater improvements in glycaemic control than active comparators or placebo when administered as monotherapy or in combination with one or two oral antidiabetic drugs (OADs) to adults with type 2 diabetes in numerous randomized, controlled phase III trials. These included six trials in the LEAD trial programme that was designed to evaluate the efficacy and safety of liraglutide across a continuum of antihyperglycaemic management for patients with type 2 diabetes. Liraglutide was generally well tolerated, with a low risk of hypoglycaemia evident, in the phase III trials. The most common adverse events were gastrointestinal and included nausea and diarrhoea; most events were mild to moderate in severity and decreased in incidence over time. In conclusion, liraglutide has an important place in the management of adults with type 2 diabetes across a continuum of care. As well as providing effective glycaemic control, liraglutide improves pancreatic β-cell function and leads to bodyweight loss, thereby addressing some of the unmet needs of patients treated with traditional OADs.     

Alogliptin: a review of its use in the management of type 2 diabetes mellitus

Alogliptin (Nesina?) is a dipeptidyl peptidase-4 inhibitor that is approved in Japan for the treatment of adult patients with type 2 diabetes mellitus that is inadequately controlled by diet and exercise alone or by diet plus treatment with an α-glucosidase inhibitor. Alogliptin plus diet and exercise is also approved in Japan for use in combination with a thiazolidinedione in patients with type 2 diabetes. In several large (n >250), double-blind, multinational trials of up to 26 weeks' duration, oral alogliptin as monotherapy or in combination with other oral antihyperglycaemic agents (metformin, glibenclamide or pioglitazone) or insulin therapy improved glycaemic control and was generally well tolerated in adult patients with inadequately controlled type 2 diabetes, including elderly patients. Significant improvements in glycaemic control were evident from as early as 1 week in terms of improvements in mean fasting plasma glucose levels and from 4 weeks onwards for improvements in mean glycosylated haemoglobin levels. In general, the incidence of hypoglycaemia was similar to that seen in placebo groups and alogliptin treatment had neutral effects on bodyweight and lipid parameters. The long-term safety of alogliptin therapy remains to be established in clinical studies and with clinical experience. A planned clinical trial evaluating long-term clinical outcomes in patients with acute coronary syndrome and other planned or ongoing short-term trials will help to more definitively determine the position of alogliptin therapy in relation to other available antihyperglycaemic therapies. In the meantime, alogliptin is a promising new option for the treatment of patients with type 2 diabetes, including elderly patients.     

Linagliptin: a review of its use in the management of type 2 diabetes mellitus

Linagliptin (Trajenta?, Tradjenta?, Trazenta?, Trayenta?) is an oral, highly selective inhibitor of dipeptidyl peptidase-4 and is the first agent of its class to be eliminated predominantly via a nonrenal route. Linagliptin is indicated for once-daily use for the treatment of adults with type 2 diabetes mellitus, and a twice-daily fixed-dose combination of linagliptin/metformin (Jentadueto?) is also available. In this article, the pharmacological, clinical efficacy and tolerability data relevant to the use of linagliptin in patients with type 2 diabetes are reviewed. The efficacy of oral linagliptin in the treatment of adults with type 2 diabetes has been investigated in several double-blind, multicentre trials. Following 12-24 weeks of treatment, improvements in glycaemic control parameters, including glycosylated haemoglobin (HbA(1c); primary endpoint in all trials), were seen with linagliptin relative to placebo when used as monotherapy, initial combination therapy (with metformin or pioglitazone) or add-on therapy to other oral antihyperglycaemia agents (metformin and/or a sulfonylurea) or basal insulin (with or without metformin and/or pioglitazone). In terms of lowering HbA(1c), linagliptin was more effective than voglibose in a 26-week monotherapy trial and noninferior to glimepiride when used as add-on therapy to metformin in a 104-week study. Additional trials and subgroup analyses of pooled data suggest that linagliptin improves glycaemic control regardless of factors such as age, duration of type 2 diabetes, ethnicity and renal function, and as linagliptin is eliminated primarily via a nonrenal route, it can be used without dosage adjustment in patients with renal impairment of any degree. Oral linagliptin was generally well tolerated and was associated with a low likelihood of hypoglycaemia (except when used in combination with a sulfonylurea) and had little effect on bodyweight. Further long-term and comparative efficacy and tolerability data are required to help position linagliptin more definitively with respect to other antihyperglycaemia agents. However, clinical data currently available indicate that linagliptin is an effective and generally well tolerated treatment option for use in patients with type 2 diabetes, including those with renal impairment for whom other antihyperglycaemia agents require dosage adjustment or are not suitable.     

Rosiglitazone: a review of its use in the management of type 2 diabetes mellitus

Rosiglitazone, a thiazolidinedione with a different side chain from those of troglitazone and pioglitazone, reduces plasma glucose levels and glucose production and increases glucose clearance in patients with type 2 diabetes mellitus. Insulin sensitivity, pancreatic beta-cell function and surrogate markers of cardiovascular risk factors are significantly improved by rosiglitazone. Double-blind trials of 8 to 26 weeks of rosiglitazone 4 or 8 mg/day monotherapy indicate significant decreases in fasting plasma glucose (-2 to -3 mmol/L with 8 mg/day) and glycosylated haemoglobin levels [HbA(1c); -0.6 to -0.7% (-0.8 to -1.1% in drug-naive patients) with 8 mg/day]. Significant decreases in hyperglycaemic markers occurred when rosiglitazone was combined with metformin (HbA(1c) -0.8 to -1.0%), a sulphonylurea (-1.4%) or insulin (-1.2%) for 26 weeks versus little change with active comparator monotherapy. Efficacy was maintained in trials of < or = 2 years, and was also apparent in various ethnic subgroups, elderly patients, and both obese and nonobese patients. Rosiglitazone is currently not indicated in combination with injected insulin. It should be administered in conjunction with diet and exercise regimens. Rosiglitazone is generally well tolerated. Despite rare individual reports of liver function abnormalities in rosiglitazone recipients, the incidence of these in clinical trials (< or = 2 years' duration) was similar to that in placebo and active comparator groups. Fluid retention associated with rosiglitazone may be the cause of the increased incidence of anaemia in clinical trials, and also means that patients should be monitored for signs of heart failure during therapy. Although bodyweight is increased overall with rosiglitazone therapy, increases are in subcutaneous, not visceral, fat; hepatic fat is decreased. The pharmacokinetic profile of rosiglitazone is not substantially altered by age or renal impairment, nor are there important drug interactions. Rosiglitazone is not indicated in patients with active liver disease or increased liver enzymes. CONCLUSIONS: Oral rosiglitazone 4 or 8 mg/day provides significant antihyperglycaemic efficacy and is generally well tolerated, both as monotherapy and in combination with other antihyperglycaemic agents, in patients with type 2 diabetes mellitus who do not have active liver disease. Long-term data are required before conclusions can be drawn about the clinical significance of positive changes to surrogate markers of cardiovascular disease risk and improvements to pancreatic beta-cell function. Rosiglitazone significantly improves insulin sensitivity and, as such, is a welcome addition to the treatment options for patients with type 2 diabetes mellitus.     

Troglitazone: a review of its use in the management of type 2 diabetes mellitus

Troglitazone is the first of a new group of oral antidiabetic drugs, the thiazolidinediones, and is indicated for the treatment of patients with type 2 (non-insulin-dependent) diabetes mellitus. Troglitazone acts by enhancing the effects of insulin at peripheral target sites and, unlike the sulphonylurea drugs, is not associated with hypoglycaemia when administered as monotherapy. Clinical trials with troglitazone (usually 200 to 600 mg/day) in patients with type 2 diabetes mellitus consistently showed marked improvement in glycaemic control, as well as reductions in fasting serum insulin, C-peptide and triglyceride levels. Comparative studies with either glibenclamide (glyburide) or metformin indicated similar glycaemic control with troglitazone or these agents. Serum insulin levels were lower with troglitazone than with glibenclamide. Clinical trials of up to approximately 2 years' duration showed that glycaemic control is maintained with troglitazone on a long term basis. In general, troglitazone is well tolerated by the majority of patients. However, discontinuation of troglitazone because of elevated liver enzyme levels occurs in approximately 2% of patients receiving the drug, and frequent monitoring of liver enzymes is required (e.g. at least 11 times during the first year of therapy). Among patients who started troglitazone therapy in 1998 (after the incorporation of a boxed warning and increased monitoring requirements in the product labelling), the estimated risk of liver-related death is approximately 1 in 100,000. CONCLUSIONS: Troglitazone improves the ability of target cells to respond to insulin. The drug has been shown to improve glycaemic control in patients with type 2 diabetes mellitus when used as monotherapy or in combination with other oral antidiabetic drugs or insulin, and its efficacy is similar to that of glibenclamide or metformin. Although troglitazone is generally well tolerated, close monitoring of liver enzyme function is required to minimise the rare occurrence of serious hepatic dysfunction. Drug acquisition and liver function monitoring costs, as well as potential adverse effects, are important factors that may ultimately determine the precise place of troglitazone in the management of type 2 diabetes mellitus. Nevertheless, as the first member of a new class of oral antidiabetic agents, the thiazolidinediones, troglitazone offers an effective treatment option in patients with type 2 diabetes mellitus through its action of improving insulin sensitivity.     

Vildagliptin: a review of its use in the management of type 2 diabetes mellitus

Vildagliptin (Galvus) is an antihyperglycaemic agent that selectively inhibits the dipeptidyl peptidase-4 (DPP-4) enzyme. Such inhibition prevents the degradation of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This results in improved glycaemic control as determined by glycated haemoglobin (HbA(1c)) and fasting plasma glucose (FPG) levels, and, in addition, an enhancement of pancreatic alpha- and beta-cell function. Vildagliptin is indicated in the EU and elsewhere in the world for the management of type 2 diabetes mellitus in combination with metformin, a sulfonylurea or a thiazolidinedione in patients with inadequate glycaemic control following monotherapy. Vildagliptin is also available as a fixed-dose formulation with metformin (Eucreas).Oral vildagliptin in combination with metformin, a sulfonylurea or a thiazolidinedione improved glycaemic control in adults with type 2 diabetes and appeared to slow the progression of beta-cell degeneration in trials of 24-52 weeks' duration. In trials in patients with diabetes inadequately controlled with metformin, vildagliptin provided an additional reduction of HbA(1c) levels of 1.1% and was shown to be as effective as pioglitazone as add-on therapy in a noninferiority trial. Vildagliptin had a low risk of hypoglycaemia, was weight-neutral overall and was generally well tolerated. Further investigation is required to accurately position vildagliptin relative to other, well established antidiabetic agents. However, the addition of vildagliptin expands the range of treatment options available, and as such, offers further potential for the management of patients with type 2 diabetes that is inadequately controlled with monotherapy.