Pharmacogenomics of oral antidiabetic medications: current data and pharmacoepigenomic perspective

Type 2 diabetes mellitus (T2DM) is an increasingly prevalent disease. Several classes of drugs are currently available to treat T2DM patients; however, clinical response to these drugs often exhibits significant variation among individuals. For the oral antidiabetic drug classes of sulfonylureas, nonsulfonylurea insulin secretagogs, biguanides and thiazolidinediones, pharmacogenomic evidence has accumulated demonstrating an association between specific gene polymorphisms and interindividual variability in their therapeutic and adverse reaction effects. These polymorphisms are in genes of molecules involved in metabolism, transport and therapeutic mechanisms of the aforementioned drugs. Overall, it appears that pharmacogenomics has the potential to improve the management of T2DM and help clinicians in the effective prescribing of oral antidiabetic medications. Although pharmacogenomics can explain some of the heterogeneity in dose requirements, response and incidence of adverse effects of drugs between individuals, it is now clearly understood that much of the diversity in drug effects cannot be solely explained by studying the genomic diversity. Epigenomics, the field that focuses on nongenomic modifications that influence gene expression, may expand the scope of pharmacogenomics towards optimization of drug therapy. Therefore, pharmacoepigenomics, the combined analysis of genetic variations and epigenetic modifications, holds promise for the realization of personalized medicine. Although pharmacoepigenomics has so far been evaluated mainly in cancer pharmacotherapy, studies on epigenomic modifications during T2DM development provide useful data on the potential of pharmacoepigenomics to elucidate the mechanisms underlying interindividual response to oral antidiabetic treatment. In summary, the present article focuses on available data from pharmacogenomic studies of oral antidiabetic drugs and also provides an overview of T2DM epigenomic research, which has the potential to boost the development of pharmacoepigenomics in antidiabetic treatment.     

口服降糖药的遗传药理学研究进展

糖尿病是一种受多基因和环境因素共同影响的代谢性疾病。药物代谢酶、受体和转运体的遗传多态性对口服降糖药的体内代谢和降糖疗效有重要作用。本文从细胞色素P450酶、转运体和受体多态性方面对5种主要口服降糖药（磺脲类、噻唑烷二酮类、氯茴苯酸类、双胍类、α-葡萄糖甙酶抑制剂）的体内代谢和药物效应的影响作一综述。     

Toxicology of oral antidiabetic medications.

PURPOSE: The toxicology of oral antidiabetic agents is reviewed. SUMMARY: Type 2 diabetes mellitus is increasing to near epidemic proportions, with a reported 190 million patients worldwide. Use of oral antidiabetic medications is increasing along with a proportional increase in adverse events. Oral antidiabetic medications can be separated by mechanism of action into two groups: hypoglycemics (sulfonylureas and meglitinides) and antihyperglycemics (biguanides and alpha-glucosidase inhibitors). The hypoglycemic agents pose a significant risk of morbidity, mortality, and permanent sequelae secondary to prolonged periods of hypoglycemia. However, outcomes are routinely good if intervention is initiated early, with the primary goal return of euglycemia using supplemental dextrose infusion and octreotide to reduce further insulin secretion. Metformin-associated lactic acidosis (MALA) can occur with both acute and chronic metformin exposure. While MALA is not common, its associated rates of morbidity and mortality can be high. Secondary to MALA, the patient may experience changes in the central nervous system, cardiovascular collapse, renal failure, and death. The primary goals of therapy are restoration of acid-base status and removal of metformin, using hemodialysis and bicarbonate therapy. There is no specific antidote for MALA. The alpha-glucosidase inhibitors and thiazolidinediones pose minimal risk of adverse events in acute overdose. However, acarbose and all thiazolidinediones have been reported to produce hepatic injury with chronic therapy. Cessation of therapy with the offending agent and supportive care are the mainstays of overdose management with these drugs. CONCLUSION: The toxicity of oral antidiabetic agents differs widely in clinical manifestations, severity, and treatment.     

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.     

Genetic polymorphisms in placental transporters: implications for fetal drug exposure to oral antidiabetic agents

INTRODUCTION: The prevalence of diabetes among women of childbearing age is increasing. This will inevitably increase the number of pregnancies complicated by diabetes. The management of diabetes mellitus often necessitates the use of oral antidiabetic drugs including biguanides, sulfonylureas, metiglinide analogs and thiazolidinediones. However, a significant concern with the use of these agents in pregnancy is the potential for developmental toxicity. Various antidiabetic drugs have been identified as substrates for transporters present in the syncytiotrophoblast. Therefore, the extent of transfer and fetal exposure to oral antidiabetic drugs used in pregnancy may be altered by polymorphisms in genes encoding these transport proteins. AREAS COVERED: This review covers current research examining genetic polymorphisms in transporters expressed in the syncytiotrophoblast and evidence supporting the involvement of these transporters in the transport of oral antidiabetic agents. The aim is to provide insight into how the transfer of antidiabetic drugs across the placental trophoblast may be altered by polymorphisms in drug transporters. EXPERT OPINION: There is a paucity of studies examining the influence of polymorphisms on transporter activity in the placenta and how the transfer of oral antidiabetics may be altered. Further research employing in vivo models is required to allow for the prediction of the potential consequences of polymorphisms on placental transporter expression and function.     

Oral antidiabetic agents: current role in type 2 diabetes mellitus

Type 2 diabetes mellitus is a progressive and complex disorder that is difficult to treat effectively in the long term. The majority of patients are overweight or obese at diagnosis and will be unable to achieve or sustain near normoglycaemia without oral antidiabetic agents; a sizeable proportion of patients will eventually require insulin therapy to maintain long-term glycaemic control, either as monotherapy or in conjunction with oral antidiabetic therapy. The frequent need for escalating therapy is held to reflect progressive loss of islet beta-cell function, usually in the presence of obesity-related insulin resistance. Today's clinicians are presented with an extensive range of oral antidiabetic drugs for type 2 diabetes. The main classes are heterogeneous in their modes of action, safety profiles and tolerability. These main classes include agents that stimulate insulin secretion (sulphonylureas and rapid-acting secretagogues), reduce hepatic glucose production (biguanides), delay digestion and absorption of intestinal carbohydrate (alpha-glucosidase inhibitors) or improve insulin action (thiazolidinediones). The UKPDS (United Kingdom Prospective Diabetes Study) demonstrated the benefits of intensified glycaemic control on microvascular complications in newly diagnosed patients with type 2 diabetes. However, the picture was less clearcut with regard to macrovascular disease, with neither sulphonylureas nor insulin significantly reducing cardiovascular events. The impact of oral antidiabetic agents on atherosclerosis--beyond expected effects on glycaemic control--is an increasingly important consideration. In the UKPDS, overweight and obese patients randomised to initial monotherapy with metformin experienced significant reductions in myocardial infarction and diabetes-related deaths. Metformin does not promote weight gain and has beneficial effects on several cardiovascular risk factors. Accordingly, metformin is widely regarded as the drug of choice for most patients with type 2 diabetes. Concern about cardiovascular safety of sulphonylureas has largely dissipated with generally reassuring results from clinical trials, including the UKPDS. Encouragingly, the recent Steno-2 Study showed that intensive target-driven, multifactorial approach to management, based around a sulphonylurea, reduced the risk of both micro- and macrovascular complications in high-risk patients. Theoretical advantages of selectively targeting postprandial hyperglycaemia require confirmation in clinical trials of drugs with preferential effects on this facet of hyperglycaemia are currently in progress. The insulin-sensitising thiazolidinedione class of antidiabetic agents has potentially advantageous effects on multiple components of the metabolic syndrome; the results of clinical trials with cardiovascular endpoints are awaited. The selection of initial monotherapy is based on a clinical and biochemical assessment of the patient, safety considerations being paramount. In some circumstances, for example pregnancy or severe hepatic or renal impairment, insulin may be the treatment of choice when nonpharmacological measures prove inadequate. Insulin is also required for metabolic decompensation, that is, incipient or actual diabetic ketoacidosis, or non-ketotic hyperosmolar hyperglycaemia. Certain comorbidities, for example presentation with myocardial infarction during other acute intercurrent illness, may make insulin the best option. Oral antidiabetic agents should be initiated at a low dose and titrated up according to glycaemic response, as judged by measurement of glycosylated haemoglobin (HbA1c) concentration, supplemented in some patients by self monitoring of capillary blood glucose. The average glucose-lowering effect of the major classes of oral antidiabetic agents is broadly similar (averaging a 1-2% reduction in HbA1c), alpha-glucosidase inhibitors being rather less effective. Tailoring the treatment to the individual patient is an important principle. Doses are gradually titrated up according to response. However, the maximal glucose-lowering action for sulphonylureas is usually attained at appreciably lower doses (approximately 50%) than the manufacturers' recommended daily maximum. Combinations of certain agents, for example a secretagogue plus a biguanide or a thiazolidinedione, are logical and widely used, and combination preparations are now available in some countries. While the benefits of metformin added to a sulphonylurea were initially less favourable in the UKPDS, longer-term data have allayed concern. When considering long-term therapy, issues such as tolerability and convenience are important additional considerations. Neither sulphonylureas nor biguanides are able to appreciably alter the rate of progression of hyperglycaemia in patients with type 2 diabetes. Preliminary data suggesting that thiazolidinediones may provide better long-term glycaemic stability are currently being tested in clinical trials; current evidence, while encouraging, is not conclusive. Delayed progression from glucose intolerance to type 2 diabetes in high-risk individuals with glucose intolerance has been demonstrated with troglitazone, metformin and acarbose. However, intensive lifestyle intervention can be more effective than drug therapy, at least in the setting of interventional clinical trials. No antidiabetic drugs are presently licensed for use in prediabetic individuals.     

噻唑烷二酮类药物与胰岛素抵抗

目的：综述噻唑烷二酮类(TZDS)药物治疗胰岛素抵抗的作用机制、在Ⅱ型糖尿病中的作用、对胰岛素敏感性的影响、副作用和临床使用。方法：文献学方法。结果：噻唑烷二酮类(TZDS)药物通过多种机制提高了胰岛素抵抗及Ⅱ型糖尿病病人对胰岛素的敏感性，改善了患者的胰岛素抵抗状态。结论：噻唑烷二酮类(TZDS)药物具有很高的临床使用价值，但使用时应注意其所带来的不良反应。     

Cardiovascular Risk Factors Associated with Insulin Resistance

Patients with type 2 diabetes mellitus have a greater risk of cardiovascular disease than nondiabetic individuals. These patients are often insulin resistant and have an associated clustering of risk factors that contribute to cardiovascular disease. The risk factors include dyslipidemia, hypertension, altered hemostasis, and chronic inflammation. A primary objective in the management of type 2 diabetes mellitus is normalization of blood glucose levels; however, some of the oral drugs used to control blood glucose levels have significant effects on these risk factors. In this article, we review the current data involving the modification of these cardiovascular risk factors by the biguanide (metformin), the thiazolidinediones (troglitazone, rosiglitazone, and pioglitazone), the alpha-glucosidase inhibitors (miglitol, acarbose), and the insulin secretagogs (glyburide [glibenclamide], glipizide, chlorpropamide, tolbutamide, tolazamide, glimepiride, repaglinide, and nateglinide). Generally, the thiazolidinediones improve hemostasis and endothelial function and reduce blood pressure, while having variable effects on dyslipidemia. Metformin improves dyslipidemia and altered hemostasis and decreases plasma C-reactive protein levels with little or no effect on blood pressure. Data on the effects of the alpha-glucosidase inhibitors and insulin secretagogs are sparse; however, these drugs appear to have little or no effect on cardiovascular risk factors.     

Potential role of oral thiazolidinedione therapy in preserving beta-cell function in type 2 diabetes mellitus

Worsening glycaemic control in type 2 diabetes mellitus relates to a decline in beta-cell function, associated with impaired negative feedback regulation of insulin release. Insulin resistance, the 'traditional' cornerstone defect of type 2 diabetes, leads to an array of adverse effects on beta cells, including hypertrophy, apoptosis and those caused by lipotoxicity and glucotoxicity. In particular, increased levels of free fatty acids and their metabolites are thought to diminish both insulin synthesis and glucose-stimulated insulin secretion. Thiazolidinediones are synthetic peroxisome proliferator-activated receptor-gamma agonists that decrease insulin resistance but, as in vitro and in vivo studies suggest, may have direct beneficial effects on pancreatic beta cells. Troglitazone, for example, demonstrated improvements in insulin secretory capacity in isolated pancreatic islets from Wistar rats and a hamster beta-cell line. In vivo studies reveal thiazolidinediones promote beta-cell survival and regranulation as well as maintenance of beta-cell mass and reduction in amyloid deposition. Clinical evidence for thiazolidinediones is largely derived from comparative trials, mainly against sulfonylureas and metformin. Data at 2 years from a number of trials are now available and establish the positive effects of thiazolidinediones on glycaemic control. Empirical evidence showing decreases in fasting plasma insulin levels with pioglitazone and rosiglitazone indicate thiazolidinediones also improve insulin sensitivity. A possible effect of thiazolidinediones on normalising asynchronous insulin secretion, as assessed in a short-term placebo-controlled study, is less established. However, recent and ongoing clinical studies are focusing attention on verifying animal and other data, which support the notion that thiazolidinediones have beneficial effects on beta-cell function. These clinical studies have shown thiazolidinediones capable of preventing or delaying the development of type 2 diabetes in a high-risk population; restoring the first-phase insulin response; and improving secretory responses to oscillations in plasma glucose levels. Many of these effects appear to be independent of improvements in insulin sensitivity. Other research efforts are examining the potential cardiovascular protective effects of thiazolidinediones. Available data imply thiazolidinediones are associated with cardiovascular risk reduction, although results from large, clinical outcome trials, currently in progress, are still needed. Improved understanding of the role that declining beta-cell function has in the development of type 2 diabetes has drawn attention to the need for hypoglycaemic agents that can address this process. Emerging evidence suggests thiazolidinediones offer specific benefits for preventing or delaying the decline in beta-cell function and, thereby, a substrate for early intervention efforts aimed at lowering the worldwide burden of type 2 diabetes.     

Oral antihyperglycemic agents during pregnancy and lactation: a review

The treatment approach of diabetes mellitus during pregnancy requires a combination of diet, exercise, multiple home glucose determinations and intensive insulin regimens. During the last decade there was an increased interest in the use of oral antihyperglycemic agents (OAHAs) as an alternative to insulin in achieving good glycemic control. OAHAs are divided into four groups: derivatives of sulfonylurea, biguanides, glucosidase inhibitors and thiazolidinediones. This review describes the possible teratogenic effects of the use of OAHAs during pregnancy and the effects of these drugs during lactation. Animal and human studies assessing the teratogenic effects of OAHAs have yielded conflicting data because the risk of major malformations in infants of mothers with diabetes appears to be related to maternal glycemic control rather than the antidiabetic therapy. A major concern with the use of OAHAs during pregnancy is neonatal hypoglycemia, which may be severe and persist for days. Therefore, insulin is still the drug of choice because it has not been implicated as a teratogen in human pregnancies. In addition, because of the lack of data regarding the use of OAHAs in pregnancy, we cannot draw firm conclusions about all of the available drugs. However, OAHAs, especially glibenclamide (glyburide), may be beneficial in a situation where the proper use of insulin is problematic. Because there are very limited clinical data on the exposure of OAHAs to the infant via breast milk, and the potentially serious effect of neonatal hypoglycemia, the safest recommendation is not to breast feed while taking OAHAs. Well-conducted, prospective, controlled studies regarding the feasibility of OAHAs in pregnant women with diabetes and during lactation are needed.     

双胍类降糖药的作用优势与评价

目的:糖尿病是一种内分泌-代谢综合征,治疗药物包括降糖药和抗糖尿病药,作用机制各异,而双胍类降糖药独树一帜,本文总结其优势和临床评价。方法:采用国内、外文献综述方法。结果及结论:双胍类降糖药并非刺激胰岛β细胞分泌胰岛素,不受累于胰岛功能与细胞作用,可降低糖合血红蛋白,降低血脂,减少诱发心肌梗死的风险,可作为肥胖和超重的2型糖尿病者的一线用药。     

Thiazolidinediones in diabetes: current status and future outlook

Thiazolidinediones have recently emerged as promising antidiabetic drugs. Unlike other oral antidiabetic drugs, thiazolidinediones function to ameliorate insulin resistance, a primary factor for the development of type 2 diabetes. Thiazolidinediones are ligands of the nuclear receptor, peroxisome proliferator-activated receptor-gamma, and their antidiabetic effects appear to be mediated by activation of this receptor. The two currently marketed thiazolidinediones, rosiglitazone and pioglitazone, display similar efficacies in their glucose lowering activities, but interestingly display slightly different clinical and side effect profiles. Understanding the molecular basis for these differences will help in the development of next generation thiazolidinediones that are more efficacious and safer for the treatment of type 2 diabetes.     

Sulfonylureas and glinides exhibit peroxisome proliferator-activated receptor gamma activity: a combined virtual screening and biological assay approach

Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating insulin release (sulfonylureas, glinides), or target the peroxisome proliferator-activated receptor (PPARgamma) improving insulin resistance (thiazolidinediones). Our work shows that sulfonylureas and glinides additionally bind to PPARgamma and exhibit PPARgamma agonistic activity. This activity was predicted in silico by virtual screening and confirmed in vitro in a binding assay, a transactivation assay, and by measuring the expression of PPARgamma target genes. Among the measured compounds, gliquidone and glipizide (two sulfonylureas), as well as nateglinide (a glinide), exhibit PPARgamma agonistic activity at concentrations comparable with those reached under pharmacological treatment. The most active of these compounds, gliquidone, is shown to be as potent as pioglitazone at inducing PPARgamma target gene expression. This dual mode of action of sulfonylureas and glinides may open new perspectives for the molecular pharmacology of antidiabetic drugs, because it provides evidence that drugs can be designed that target both the sulfonylurea receptor and PPARgamma. Targeting both receptors could increase pancreatic insulin secretion and improve insulin resistance. Glinides, sulfonylureas, and other acidified sulfonamides may be promising leads in the development of new PPARgamma agonists. In addition, we provide a unified concept of the PPARgamma binding ability of seemingly disparate compound classes.     

Drug interactions with oral antidiabetic agents: pharmacokinetic mechanisms and clinical implications

There is a growing epidemic of type 2 diabetes (T2DM), and it is associated with various comorbidities. Patients with T2DM are usually treated with multiple drugs, and are therefore at an increased risk of harmful drug-drug interactions (DDIs). Several potentially life-threatening DDIs concerning oral antidiabetic drugs have been identified. This has mostly been initiated by case reports but, more recently, the understanding of their mechanisms has greatly increased. In this article, we review the pharmacokinetic DDIs concerning oral antidiabetics, including metformin, sulfonylureas, meglitinide analogs, thiazolidinediones and dipeptidyl peptidase-4 inhibitors, and the underlying mechanistic basis that can help to predict and prevent DDIs. In particular, the roles of membrane transporters and cytochrome P450 (CYP) enzymes in these DDIs are discussed.     

Comparative safety of newer oral antidiabetic drugs

Oral antidiabetic agents were introduced into clinical practice during the 1950s. Biguanides and sulfonylureas are still used extensively today and their safety and tolerability profiles are well defined. Developments and refinements within these classes have included the introduction of second- and third-generation sulfonylureas, the introduction of modified-release preparations, and the emergence of fixed-dose preparations with metformin and with novel drugs. The latter include the thiazolidinediones, agents with a putative genomic mechanism of action that have been under intense scrutiny since the emergence of severe hepatotoxicity with troglitazone. Recent concerns about thiazolidinediones have centred on the issue of oedema and the risk of precipitating heart failure in vulnerable patients. Only prolonged exposure will determine the long-term safety of thiazolidinediones. Rapid-acting non-sulfonylurea secretagogues appear to be effective and perhaps safer than sulfonylureas in some groups of patients with certain comorbidities (e.g., those with renal impairment). α-Glucosidase inhibitors have an excellent safety record and acarbose has been shown to retard the progression from impaired glucose tolerance to Type 2 diabetes. However, their use is limited by tolerability issues.     

Comparative safety of newer oral antidiabetic drugs

Oral antidiabetic agents were introduced into clinical practice during the 1950s. Biguanides and sulfonylureas are still used extensively today and their safety and tolerability profiles are well defined. Developments and refinements within these classes have included the introduction of second- and third-generation sulfonylureas, the introduction of modified-release preparations, and the emergence of fixed-dose preparations with metformin and with novel drugs. The latter include the thiazolidinediones, agents with a putative genomic mechanism of action that have been under intense scrutiny since the emergence of severe hepatotoxicity with troglitazone. Recent concerns about thiazolidinediones have centred on the issue of oedema and the risk of precipitating heart failure in vulnerable patients. Only prolonged exposure will determine the long-term safety of thiazolidinediones. Rapid-acting non-sulfonylurea secretagogues appear to be effective and perhaps safer than sulfonylureas in some groups of patients with certain comorbidities (e.g., those with renal impairment). alpha-Glucosidase inhibitors have an excellent safety record and acarbose has been shown to retard the progression from impaired glucose tolerance to Type 2 diabetes. However, their use is limited by tolerability issues.     

Antidiabetic drugs present and future: will improving insulin resistance benefit cardiovascular risk in type 2 diabetes mellitus?

Results from the United Kingdom Prospective Diabetes Study showed that intensive treatment of type 2 (non-insulin-dependent) diabetes mellitus, with sulphonylureas or insulin, significantly reduced microvascular complications but did not have a significant effect on macrovascular complications after 10 years. Insulin resistance plays a key role in type 2 diabetes mellitus and is linked to a cluster of cardiovascular risk factors. Optimal treatment for type 2 diabetes mellitus should aim to improve insulin resistance and the associated cardiovascular risk factors in addition to achieving glycaemic control. Treatment with sulphonylureas or exogenous insulin improves glycaemic control by increasing insulin supplies rather than reducing insulin resistance. Metformin and the recently introduced thiazolidinediones have beneficial effects on reducing insulin resistance as well as providing glycaemic control. There is evidence that, like metformin, thiazolidinediones also improve cardiovascular risk factors such as dyslipidaemia and fibrinolysis. Whether these differences will translate into clinical benefit remains to be seen. The thiazolidinediones rosiglitazone and pioglitazone have been available in the US since 1999 (with pioglitazone also being available in Japan). Both products are now available to physicians in Europe.     

Thiazolidinediones in Patients with Diabetes Mellitus and Heart Failure

Individuals with diabetes mellitus have an increased risk of developing heart failure, usually as a consequence of coronary artery disease, although a specific diabetic cardiomyopathy, secondary to a microangiopathy, may also exist. The thiazolidinediones, a relatively new class of insulin-sensitizing agents used in the management of type 2 diabetes mellitus, have a number of complex metabolic actions on surrogate markers of atherogenesis, supported by the results of the recently published PROACTIVE (PROspective pioglitAzone Clinical Trial In macroVascular Events) trial. Unfortunately, the use of thiazolidinediones in individuals with diabetes mellitus and heart failure is limited because of a propensity to cause fluid retention. The underlying mechanisms of fluid retention have yet to be fully elucidated, but appear to be a dose-related class effect, exacerbated by combination therapy with insulin, and in some cases may be localized to peripheral edema. In parallel, echocardiographic studies show no significant effect of thiazolidinediones on cardiac structure or function. The design of epidemiologic studies describing an increased risk of developing heart failure in individuals with type 2 diabetes mellitus prescribed thiazolidinediones has been questioned, and a study of 'new users' of antihyperglycemic treatments found no increased risk of hospitalization for heart failure with thiazolidinedione therapy. There is also increasing evidence for the potential benefits of insulin sensitization in patients with diabetes mellitus and known heart failure, and a large observational study of over 16 000 patients with a principal discharge diagnosis of heart failure found a reduced mortality (hazard ratio [HR] 0.87; 95% CI 0.80, 0.94) in those prescribed thiazolidinediones. This benefit was offset by an increased risk of readmission with heart failure (HR 1.06; 95% CI 1.00, 1.09). Despite an increase in fluid-related events, recent studies suggest that individuals with type 2 diabetes mellitus and heart failure (New York Heart Association grade I/II) can be treated with thiazolidinediones with appropriate monitoring and adjustment of heart failure therapies. These findings would suggest the need for large-scale, prospective trials to investigate the safety and potential benefits of thiazolidinedione use in patients with diabetes mellitus and heart failure.     

Vildagliptin: the evidence for its place in the treatment of type 2 diabetes mellitus

Introduction:

Type 2 diabetes is increasing in prevalence worldwide and is a leading cause of morbidity and mortality, mainly due to the development of complications. Vildagliptin is an inhibitor of dipeptidyl peptidase 4 (DPP-4), a new class of oral antidiabetic agents.

Aims:

To evaluate the role of vildagliptin in the management of type 2 diabetes.

Evidence review:

Clear evidence shows that vildagliptin improves glycemic control (measured by glycosylated hemoglobin and blood glucose levels) more than placebo in adults with type 2 diabetes, either as monotherapy or in combination with metformin. Vildagliptin is as effective as pioglitazone and rosiglitazone, and slightly less effective than metformin, although better tolerated. Further glycemic control is achieved when adding vildagliptin to metformin, pioglitazone, or glimepride. There is evidence that vildagliptin improves beta-cell function and insulin sensitivity. Vildagliptin does not appear to be associated with weight gain or with a higher risk of hypoglycemia than placebo or other commonly used oral antidiabetic agents. Economic evidence is currently lacking.

Place in therapy:

Vildagliptin improves glycemic control with little if any weight gain or hypoglycemia in adult patients with type 2 diabetes when given alone or in combination with metformin, thiazolidinediones, or sulfonylureas. Since many diabetic patients require combination therapy, the complementary mechanism of action of vildagliptin and other commonly prescribed antidiabetic drugs represents an important new therapeutic option in diabetes management.     

Insulin sensitisation in the treatment of Type 2 diabetes

Type 2 diabetes is reaching epidemic proportions worldwide, fuelled by the increasing prevalence of obesity as many populations adopt a western lifestyle. Secondary complications affecting both the microvascular and macrovascular systems are responsible for premature mortality in Type 2 diabetes, with two thirds or more dying of cardiovascular disease. Two interacting metabolic defects, insulin resistance and β-cell dysfunction are present in Type 2 diabetes. It is now recognised that insulin resistance is central to a cluster of metabolic abnormalities – called the insulin resistance syndrome – that are responsible for the excess of cardiovascular disease. Older antidiabetic agents such as the sulfonylureas, metformin and insulin are more effective than lifestyle modification in reducing microvascular complications of Type 2 diabetes, but overall do not reduce cardiovascular risk. Metformin, although no more effective as a glucose-lowering agent than sulfonylureas or insulin, does significantly reduce cardiovascular disease, probably as a result of its weak insulin-sensitising action. The newly-marketed thiazolidinedione insulin-sensitising antidiabetic agents also improve multiple biomarkers of cardiovascular risk, suggesting that novel approaches to insulin sensitisation will not only provide effective long-term glycaemic control but improve cardiovascular outcomes in Type 2 diabetes. Multiple therapeutic targets within the insulin signalling cascade are being explored, together with follow-up compounds to the first generation thiazolidinediones. These initiatives, together with developments in β₃-adrenoceptor agonists, 11βhydroxysteroid dehydrogenase Type 1 inhibitors and modulators of the glucagon-like peptide 1 axis, all of which also potentially enhance insulin sensitivity, are critically evaluated.