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.     

Treatment of type 2 diabetes: inadequate assessment of oral antidiabetic combinations

(1) Metformin and glibenclamide are the only oral antidiabetics with a proven impact on the complications of type 2 diabetes. (2) Treatment with one of these drugs often fails to achieve the recommended target in HbA1c level (below 7%). (3) Only one randomised trial has assessed the preventive efficacy of a combination of oral antidiabetics when hyperglycaemia persists despite treatment with a glucose-lowering sulphonylurea. The trial showed that combining metformin and a glucose-lowering sulphonylurea is associated with a higher mortality than therapy with a sulphonylurea alone. (4) Despite this result, most clinical guidelines recommend the metformin + glucose-lowering sulphonylurea combination when oral antidiabetic monotherapy fails. (5) In the absence of convincing data supporting any particular strategy, all options should be discussed with patients including continuing with oral antidiabetic monotherapy, or starting insulin.     

Effects of the combination of SGLT2 selective inhibitor ipragliflozin and various antidiabetic drugs in type 2 diabetic mice

The sodium-glucose cotransporter 2 (SGLT2) is responsible for most glucose reabsorption in the kidney and has been proposed as a novel therapeutic target for the treatment of type 2 diabetes. In the present study, the combinatory effects of SGLT2 selective inhibitor ipragliflozin and various antidiabetic drugs in high-fat diet and streptozotocin-nicotinamide-induced type 2 diabetic mice were investigated. Ipragliflozin dose-dependently increased urinary glucose excretion and improved glucose tolerance. In addition, each antidiabetic drug (mitiglinide, glibenclamide, sitagliptin, insulin, metformin, voglibose, or rosiglitazone) also significantly improved glucose tolerance without affecting urinary glucose excretion. Combination treatment of ipragliflozin with each antidiabetic drug additively improved glucose tolerance. In these experiments, ipragliflozin-induced increases in urinary glucose excretion were not influenced by combination treatment with antidiabetic drugs. Further, ipragliflozin did not affect antidiabetic drug-induced insulinotropic action (mitiglinide and glibenclamide), increases in plasma glucagon-like peptide-1 and insulin levels via inhibition of dipeptidyl peptidase 4 activity (sitagliptin), increases in plasma insulin level (insulin), decreases in hepatic phosphoenolpyruvate carboxykinase activity (metformin), inhibition of small intestinal disaccharidase activity (voglibose), or improvement of impaired insulin secretion (rosiglitazone). These results suggest that combination treatment of ipragliflozin with various antidiabetic drugs additively enhances the improvement in glucose tolerance without affecting each drug’s unique pharmacological effects. Ipragliflozin may therefore be expected to be effective when administered as part of a combination regimen in the treatment of type 2 diabetes.     

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.     

Hypoglycaemic effects of antidiabetic drugs in streptozotocin-nicotinamide-induced mildly diabetic and streptozotocin-induced severely diabetic rats

In this study, streptozotocin-induced severely diabetic rats and streptozotocin-nicotinamide-induced mildly diabetic rats were established to compare their characteristics and to investigate the hypoglycaemic effects of antidiabetic drugs. Results show that in streptozotocin-induced severely diabetic rats, the pancreatic insulin content decreased to approximately 10% of that in normal rats. These severely diabetic rats also exhibited marked hyperglycaemia and impaired glucose tolerance due to insulin secretory deficiency. In contrast, the pancreatic insulin content was approximately 50% of normal levels in streptozotocin-nicotinamide-induced mildly diabetic rats. These mildly diabetic rats exhibited moderate hyperglycaemia and impaired glucose tolerance due to loss of early-phase insulin secretion. Voglibose (alpha-glucosidase inhibitor), metformin (biguanide), glibenclamide (sulfonylurea), sitagliptin (dipeptidyl peptidase-4 inhibitor) and insulin significantly improved glucose tolerance in streptozotocin-nicotinamide-induced mildly diabetic rats. In contrast, in streptozotocin-induced severely diabetic rats, voglibose, metformin and insulin significantly improved glucose tolerance, but no significant effect was observed for glibenclamide and sitagliptin due to a decreased insulinotropic effect. These results suggest that streptozotocin-nicotinamide-induced mildly diabetic rats, which exhibit a mild decline in glucose tolerance due to loss of early-phase insulin secretion, are sensitive to the hypoglycaemic effects of insulinotropic agents and have many pathological features resembling type 2 diabetes, which may be useful in the pharmacological investigation of numerous antidiabetic drugs.     

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.     

Insulin glargine added to therapy with oral antidiabetic agents improves glycemic control and reduces long-term complications in patients with type 2 diabetes - a simulation with the Diabetes Mellitus Model (DMM)

OBJECTIVE: The purpose of this study was to compare the effect of two insulin therapies with respect to long-term complications in type 2 diabetes patients using the Diabetes Mellitus Model (DMM). The therapies under investigation were insulin glargine combined with the oral antidiabetic agents, glimepiride and metformin, (BOT = basal supported oral treatment) and premixed insulin (CT = conventional therapy). METHODS: The DMM predicts complications over a 10-year period using data from published studies. Particular interest is placed on the influence of HbA1c levels related to time. The simulations are based on 10,000 virtual patients taking BOT and CT and the clinical data are based on the results of the LAPTOP study (Lantus + Amaryl + metformin versus premixed insulin in patients with type 2 diabetes mellitus after failing oral treatment pathways) comparing BOT and CT for 24 weeks. The simulations were performed in patients aged 60 A+/- 9 years with type 2 diabetes in which the duration of disease had a baseline of 9 A+/- 7 years. Sensitivity analyses were carried out by changing the response rate of those on BOT, the age of patients and duration of diabetes. RESULTS: The overall relative risk reductions obtained with BOT versus CT for the base case are, 11% for the nervous and vascular systems, 7% for the renal system, 5% for ophthalmic disorders, 3% for the cardiovascular system and mortality and 6% for any kind of event after 10 years. The advantages of BOT were robust to all the changes in the sensitivity analyses. When compared with the base case, the best therapeutic effects were obtained in younger patients who had been diabetic for a shorter period. CONCLUSIONS: Using the DMM data from the LAPTOP study, simulations based on both therapies showed that the BOT regimen provides better glycemic control and reduction in HbA1c thereby leading to a reduction in the long-term complications of diabetes and mortality.     

Antidiabetic agents in patients with chronic kidney disease and end-stage renal disease on dialysis: metabolism and clinical practice

Numerous drugs with different mechanisms of action and different pharmacologic profiles are being used with the aim of improving glycemic control in patients with type 2 diabetes. Therapeutic options for patients with type 2 diabetes and chronic kidney disease (CKD) are limited because a reduced glomerular filtration rate results in the accumulation of certain drugs and/or their metabolites. Conventional oral hypoglycemic agents, such as sulfonylurea (SU), are not suitable due to the risk of prolonged hypoglycemia; furthermore, metformin is contraindicated for moderate to advanced CKD. Therefore, in order to achieve good glycemic control, insulin injection therapy remains the mainstay of treatment in diabetic patients with moderate to advanced CKD, particularly in those receiving dialysis therapy. However, some agents have been used even in patients with CKD. Repaglinide and mitiglinide are rapid- and short-acting insulinotropic SU receptor ligands. They are rarely accompanied by hypoglycemia, and are attractive therapeutic options even in the dialysis population. In addition, alpha-glucosidase inhibitors are rarely accompanied by hypoglycemia and are administered without dose adjustments in dialysis patients. However, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines recommended that alpha-glucosidase inhibitors should be avoided in patients with advanced stage CKD and on dialysis. Furthermore, mitiglinide is not currently used in the US. Thus, recommended oral antidiabetic agents differ between countries. Moreover, dipeptidyl peptidase-4 inhibitors and incretin mimetics are new antihyperglycemic agents, which may be used more frequently in the future in patients with type 2 diabetes and CKD. Here, we describe the pharmacokinetics, metabolism, clinical efficacy, and safety of oral Antidiabetic agents for patients with CKD, including those receiving dialysis.     

Interindividual variability in oral antidiabetic drug disposition and response: the role of drug transporter polymorphisms

BACKGROUND: Numerous effective oral pharmacologic therapies are available to treat type 2 diabetes. However, a substantial number of patients do not achieve the expected glucose-lowering response, or may be predisposed to adverse effects, from these agents. The application of pharmacogenetics to the field of type 2 diabetes is one step towards the goal of improved pharmacotherapeutic management of this progressive disease. METHODS: A PubMed literature search was conducted to identify clinical studies that have examined the extent to which drug-transporter gene polymorphisms influence interindividual variability in oral antidiabetic drug disposition and response in humans. RESULTS/CONCLUSION: Available data suggest that drug transporters play an important role in the disposition of some oral antidiabetic drugs in the body, particularly the meglitinides and metformin. Moreover, polymorphisms in genes encoding drug transport proteins may alter the pharmacodynamic profile of these agents. Drug transporters, drug-metabolizing enzymes, and drug targets each play a distinct and important role in the disposition and action of many oral antidiabetic agents. Thus, future studies may need to take a pharmacogenomic (i.e., multiple gene) approach in order to comprehensively understand the extent to which genetic variation contributes to interindividual differences in oral antidiabetic drug clinical pharmacology.     

Effects of antidiabetic drugs in high-fat diet and streptozotocin-nicotinamide-induced type 2 diabetic mice

Based on previously established methods, we developed an easily available type 2 diabetic mouse model that exhibits obesity and insulin resistance. We investigated the effects of several antidiabetic drugs on this new model, which was induced by a high-fat diet in combination with streptozotocin and nicotinamide injection. Male ICR mice were fed a high-fat diet (45% of calories as fat) for 3weeks and then intraperitoneally administered with nicotinamide (1000mg/kg) and streptozotocin (150mg/kg). These diabetic mice exhibited hyperglycemia and glucose intolerance as a result of the loss of early-phase insulin secretion. The mice also developed significant insulin resistance, hyperlipidemia and obesity. A single dose of mitiglinide, glibenclamide, sitagliptin, insulin, metformin and voglibose significantly improved glucose tolerance during a liquid meal tolerance test. Repeated administration of sitagliptin and rosiglitazone also improved hyperglycemia and insulin resistance. These results demonstrate that a high-fat diet combined with nicotinamide and streptozotocin injection induces a diabetic mouse model that replicates the metabolic characteristics of human type 2 diabetes. This diabetic model, which exhibits impaired insulin secretion, glucose intolerance, insulin resistance, and obesity, may be suitable to evaluate antidiabetic agents for the treatment of type 2 diabetes.     

Insulin in type 2 diabetes: a useful alternative despite limited assessment based on surrogate endpoints

(1) There are few clinical trials comparing combination therapy with a sulphonylurea and metformin after oral antidiabetic monotherapy fails to provide adequate glycaemic control. The UKPDS study suggested that this combination had a negative impact on mortality. (2) The assessment of insulin therapy in patients in whom oral antidiabetic therapy fails is based solely on surrogate endpoints: mainly HbA1c (glycated haemoglobin), bodyweight, and the frequency of hypoglycaemia. (3) In a comparative randomised trial involving patients whose glucose levels were no longer controlled by a sulphonylurea, the addition of metformin or a daily injection of insulin isophane (NPH) was similarly effective in reducing HbA1c levels. However, metformin caused less weight gain. (4) There are no randomised controlled trials comparing the addition of insulin versus a sulphonylurea when ongoing metformin monotherapy is inadequate. (5) Randomised comparative trials show that, when glycaemia is no longer controlled by a sulphonylurea plus metformin, adding a daily insulin injection is more effective in lowering HbA1c levels than the addition of acarbose and as effective as adding a glitazone. The adjunction of insulin appears to have a better risk-benefit balance than an oral three-drug regimen. (6) Several randomised controlled trials have shown that the addition of an oral antidiabetic to ongoing insulin therapy reduces HbA1c levels in patients with type 2 diabetes. The addition of metformin is also beneficial in terms of body weight changes. (7) Nine randomised controlled trials involving patients whose glycaemia was inadequately controlled by a sulphonylurea, alone or in combination with metformin, have compared the addition of a bedtime injection of insulin isophane versus replacement of the oral antidiabetics by several daily insulin injections. The two strategies had a similar impact on HbA1c (-1.5% to -2.5%), but patients experienced less weight gain when the oral antidiabetics were continued and a single insulin injection was added. (8) The few available comparative trials fail to show which oral treatment (a sulphonylurea, metformin, or a combination of the two) has the best risk-benefit balance when combined with a bedtime injection of insulin isophane. (9) Insulin isophane is the first-choice insulin for combination therapy with an oral antidiabetic. In comparative trials, when combined with an oral antidiabetic, insulin glargine was no more effective than insulin isophane in terms of HbA1c levels or weight gain. Insulin glargine seems to provoke less hypoglycaemia but, in the absence of adequate follow-up, its long-term adverse effects are not known. (10) When a bedtime insulin injection plus an oral antidiabetic fail to control hyperglycaemia, indirect comparisons support the use of several daily insulin injections plus metformin, or three injections of an ultrarapid insulin analogue plus a sulphonylurea.     

Sitagliptin with metformin: profile of a combination for the treatment of type 2 diabetes

Sitagliptin, a novel orally-active dipeptidyl-peptidase (DPP-4) inhibitor has been introduced into type 2 diabetes therapy. Sitagliptin inhibits the degradation of glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), as well as that of other regulatory peptides important for glucose homeostasis. It reduces haemoglobin A1c (HbA1c), fasting and postprandial glucose by glucose- dependent stimulation of insulin secretion and inhibition of glucagon secretion. Sitagliptin is weight neutral. Indirect measures show a possible improvement of beta-cell function. Sitagliptin does not cause hypoglycemia when compared to metformin or placebo. Metformin, which has a different unique mechanism, has been used in type 2 diabetes for approximately 50 years. Metformin improves insulin resistance and is the first-line antidiabetic drug in use today. The combination of a DPP-4 inhibitor with metformin allows a broad and complementary spectrum of antidiabetic actions. This combination does not increase the risk of hypoglycaemia nor does it promote weight gain, an adverse effect of various other oral antidiabetic combinations. This article gives an overview of the data available on the combined antidiabetic effects of metformin and sitagliptin.     

Pioglitazone and rosiglitazone for diabetes

Pioglitazone (Actos-Takeda) and rosiglitazone (Avandia-GlaxoSmithKline) belong to a new class of oral antidiabetic medicines (the glitazones or thiazolidinediones). Both are licensed in the UK for "oral combination treatment of type 2 diabetes mellitus in [narrowly defined groups of] patients with insufficient glycaemic control despite maximal tolerated dose of oral monotherapy with either metformin or a sulphonylurea". They are not licensed for use as monotherapy, in combination with insulin, or as part of triple therapy with metformin or a sulphonylurea. What can pioglitazone and rosiglitazone offer in the management of patients with type 2 diabetes?     

Lack of pharmacokinetic interaction for ISIS 113715, a 2'-0-methoxyethyl modified antisense oligonucleotide targeting protein tyrosine phosphatase 1B messenger RNA, with oral antidiabetic compounds metformin, glipizide or rosiglitazone

BACKGROUND: ISIS 113715 is a 20-mer phosphorothioate antisense oligonucleotide (ASO) that is complementary to the protein tyrosine phosphatase 1B (PTP-1B) messenger RNA and subsequently reduces translation of the PTP-1B protein, a negative regulator of insulin receptor. ISIS 113715 is currently being studied in early phase II clinical studies to determine its ability to improve or restore insulin receptor sensitivity in patients with type 2 diabetes mellitus. Future work will investigate the combination of ISIS 113715 with antidiabetic compounds. METHODS: In vitro ultrafiltration human plasma protein binding displacement studies and a phase I clinical study were used to characterise the potential for pharmacokinetic interaction of ISIS 113715 and three marketed oral antidiabetic agents. ISIS 113715 was co-incubated with glipizide and rosiglitazone in whole human plasma and tested for increased free drug concentrations. In a phase I clinical study, 23 healthy volunteers received a single oral dose of an antidiabetic compound (either metformin, glipizide or rosiglitazone) both alone and together with subcutaneous ISIS 113715 200 mg in a sequential crossover design. A comparative pharmacokinetic analysis was performed to determine if there were any effects that resulted from coadministration of ISIS 113715 with these antidiabetic compounds. RESULTS: In vitro human plasma protein binding displacement studies showed only minor effects on rosiglitazone and no effect on glipizide when co-incubated with ISIS 113715. The results of the phase I clinical study further indicate that there were no measurable changes in glipizide (5 mg), metformin (500 mg) or rosiglitazone (2 mg) exposure parameters, maximum plasma concentration and the area under the concentration-time curve, or pharmacokinetic parameter, elimination half-life when coadministered with ISIS 113715. Furthermore, there was no effect of ISIS 113715, administered in combination with metformin, on the urinary excretion of metformin. Conversely, there were no observed alterations in ISIS 113715 pharmacokinetics when administered in combination with any of the oral antidiabetic compounds. CONCLUSION: These data provide evidence that ISIS 113715 exhibits no clinically relevant pharmacokinetic interactions on the disposition and clearance of the oral antidiabetic drugs. The results of these studies support further study of ISIS 113715 in combination with antidiabetic compounds.     

Insulin and GLP-1 analog combinations in type 2 diabetes mellitus: a critical review

Introduction: Glucagon-like peptide-1 (GLP-1) receptor agonists have been used in clinical management of type 2 diabetes since 2005. Currently approved agents were initially developed and approved for combination therapy with oral antidiabetic drugs (OADs). The potential for combined use with insulin has garnered increasing attention due to the potential to reduce side effects associated with insulin therapy and improve glycemic control. Areas covered: We reviewed published and other publicly released data from controlled and uncontrolled studies that included subjects treated with insulin/GLP-1 analog combination therapy. The currently available guidance for clinical practice when combining insulin and GLP-1 analogs was also summarized. Expert opinion: Limited data currently available from placebo-controlled trials support the use of exenatide twice daily or liraglutide once daily in combination with basal insulin and metformin in subjects with type 2 diabetes unable to attain treatment goals. Several randomized controlled trials are currently studying combinations of insulin with various GLP-1 analogs. Additional guidance on the clinical use of these combinations will likely be forthcoming once these studies are reported. Insulin/GLP-1 analog combinations will require optimization of blood glucose monitoring strategies and delivery systems to decrease the risk of administration errors and reduce the potential complexity of these regimens.     

The development of an oral antidiabetic combination tablet: design,evaluation and clinical benefits for patients with type 2 diabetes

Type 2 diabetes is a chronic and progressive disease. Oral antidiabetic monotherapies directly address only one defect as their primary mechanism of action, and do not control blood glucose sufficiently well to meet current glycaemic targets. In consequence, most patients need combination therapy within a few years. However, the co-administration of two or more oral antidiabetic drugs may render treatment regimens difficult to follow. Combining oral antidiabetic agents into a single tablet provides a means of intensifying antidiabetic therapy while supporting good patient compliance. An insulin sensitiser and an insulin secretagogue represent a rational oral antidiabetic combination, as they address the dual endocrine defects of insulin resistance and impaired beta-cell function in type 2 diabetes. Nevertheless, the components of a combination tablet must be carefully chosen. Metformin (an insulin sensitiser) and glibenclamide (an insulin secretagogue) are well supported by decades of clinical evidence, and the pharmacokinetics of these agents support twice-daily co-administration. The final technical challenge is to optimise their delivery within a single-tablet combination. A recently-introduced metformin-glibenclamide combination tablet (Glucovance) has been extensively studied in well-designed clinical trials, where it has been shown to be more effective than its component monotherapies in controlling fasting and postprandial glycaemia. This treatment provides a case study in the development of a single-tablet oral antidiabetic combination, in terms of the pharmacokinetic issues facing the development of this preparation, and the implications of the pharmacokinetic properties of the components of the combination tablet on their pharmacodynamic actions and risk-benefit profile.     

Role of antioxidants, essential fatty acids, carnitine, vitamins, phytochemicals and trace elements in the treatment of diabetes mellitus and its chronic complications

Nowadays, the treatment of diabetes mellitus is based on the variable use and combination of diet, antidiabetic oral agents (metformin, sulphanylureas, glynides, acarbose and thiazolidinediones) and insulin or its analogs, depending on the type of diabetes and the needs of the patient. The prevention and treatment of chronic micro- and macrovascular complications, on the other hand, is based on the achievement and maintenance of an optimal glycaemic control and requires the combined use of adjunctive therapy such as antihypertensive drugs and cholesterol-lowering medications. Furthermore, several herbal preparations and dietary supplements, such as antioxidants, essential fatty acids, lipid metabolism activators, vitamins and trace elements, are advertised and prescribed to patients as a useful adjuvant to a diabetic diet and conventional medications in order to improve glycaemic control and reduce the impact of chronic complications. In this regard, we have attempted to review the current concepts dealing with the usefulness of these complementary therapies in treating diabetic patients.     

Diabetes mellitus and increased risk of cancer: focus on metformin and the insulin analogs

Type 2 diabetes mellitus has been associated with an increased risk of hepatic, pancreatic, colon, endometrial, breast, and bladder cancer. Although a mechanism of action for the increased risk has been postulated, no definitive evidence has been completely elucidated in the medical literature. Results of recently released studies documented the use of specific antidiabetic drugs with increased rates of cancer. The insulin analog glargine was the focus of four observational studies published in 2009 that outlined an increase in the rates of cancer associated with its use. In contrast, the use of metformin has been shown to possibly decrease the rate of specific cancers when used in the treatment of type 2 diabetes. These data regarding cancer risk and antidiabetic drugs are contradictory and at this time are inconclusive. Until results of long-term randomized prospective studies are available to elucidate a correlation with cancer and insulin, we must continue treating diabetes in order to avert the long-term complications of the disease.     

Evolving strategies for insulin delivery and therapy

It has now been conclusively proven that adequate control of blood glucose delays or prevents the progression of diabetic complications. In order to achieve the suggested targets for glycaemic control necessary to reduce the incidence of diabetic complications, it has been established that a more intensive insulin regimen requiring multiple insulin injections is required for patients with type 1 diabetes mellitus. For patients with type 2 diabetes, oral antidiabetic therapy is generally used initially, but given the natural history of type 2 diabetes and the need to achieve improved glycaemic control, earlier use of insulin has been promoted. However, the use of insulin in more intensive regimens for the patient with type 1 diabetes or for earlier treatment of the patient with type 2 diabetes is not routine. Many factors are responsible for this observation. Nevertheless, available device options such as insulin pens or insulin pumps are routinely available for implementation of intensive insulin therapy. However, a major limitation for advancing to intensive insulin therapy is that the only viable way to administer insulin is through injection. Delivery options that use dermal, nasal and oral approaches have been explored. The oral approach may include gastrointestinal, buccal or pulmonary uptake. Recent evidence shows that delivery of insulin via the oral cavity with uptake occurring in the pulmonary alveoli may be the most viable clinical option in the future.     

清远市清新区2型糖尿病患者降糖药物的用药分析

目的：调查分析广东省清远市清新区2型糖尿病患者的降糖药物使用情况,为临床合理用药提供参考。方法：选择广东省清远市清新区2380例2型糖尿病患者作为研究对象,发放调查问卷进行调查,并对降糖药物使用情况进行总结分析。结果：药物使用中使用比例较高的为双胍类,使用率为89.97%,其次为磺脲类和α-糖苷酶抑制剂,使用率分别为71.97%和55.97%。药物使用频率较高的则是盐酸二甲双胍与阿卡波糖,使用频率分别为79.03%和57.02%。双胍类+磺脲类降糖药物组合使用率为71.47%,是既往使用药物类别组合中比例最大的,其次为双胍类+磺脲类+α-糖苷酶抑制剂药物组合,占50.63%。空腹血糖（FBG）和2hPBG水平较低的患者的病程相对较短、服用降糖药物品种较少,FBG和2hPBG水平较高的患者,病程相对较长、服用降糖药物品种较多。病程较短的患者合并症与服用降糖药物品种相对较少,病程较长的患者的合并症与服用降糖药物品种相对较多。结论：广东省清远市清新区2型糖尿病患者降糖药物的用药较为科学合理,符合临床治疗规范,部分通过降糖药物控制血糖不理想的患者,可应用胰岛素进行治疗。