Exenatide extended-release: a review of its use in type 2 diabetes mellitus

Subcutaneous exenatide extended-release (ER; Bydureon?; also known as exenatide once weekly), a glucagon-like peptide-1 receptor agonist, provides a convenient, simple, once-weekly regimen that is approved in adult patients with type 2 diabetes as adjunctive monotherapy to diet plus exercise (in the US; not as first-line therapy) and/or as combination therapy with specific oral antihyperglycaemic drugs (OADs) in patients with inadequately controlled type 2 diabetes despite treatment with these OADs (US and Europe). This article reviews the clinical efficacy and tolerability of exenatide ER in the treatment of adult patients with type 2 diabetes and gives a brief overview of its pharmacological properties. In several short-term (24-30 weeks) well designed trials, adjunctive subcutaneously injectable exenatide ER once weekly, as monotherapy or in combination with OADs, significantly improved glycaemic control, bodyweight and some surrogate markers of cardiovascular risk in adult patients with inadequately controlled type 2 diabetes despite diet and exercise and/or treatment with OADs. Furthermore, the beneficial effects of adjunctive exenatide ER therapy were sustained in extension studies of up to 3 years of treatment. Overall, the intensity of glycaemic control with exenatide ER was generally better than that observed with the exenatide immediate-release formulation (twice daily), sitagliptin or insulin glargine. Exenatide ER was shown to be noninferior to metformin in terms of glycaemic efficacy, but did not meet the criteria for noninferiority versus liraglutide. In treatment-naive patients, exenatide ER treatment did not meet noninferiority criteria versus pioglitazone, whereas in treatment-experienced patients, exenatide ER provided better glycaemic control than pioglitazone. Improvements in glycaemic control with exenatide ER and, in general, with other antihyperglycaemic agents were reflected in significant improvements from baseline in treatment satisfaction and health-related quality-of-life measures. Exenatide ER was generally well tolerated in patients participating in these trials, with most treatment-emergent adverse events being of a gastrointestinal nature, of mild to moderate severity, transient and of a similar nature and incidence to those occurring with the exenatide immediate-release formulation. Thus, exenatide ER is a useful option for the treatment of type 2 diabetes, particularly in patients where bodyweight loss is an essential aspect of the individual patient's management.     

Empagliflozin added to metformin and sulfonylurea therapy in patients with sub-optimally controlled type 2 diabetes mellitus

The combination of metformin and a sulfonylurea is commonly used in type 2 diabetes mellitus. Many patients on this combination therapy do not achieve or maintain glycemic targets and require the addition of a third antihyperglycemic agent. Among the options are the sodium glucose cotransporter 2 (SGLT2) inhibitors, a recently developed class of medications that effectively improve glycemic control and are associated with reduction in body weight and blood pressure. This article evaluates a 24-week, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin, added to metformin plus sulfonylurea regimens. Empagliflozin led to significant reductions in glycated hemoglobin and fasting plasma glucose, as well as body weight and systolic blood pressure. Adverse events typically recorded with SGLT2 inhibitors were observed; notably, genital infections occurred in more patients on empagliflozin than placebo. Overall, empagliflozin was well tolerated. These results indicate that SGLT2 inhibitors can be successfully added to metformin plus sulfonylurea regimens. SGLT2 inhibitors are not the only therapeutic option in this clinical situation; however, based on the secondary effects observed in this and other studies, they appear to be of particular value for patients who are obese or overweight.     

Pioglitazone as monotherapy or in combination with sulfonylurea or metformin enhances insulin sensitivity (HOMA-S or QUICKI) in patients with type 2 diabetes

BACKGROUND: Miyazaki et al. demonstrated using the hyperinsulinemic, euglycemic clamp that pioglitazone (PIO) enhanced insulin sensitivity in patients (n = 23) with type 2 diabetes (T2D). Although considered the reference method for measuring insulin sensitivity, the clamp is seldom used in large clinical trials because of its complexity.The Homeostasis Model Assessment Insulin Sensitivity (HOMA-S) and Quantitative Insulin Sensitivity Check Index (QUICKI) are two alternative insulin sensitivity surrogates that correlate with the clamp method and are suitable for use with large study populations. STUDY AIM: To evaluate the effect of PIO monotherapy and in combination therapy with sulfonylurea (SU) or metformin (MET) on insulin sensitivity as assessed by HOMA-S and QUICKI in a large group of patients (approximately 1000). Research design and methods: Patient data from three randomized, double blind, multicenter, parallel group, placebo-controlled registration trials (Studies-001 PIO monotherapy and 010 and 027 combination therapy with SU or MET, respectively) were analyzed for this study.We evaluated insulin sensitivity for all three studies using HOMA-S and QUICKI. RESULTS: PIO 15, 30 and 45 mg enhanced HOMA-S compared with baseline (56.9-63.6%, p = 0.0298); (53.7-64.7%, p = 0.0008); (59.0-75.9%, p < 0.0001), respectively. Only the 45 mg dose showed a difference from placebo (p = 0.0025). Similarly, PIO enhanced QUICKI versus baseline (0.290-0.296, p = 0.0026); (0.287-0.299, p = 0.0001); (0.290-0.306, p = 0.0001), respectively. Both the 30 and 45 mg doses were different from placebo for QUICKI (p = 0.0005, p < 0.0001). PIO 15 and 30 mg plus SU enhanced HOMA-S compared with baseline (58.4-66.7%, p = 0.0007; 53.2-68.4%, p < 0.0001) and placebo plus SU (p = 0.0129, p < 0.0001, respectively). Likewise, PIO 15 and 30 mg plus SU enhanced QUICKI versus baseline (0.289-0.300, p = 0.0001; 0.287-0.305, p = 0.0001, respectively). Both doses had different effects from placebo plus SU (p = 0.0001) for QUICKI. PIO 30mg combined with MET enhanced HOMA-S versus baseline (66.2-82.2%, p < 0.0001) and placebo plus MET (p = 0.0002). Similarly, PIO 30 mg plus MET enhanced QUICKI compared with baseline (0.295-0.309, p = 0.0001) and placebo plus MET (p = 0.0001). CONCLUSION: PIO monotherapy and combination therapy with SU or MET enhanced insulin sensitivity as evaluated by HOMA-S and QUICKI. Both measures can detect changes in sensitivity for large numbers of subjects when the reference method hyperinsulinemic euglycemic clamp, or other complex methods are not feasible.     

Pioglitazone as monotherapy or in combination with sulfonylurea or metformin enhances insulin sensitivity (HOMA-S or QUICKI) in patients with type 2 diabetes

Background: Miyazaki etal, demonstrated using the hyperinsulinemic, euglycemic clamp that pioglitazone (PIO) enhanced insulin sensitivity in patients (n?=?23) with type 2 diabetes (T2D). Although considered the reference method for measuring insulin sensitivity, the clamp is seldom used in large clinical trials because of its complexity. The Homeostasis Model Assessment-Insulin Sensitivity (HOMA-S) and Quantitative Insulin Sensitivity Check Index (QUICKI) are two alternative insulin sensitivity surrogates that correlate with the clamp method and are suitable for use with large study populations.

Study aim: To evaluate the effect of PIO monotherapy and in combination therapy with sulfonylurea (SU) or metformin (MET) on insulin sensitivity as assessed by HOMA-S and QUICKI in a large group of patients (～1000).

Research design and methods: Patient data from three randomized, double blind, multicenter, parallel group, placebo-controlled registration trials (Studies-001 PIO monotherapy and 010 and 027 combination therapy with SU or MET, respectively) were analyzed for this study. We

evaluated insulin sensitivity for all three studies using HOMA-S and QUICKI.

Results: PIO 15, 30 and 45?mg enhanced HOMA-S compared with baseline (56.9-63.6%, p?=?0.0298); (53.7-64.7%, p?=?0.0008); (59.0-75.9%, p?<?0.0001), respectively. Only the 45?mg dose showed a difference from placebo (p?=?0.0025). Similarly, PIO enhanced QUICKI versus baseline (0.290-0.296, p?=?0.0026); (0.287-0.299, p?=?0.0001); (0.290-0.306, p?=?0.0001), respectively. Both the 30 and 45mg doses were different from placebo for QUICKI (p?=?0.0005, p?<?0.0001). PIO 15 and 30mg plus SU enhanced HOMA-S compared with baseline (58.4–.7%, p?=?0.0007; 53.2–68.4%, p?<?0.0001) and placebo plus SU (p?=?0.0129, p?<?0.0001, respectively). Likewise, PIO 15 and 30?mg plus SU enhanced QUICKI versus baseline (0.289-0.300, p?=?0.0001; 0.287-0.305, p?=?0.0001, respectively). Both doses had different effects from placebo plus SU (p?=?0.0001) for QUICKI. PIO 30mg combined with MET enhanced HOMA-S versus baseline (66.2–82.2%, p?<?0.0001) and placebo plus MET (p?=?0.0002).     

Pioglitazone: a review of its use in type 2 diabetes mellitus

Pioglitazone is an antihyperglycaemic agent that, in the presence of insulin resistance, increases hepatic and peripheral insulin sensitivity, thereby inhibiting hepatic gluconeogenesis and increasing peripheral and splanchnic glucose uptake. Pioglitazone is generally well tolerated, weight gain and oedema are the most common emergent adverse events, and there are no known drug interactions between pioglitazone and other drugs. In clinical trials in patients with type 2 diabetes mellitus, pioglitazone as monotherapy, or in combination with metformin, repaglinide, insulin or a sulphonylurea, induced both long- and short-term improvements in glycaemic control and serum lipid profiles. Pioglitazone was also effective in reducing some measures of cardiovascular risk and arteriosclerosis. Pioglitazone thus offers an effective treatment option for the management of patients with type 2 diabetes.     

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

Rosiglitazone (Avandia) is an antihyperglycaemic agent of the thiazolidinedione class that improves glycaemic control (as indicated by glycosylated haemoglobin [HbA1c] and fasting plasma glucose [FPG] levels) primarily by increasing hepatic and peripheral insulin sensitivity, and in addition may help to preserve pancreatic beta-cell function. In general, rosiglitazone as monotherapy or in combination with other antihyperglycaemic agents, including metformin or sulfonylureas, improves glycaemic control in adults with type 2 diabetes mellitus and may slow disease progression associated with pancreatic beta-cell function decline. Rosiglitazone is generally well tolerated; however, additional long-term and comparative studies are required to further evaluate the effects of rosiglitazone on bone and the potential cardiovascular risk of the drug, including the risk relative to pioglitazone. Thus, in light of recent cardiovascular safety concerns and the need for further long-term data to clarify the potential risk of rosiglitazone in this regard, it would be prudent to use rosiglitazone in the treatment of type 2 diabetes on a case-by-case basis, taking into account individual patient cardiovascular risk factors.     

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

Vildagliptin (Galvus?, Jalra?, Xiliarx?) is an orally administered dipeptidyl peptidase-4 (DPP-4) inhibitor. In patients with type 2 diabetes mellitus, vildagliptin 50?mg twice daily is indicated for use in combination with metformin or a thiazolidinedione, and vildagliptin 50?mg once daily is indicated for use in combination with a sulfonylurea. A fixed-dose combination of vildagliptin/metformin (Eucreas?, Icandra?, Zomarist?) is also available. This article reviews the clinical efficacy and tolerability of vildagliptin in patients with type 2 diabetes, as well as summarizing its pharmacological properties. The efficacy of monotherapy or combination therapy with oral vildagliptin in patients with type 2 diabetes has been examined in randomized, double-blind, multicentre trials. Monotherapy with vildagliptin 50?mg once or twice daily reduced glycosylated haemoglobin (HbA(1c)) from baseline to a significantly greater extent than placebo, according to the results of 12- to 52-week trials in patients with type 2 diabetes. In terms of the reduction from baseline in HbA(1c) seen in active comparator trials of 12-104 weeks' duration, the noninferiority of vildagliptin 50?mg twice daily was established versus acarbose or rosiglitazone, the noninferiority of vildagliptin 100?mg once daily (an off-label dosage) versus metformin was established in elderly patients and vildagliptin 50?mg twice daily was more effective than voglibose; however, the noninferiority of vildagliptin 50?mg twice daily versus metformin or gliclazide was not established in two other trials. Combination therapy with vildagliptin 50?mg twice daily plus metformin improved HbA(1c) to a significantly greater extent than monotherapy with metformin and/or vildagliptin alone in patients with type 2 diabetes whose disease was inadequately controlled by metformin monotherapy or who were treatment naive, according to the results of 12- or 24-week trials. In addition, vildagliptin 50?mg twice daily plus metformin demonstrated noninferiority to pioglitazone plus metformin, glimepiride plus metformin or gliclazide plus metformin in terms of the change from baseline in HbA(1c) after 24 or 52 weeks' therapy in patients with inadequately controlled type 2 diabetes. The addition of vildagliptin 50?mg twice daily to pioglitazone or vildagliptin 50?mg once daily to glimepiride improved HbA(1c) to a significantly greater extent than a thiazolidinedione or glimepiride alone in patients with type 2 diabetes whose disease was inadequately controlled, according to the results of 24-week trials. Oral vildagliptin 50?mg once or twice daily was generally well tolerated in patients with type 2 diabetes. In particular, vildagliptin was associated with a low risk of hypoglycaemia and was weight neutral. Increases in transaminase levels were sometimes observed with a vildagliptin dosage of 100?mg once daily in clinical trials, and liver function should be monitored in patients receiving vildagliptin. However, meta-analyses of clinical trial data suggested that vildagliptin 50?mg once or twice daily was not associated with an increased risk of hepatic adverse events, transaminase elevations ≥3?×?the upper limit of normal, pancreatitis, cardiovascular or cerebrovascular events, infections or skin-related toxicity. In conclusion, vildagliptin is an important option for use in combination with metformin, a sulfonylurea or a thiazolidinedione in patients with type 2 diabetes who require combination therapy.     

Repaglinide: a review of its use in type 2 diabetes mellitus

Oral repaglinide (GlucoNorm?; NovoNorm?; Prandin?; Surepost?) is a rapid-acting insulin secretagogue that lowers postprandial glucose (PPG) excursions by targeting early-phase insulin release, with reductions in PPG considered to be important in reducing long-term cardiovascular complications of diabetes mellitus. Repaglinide, a carbamoylbenzoic acid derivative, is chemically related to the meglitinide class of insulin secretagogues, but unrelated to the sulfonylurea insulin secretagogues. Meglitinides, including repaglinide, have a distinct binding site at the β-cell membrane, which differs from that of sulfonylureas, and corresponds to greater insulinotropic effects with repaglinide than with glibenclamide and/or glimepiride and a more rapid onset of action in in vitro and in vivo studies. This article reviews the clinical efficacy and tolerability of oral repaglinide in the treatment of patients with type 2 diabetes and provides an overview of its pharmacological properties. In well designed clinical trials of up to 52 weeks' duration and in the clinical practice setting, recommended dosages of repaglinide (0.5-4?mg three times daily up to 30?minutes prior to a meal) provided effective glycaemic control and were generally well tolerated in treatment-naive or -experienced adult patients with type 2 diabetes, including elderly patients and those with renal impairment. Furthermore, as monotherapy or in combination with other oral antihyperglycaemic drugs, repaglinide was at least as effective as other oral antihyperglycaemic drugs at improving or maintaining glycaemic control, with a tolerability profile that was generally similar to that of sulfonylurea drugs and nateglinide. Thus, repaglinide remains an effective option for the management of patients with type 2 diabetes.     

Combination therapy in type 2 diabetes mellitus: adding linagliptin to a stable regimen of metformin and a sulfonylurea

Linagliptin, the most recently approved drug of the dipeptidyl peptidase-4 (DPP-4) inhibitor class, is an oral agent used to improve glycemic control in type 2 diabetes mellitus (T2DM). By inhibiting the DPP-4 enzyme, these drugs slow the inactivation of the endogenous incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), in turn reducing blood glucose levels in a glucose-dependent manner. As well as significantly reducing glycosylated hemoglobin, the class has a good safety profile, with a low incidence of hypoglycemia, and is not associated with weight gain. From a practical point of view, they also have simple regimens, generally with once-daily oral administration, and can be used as monotherapy or in combination with other anti-diabetic drugs. Owens and colleagues have reported a 6-month study of linagliptin add-on therapy in patients who were receiving a stable regimen of metformin and a sulfonylurea, but needed additional glycemic control. Linagliptin was associated with significant improvement in glycemic control and was well-tolerated by patients, indicating that it provides a valuable option for a large number of patients with T2DM, especially for those who would prefer to add an oral therapy to a current regimen.     

Combination therapy in type 2 diabetes mellitus: adding linagliptin to a stable regimen of metformin and a sulfonylurea

Linagliptin, the most recently approved drug of the dipeptidyl peptidase-4 (DPP-4) inhibitor class, is an oral agent used to improve glycemic control in type 2 diabetes mellitus (T2DM). By inhibiting the DPP-4 enzyme, these drugs slow the inactivation of the endogenous incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), in turn reducing blood glucose levels in a glucose-dependent manner. As well as significantly reducing glycosylated hemoglobin, the class has a good safety profile, with a low incidence of hypoglycemia, and is not associated with weight gain. From a practical point of view, they also have simple regimens, generally with once-daily oral administration, and can be used as monotherapy or in combination with other anti-diabetic drugs. Owens and colleagues have reported a 6-month study of linagliptin add-on therapy in patients who were receiving a stable regimen of metformin and a sulfonylurea, but needed additional glycemic control. Linagliptin was associated with significant improvement in glycemic control and was well-tolerated by patients, indicating that it provides a valuable option for a large number of patients with T2DM, especially for those who would prefer to add an oral therapy to a current regimen.     

Sitagliptin/metformin fixed-dose combination: in patients with type 2 diabetes mellitus

Sitagliptin/metformin is a single-tablet, fixed-dose combination of the dipeptidyl peptidase-4 inhibitor sitagliptin and the biguanide antihyperglycaemic metformin that achieves greater improvements in glycaemic control than either component alone in patients with type 2 diabetes mellitus. Recommended dosages of sitagliptin plus metformin, either as the fixed-dose tablet or a combination of the individual agents, significantly reduced glycosylated haemoglobin (HbA(1c)) levels in two well designed clinical trials in treatment-naive patients with type 2 diabetes. The improvements in glycaemic control seen with sitagliptin plus metformin therapy after 18 or 24 weeks were greater than those observed with the individual components alone and/or placebo, and sustained over treatment durations of up to 2 years. As add-on therapy in treatment-experienced patients with inadequate glycaemic control, the HbA(1c)-lowering efficacy of sitagliptin plus metformin was noninferior to that of glimepiride plus metformin in a 30-week, double-blind trial. Sitagliptin plus metformin and glipizide plus metformin lowered HbA(1c) levels by generally similar magnitudes, with the noninferiority of sitagliptin plus metformin to glipizide plus metformin being established in one 52-week study. As part of triple combination therapy, also in treatment-experienced patients with inadequate glycaemic control, sitagliptin added to ongoing glimepiride with or without metformin or ongoing insulin with or without metformin significantly improved glycaemic control over 24 weeks. Sitagliptin plus metformin, as the fixed-dose tablet or a combination of the individual agents, was generally well tolerated in patients with type 2 diabetes, and was associated with a low risk of hypoglycaemia.     

Empagliflozin/metformin fixed-dose combination: a review in patients with type 2 diabetes

Introduction: Most patients with type 2 diabetes, who receive monotherapy, are unable to maintain glucose levels with the progress of disease. Therefore, combination therapy with two or more anti-diabetic agents of different classes is highly desired. Sodium glucose co-transporter 2 (SGLT2) inhibitors improve glycemic control through increasing urinary glucose excretion, which is independent of β-cell function. In addition, they are generally well tolerated and associated with a low risk of hypoglycaemia. SGLT2 inhibitors as add-on therapy to metformin have an additive effect on glycemic control in patients with type 2 diabetes, and fixed-dose tablet is likely to reduce pill burden and then improve patients’ adherence.

Areas covered: This article reviews empagliflozin/metformin combination therapy for the treatment of type 2 diabetes. The clinical efficacy and tolerability of empagliflozin/metformin in patients with type 2 diabetes are discussed based on the available literature.

Expert opinion: It was found that empagliflozin/metformin combination therapy could significantly improve glycemic control, body weight and blood pressure with a low risk of hypoglycaemia. In addition, the empagliflozin/metformin fixed-dose tablets, supported by bioequivalence studies, could reduce pill burden to further achieve the improved patients’ adherence, better glycemic control and optimized cost-effectiveness.     

Repaglinide : a pharmacoeconomic review of its use in type 2 diabetes mellitus

Repaglinide (Prandin), NovoNorm, GlucoNorm, an oral insulin secretagogue, was the first meglitinide analogue to become available for use in patients with type 2 diabetes mellitus. The drug lowers postprandial glucose excursions by targeting early-phase insulin release, an effect thought to be important in reducing long-term cardiovascular complications of diabetes. Repaglinide provided similar overall glycaemic control to that achieved with glibenclamide (glyburide), as assessed by glycosylated haemoglobin (HbA(1c)) and fasting blood glucose levels, and was generally well tolerated in well designed clinical trials. Its rapid onset and relatively short duration of action allow for flexible meal schedules. Two modelled US cost-effectiveness analyses projected lifetime costs and outcomes for a hypothetical cohort of patients with type 2 diabetes. Both analyses projected long-term complications using data on HbA(1c) level changes from short-term clinical trials. Repaglinide plus rosiglitazone was dominant over rosiglitazone in one analysis, and repaglinide plus metformin was dominant over nateglinide plus metformin in the other. A similar Canadian analysis showed a favourable incremental cost-effectiveness ratio (相似文献   

Repaglinide: a review of its therapeutic use in type 2 diabetes mellitus

Repaglinide, a carbamoylmethyl benzoic acid derivative, is the first of a new class of oral antidiabetic agents designed to normalise postprandial glucose excursions in patients with type 2 diabetes mellitus. Like the sulphonylureas, repaglinide reduces blood glucose by stimulating insulin release from pancreatic beta-cells, but differs from these and other antidiabetic agents in its structure, binding profile, duration of action and mode of excretion. In clinical trials of up to 1-year's duration, repaglinide maintained or improved glycaemic control in patients with type 2 diabetes mellitus. In comparative, 1-year, double-blind, randomised trials (n = 256 to 544), patients receiving repaglinide (0.5 to 4mg before 3 daily meals) achieved similar glycaemic control to that in patients receiving glibenclamide (glyburide) < or = 15 mg/day and greater control than patients receiving glipizide < or = 15 mg/day. Changes from baseline in glycosylated haemoglobin and fasting blood glucose levels were similar between patients receiving repaglinide and glibenclamide in all studies; however, repaglinide was slightly better than glibenclamide in reducing postprandial blood glucose in I short term study (n = 192). Patients can vary their meal timetable with repaglinide: the glucose-lowering efficacy of repaglinide was similar for patients consuming 2, 3 or 4 meals a day. Repaglinide showed additive effects when used in combination with other oral antidiabetic agents including metformin, troglitazone, rosiglitazone and pioglitazone, and intermediate-acting insulin (NPH) given at bedtime. In 1-year trials, the most common adverse events reported in repaglinide recipients (n = 1,228) were hypoglycaemia (16%), upper respiratory tract infection (10%), rhinitis (7%), bronchitis (6%) and headache (9%). The overall incidence of hypoglycaemia was similar to that recorded in patients receiving glibenclamide, glipizide or gliclazide (n = 597) [18%]; however, the incidence of serious hypoglycaemia appears to be slightly higher in sulphonylurea recipients. Unlike glibenclamide, the risk of hypoglycaemia in patients receiving repaglinide was not increased when a meal was missed in 1 trial. In conclusion, repaglinide is a useful addition to the other currently available treatments for type 2 diabetes mellitus. Preprandial repaglinide has displayed antihyperglycaemic efficacy at least equal to that of various sulphonylureas and is associated with a reduced risk of serious hypoglycaemia. It is well tolerated in a wide range of patients, including the elderly, even if a meal is missed. Furthermore, glycaemic control is improved when repaglinide is used in combination with metformin. Thus, repaglinide should be considered for use in any patient with type 2 diabetes mellitus whose blood glucose cannot be controlled by diet or exercise alone, or as an adjunct in patients whose glucose levels are inadequately controlled on metformin alone.     

Contraindications to metformin therapy among patients with type 2 diabetes mellitus

Objective The biguanide, metformin, is a commonly prescribed oral antihyperglycemic agent. However, there are several clinical conditions that are considered as contraindications to the use of metformin among patients with type 2 diabetes mellitus. The aim of this study was to investigate the presence and nature of contraindications to metformin therapy among patients with type 2 diabetes mellitus. Method A retrospective study of the medical files of diabetic patients available at Alwosta clinic, north Palestine was carried out. Information about disease and medication profile of the patients was retrieved and analyzed using SPSS during the study period in 2004/2005. Focus was on metformin users who have contraindications to metfromin therapy. Main outcome measure Presence and number of contraindications to metformin therapy. Results Two hundred and seventy-two type 2 diabetic patients were identified. One hundred and twenty four of those diabetic patients were metformin users. Approximately, 60% of patients in the metformin group had a least one contraindication. Congestive heart failure and renal impairment were the most quantitatively present contraindications. Conclusion Contraindications to metformin therapy are common among type 2 diabetic patients and mostly disregarded. Patients have to be critically assessed before starting therapy and in case of metformin prescribing; dose should be adjusted based on the presence of risk factors for metformin adverse effects.     

Network meta-analysis of treatments for type 2 diabetes mellitus following failure with metformin plus sulfonylurea

Aims The efficacy and safety of sodium–glucose linked transporters (SGLT2s) plus metformin and a sulfonylurea (MET?+?SU) for the treatment of type 2 diabetes mellitus (T2DM) in patients who fail to achieve glycemic control with MET?+?SU, relative to other triple therapies licensed in the EU, were estimated.

Methods A systematic literature review and network meta-analysis (NMA) of randomized controlled trials (RCTs) involving anti-diabetes treatments added to MET?+?SU were conducted.

Results: Of 2236 abstracts identified through a systematic literature review, 30 RCTs published between 2003 and 2013 were included. RCTs ranged from 12 to 52 weeks in duration, included 28 to 1274 patients, were of parallel design, and most were open-label. Comparators included placebo (reference treatment), SGLT2 inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, thiazolidinediones (TZDs), alpha-glucosidase inhibitors (AGIs), meglitinides, glucagon-like peptide 1 (GLP-1) analogues, and basal, bolus, and biphasic insulin, all added on to MET?+?SU, as well as basal and biphasic insulin added to MET and monotherapy. The mean change (%) in HbA1c levels compared to placebo was -0.86 for SGLT2 inhibitors, ?0.68 for DPP-4 inhibitors, ?0.93 for TZDs, and ?1.07 for GLP-1 analogues, respectively. Only SGLT2 inhibitors and GLP-1 analogues led to a weight loss (?1.71 kg and ?1.14 kg, respectively) and decrease in systolic blood pressure (SBP; ?3.73 mmHg and ?2.90 mmHg, respectively), while all other treatments showed either an increase or no changes in weight or SBP.

Conclusion SGLT2 inhibitors are at least as effective as other classes of antidiabetic agents at controlling HbA1c levels, while providing the additional benefits of weight loss and reducing SBP. Additionally, since the risk of hypoglycemia is similar or reduced with SGLT2 inhibitors, patients do not have to trade off efficacy for tolerability. Similar findings were observed for GLP-1 analogues.     

Pioglitazone and metformin fixed-dose combination in type 2 diabetes mellitus: an evidence-based review of its place in therapy

Introduction:

Type 2 diabetes mellitus, a metabolic disease with increasing incidence, is one of the most important cardiovascular risk factors. Insulin resistance represents the common mechanism that leads to type 2 diabetes in obese subjects. Metformin and the thiazolidinediones, pioglitazone and rosiglitazone, are insulin-sensitizing agents available for treatment of type 2 diabetes. Large clinical trials have demonstrated the effectiveness of both metformin and pioglitazone in reducing cardiovascular morbidity and mortality. The fixed-dose combination of metformin and pioglitazone appears to be a good option for treating diabetes in insulin-resistant patients.

Aims:

The purpose of this article is to review the place in therapy of a fixed-dose combination of pioglitazone and metformin in the management of patients with type 2 diabetes.

Evidence review:

The current evidence suggests that combined therapy may help to achieve the recommended goals in the management of diabetes. A fixed-dose formulation of pioglitazone and metformin may provide advantages in terms of glycemic control and other cardiovascular risk factors frequently associated with diabetes.

Place in therapy:

The current evidence shows that a fixed-dose formulation of pioglitazone and metformin offers an effective option for the management of patients with type 2 diabetes when monotherapy fails in the achievement of the recommended standards of care.     

Pioglitazone and metformin fixed-dose combination in type 2 diabetes mellitus: an evidence-based review of its place in therapy

INTRODUCTION: Type 2 diabetes mellitus, a metabolic disease with increasing incidence, is one of the most important cardiovascular risk factors. Insulin resistance represents the common mechanism that leads to type 2 diabetes in obese subjects. Metformin and the thiazolidinediones, pioglitazone and rosiglitazone, are insulin-sensitizing agents available for treatment of type 2 diabetes. Large clinical trials have demonstrated the effectiveness of both metformin and pioglitazone in reducing cardiovascular morbidity and mortality. The fixed-dose combination of metformin and pioglitazone appears to be a good option for treating diabetes in insulin-resistant patients. AIMS: The purpose of this article is to review the place in therapy of a fixed-dose combination of pioglitazone and metformin in the management of patients with type 2 diabetes. EVIDENCE REVIEW: The current evidence suggests that combined therapy may help to achieve the recommended goals in the management of diabetes. A fixed-dose formulation of pioglitazone and metformin may provide advantages in terms of glycemic control and other cardiovascular risk factors frequently associated with diabetes. PLACE IN THERAPY: The current evidence shows that a fixed-dose formulation of pioglitazone and metformin offers an effective option for the management of patients with type 2 diabetes when monotherapy fails in the achievement of the recommended standards of care.