Effects Of Glucose-lowering Agents Research Articles

Recent advances in glucokinase activators for the treatment of type 2 diabetes

Glucokinase is a member of the hexokinase family of enzymes that are responsible for the phosphorylation of glucose to glucose-6-phosphate for further utilization in cells. The enzyme plays a key role in glucose homeostasis. Phosphorylation of glucose by glucokinase in the liver promotes glycogen synthesis, while in the beta-cell it results in insulin release. Activators of glucokinase increase the sensitivity of the enzyme to glucose, leading to increased insulin secretion and liver glycogen synthesis and a decrease in liver glucose output. Thus, small molecule glucokinase activators have been demonstrated to be effective glucose-lowering agents in animal models of type 2 diabetes and have advanced into clinical studies.

Megatrials in type 2 diabetes. From excitement to frustration?

Whether glycaemic control may result in a reduction of cardiovascular (CV) risk has been a matter of continuous discussion and investigation. Epidemiological analyses have extensively suggested a relationship between glycaemic control and CV events; however, the results of intervention trials have been less conclusive. The UKPDS reported a 16% reduction in the risk of myocardial infarction, but this reduction was not statistically significant. The results of the Kumamoto and PROactive studies could not allow any firm conclusions to be drawn either, because of limited size and the defined primary endpoint, respectively. The results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trials and the Veteran Administration Diabetes Trial (VADT) were published in rapid succession over the second half of 2008 and at the beginning of 2009. A total number of almost 25,000 type 2 diabetic patients were recruited in these three trials, which assessed the effect of intensive glycaemic control vs conventional treatment on well-defined CV endpoints. In spite of the achievement and maintenance of strict glycaemic control (HbA(1c) <7.0%), no beneficial effect of intensive therapy was apparent in any of the studies. At the same time these results were presented, the results of an analysis of the 10 year follow-up of the UKPDS also became available and provided a more optimistic view of the potential benefit of achieving good glycaemic control. The relative risk reductions for myocardial infarction and all-cause mortality were significantly lower in the patients who initially received the intensive treatment compared with those in the conventional treatment arm. Moreover, the initial benefit in terms of microvascular complications observed at the end of the intervention trial remained unaltered at follow-up. Once again the debate on the importance of glycaemic control in preventing macrovascular complications remains unsettled. These results, however, require some reconciliation, and the objective of this commentary is to analyse a series of elements, including the changes in the treatment approach to CV risk factors in type 2 diabetes, the effect of glucose-lowering agents, and the characteristics of the patients included in the different trials, that should be taken into account when interpreting the results of intervention trials in type 2 diabetes.

The role of glucose lowering agents on restenosis after percutaneous coronary intervention in patients with diabetes mellitus

IntroductionThe prevalence of diabetes is increasing rapidly, and individuals with diabetes are at high risk for cardiovascular disorders. Subsequently the percentage of patients with diabetes subjected to revascularisation, i.e. either percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) also rises rapidly. The outcome of patients with diabetes after PCI is worse than for patients without diabetes. Restenosis is the main limiting factor of the long-term success of PCI. Although stents and antithrombotics improved outcome after PCI in both diabetics and non-diabetics, diabetics still have a worse prognosis. This leads to the suggestion that the restenosis mechanism in diabetics might be different from that in non-diabetics.ConclusionSeveral glucose lowering agents have been shown to influence the restenosis process and thus the outcome after PCI. Current data of especially metformin and thiazolidinediones indicate beneficial results as compared to insulin and sulfonylurea on restenosis. However, no large trials have been undertaken in which the effect of glucose lowering agents on restenosis is associated with improved outcome.The purpose of this review is to summarize the effect of diabetes and glucose lowering agents on restenosis.

Thiazolidinediones and cardiovascular outcomes

Diabetes mellitus is associated with a number of serious microvascular and macrovascular complications that have a devastating effect on quality of life and impose a heavy burden on healthcare systems. In order to decrease the risk of diabetes-related complications, individuals with diabetes should normally receive intensive and effective treatment for all metabolic disturbances, including hyperglycaemia. Thiazolidinediones are an important part of this therapeutic armamentarium, but are currently the subject of intense scrutiny following the publication of a meta-analysis reporting increased cardiovascular risk with rosiglitazone. Based on available data, the FDA has concluded that the use of rosiglitazone for the treatment of type 2 diabetes may be associated with a greater risk of myocardial ischaemic events than placebo, metformin or sulphonylureas and have added label warnings to the prescribing information until the results of long-term cardiovascular outcome trials become available. To date, increased cardiovascular risk has not been reported with pioglitazone and indeed there is evidence suggestive of cardiovascular protection. Thiazolidinediones are effective glucose-lowering agents, complementing existing treatment approaches and thus have a continuing role to play in the management of diabetes.

Efficacy and Safety of Mitiglinide in Korean Type 2 Diabetic Patients: Prospective Randomised Multicenter Comparative Phase III Study

Background: Mitiglinide, one of the meglitinides, is expected to prevent postprandial hyperglycemia of type 2 diabetes by enhancing early phase insulin secretion. The aim of this study was to verify the efficacy and safety of mitiglinide compared to nateglinide. Methods: One hundred eleven of diabetic patients were randomised and administered of mitiglinide (n = 56) and nateglinide (n = 55) before a meal time for 12 weeks. The changes of HbA1c, fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) were analyzed. The safety of this drug was investigated as well. Results: The change of HbA1c was not significantly different between two groups (-0.77 ± 1.08% in mitiglinide vs. -0.66 ± 0.79% in nateglinide, P = 0.57). The reduction of FPG (-12.2 ± 25.0 mg/dL vs. -6.1 ± 22.3 mg/dL, P = 0.218), PPG 1 hr (-48.0 ± 47.1 mg/dL, vs. -29.4 ± 43.2 mg/dL, P = 0.051), and PPG 2 hr (-59.2 ± 58.0 mg/dL vs. -43.3 ± 59.0 mg/dL, P = 0.194) were not significantly different between the mitiglinide and the nateglinide, respectively. Drug-related adverse effects were not different between two groups (16.1% in mitiglinide vs. 27.8% in nateglinide, P = 0.137). The frequency of hypoglycemic events were not different between two groups (8.9% in mitiglinide vs. 14.8% in nateglinide, P = 0.339). There were two patients who had complained shoulder pain in the mitiglinide or deterioration of visual acuity in the nateglinide, but those were found to be unrelated with medications. Conclusion: This study showed that mitiglinide had reduced HbA1c as similar to nateglinide and that significantly improved HbA1c, FPG and PPG during 12 weeks of treatment. The safety of mitiglinide was also comparable to nateglinide. Mitiglinide could be used as an effective glucose-lowering agent by enhancing early insulin secretion and reducing postprandial glucose excursion, and thereby might contribute long-term cardioprotective effect in Korean type 2 diabetic patients. (J Kor Diabetes Assoc 31:163~174, 2007)

A risk-benefit assessment of metformin in type 2 diabetes mellitus.

Metformin has been used for over 40 years as an effective glucose-lowering agent in type 2 (noninsulin-dependent) diabetes mellitus. Typically it reduces basal and postprandial hyperglycaemia by about 25% in more than 90% of patients when either given alone or coadministered with other therapies including insulin during a programme of managed care. Metformin counters insulin resistance and offers benefits against many features of the insulin resistance syndrome (Syndrome X) by preventing bodyweight gain, reducing hyperinsulinaemia and improving the lipid profile. In contrast to sulphonylureas, metformin does not increase insulin secretion or cause serious hypoglycaemia. Treatment of type 2 diabetes mellitus with metformin from diagnosis also offers greater protection against the chronic vascular complications of type 2 diabetes mellitus. The most serious complication associated with metformin is lactic acidosis which has an incidence of about 0.03 cases per 1000 patients years of treatment and a mortality risk of about 0.015 per 1000 patient-years. Most cases occur in patients who are wrongly prescribed the drug, particularly patients with impaired renal function (e.g. serum creatinine level > 130 micromol/L or > 1.5 g/L). Other major contraindications include congestive heart failure, hypoxic states and advanced liver disease. Serious adverse events with metformin are predictable rather than spontaneous and are potentially preventable if the prescribing guidelines are respected. Gastrointestinal adverse effects, notably diarrhoea, occur in less than 20% of patients and remit when the dosage is reduced. The life-threatening risks associated with metformin are rare and could mostly be avoided by strict adherence to the prescribing guidelines. Given the 4 decades of clinical experience with metformin, its antihyperglycaemic efficacy and benefits against Syndrome X, metformin offers a very favourable risk-benefit assessment when compared with the chronic morbidity and premature mortality among patients with type 2 diabetes mellitus.

Worldwide experience of metformin as an effective glucose-lowering agent: a meta-analysis.

Diabetes/Metabolism ReviewsVolume 11, Issue S1 p. S57-S62 Article Worldwide Experience of Metformin as an Effective Glucose-lowering Agent: A Meta-analysis I. W. Campbell, Corresponding Author I. W. Campbell Victoria Hospital, Kirkcaldy, Fife, and Department of Medicine, University of Edinburgh, UKDiabetic Department, Victoria Hospital, Kirkcaldy, Fife KY2 5AH, U.K.Search for more papers by this authorH. C. S. Howlett, H. C. S. Howlett Lipha Pharmaceuticals Ltd, Middlesex, UKSearch for more papers by this author I. W. Campbell, Corresponding Author I. W. Campbell Victoria Hospital, Kirkcaldy, Fife, and Department of Medicine, University of Edinburgh, UKDiabetic Department, Victoria Hospital, Kirkcaldy, Fife KY2 5AH, U.K.Search for more papers by this authorH. C. S. Howlett, H. C. S. Howlett Lipha Pharmaceuticals Ltd, Middlesex, UKSearch for more papers by this author First published: September 1995 https://doi.org/10.1002/dmr.5610110509Citations: 74AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume11, IssueS1Supplement: Diabetes/Metabolism ReviewsSeptember 1995Pages S57-S62 RelatedInformation