Background Metformin is an oral anti-hyperglycemic agent that has been shown to reduce total mortality compared to other anti-hyperglycemic agents, in the treatment of type 2 diabetes mellitus. Metformin, however, is thought to increase the risk of lactic acidosis, and has been considered to be contraindicated in many chronic hypoxemic conditions that may be associated with lactic acidosis, such as cardiovascular, renal, hepatic and pulmonary disease, and advancing age. Objectives To assess the incidence of fatal and nonfatal lactic acidosis, and to evaluate blood lactate levels, for those on metformin treatment compared to placebo or non-metformin therapies. Search strategy A comprehensive search was performed of electronic databases to identify studies of metformin treatment. The search was augmented by scanning references of identified articles, and by contacting principal investigators. Selection criteria Prospective trials and observational cohort studies in patients with type 2 diabetes of least one month duration were included if they evaluated metformin, alone or in combination with other treatments, compared to placebo or any other glucose-lowering therapy. Data collection and analysis The incidence of fatal and nonfatal lactic acidosis was recorded as cases per patient-years, for metformin treatment and for non-metformin treatments. The upper limit for the true incidence of cases was calculated using Poisson statistics. In a second analysis lactate levels were measured as a net change from baseline or as mean treatment values (basal and stimulated by food or exercise) for treatment and comparison groups. The pooled results were recorded as a weighted mean difference (WMD) in mmol/L, using the fixed-effect model for continuous data. Main results Pooled data from 347 comparative trials and cohort studies revealed no cases of fatal or nonfatal lactic acidosis in 70,490 patient-years of metformin use or in 55,451 patients-years in the non-metformin group. Using Poisson statistics the upper limit for the true incidence of lactic acidosis per 100,000 patient-years was 4.3 cases in the metformin group and 5.4 cases in the non-metformin group. There was no difference in lactate levels, either as mean treatment levels or as a net change from baseline, for metformin compared to non-metformin therapies. Authors' conclusions There is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared to other anti-hyperglycemic treatments.

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Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus

Complex diseases, such as Type 2 Diabetes, are generally caused by multiple factors, which hamper effective drug discovery. To combat these diseases, combination regimens or combination drugs provide an alternative way, and are becoming the standard of treatment for complex diseases. However, most of existing combination drugs are developed based on clinical experience or test-and-trial strategy, which are not only time consuming but also expensive. In this paper, we presented a novel network-based systems biology approach to identify effective drug combinations by exploiting high throughput data. We assumed that a subnetwork or pathway will be affected in the networked cellular system after a drug is administrated. Therefore, the affected subnetwork can be used to assess the drug's overall effect, and thereby help to identify effective drug combinations by comparing the subnetworks affected by individual drugs with that by the combination drug. In this work, we first constructed a molecular interaction network by integrating protein interactions, protein-DNA interactions, and signaling pathways. A new model was then developed to detect subnetworks affected by drugs. Furthermore, we proposed a new score to evaluate the overall effect of one drug by taking into account both efficacy and side-effects. As a pilot study we applied the proposed method to identify effective combinations of drugs used to treat Type 2 Diabetes. Our method detected the combination of Metformin and Rosiglitazone, which is actually Avandamet, a drug that has been successfully used to treat Type 2 Diabetes. The results on real biological data demonstrate the effectiveness and efficiency of the proposed method, which can not only detect effective cocktail combination of drugs in an accurate manner but also significantly reduce expensive and tedious trial-and-error experiments.

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A systems biology approach to identify effective cocktail drugs

The clinical efficacy of currently available thiazolidinediones (TZDs) in improving glycaemic control and ameliorating several risk factors for cardiovascular disease (linked to their insulin-sensitising actions as well as direct vascular effects) is well established. Treatment-associated weight gain, however, which has been identified as a class effect of the TZDs, is seen in a number of patients. The magnitude of weight gain correlates in part with improved metabolic control, i.e. better responders are more prone to increases in body weight. The cardiovascular risk associated with obesity appears to be depot specific; while peripheral obesity is associated with a low risk of cardiovascular complications, central obesity confers a greater degree of risk. Evidence is reviewed that increases in body weight associated with TZD treatment are associated with neutral effects (or even, decreases) in visceral fat, the adipose depot that is associated with central obesity.

Thiazolidinediones, insulin resistance and obesity: finding a balance

Thiazolidinedione (TZD) drugs used in the treatment of type 2 diabetes mellitus (T2DM) have proven effective in improving insulin sensitivity, hyperglycemia, and lipid metabolism. Though well tolerated by some patients, their mechanism of action as ligands of peroxisome proliferator-activated receptors (PPARs) results in the activation of several pathways in addition to those responsible for glycemic control and lipid homeostasis. These pathways, which include those related to inflammation, bone formation, and cell proliferation, may lead to adverse health outcomes. As treatment with TZDs has been associated with adverse hepatic, cardiovascular, osteological, and carcinogenic events in some studies, the role of TZDs in the treatment of T2DM continues to be debated. At the same time, new therapeutic roles for TZDs are being investigated, with new forms and isoforms currently in the pre-clinical phase for use in the prevention and treatment of some cancers, inflammatory diseases, and other conditions. The aims of this review are to provide an overview of the mechanism(s) of action of TZDs, a review of their safety for use in the treatment of T2DM, and a perspective on their current and future therapeutic roles.

Thiazolidinedione drugs in the treatment of type 2 diabetes mellitus: past, present and future.

Insulin resistance has been proposed to be the underlying disorder of the so-called metabolic or insulin resistance syndrome, which represents the clustering in the same individual of several cardiovascular risk factors, such as type 2 diabetes mellitus, hypertension, abdominal obesity, elevated triglycerides and low high-density lipoprotein-cholesterol. As far as the connection of insulin resistance and compensatory hyperinsulinaemia with hypertension is concerned, a number of mechanisms possibly linking these disturbances have been described, such as activation of sympathetic nervous system, enhancement of renal sodium reabsorption, or impairment of endothelium-dependent vasodilatation. Thiazolidinediones (TZDs) constitute a class of oral antihyperglycaemic agents that act by decreasing insulin resistance, and apart from their action on glycaemic control, they have been also reported to exert beneficial effects on other parameters of the metabolic syndrome. In particular, during recent years a considerable number of animal and human studies have shown that the use of TZDs was associated with usually small but significant reductions of blood pressure (BP) levels. Since a possible beneficial action of these compounds on BP could be of particular value for patients with the metabolic syndrome, this review aimed to summarize and evaluate the literature data in the field, derived either from studies that just examined BP levels among other parameters or from studies that were specifically designed to determine the effect of a TZD on BP.

The effects of thiazolidinediones on blood pressure levels - A systematic review

This study investigated the efficacy during daily practice of rosiglitazone (RSG) added to metformin (MET) in poorly controlled type 2 diabetes mellitus. Two post-marketing observational studies were conducted in Germany over 6 months. RSG (4 mg/day titrated to 8 mg/day as required) was added to existing MET in 11,014 subjects. Subjects were maintained on diet and exercise. Addition of RSG to MET significantly reduced median HbA 1c by 1.3% (8.1 vs. 6.8%; p < 0.0001) and median fasting blood glucose (FBG) by 47.0 mg/dl (171.0 vs. 124.0 mg/dl; p < 0.0001) after 6 months. The proportion of subjects achieving HbA(1c) targets of < or = 6.5 and < or = 7.0% increased from 3.5 to 38.8% and from 13.5 to 63.7%, respectively. Mean systolic and diastolic blood pressure decreased by 7 and 3 mmHg, respectively (p < 0.0001). Mean weight decreased by 1.7 kg and was constant or reduced in most (74.1%) subjects. Addition of RSG to MET significantly reduces median HbA 1c and FBG in clinical practice and is generally well tolerated.

Rosiglitazone plus metformin is effective and well tolerated in clinical practice: results from large observational studies in people with type 2 diabetes.

R. Petzoldt

Papers

Rosiglitazone plus metformin is effective and well tolerated in clinical practice: results from large observational studies in people with type 2 diabetes.