Characteristic features of polycystic ovary syndrome (PCOS) include insulin resistance and an increased risk for type 2 diabetes. To promote improved insulin sensitivity, insulin sensitisers have been used in PCOS. However, direct comparisons across these agents are limited. This study compared the effects of metformin, rosiglitazone and pioglitazone in the management of PCOS to inform the 2023 International Evidence-based PCOS Guideline.

Systematic review and meta-analysis of the literature.

Women with PCOS and treatment with insulin sensitisers.

Hormonal and clinical outcomes, as well as side effects.

Of 1660 publications identified, 13 randomised controlled trials were included. Metformin was superior in lowering weight (mean difference [MD]: -4.39, 95% confidence interval [CI]: -7.69 to -1.08 kg), body mass index (MD: -0.95, 95% CI: -1.41 to -0.49 kg/m2 ) and testosterone (MD: -0.10, 95% CI: -0.18 to -0.03 nmol/L) versus rosiglitazone, whereas there was no difference when comparing metformin to pioglitazone. Adding rosiglitazone or pioglitazone to metformin did not improve metabolic outcomes. However, rosiglitazone seemed superior to metformin in lowering lipid concentrations.

Metformin should remain the first-line insulin sensitising treatment in adults with PCOS for the prevention and management of weight and metabolic features. The addition of thiazolidinediones appears to offer little benefit.

Thiazolidine-2,4-dione (2,4-TZD) is a flexible pharmacophore and a privileged platform and contains a five-membered ring with a 2-oxygen atom with double bond 2,4- position and one nitrogen atom as well as sulphur containing in the heterocyclic compound. A famous electron-rich nitrogen transporter combines invigorating electronic properties with the prospective for elemental applications. Thiazolidine-2,4-dione analogues have been synthesized using a variety of methods, all of which have shown to have a strong biological effect.

The study of the biological activity of Thiazolidine-2,4-dione derivatives has been a fascinating field of pharmaceutical chemistry and has many purposes. This derivative described in the literature between 1995 to 2023 was the focus of this study. Thiazolidine-2,4-diones have been discussed in terms of their introduction, general method, synthetic scheme and antidiabetic significance in the current review.

Thiazolidine-2,4-diones are well-known heterocyclic compounds. The synthesis of Thiazolidine-2,4-diones has been described using a variety of methods. Antidiabetic activity has been discovered in several Thiazolidine-2,4-dione derivatives, which enhance further research. The use of Thiazolidine-2,4-diones to treat antidiabetics has piqued researchers' interest in learning more about thiazolidine-2,4-diones.

Mounting evidence of the ability of aspalathin to target underlying metabolic dysfunction relevant to the development or progression of obesity and type 2 diabetes created a market for green rooibos extract as a functional food ingredient. Aspalathin is the obvious choice as a chemical marker for extract standardisation and quality control, however, often the concentration of a single constituent of a complex mixture such as a plant extract is not directly related to its bio-capacity, i.e. the level of in vitro bioactivity effected in a cell system at a fixed concentration. Three solvents (hot water and two EtOH-water mixtures), previously shown to produce bioactive green rooibos extracts, were selected for extraction of different batches of rooibos plant material (n = 10). Bio-capacity of the extracts, tested at 10 μg ml^-1, was evaluated in terms of glucose uptake by C2C12 and C3A cells and lipid accumulation in 3T3-L1 cells. The different solvents and inter-batch plant variation delivered extracts ranging in aspalathin content from 54.1 to 213.8 g kg^-1. The extracts were further characterised in terms of other major flavonoids (n = 10) and an enolic phenylpyruvic acid glucoside, using HPLC-DAD. The 80% EtOH-water extracts, with the highest mean aspalathin content (170.9 g kg^-1), had the highest mean bio-capacity in the respective assays. Despite this, no significant (P≥ 0.05) correlation existed between aspalathin content and bio-capacity, while the orientin, isoorientin and vitexin content correlated moderately (r≥ 0.487; P < 0.05) with increased glucose uptake by C2C12 cells. Various multivariate analysis methods were then applied with Evolution Program-Partial Least Squares (EP-PLS) resulting in models with the best predictive power. These EP-PLS models, based on all quantified compounds, predicted the bio-capacity of the extracts for the respective cell types with RMSECV values ≤ 11.5, confirming that a complement of compounds, and not aspalathin content alone, is needed to predict the in vitro bio-capacity of green rooibos extracts. Additionally, the composition of hot water infusions of different production batches of green rooibos (n = 29) at 'cup-of-tea' equivalence was determined to relate dietary supplementation with the extract to intake in the form of herbal tea.

Type 2 diabetes mellitus (DM) is a lifelong metabolic disease, characterized by hyperglycaemia which gradually leads to the development and progression of vascular complications. It is recognized as a global burden disease, with substantial consequences on human health (fatality) as well as on health-care system costs. This review focuses on the topic of historical discovery and understanding the complexity of the disease in the field of pathophysiology, as well as development of the pharmacotherapy beyond insulin. The complex interplay of insulin secretion and insulin resistance developed from previously known "ominous triumvirate" to "ominous octet" indicate the implication of multiple organs in glucose metabolism. The pharmacological approach has progressed from biguanides to a wide spectrum of medications that seem to provide a beneficial effect on the cardiovascular system. Despite this, we are still not achieving the target treatment goals. Thus, the future should bring novel antidiabetic drug classes capable of acting on several levels simultaneously. In conclusion, given the raising burden of type 2 DM, the best present strategy that could contribute the most to the reduction of morbidity and mortality should be focused on primary prevention.

Type 2 diabetes is a disease of metabolism in which the afflicted patient cannot properly utilize carbohydrates, fats, and proteins. Because the prevalence of type 2 diabetes is rapidly increasing throughout the general population, anesthesia providers must realize that a significant percentage of their patients will present with the disease. Anesthesia providers should have an intimate knowledge of the comorbidities and complications that are associated with type 2 diabetes and know the specific pharmacokinetics and pharmacodynamics of the drugs used to treat the disease. Part 1 of this series on the anesthetic management of type 2 diabetes in the ambulatory theater addressed the pathology of diabetes and its comorbid disease states. Part 2 of the series now focuses on the pharmacology associated with the many medications used to treat the disorder and the most recent guidelines for blood glucose management recommended for patients in an ambulatory surgery setting.

Diabetes mellitus is a group of metabolic disorders characterized by hyperglycaemia, and predicted by the World Health Organization as the expected 7th leading cause of death in 2030. Diabetes mellitus type 2 (DMT2) comprises the majority of diabetic individuals around the world (90%-95%). Pathophysiologically, this disorder results from a deregulation of glucose homeostasis, worsened by overweight and by a sedentary lifestyle, culminating in life-threatening cardiovascular events. The currently available anti-diabetic drugs are not devoid of undesirable side effects, sometimes responsible for poor therapeutic compliance. This represents a challenge for contemporary medicine, and stimulates research focused on the development of safer and more efficient anti-diabetic therapies. Amongst the most promising sources of new bioactive molecules, seaweeds represent valuable, but still underexploited, biofactories for drug discovery and product development. In this review, the role of phlorotannins, a class of polyphenols exclusively produced by brown seaweeds, in the management of DMT2 will be discussed, focusing on various pharmacologically relevant mechanisms and targets, including pancreatic, hepatic and intestinal enzymes, glucose transport and metabolism, glucose-induced toxicity and β-cell cytoprotection, and considering numerous in vitro and in vivo surveys.

The relationship between the beneficial effects of pioglitazone in reducing clinical events and plaque inflammatory burden remains unknown. This study aimed to determine whether pioglitazone can reduce the number of plaque thrombosis incidences and whether decreasing plaque inflammation is the mechanism by which pioglitazone reduces plaque thromboses.

therosclerotic rabbits were divided into two groups: the atherosclerosis group (n = 13) and pioglitazone group (n = 10). The rabbits underwent pharmacological triggering to induce thrombosis. Serum inflammatory markers, FDG uptake, macrophage, and neovessel staining detected arterial inflammation. PET/CT scans were performed twice (baseline and posttreatment scans). Plaque area, macrophages, and neovessels were measured and the histologic sections were matched with the PET/CT scans. Serum MMP-9 and hsCRP were lower in the pioglitazone group compared to the atherosclerosis group. The SUVmean significantly decreased in the pioglitazone group (0.62 ± 0.21 vs. 0.55 ± 0.19, P = 0.008), but increased in the atherosclerosis group (0.61 ± 0.15 vs. 0.91 ± 0.20, P < 0.000). The incidence rate of plaque rupture, plaque area, macrophage density, and neovessel density was significantly lower in rabbits with pioglitazone than without (15% vs. 38%, P < 0.001; 18.00 ± 2.30 vs. 27.00 ± 1.60; P < 0.001; 8.80 ± 3.94 vs. 28.26 ± 2.49; P < 0.001; 16.50 ± 3.09 vs. 29.00 ± 2.11; P < 0.001, respectively). Moreover, plaque area and macrophage density were positively correlated with SUV values.

Our study suggests that pioglitazone can reduce the number of plaque thrombosis incidences by decreasing plaque inflammation. (18)F-FDG-PET/CT can detect plaque inflammation and assess the effects of antiatherosclerotic drugs.

Table 3 provides an overview of the oral antihyperglycemic drugs reviewed in this article. A 2011 meta-analysis by Bennett and colleagues found low or insufficient quality of evidence favoring an initial choice of metformin, SUs, glinides, TZDs, or (table see text) DPP-4 inhibitors (alpha-glucosidase inhibitors, bromocriptine mesylate, and SGLT2 inhibitors were not included in this meta-analysis) with regard to the outcomes measures of all-cause mortality, cardiovascular events and mortality, and incidence of microvascular disease (retinopathy, nephropathy, and neuropathy) in previously healthy individuals with newly diagnosed T2DM. Likewise, the Bennett and colleagues meta-analysis judged these drugs to be of roughly equal efficacy with regard to reduction of HbA1c (1%–1.6%) from the pretreatment baseline. The ADOPT clinical trial of 3 different and, at the time, popular, oral monotherapies for T2DM provides support for the consensus recommendation of metformin as first-line therapy. The ADOPT trial showed slightly superior HbA1c reduction for rosiglitazone compared with metformin, which was in turn superior to glyburide. However, significant adverse events, including edema, weight gain, and fractures, were more common in the rosiglitazone-treated patients. The implication of this trial is that the combination of low cost, low risk, minimal adverse effects, and efficacy of metformin justifies use of this agent as the cornerstone of oral drug treatment of T2DM. Judicious use of metformin in groups formerly thought to be at high risk for lactic acidosis (ie, those with CHF, chronic kidney disease [eGFR >30 mL/min/1.73 m2], and the elderly) may be associated with mortality benefit rather than increased risk. Secondary and tertiary add-on drug therapy should be individualized based on cost, personal preferences, and overall treatment goals, taking into account the wishes and priorities of the patient.

This article provides an overview of the development of insulins, oral agents, and noninsulin injectable agents used in the management of hyperglycemia in patients with diabetes. It also briefly reviews the pharmacological impact and salient side effects of these medications.

Type 2 Diabetes Mellitus (T2DM) is characterized by chronic hyperglycemia with disturbance in carbohydrate, lipid, and protein metabolism due to insulin resistance and beta cell dysfunction. Epidemiological studies have confirmed a global pandemic of T2DM, which has created an enormous burden on society, with regard to morbidity, mortality, and health care expenditures. Life style modifications are fundamental not only in early stages of disease management but need to be intensified as disease progresses. United Kingdom Prospective Diabetes Study (UKPDS) has demonstrated the progressive nature of T2DM, and as disease progresses, a combination agents-oral antidiabetic drugs (OAD) and insulin-are needed in order to maintain good sugar control. The general consensus of HbA1c target for most patients is less than 7%, and various guidelines and algorithms have provided guidance in patient management to keep patient at goal. As our understanding of pathophysiological defects advances, targeting treatment at underlying defects not only enables us to achieve HbA1c goal but also reduces morbidities, mortalities, and progression of the disease. Traditional oral agents like metformin and sulfonylureas have failed to arrest the progression of T2DM. New agents such as TZD, DPP-4 inhibitor, and SGLT-2 may increase our armamentariums against T2DM.

Thiazolidinediones (TZDs) are anti-diabetic drugs that act as insulin sensitizers and are used in the management of type 2 diabetes mellitus. TZDs, which are ligands for the transcription factor peroxisome proliferator-activated receptor PPARγ, have a wide spectrum of action, including modulation of glucose and lipid homeostasis, inflammation, atherosclerosis, bone remodeling and cell proliferation. Randomized clinical trials have demonstrated the efficacy and durability of the anti-hyperglycemic action of TZDs, and have suggested that the TZD pioglitazone also exerts cardioprotective action. However, the clinical use of TZDs is limited by the occurrence of several adverse events, including body-weight gain, congestive heart failure, bone fractures and possibly bladder cancer. Therefore, there is an unmet need for the development of new safer PPARγ-modulating drugs.

The published evidence on the role of various drugs and medication classes in causing or exacerbating heart failure (HF) is reviewed, with discussion of precautions and management strategies for use in clinical practice.

A literature search was conducted to identify reports of new-onset HF and exacerbations of HF associated with medication use published from 1960 to January 2011. A large body of evidence from controlled clinical trials has led to an improved understanding of well-established causes of drug-induced HF symptoms (e.g., thiazolidinediones, certain older chemotherapy agents) while implicating a wide range of other commonly used drugs and drug classes (e.g., tyrosine kinase inhibitors, biological response modifiers) as having causal or contributory roles. Among the various medications cited in cases of drug-induced HF, some have been linked to significantly increased risks of stroke, myocardial infarction, and death, particularly in patients with existing cardiovascular (CV) disorders or CV risk factors. In recent years, postmarketing and surveillance data have linked a number of newer medications--including the antiarrhythmic dronedarone, the antifungal itraconazole, and the anti-cancer drugs trastuzumab, lapatinib, and bevacizumab--to serious cardiac effects not reported during clinical trials.

A variety of agents have been associated with drug-induced HF. Patients receiving agents that have been implicated in cases of new-onset HF or exacerbations of HF should be monitored for signs and symptoms of CV effects.

Type 2 diabetes mellitus (T2DM) results in significant morbidity and mortality. Results of recent randomized controlled trials demonstrated the ability of early and intensive therapy to reduce the risk of microvascular complications. However, controversy surrounds the ability of such therapy to reduce the risk for macrovascular complications.

This article reviews results from recent clinical trials in patients with T2DM as well as extended follow-up of earlier trials to determine if early, intensive, and individualized therapy aimed at the underlying pathogenesis of the disease could decrease the risk for long-term complications, including cardiovascular disease (CVD).

Information was obtained by a search of the PUBMED and EMBASE databases using the search terms type 2 diabetes mellitus, glycosylated hemoglobin, pathophysiology of type 2 diabetes, glycemic control, early intervention, multifactorial intervention, cardiovascular disease, β-cell function, and antidiabetes therapy for the period between 1995 and 2010. Articles dealing with outcomes trials, impact of therapy on microvascular and macrovascular complications, effects of therapeutic agents on the pathophysiology of T2DM, and the impact of agents on CV risk factors were then preferentially selected for in-depth review.

Large-scale clinical trials in patients with T2DM, although largely negative at 5 years for macrovascular end points, suggested benefit for patients with a shorter duration of T2DM (ie, <10 years) and still supported a treatment strategy of early, intensive, and individualized therapy to prevent long-term complications of the disease. In Steno-2, after 13 years of follow-up, early, intensive, multifactorial therapy was associated with a 56% lower risk of all-cause death (P = 0.02) and a 57% lower risk of death from CVD (P = 0.04). In the 10-year follow-up to the United Kingdom Prospective Diabetes Study, intensive therapy was associated with a significant 15% reduction in the risk of myocardial infarction (P = 0.01) and a significant 13% reduction in the risk of death from any cause (P = 0.007). Therapy should be aimed at correcting underlying pathophysiologic defects, including β-cell failure and insulin resistance, and should also correct underlying risk factors for CVD whenever possible.

Early and intensive antidiabetes treatment was recommended in patients with T2DM, particularly those with a shorter duration of disease and without a history of CVD. The goal was to safely lower glycosylated hemoglobin to <7%, therefore providing beneficial effects on the risk for complications. Hypoglycemia should be avoided. In addition, less aggressive treatment might be suitable for older patients with longstanding diabetes and a history of CVD events. Clinical trial results also provided support for a second important aspect of individualized treatment for patients with T2DM-multifactorial intervention aimed at controlling CVD risk factors.

The pathophysiology of hyperglycemia in type 2 diabetes (T2DM) involves 3 main defects: insulin deficiency, excess hepatic glucose output, and insulin resistance. Oral anti-diabetic agents act in a variety of ways. These include agents that stimulate insulin secretion, reduce hepatic glucose production, delay digestion and absorption of intestinal carbohydrate or improve insulin action. Because of improved knowledge of pathophysiology, new drugs with mechanisms of action focussed on specific pathophysiological alterations have appeared, in order to utilize all the possibilities of treating this condition. Here, we focus on the new agents used in the latest years and the overcoming ones in future, in particular incretin-based therapies, drugs inhibiting kidney glucose reabsorption (SGLT2 inhibitors), and glucokinase activators. The strategy for new drug development advocated here is to establish a broad range of anti-diabetic medicines with different mechanisms of action and potential opportunities for effective combination therapies.

Traditional treatment of type 2 diabetes mellitus (T2DM) has focused on correcting hyperglycemia. However, T2DM is often accompanied by other conditions and risk factors, including hypertension, overweight/obesity, and dyslipidemia, that affect morbidity and mortality. A broader view toward treating the array of physiologic derangements may provide significant long-term outcomes benefits.

This perspective paper reviews recent data regarding the pathophysiology of T2DM, evaluates current treatment recommendations/algorithms, and discusses potential risks and benefits associated with the various therapeutic options and their combinations.

Information was obtained by a search of the PubMed and Embase databases using the key words type 2 diabetes mellitus, glycosylated hemoglobin, pathophysiology of type 2 diabetes, glycemic control, antidiabetes therapy, multifactorial therapy, and treatment algorithms for the period of 1985 to 2010. A representative number of relevant articles dealing with these topics was then selected for review.

Three recently proposed treatment algorithms, the American Diabetes Association/European Association for the Study of Diabetes less well-validated algorithm, the American Association of Clinical Endocrinologists/American College of Endocrinology algorithm, and the DeFronzo algorithm, were compared and contrasted. Metformin is usually the first oral agent to be used when not contraindicated because of its ability to suppress hepatic glucose production. Some recommended agents, such as sulfonylureas, drive β-cell failure even as they improve glycosylated hemoglobin. Others, such as glucagon-like peptide-1 (GLP-1) receptor agonists and thiazolidinediones, support and enhance β-cell function. Also, some agents predispose to weight gain (eg, sulfonylureas and insulin), whereas others are weight neutral (eg, dipeptidyl-peptidase-4 inhibitors) or result in weight loss (eg, GLP-1 receptor agonists, pramlintide). Finally, the impact of these agents on associated cardiovascular risk factors is varied. Agents that improve glycemic control while favorably affecting blood lipid levels and/or systemic blood pressure may lead to improvements in morbidity and mortality. Attention to the mechanisms of action and associated consequences of the numerous pharmacologic treatment choices may provide clinicians a better selection of agents in treating patients with T2DM.

Physicians should evaluate the array of treatment options available for patients with T2DM. An aggressive regimen including metformin, a thiazolidinedione, and a GLP-1 receptor agonist may improve insulin sensitivity and enhance β-cell function. Addressing the pathophysiologic defects associated with T2DM, as well as the various associated cardiovascular risk factors, with combination therapy may slow the natural progression of the disease and development of its associated complications.

In addition to progressive pancreatic β-cell failure resulting in impaired insulin secretion, and increased insulin resistance in muscle and liver, incretin hormone-related abnormalities have been identified as key underlying defects in patients with type 2 diabetes mellitus. Treatment goals for patients with type 2 diabetes should be aligned with the basic defects of the disease. Many of the available antidiabetes agents correct hyperglycemia but do not impact other cardiovascular risk factors, and may actually aggravate some. This paper reviews the role of defects in the incretin system in the pathophysiology of type 2 diabetes, and discusses recent advances in the use of incretinbased agents that target the fundamental disease mechanisms of type 2 diabetes. The incretinbased agents reduce hyperglycemia and provide beneficial effects on surrogate markers of cardiovascular risk, including weight gain, elevated blood pressure, and dyslipidemia.

Traditionally, successful treatment of patients with type 2 diabetes mellitus (DM) has been defined strictly by achievement of targeted glycemic control, primarily using a stepped-care approach that begins with changes in lifestyle combined with oral therapy that is slowly intensified as disease progression advances and β-cell function declines. However, stepped care is often adjusted without regard to the mechanism of hyperglycemia or without long-term objectives. A more comprehensive definition of treatment success in patients with type 2 DM should include slowing or stopping disease progression and optimizing the reduction of all risk factors associated with microvascular and macrovascular disease complications. To achieve these broader goals, it is important to diagnose diabetes earlier in the disease course and to consider use of more aggressive combination therapy much earlier with agents that have the potential to slow or halt the progressive β-cell dysfunction and loss characteristic of type 2 DM. A new paradigm for managing patients with type 2 DM should address the concomitant risk factors and morbidities of obesity, hypertension, and dyslipidemia with equal or occasionally even greater aggressiveness than for hyperglycemia. The use of antidiabetes agents that may favorably address cardiovascular risk factors should be considered more strongly in treatment algorithms, although no pharmacological therapy is likely to be ultimately successful without concomitant synergistic lifestyle changes. Newer incretin-based therapies, such as glucagon-like peptide 1 receptor agonists and dipeptidyl peptidase 4 inhibitors, which appear to have a favorable cardiovascular safety profile as well as the mechanistic possibility for a favorable cardiovascular risk impact, are suitable for earlier inclusion as part of combination regimens aimed at achieving comprehensive treatment success in patients with type 2 DM.

Insulin resistance is the main pathologic mechanism that links the constellation of clinical, metabolic and anthropometric traits with increased risk for cardiovascular disease and type II diabetes mellitus. These traits include hyperinsulinemia, impaired glucose intolerance, endothelial dysfunction, dyslipidemia, hypertension, and generalized and upper body fat redistribution. This cluster is often referred to as insulin resistance syndrome. The progression of insulin resistance to diabetes mellitus parallels the progression of endothelial dysfunction to atherosclerosis leading to cardiovascular disease and its complications. In fact, insulin resistance assessed by homeostasis model assessment (HOMA) has shown to be independently predictive of cardiovascular disease in several studies and one unit increase in insulin resistance is associated with a 5.4% increase in cardiovascular disease risk. This review article addresses the role of insulin resistance as a main causal factor in the development of metabolic syndrome and endothelial dysfunction, and its relationship with cardiovascular disease. In addition to this, we review the type of lifestyle modification and pharmacotherapy that could possibly ameliorate the effect of insulin resistance and reverse the disturbances in insulin, glucose and lipid metabolism.

Thiazolidinediones (TZDs) are relatively new agents for the treatment of type 2 diabetes. They act as agonists at the PPAR-gamma nuclear receptor and their therapeutic effects include decreased insulin resistance and hyperglycaemia, an improved plasma lipid, inflammation and pro-coagulant profile, and amelioration of hypertension, microalbuminuria and hepatic steatosis. The most common side effects of TZDs include weight gain and oedema, with occasional reports of congestive heart failure (CHF). This review discusses the benefit-risk profile of TZDs in treating patients with type 2 diabetes, with particular reference to the heart. To provide context, we explore briefly the epidemiology and pathophysiology of heart failure in patients with type 2 diabetes, touch on the association of heart disease and cardiovascular mortality with antihyperglycaemic treatment modalities other than TZDs, and then focus on the effects of TZDs on the heart, cardiovascular risk factors and outcomes. We describe the cluster of host factors, which seems to predispose patients with type 2 diabetes to TZD-induced or TZD-exacerbated oedema and CHF and then provide an overview of the putative mechanisms of these TZD-related side effects. We also propose that certain diuretics (amiloride and spironolactone), by targeting the distal nephron that expresses PPARgamma in collecting duct cells, might be of benefit in ameliorating the fluid retention and oedema associated with TZDs.

Thiazolidinediones (TZDs) have been used for the treatment of hyperglycaemia in type 2 diabetes for the past 10 years. They may delay the development of type 2 diabetes in individuals at high risk of developing the condition, and have been shown to have potentially beneficial effects on cardiovascular risk factors. TZDs act as agonists of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) primarily in adipose tissue. PPAR-gamma receptor activation by TZDs improves insulin sensitivity by promoting fatty acid uptake into adipose tissue, increasing production of adiponectin and reducing levels of inflammatory mediators such as tumour necrosis factor-alpha (TNF-alpha), plasminogen activator inhibitor-1(PAI-1) and interleukin-6 (IL-6). Clinically, TZDs have been shown to reduce measures of atherosclerosis such as carotid intima-media thickness (CIMT). However, in spite of beneficial effects on markers of cardiovascular risk, TZDs have not been definitively shown to reduce cardiovascular events in patients, and the safety of rosiglitazone in this respect has recently been called into question. Dual PPAR-alpha/gamma agonists may offer superior treatment of insulin resistance and cardioprotection, but their safety has not yet been assured.

The increasing prevalence of diabetes worldwide is cause for concern both in terms of associated morbidity and increasing health costs. This review aims to focus on new and emerging treatments for type 1 and type 2 diabetes. There has been recent focus on diabetes prevention both for type 1 and type 2 diabetes. Prevention programme including lifestyle measures and oral hypoglycaemic agents have shown up to 61% reduction in the development of type 2 diabetes in patients with impaired glucose tolerance or impaired fasting glucose. Little progress has been made to date on type 1 diabetes prevention although current work is focusing on T-cell immunomodulation therapy and beta cell regeneration. Management of type 2 diabetes has been improved by the recent introduction of the peroxisome proliferator-activated receptor-gamma agonists and more recently by the incretins including glucagons like peptide analogues and dipeptidyl peptidase-4 inhibitors. This article focuses on the benefits and restrictions of these new agents. The new insulin analogues glargine and detemir have made significant improvements in the management of type 1 diabetes both in terms of improvement in glycaemic control and in reducing hypoglycaemia rates. Inhaled insulin also shows promise for needle-free treatment of diabetes and these insulins are currently undergoing phase 3 trials. Insulin infusion pumps are becoming more sophisticated and increasingly popular in the management of type 1 diabetes. Many studies have shown benefits for improved glycaemic control and reduced rates of hypoglycaemia with pump treatment compared with multiple daily injections. Pancreas and islet cell transplantation are the subject of ongoing research, but currently require immunosuppressive treatment regimes. The main limitation is lack of availability of donor pancreases. There is much hope that new treatments outlined in this review will result in improved outcomes in the treatment of diabetes.

Type 2 diabetes mellitus (T2DM) is a leading cause of morbidity and mortality that places a substantial economic and health burden on the public. Successful management of T2DM requires strict control of glycemia as well as other risk factors to prevent disease progression. Despite the availability of multiple classes of oral antidiabetic drugs and insulin, the majority of patients fail to attain or maintain tight glycemic control over time, raising their risk of serious microvascular and macrovascular complications.

This review briefly outlines current standards of diabetes treatment and explores several new and investigational approaches. It is based on MEDLINE literature searches (1966-August 2006) and on abstracts from the American Diabetes Association Scientific Sessions (2002-2006) and the European Association for the Study of Diabetes Annual Meetings (1998-2006). Articles concerning basic science, preclinical, and clinical trial results were selected for this review based on their originality and relevance.

Medical professional societies and other specialist groups have proposed a series of practical steps to enable more patients with T2DM to reach treatment goals. Among their most important recommendations is a call for new drugs to stabilize or reverse the progressive pancreatic islet-cell dysfunction that characterizes the disease. New modalities, such as incretin mimetics and DPP-4 inhibitors, are now emerging from clinical development and will provide patients with more treatment options.

It appears likely that early and aggressive treatment with multiple drug combinations will become more common in the management of T2DM. The new treatment modalities discussed here offer hope for improved outcomes and for meeting the considerable public health challenges posed by this complex condition. However, long-term studies are needed to determine durability of treatment effects, as well as the ultimate role of these new agents in the management of patients with T2DM.

Thiazolidinediones, which are peroxisome proliferator-activated receptor-gamma agonists, are widely prescribed to patients with disorders characterized by insulin resistance. Preclinical studies suggest that peroxisome proliferator-activated receptor-gamma signaling negatively regulates bone formation and bone density. Human data on the skeletal effects of thiazolidinediones are currently available only from observational studies.

The objective of the study was to determine whether rosiglitazone, a thiazolidinedione, inhibits bone formation.

The study was a 14-wk randomized, double-blind, placebo-controlled trial.

The study was conducted in the general community.

Fifty healthy, postmenopausal women participated in the study.

Intervention was rosiglitazone 8 mg/d.

The primary end point was biochemical markers of bone formation, and secondary end points were a bone resorption marker and bone mineral density.

The osteoblast markers procollagen type I N-terminal propeptide and osteocalcin declined by 13% (P<0.005 vs. placebo) and 10% (P=0.04 vs. placebo), respectively, in the rosiglitazone group. These changes were evident by 4 wk and persisted for the duration of the study. There was no change in the serum beta-C-terminal telopeptide of type I collagen, a marker of bone resorption (P=0.9 vs. placebo). Total hip bone density fell in the rosiglitazone group (mean change from baseline rosiglitazone -1.9%, placebo -0.2%; between-group difference 1.7%, 95% confidence interval 0.6-2.7, P<0.01); lumbar spine bone density fell significantly from baseline values in the rosiglitazone group (P=0.02 vs. baseline) but was not significantly different between groups (mean change from baseline rosiglitazone -1.2%, placebo -0.2%; between-group difference 1.0%, 95% confidence interval -0.2-2.3, P=0.13).

Short-term therapy with rosiglitazone exerts detrimental skeletal effects by inhibiting bone formation. Skeletal end points should be included in future long-term studies of thiazolidinedione use.

Significant race and ethnic disparities exist in diabetes-related health care. Using a nationally representative database, we sought to determine if use of thiazolidinediones (TZDs) differs by race and ethnicity. As a secondary objective, we sought to determine if race and ethnicity is associated with use of older oral antidiabetic agents, such as sulfonylureas and metformin.

Adult respondents to the 2003 Medical Expenditure Panel Survey with diabetes, identified by diagnosis code or self-report, were included. Race/ethnic groups were defined as: White/not-Hispanic; Black/not-Hispanic; Hispanic; or Other/not-Hispanic. Associations between use of oral antidiabetic agents (defined as > or = 1 prescription for a TZD, sulfonylurea, or metformin) and race/ethnicity, sex, age, insurance status, poverty status, and having a usual source of care were evaluated in univariate analyses with chi(2) tests and in adjusted analyses using logistic regression methods for survey data.

A total of 1873 US adults with diabetes were identified, with use of oral antidiabetic agents varying by drug class: 23.1% received TZDs, 45.3% received metformin, and 43.8% received sulfonylureas. Use of oral antidiabetic agents, by drug class, did not differ significantly by race/ethnicity (p = 0.33 for TZDs, p = 0.43 for metformin, p = 0.38 for sulfonylureas). In univariate analyses, only insurance status was significantly associated with use of TZDs (p = 0.03), and no variables were associated with use of sulfonylureas or metformin. In adjusted logistic regression analyses, there were no significant predictors of the use of TZDs or metformin, and only age was significantly associated with the use of sulfonylureas.

In a nationally representative database, fewer US adults with diabetes received TZDs compared with sulfonylureas or metformin in 2003. Although we were not able to differentiate between type 1 and type 2 diabetes, nor did we assess oral agent monotherapy versus combination therapy, we found that use of TZDs, sulfonylureas, and metformin did not differ based on race/ethnicity or other demographic variables such as sex, insurance status, poverty status, or having a usual source of health care.

Thiazolidinediones (TZD), or glitazones, represent a new generation of antidiabetic drugs that have recently been introduced in Europe. They improve insulin resistance, one of the key anomalies involved in the pathogenesis of type 2 diabetes mellitus, by activating the nuclear peroxoxisome proliferator activated receptor-gamma (PPAR-gamma), leading to crucial metabolic alterations in adipose tissue. Rosiglitazone and pioglitazone have been shown to be active as monotherapy, in combination therapy with metformin or sulfonylureas, and even in triple therapy. They are generally well tolerated but can induce fluid retention. Cardiac failure is a contraindication for the use of TZDs, as is the concomitant administration of insulin. Aside from their effect on glycemic control, TZDs act on several cardiovascular risk factors and may protect pancreatic beta cells from apoptosis. The cardiovascular protective effect of TZDs has recently been demonstrated with the results of the PROactive study, and long-term preservation of beta-cell function is currently under further investigation.

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