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Metformin improves insulin sensitivity and was compared with placebo in this study involving obese pregnant women without diabetes. Antenatal administration of metformin was associated with lower maternal weight gain but not in lower birth weight of the baby. The prevalence of obesity is increasing both in developed countries and in developing countries, and obesity is considered to be a global pandemic. 1 An estimated one fifth of pregnant women in the United Kingdom and one third of those in the United States are obese. 2 , 3 Obesity during pregnancy is associated with an increased risk of adverse short-term and long-term consequences for both mother and baby. 4 – 11 Attempts at reducing the incidence of pregnancy complications associated with obesity have focused on dietary and lifestyle interventions, but these have generally been unsuccessful. 12 – 17 An alternative strategy is the use of metformin, . . .

In this trial in nondiabetic patients with insulin resistance and a recent ischemic stroke or transient ischemic attack, pioglitazone was associated with a lower risk of stroke and MI than was placebo but with a higher risk of weight gain, edema, and bone fracture. Ischemic stroke and transient ischemic attack (TIA) affect more than 14 million persons worldwide annually. 1 , 2 Affected patients are at increased risk for future cardiovascular events, 3 , 4 and prevention of these adverse outcomes is a major goal in their care. Treatment of insulin resistance represents a potential new preventive strategy that could be added to standard care after ischemic stroke or TIA. 5 Insulin resistance is nearly universal in patients with type 2 diabetes but is also present in more than 50% of patients without diabetes who have had an ischemic stroke or a TIA. 6 The presence of insulin resistance increases . . .

In this randomized trial comparing vitamin E, pioglitazone, and placebo in adults without diabetes who had nonalcoholic steatohepatitis, vitamin E therapy was associated with a significantly higher rate of improvement in nonalcoholic steatohepatitis than was placebo (43% vs. 19%). Significant benefits of pioglitazone over placebo were shown for some secondary outcomes but not for the primary outcome. In adults who had nonalcoholic steatohepatitis, vitamin E therapy was associated with a significantly higher rate of improvement than was placebo. Significant benefits of pioglitazone over placebo were shown for some secondary outcomes. Nonalcoholic steatohepatitis is a common liver disease that is characterized histologically by hepatic steatosis, lobular inflammation, and hepatocellular ballooning 1 , 2 ; it can progress to cirrhosis in up to 15% of patients. 3 , 4 There is currently no therapy that is of proven benefit for nonalcoholic steatohepatitis. The disease is closely associated with insulin resistance and features of the metabolic syndrome such as obesity, hypertriglyceridemia, and type 2 diabetes. 5 , 6 In addition to insulin resistance, oxidative stress has been implicated as a key factor contributing to hepatic injury in patients with nonalcoholic steatohepatitis. 6 , 7 Thus, both insulin resistance and oxidative stress . . .

Background. Fat gain after antiretroviral therapy (ART) occurs, and its association with protease inhibitors (PIs) is unclear. Methods. Peripheral and central fat depots and lean mass were measured using standardized and centrally read abdominal CT scans and whole-body dual-energy absorptiometry scans over a 96-week period in human immunodeficiency virus (HIV)–infected treatment-naive participants. The patients were randomized to tenofovir-emtricitabine (TDF/FTC) plus atazanavir-ritonavir (ATV/r), darunavir-ritonavir (DRV/r), or raltegravir (RAL) in ACTG A5260s, a substudy of A5257. Within arm changes were assessed with signed-rank tests. The 96-week percentage changes in fat and lean mass in the 2 PI arms were not different, thus the PI arms were combined and compared to the RAL arm. Associations between baseline biomarkers and changes in body composition were assessed. All analyses used linear regression models. Results. 328 patients were randomized (90% male, 44% white non-Hispanic). The median age was 36 years, HIV-1 RNA 4.6 log 10 copies/mL, and CD4 349 cells/μL. Overall, at week 96, increases in limb fat (13.4%), subcutaneous (19.9%) and visceral abdominal fat (25.8%), trunk fat (18%), and lean mass (1.8%) were apparent (P< .001 for changes within each arm). Changes for all fat and lean outcomes were not different between the PI arms or between the RAL and the combined PI arms. Higher baseline HIV-1 RNA levels were associated with greater gains in peripheral and central fat. Conclusions. In treatment-naive participants initiating ART with TDF/FTC, no differences in lean mass and regional fat were found with RAL when compared with ATV/r or DRV/r over 96 weeks. Clinical Trials Registration. NCT00811954 and NCT00851799.

Cancer anorexia-cachexia syndrome is associated with increased morbidity and mortality. Anamorelin is an oral ghrelin-receptor agonist with appetite-enhancing and anabolic activity. We assessed the effects of anamorelin on body composition, strength, quality of life, biochemical markers, and safety in patients with cancer anorexia-cachexia. Data were pooled, a priori, from two completed phase 2, multicentre, placebo-controlled, double-blind trials in patients with advanced or incurable cancer and weight loss of 5% or more. Patients were stratified by weight loss severity (5–15%, >15%) and randomly allocated (1:1) with a computer-generated randomisation schedule to anamorelin hydrochloride 50 mg or placebo once-daily for 12 weeks. Primary outcome was lean body mass by dual-energy x-ray absorptiometry over the 12 week treatment period in eligible patients who had at least one dose of study drug and post-treatment efficacy assessment. We assessed safety in all patients who received at least one dose of study drug. The trials are registered with ClinicalTrials.gov, numbers NCT00219817 and NCT00267358. Between June 29, 2005, and Oct 26, 2006, we enrolled 44 patients in the anamorelin group and 38 patients in the placebo group. 74 patients were eligible for the efficacy analyses. Over 12 weeks, lean body mass increased in 38 patients in the anamorelin group by a least-squares mean of 1·89 kg (95% CI 0·84 to 2·95) compared with a decrease of a least-squares mean of −0·20 kg (−1·23 to 0·83) for 36 patients in the placebo group (difference 2·09 kg [0·94–3·25]; p=0·0006). 42 (95%) of 44 patients treated with anamorelin and 33 (87%) of 38 patients treated with placebo had adverse events. The most common grade 3–4 adverse events (treatment-related or not) in the anamorelin group were fatigue, asthenia, atrial fibrillation, and dyspnoea (two [5%] each); in the placebo group, such events were pneumonia (three [8%]) and anaemia, thrombocytopenia, abdominal pain, anxiety, and dyspnoea (two [5%] each). Anamorelin treatment for 12 weeks had a favourable clinical response profile in patients with cancer anorexia-cachexia syndrome. These findings support further investigation in this setting. Helsinn Therapeutics (US), Helsinn Healthcare SA.

This study examined whether pioglitazone can reduce the risk of type 2 diabetes mellitus in adults with impaired glucose tolerance. As compared with placebo, pioglitazone reduced the conversion of IGT to diabetes by 72% but was associated with significant weight gain and edema. Type 2 diabetes mellitus affects 21 million Americans, 1 and its prevalence is increasing. 2 Microvascular and macrovascular complications are common in type 2 diabetes mellitus and are related to both the severity and the duration of hyperglycemia. 3 The natural history of type 2 diabetes mellitus has been well defined, 4 starting with a genetic predisposition and progression from normal glucose tolerance with insulin resistance to impaired glucose tolerance and eventually type 2 diabetes mellitus with the superimposition of beta-cell failure. Because hyperglycemia plays a central role in the microvascular and macrovascular complications of diabetes, 3 , 5 , 6 it is possible that interventions that . . .

Rationale Weight gain during treatment with antipsychotics is a prominent side-effect, especially with some second-generation antipsychotics, such as olanzapine and clozapine, and pharmacological treatments which ameliorate this side-effect are important to investigate. Decreases in histaminergic transmission in the brain induced by antipsychotics may be one of the mechanisms contributing to weight gain. Since betahistine is a histaminergic agonist, it may potentially counteract the weight gain effects of antipsychotics. Method We conducted a double-blind placebo-controlled study to evaluate the effects of 12 weeks of treatment with betahistine ( N  = 29) or placebo ( N  = 22) in adolescents and adults on anthropomorphically measured weight-related parameters, appetite, and fasting glucose-lipid and leptin levels in 51 patients treated with first and/or second-generation antipsychotics who had gained weight during treatment or had high body-mass-index (BMI). Psychopathology and side-effects were also assessed with relevant scales. Results In a sub-group of patients being treated with olanzapine or clozapine ( n  = 26), betahistine was significantly ( P  < .05) better than placebo in preventing increases in weight (3.1 kg less weight gain than placebo), BMI, and waist circumference. Betahistine did not decrease weight or BMI in patients treated with other antipsychotics. There was also no effect of betahistine on preventing weight or BMI gain in the total combined sample of all subjects. Betahistine did not significantly improve appetite or glucose-lipid measures in either subgroup. There were no significant differences in side-effects or psychopathology changes in the betahistine- vs. placebo-treated patients. Conclusions These results suggest that betahistine may potentially be a useful adjunctive drug for decreasing weight gain in patients treated with antipsychotics that are potent histamine antagonists, such as olanzapine or clozapine, but may not be useful for this purpose in patients on other antipsychotic medications. The results justify larger placebo-controlled studies to further confirm these effects before specific recommendations can be made for routine use.

Background. Both wasting and obesity are associated with inflammation, but the extent to which body weight changes influence inflammation during human immunodeficiency virus infection is unknown. Methods. Among a random virologically suppressed participants of the Prospective Evaluation of Antiretrovirals in Resource-Limited Settings trial, inflammatory markers were measured at weeks 0, 24, and 48 after antiretroviral therapy (ART) initiation. Associations between both baseline and change in body mass index (BMI; calculated as the weight in kilograms divided by the height in meters squared) and changes in inflammation markers were assessed using random effects models. Results. Of 246 participants, 27% were overweight/obese (BMI, ≥ 25), and 8% were underweight (BMI < 18.5) at baseline. After 48 weeks, 37% were overweight/obese, and 3% were underweight. While level of many inflammatory markers decreased 48 weeks after ART initiation in the overall group, the decrease in C-reactive protein (CRP) level was smaller in overweight/obese participants (P = .01), and the decreases in both CRP (P = .01) and interleukin 18 (P = .02) levels were smaller in underweight participants. Each 1-unit gain in BMI among overweight/obese participants was associated with a 0.02-log10 increase in soluble CD14 level (P = .05), while each 1-unit BMI gain among underweight participants was associated with a 9.32-mg/L decrease in CRP level (P = .001). Conclusions. Being either overweight or underweight at ART initiation was associated with heightened systemic inflammation. While weight gain among overweight/obese persons predicted increased inflammation, weight gain among underweight persons predicted reduced inflammation.

In this 3-year multicenter trial, patients with suboptimal glycated hemoglobin levels while receiving metformin and sulfonylurea therapy were randomly assigned to add biphasic, prandial, or basal insulin. During the first year, sulfonylurea therapy was replaced by additional insulin for unacceptable hyperglycemia or subsequently for a glycated hemoglobin level of more than 6.5%. Basal- or prandial-based insulin regimens more often achieved glycated hemoglobin targets. Fewer hypoglycemic episodes and less weight gain occurred with regimens initiated with basal insulin. Basal- or prandial-based insulin regimens more often achieved glycated hemoglobin targets. Fewer hypoglycemic episodes and less weight gain occurred with regimens initiated with basal insulin. Most patients with type 2 diabetes require insulin therapy when oral antidiabetic agents provide suboptimal glycemic control, since long-term glycemic improvement reduces the risks of both microvascular 1 and macrovascular 1 , 2 complications. However, different insulin regimens have varying effects on glycemic control, weight gain, and the risk of hypoglycemia. 3 In the first phase of the Treating to Target in Type 2 Diabetes (4-T) study, we evaluated patients with type 2 diabetes who had suboptimal glycemic control despite maximally tolerated doses of metformin and sulfonylurea to see whether the randomized addition of a biphasic, prandial, or basal analogue insulin would lead to . . .

This double-blind, randomized, controlled trial evaluated rosiglitazone, metformin, and glyburide as an initial treatment in patients with type 2 diabetes. Rosiglitazone reduced the risk of treatment failure (the primary outcome) by 32% as compared with metformin and by 63% as compared with glyburide. The potential risks, benefits, and costs of these medications should all be considered to help inform the choice of pharmacotherapy for patients with type 2 diabetes. In patients with type 2 diabetes, rosiglitazone reduced the risk of treatment failure by 32% as compared with metformin and by 63% as compared with glyburide. The attainment and maintenance of near-normal glycemia reduces the risk of long-term complications of diabetes. 1 – 3 Despite lifestyle and pharmacologic interventions, glucose levels increase over time in type 2 diabetes, probably as a consequence of declining β-cell function. 4 The progressive nature of type 2 diabetes makes it difficult to maintain target levels of glycated hemoglobin with traditional glucose-lowering agents 5 , 6 and generally necessitates the escalation of drug doses and the use of combination therapies or insulin. 7 Thiazolidinediones reduce insulin resistance by sensitizing muscle, liver, and adipose tissue to insulin 8 and delay progression to type 2 diabetes in patients with glucose . . .