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In this phase 3b, open-label, randomized, controlled trial involving adults with obesity without type 2 diabetes, tirzepatide was superior to semaglutide in reducing body weight and waist circumference.

Aims/hypothesis We previously reported that obese individuals with the metabolic syndrome (at risk), compared with obese individuals without the metabolic syndrome (healthy obese), have elevated serum AGEs that strongly correlate with insulin resistance, oxidative stress and inflammation. We hypothesised that a diet low in AGEs (L-AGE) would improve components of the metabolic syndrome in obese individuals, confirming high AGEs as a new risk factor for the metabolic syndrome. Methods A randomised 1 year trial was conducted in obese individuals with the metabolic syndrome in two parallel groups: L-AGE diet vs a regular diet, habitually high in AGEs (Reg-AGE). Participants were allocated to each group by randomisation using random permuted blocks. At baseline and at the end of the trial, we obtained anthropometric variables, blood and urine samples, and performed OGTTs and MRI measurements of visceral and subcutaneous abdominal tissue and carotid artery. Only investigators involved in laboratory determinations were blinded to dietary assignment. Effects on insulin resistance (HOMA-IR) were the primary outcome. Results Sixty-one individuals were randomised to a Reg-AGE diet and 77 to an L-AGE diet; the data of 49 and 51, respectively, were analysed at the study end in 2014. The L-AGE diet markedly improved insulin resistance; modestly decreased body weight; lowered AGEs, oxidative stress and inflammation; and enhanced the protective factors sirtuin 1, AGE receptor 1 and glyoxalase I. The Reg-AGE diet raised AGEs and markers of insulin resistance, oxidative stress and inflammation. There were no effects on MRI-assessed measurements. No side effects from the intervention were identified. HOMA-IR came down from 3.1 ± 1.8 to 1.9 ± 1.3 ( p  < 0.001) in the L-AGE group, while it increased from 2.9 ± 1.2 to 3.6 ± 1.7 ( p  < 0.002) in the Reg-AGE group. Conclusions / interpretation L-AGE ameliorates insulin resistance in obese people with the metabolic syndrome, and may reduce the risk of type 2 diabetes, without necessitating a major reduction in adiposity. Elevated serum AGEs may be used to diagnose and treat ‘at-risk’ obesity. Trial registration ClinicalTrials.gov NCT01363141 Funding The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (DK091231)

The frequency of obesity has risen dramatically in recent years but only few safe and effective drugs are currently available. We assessed the effect of liraglutide on bodyweight and tolerability in obese individuals without type 2 diabetes. We did a double-blind, placebo-controlled 20-week trial, with open-label orlistat comparator in 19 sites in Europe. 564 individuals (18–65 years of age, body-mass index 30–40 kg/m 2) were randomly assigned, with a telephone or web-based system, to one of four liraglutide doses (1·2 mg, 1·8 mg, 2·4 mg, or 3·0 mg, n=90–95) or to placebo (n=98) administered once a day subcutaneously, or orlistat (120 mg, n=95) three times a day orally. All individuals had a 500 kcal per day energy-deficit diet and increased their physical activity throughout the trial, including the 2-week run-in. Weight change analysed by intention to treat was the primary endpoint. An 84-week open-label extension followed. This study is registered with ClinicalTrials.gov, number NCT00422058. Participants on liraglutide lost significantly more weight than did those on placebo (p=0·003 for liraglutide 1·2 mg and p<0·0001 for liraglutide 1·8–3·0 mg) and orlistat (p=0·003 for liraglutide 2·4 mg and p<0·0001 for liraglutide 3·0 mg). Mean weight loss with liraglutide 1·2–3·0 mg was 4·8 kg, 5·5 kg, 6·3 kg, and 7·2 kg compared with 2·8 kg with placebo and 4·1 kg with orlistat, and was 2·1 kg (95% CI 0·6–3·6) to 4·4 kg (2·9–6·0) greater than that with placebo. More individuals (76%, n=70) lost more than 5% weight with liraglutide 3·0 mg that with placebo (30%, n=29) or orlistat (44%, n=42). Liraglutide reduced blood pressure at all doses, and reduced the prevalence of prediabetes (84–96% reduction) with 1·8–3·0 mg per day. Nausea and vomiting occurred more often in individuals on liraglutide than in those on placebo, but adverse events were mainly transient and rarely led to discontinuation of treatment. Liraglutide treatment over 20 weeks is well tolerated, induces weight loss, improves certain obesity-related risk factors, and reduces prediabetes. Novo Nordisk A/S, Bagsvaerd, Denmark.

Regular consumption of flavonoids may reduce the risk for CVD. However, the effects of individual flavonoids, for example, quercetin, remain unclear. The present study was undertaken to examine the effects of quercetin supplementation on blood pressure, lipid metabolism, markers of oxidative stress, inflammation, and body composition in an at-risk population of ninety-three overweight or obese subjects aged 25–65 years with metabolic syndrome traits. Subjects were randomised to receive 150 mg quercetin/d in a double-blinded, placebo-controlled cross-over trial with 6-week treatment periods separated by a 5-week washout period. Mean fasting plasma quercetin concentrations increased from 71 to 269 nmol/l (P < 0·001) during quercetin treatment. In contrast to placebo, quercetin decreased systolic blood pressure (SBP) by 2·6 mmHg (P < 0·01) in the entire study group, by 2·9 mmHg (P < 0·01) in the subgroup of hypertensive subjects and by 3·7 mmHg (P < 0·001) in the subgroup of younger adults aged 25–50 years. Quercetin decreased serum HDL-cholesterol concentrations (P < 0·001), while total cholesterol, TAG and the LDL:HDL-cholesterol and TAG:HDL-cholesterol ratios were unaltered. Quercetin significantly decreased plasma concentrations of atherogenic oxidised LDL, but did not affect TNF-α and C-reactive protein when compared with placebo. Quercetin supplementation had no effects on nutritional status. Blood parameters of liver and kidney function, haematology and serum electrolytes did not reveal any adverse effects of quercetin. In conclusion, quercetin reduced SBP and plasma oxidised LDL concentrations in overweight subjects with a high-CVD risk phenotype. Our findings provide further evidence that quercetin may provide protection against CVD.

Prader-Willi syndrome (PWS) is a complex genetic condition characterized by hyperphagia, hypotonia, low muscle mass, excess body fat, developmental delays, intellectual disability, behavioral problems, and growth hormone deficiency. This study evaluated the safety and efficacy of orally administered Diazoxide Choline Controlled-Release Tablets (DCCR) in subjects with PWS. This was a single-center, Phase II study and included a 10-week Open-Label Treatment Period during which subjects were dose escalated, followed by a 4-week Double-Blind, Placebo-Controlled Treatment Period. Five female and eight male overweight or obese, adolescent and adult subjects with genetically-confirmed PWS with an average age of 15.5±2.9 years were enrolled in the study. There was a statistically significant reduction in hyperphagia at the end of the Open-Label Treatment Period (-4.32, n = 11, p = 0.006). The onset of effect on hyperphagia was rapid and greater reductions in hyperphagia were seen in subjects with moderate to severe Baseline hyperphagia (-5.50, n = 6, p = 0.03), in subjects treated with the highest dose (-6.25, n = 4, p = 0.08), and in subjects with moderate to severe Baseline hyperphagia treated with the highest dose (-7.83, n = 3, p = 0.09). DCCR treatment resulted in a reduction in the number of subjects displaying aggressive behaviors (-57.1%, n = 10, p = 0.01), clinically-relevant reductions in fat mass (-1.58 kg, n = 11, p = 0.02) and increases in lean body mass (2.26 kg, n = 11, p = 0.003). There was a corresponding decrease in waist circumference, and trends for improvements in lipids and insulin resistance. The most common adverse events were peripheral edema and transient increases in glucose. Many of the adverse events were common medical complications of PWS and diazoxide. DCCR treatment appears to address various unmet needs associated with PWS, including hyperphagia and aggressive behaviors in this proof-of-concept study. If the results were replicated in a larger scale study, DCCR may be a preferred therapeutic option for patients with PWS.

•Inflammatory bowel disease (IBD) refers to diseases that cause inflammation of the intestinal wall.•Flaxseed is a rich source of omega-3 fatty acids (α-linolenic acid; ALA), phytoestrogens and soluble fiber.•flaxseed and flaxseed oil, attenuate inflammatory markers, disease severity, blood pressure, and WC. The present study aimed to evaluate the possible effect of grounded flaxseed and flaxseed oil on serum levels of inflammatory markers, metabolic parameters, and the severity of disease in patients with UC. In this open-labeled randomized controlled trial, 90 UC patients were randomly assigned to one of the 3 groups for 12 weeks: grounded flaxseed (GF; 30 g/day), flaxseed oil (FO; 10 g/day) and control group. The weight, waist circumference, systolic and diastolic blood pressure, serum inflammatory markers (interleukin-6 (IL-6), interferon gamma (INF-γ), transforming growth factor beta (TGF-β), and Erythrocyte Sedimentation Rate (ESR)), and fecal calprotectin were measured at the baseline and end of the study. Totally, 75 patients (43 men and 32 women) with a mean age of 31.54 ± 9.84 years participated in the present study. Comparing the change of the variables indicated a significant decrease in fecal calprotectin (P < 0.001), Mayo score (P < 0.001), ESR (P < 0.001), INF-γ (P < 0.001), IL-6 (P < 0.001), waist circumference (P = 0.02), Diastolic Blood Pressure (DBP) (P < 0.001), and Systolic Blood Pressure (SBP) (P < 0.001) and a significant increase in TGF-β (P < 0.001) and Inflammatory Bowel Disease Questionnaire-Short form (IBDQ-9) score (P < 0.001) in the GF and FO groups compared to the control. No difference was obvious between the FO and GF groups except for TGF-β. The present study showed that both flaxseed and flaxseed oil, attenuate inflammatory markers, disease severity, blood pressure, and WC. However, the effect of flaxseed on weight and BMI was not evident.

PurposeNature is a phenomenal treasure of remedies. Numerous previous studies reported that Nigella sativa NS improved glycemic control, reduced insulin resistance, and improved lipid profile. NS was never investigated before as a monotherapy for newly diagnosed type 2 diabetes mellitus T2DM patients. Our aim was to investigate the potential metabolic benefits of NS monotherapy in newly diagnosed T2DM patients.MethodProspective, open-label randomized clinical trial at outpatient endocrinology clinic at Ain-Shams University hospital. Eligible patients were randomly assigned to either metformin tablets or NS oil capsules. Both groups received treatment for 3 months. Glycemic index (FBG, 2 h pp, A1C, insulin sensitivity %S, secretory function %B, insulin resistance IR), lipid profile (TC, LDL, HDL, TG), liver and kidney functions (AST, ALT, Sr cr), total antioxidant capacity TAC, weight, waist circumference WC and body mass index BMI were assessed at baseline and at the end of treatment period.ResultsA concentration of 1350 mg/day NS in newly diagnosed T2DM patients was inferior to metformin in terms of lowering FBG, 2 h pp, and A1C or increasing %B. However, NS was comparable to metformin in lowering weight, WC, and BMI significantly. NS was comparable to metformin in regards of their effects on fasting insulin, %S, IR, ALT, TC, LDL, HDL, TG, and TAC. Metformin showed significant increase in AST and creatinine which was reserved in NS group.ConclusionNS administration in newly diagnosed T2DM was tolerable with no side effects as compared to metformin; however, it was inferior to metformin in terms of diabetes management.

Background/Objectives:Vitamin K status has been linked to fat and glucose metabolism by several authors, but whether high vitamin K intake influences body weight or composition has remained unclear. Here we tested the hypothesis that increased vitamin K intake decreases body fat or fat distribution.Subjects/Methods:In a randomized placebo-controlled human intervention trial, 214 postmenopausal women, 55-65 years of age, received either 180 mcg/day of vitamin K2 (menaquinone-7, MK-7) or placebo for 3 years. Osteocalcin (OC) carboxylation was used as a marker for vitamin K status, and fat distribution was assessed by dual-energy X-ray absorptiometry total body scan.Results:In the total cohort, MK-7 supplementation increased circulating carboxylated OC (cOC) but had no effect on body composition. In those with an above-median response in OC carboxylation ('good responders'), MK-7 treatment resulted in a significant increase in total and human molecular weight adiponectin and a decrease in abdominal fat mass and in the estimated visceral adipose tissue area compared with the placebo group and the poor responders.Conclusions:The fact that changes in body composition measures or markers for fat or glucose metabolism were not associated with changes in uncarboxylated OC (ucOC) does not support the assumption that ucOC stimulates fat metabolism in humans. Instead, high vitamin K2 intake may support reducing body weight, abdominal and visceral fat, notably in subjects showing a strong increase in cOC. A causal relation between the changes in cOC and body fat or distribution cannot be concluded from these data.

Understanding individual differences in the susceptibility to metabolic side effects as a response to antipsychotic therapy is essential to optimize the treatment of schizophrenia. Here, we perform genomewide association studies (GWAS) to search for genetic variation affecting the susceptibility to metabolic side effects. The analysis sample consisted of 738 schizophrenia patients, successfully genotyped for 492K single nucleotide polymorphisms (SNPs), from the genomic subsample of the Clinical Antipsychotic Trial of Intervention Effectiveness study. Outcomes included 12 indicators of metabolic side effects, quantifying antipsychotic-induced change in weight, blood lipids, glucose and hemoglobin A1c, blood pressure and heart rate. Our criterion for genomewide significance was a pre-specified threshold that ensures, on average, only 10% of the significant findings are false discoveries. A total of 21 SNPs satisfied this criterion. The top finding indicated that a SNP in Meis homeobox 2 ( MEIS2 ) mediated the effects of risperidone on hip circumference ( q =0.004). The same SNP was also found to mediate risperidone's effect on waist circumference ( q =0.055). Genomewide significant finding were also found for SNPs in PRKAR2B , GPR98, FHOD3, RNF144A, ASTN2, SOX5 and ATF7IP2 , as well as in several intergenic markers. PRKAR2B and MEIS2 both have previous research indicating metabolic involvement, and PRKAR2B has previously been shown to mediate antipsychotic response. Although our findings require replication and functional validation, this study shows the potential of GWAS to discover genes and pathways that potentially mediate adverse effects of antipsychotic medication.

To study the effect of exenatide on body composition and circulating cardiovascular risk biomarkers. Metformin-treated patients with type 2 diabetes (N = 69) were randomized to exenatide or insulin glargine and treated for 1 year. Body composition was evaluated by dual-energy X-ray absorptiometry. Additionally, body weight, waist circumference, and cardiovascular biomarkers were measured. Treatment with exenatide for 1 year significantly reduced body weight, waist circumference, and total body and trunkal fat mass by 6, 5, 11, and 13%, respectively. In addition, exenatide increased total adiponectin by 12% and reduced high-sensitivity C-reactive protein by 61%. Insulin glargine significantly reduced endothelin-1 by 7%. These changes were statistically independent of the change in total body fat mass and body weight. Exenatide treatment for 1 year reduced body fat mass and improved the profile of circulating biomarkers of cardiovascular risk. No significant changes were seen with insulin glargine except a trend for reduced endothelin-1 levels.