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Objective: Having demonstrated short-term weight loss with liraglutide in this group of obese adults, we now evaluate safety/tolerability (primary outcome) and long-term efficacy for sustaining weight loss (secondary outcome) over 2 years. Design: A randomized, double-blind, placebo-controlled 20-week study with 2-year extension (sponsor unblinded at 20 weeks, participants/investigators at 1 year) in 19 European clinical research centers. Subjects: A total of 564 adults ( n =90–98 per group; body mass index 30–40 kg m −2 ) enrolled, 398 entered the extension and 268 completed the 2-year trial. Participants received diet (500 kcal deficit per day) and exercise counseling during 2-week run-in, before being randomly assigned (with a telephone or web-based system) to once-daily subcutaneous liraglutide (1.2, 1.8, 2.4 or 3.0 mg, n =90–95), placebo ( n =98) or open-label orlistat (120 mg × 3, n =95). After 1 year, liraglutide/placebo recipients switched to liraglutide 2.4 mg, then 3.0 mg (based on 20-week and 1-year results, respectively). The trial ran from January 2007–April 2009 and is registered with Clinicaltrials.gov , number NCT00480909. Results: From randomization to year 1, liraglutide 3.0 mg recipients lost 5.8 kg (95% confidence interval 3.7–8.0) more weight than those on placebo and 3.8 kg (1.6–6.0) more than those on orlistat ( P ⩽0.0001; intention-to-treat, last-observation-carried-forward). At year 2, participants on liraglutide 2.4/3.0 mg for the full 2 years (pooled group, n =184) lost 3.0 kg (1.3–4.7) more weight than those on orlistat ( n =95; P <0.001). Completers on liraglutide 2.4/3.0 mg ( n =92) maintained a 2-year weight loss of 7.8 kg from screening. With liraglutide 3.0 mg, 20-week body fat decreased by 15.4% and lean tissue by 2.0%. The most frequent drug-related side effects were mild to moderate, transient nausea and vomiting. With liraglutide 2.4/3.0 mg, the 2-year prevalence of prediabetes and metabolic syndrome decreased by 52 and 59%, with improvements in blood pressure and lipids. Conclusion: Liraglutide is well tolerated, sustains weight loss over 2 years and improves cardiovascular risk factors.

Objective: Type 2 diabetes (T2DM) is known to be underdiagnosed. Tests for diagnosis include fasting plasma glucose (FPG), oral glucose tolerance test (OGTT) and HbA1c. HbA1c can be tested in non-fasting conditions. Therefore, general practitioners almost no longer execute OGTT’s. We evaluated the performance of OGTT versus HbA1c in a population consisting of overweight and obese subjects, which can be considered a ‘high risk’ population. Research design and methods: A total of, 1241 overweight and obese subjects without a history of diabetes (male/female: 375/866, age 44±13 years, body mass index 38.0±6.1 kg m −2 ) were tested for glucose tolerance status using FPG, OGTT and HbA1c. Results: Exactly, 46.8% were found to have prediabetes and 11.9% were newly diagnosed with T2DM (male/female=18.9/8.9%) using ADA criteria. Testing only HbA1c would have resulted in 78 subjects being diagnosed with T2DM, but 47.3% of newly diagnosed patients would have been missed if OGTT would not have been done. Exactly 581 subjects were diagnosed with prediabetes, 1.4% subjects had impaired fasting glucose (IFG) 30.5% had impaired glucose tolerance (IGT), 5.1% subjects had a combined IFG+IGT, and 9.8% had an isolated elevated HbA1c (5.7–6.4%). Of the 581 subjects with prediabetes, 257 had an HbA1c <5.7%. Therefore, 44.2% subjects would have been missed when OGTT would not have been done. Conclusion: In a population with only overweight and obese adult subjects, 46.8% were diagnosed with prediabetes and 11.9% were newly diagnosed with diabetes. Exactly, 5.6 and 20.7% of total population met the diagnostic criteria of the OGTT for diabetes and prediabetes, respectively, but did not meet the diagnostic criteria of the HbA1c. These data suggest that not performing an OGTT results in significant underdiagnose of T2DM in an overweight and obese adult population.

The prevalence of diabetes mellitus is currently at epidemic proportions and it is estimated that it will increase even further over the next decades. Although genetic predisposition and lifestyle choices are commonly accepted reasons for the occurrence of type 2 diabetes, it has recently been suggested that environmental pollutants are additional risk factors for diabetes development and this review aims to give an overview of the current evidence for this. More specifically, because of the crucial role of pancreatic beta cells in the development and progression of type 2 diabetes, the present work summarises the known effects of several compounds on beta cell function with reference to mechanistic studies that have elucidated how these compounds interfere with the insulin secreting capacity of beta cells. Oestrogenic compounds, organophosphorus compounds, persistent organic pollutants and heavy metals are discussed, and a critical reflection on the relevance of the concentrations used in mechanistic studies relative to the levels found in the human population is given. It is clear that some environmental pollutants affect pancreatic beta cell function, as both epidemiological and experimental research is accumulating. This supports the need to develop a solid and structured platform to fully explore the diabetes-inducing potential of pollutants.

Background: Liraglutide 3.0 mg, with diet and exercise, produced substantial weight loss over 1 year that was sustained over 2 years in obese non-diabetic adults. Nausea was the most frequent side effect. Objective: To evaluate routinely collected data on nausea and vomiting among individuals on liraglutide and their influence on tolerability and body weight. Design: A randomized, placebo-controlled, double-blind 20-week study with an 84-week extension (sponsor unblinded at 20 weeks, open-label after 1 year) in eight European countries (Clinicaltrials.gov: NCT00422058). Subjects: After commencing a 500-kcal/day deficit diet plus exercise, 564 participants (18–65 years, body mass index (BMI) 30–40 kg m −2 ) were randomly assigned (after a 2-week run-in period) to once-daily subcutaneous liraglutide (1.2, 1.8, 2.4 or 3.0 mg), placebo or open-label orlistat (120 mg × 3 per day). After 1 year, participants on liraglutide/placebo switched to liraglutide 2.4 mg, and subsequently, to liraglutide 3.0 mg (based on 20-week and 1-year results, respectively). Results: The intention-to-treat population comprised 561 participants ( n= 90–98 per arm, age 45.9±10.3 years, BMI 34.8±2.7 kg m −2 (mean±s.d.)). In year 1, more participants reported ⩾1 episode of nausea/vomiting on treatment with liraglutide 1.2–3.0 mg (17–38%) than with placebo or orlistat (both 4%, P ⩽0.001). Most episodes occurred during dose escalation (weeks 1–6), with ‘mild’ or ‘moderate’ symptoms. Among participants on liraglutide 3.0 mg, 48% reported some nausea and 13% some vomiting, with considerable variation between countries, but only 4 out of 93 (4%) reported withdrawals. The mean 1-year weight loss on treatment with liraglutide 3.0 mg from randomization was 9.2 kg for participants reporting nausea/vomiting episodes, versus 6.3 kg for those with none (a treatment difference of 2.9 kg (95% confidence interval 0.5–5.3); P =0.02). Both weight losses were significantly greater than the respective weight losses for participants on placebo ( P <0.001) or orlistat ( P <0.05). Quality-of-life scores at 20 weeks improved similarly with or without nausea/vomiting on treatment with liraglutide 3.0 mg. Conclusion: Transient nausea and vomiting on treatment with liraglutide 3.0 mg was associated with greater weight loss, although symptoms appeared tolerable and did not attenuate quality-of-life improvements. Improved data collection methods on nausea are warranted.

Background Epidemiological data on obesity are needed, particularly in patients with type 2 diabetes mellitus (T2DM) and high cardiovascular (CV) risk. We used the baseline data of liraglutide effect and action in diabetes: evaluation of CV outcome results—A long term Evaluation (LEADER) (a clinical trial to assess the CV safety of liraglutide) to investigate: (i) prevalence of overweight and obesity; (ii) relationship of the major cardiometabolic risk factors with anthropometric measures of adiposity [body mass index (BMI) and waist circumference (WC)]; and (iii) cardiometabolic treatment intensity in relation to BMI and WC. Methods LEADER enrolled two distinct populations of high-risk patients with T2DM in 32 countries: (1) aged ≥50 years with prior CV disease; (2) aged ≥60 years with one or more CV risk factors. Associations of metabolic variables, demographic variables and treatment intensity with anthropometric measurements (BMI and WC) were explored using regression models (ClinicalTrials.gov identifier: NCT01179048). Results Mean BMI was 32.5 ± 6.3 kg/m 2 and only 9.1 % had BMI <25 kg/m 2 . The prevalence of healthy WC was also extremely low (6.4 % according to International Joint Interim Statement for the Harmonization of the Metabolic Syndrome criteria). Obesity was associated with being younger, female, previous smoker, Caucasian, American, with shorter diabetes duration, uncontrolled blood pressure (BP), antihypertensive agents, insulin plus oral antihyperglycaemic treatment, higher levels of triglycerides and lower levels of high-density lipoprotein cholesterol. Conclusions Overweight and obesity are prevalent in high CV risk patients with T2DM. BMI and WC are related to the major cardiometabolic risk factors. Furthermore, treatment intensity, such as insulin, statins or oral antihypertensive drugs, is higher in those who are overweight or obese; while BP and lipid control in these patients are remarkably suboptimal. LEADER confers a unique opportunity to explore the longitudinal effect of weight on CV risk factors and hard endpoints.

BACKGROUND: Treatment of obese subjects with topiramate has recently been associated with significant weight loss in a 6-month dose-ranging study. OBJECTIVE: To investigate the long-term efficacy and safety of topiramate in obese subjects. DESIGN: Randomised, double-blind, placebo-controlled study investigating three doses of topiramate: 96, 192, and 256 mg/day. All subjects also participated in a nonpharmacological weight-loss programme. SUBJECTS: The study included 1289 subjects 18–75 y with a body mass index ≥30 kg/m 2 and <50 kg/m 2 in the absence of comorbidities, or ≥27 kg/m 2 and <50 kg/m 2 in the presence of controlled hypertension and/or dyslipidaemia. DURATION: The original study design was for a 6-week, single-blind, placebo run-in phase followed by an 8-week titration phase and 2 y of maintenance at the assigned dose. Sponsor ended study early in order to develop a new controlled-release formulation with the potential to enhance tolerability and simplify dosing in this patient population. Therefore, none of the subjects completed the full 2 y of treatment. Efficacy results are based on subjects who were enrolled early enough to have had an opportunity to complete 1 y at their assigned dose (modified intent-to-treat population, MITT) before learning of the decision to terminate the study. Safety results are based on all subjects who took at least one dose of study medication. RESULTS: The safety population consisted of 1282 subjects, and the MITT efficacy population was 854 subjects. At 60 weeks, subjects in the placebo group lost 1.7% of their baseline body weight, while subjects in the topiramate 96, 192, and 256 mg/day treatment groups lost 7.0, 9.1, and 9.7%, respectively ( P <0.001, MITT, last observation carried forward). Weight loss ≥5% of baseline weight was achieved by 18% of subjects in the placebo arm vs 54, 61, and 67% of subjects receiving topiramate 96, 192, and 256 mg/day, respectively; weight loss ≥10% was achieved by 6 vs 29, 40, and 44%, respectively ( P <0.001). Weight loss was accompanied by significant improvements in blood pressure (systolic/diastolic changes of +0.4/+1.0, −3.1/−1.3, −5.7/−3.4, and −4.6/−2.4 mmHg were observed for placebo, topiramate 96 mg/day, 192 mg/day, and 256 mg/day, respectively, P <0.001) and glucose and insulin. The most common adverse events more frequently observed in topiramate-treated subjects occurred mostly during the titration phase and were related to the central or peripheral nervous system and included paresthesia, difficulty with concentration/attention, depression, difficulty with memory, language problems, nervousness, and psychomotor slowing. CONCLUSION: Topiramate treatment of obese subjects over the course of 1 y resulted in clinically significant weight loss. Improvements were also observed in blood pressure and glucose tolerance.

Objectives: To examine the specific distribution of liver fat content, visceral and subcutaneous adiposity in normal glucose tolerance (NGT/NGT), isolated impaired fasting glucose (iIFG), isolated impaired glucose tolerance (iIGT) and combined conditions (IFG+IGT), as well as with newly diagnosed type 2 diabetes (nT2D). Design: Multicenter, international observational study: cross-sectional analysis. Subjects: Two thousand five hundred and fifteen patients (50.0% women, 54.5% non-Caucasian) without previously known diabetes were recruited from 29 countries. Abdominal fat distribution was measured by computed tomography (CT). Liver fat was estimated using the CT-liver mean attenuation. Results: Compared with NGT/NGT patients, increased visceral adiposity was found in iIFG, iIGT, IFG+IGT and nT2D; estimated liver fat progressively increased across these conditions. A one-s.d. increase in visceral adiposity was associated with an increased risk of having iIFG (men: odds ratio (OR) 1.41 (95% confidence interval (CI) 1.15–1.74), women: OR 1.62 (1.29–2.04)), iIGT (men: OR 1.59 (1.15–2.01), women: OR 1.30 (0.96–1.76)), IFG+IGT (men: OR 1.64 (1.27–2.13), women: OR 1.83 (1.36–2.48)) and nT2D (men: OR 1.80 (1.35–2.42), women: OR 1.73 (1.25–2.41)). A one-s.d. increase in estimated liver fat was associated with iIGT (men: OR 1.46 (1.12–1.90), women: OR 1.81 (1.41–2.35)), IFG+IGT (men: OR 1.42 (1.14–1.77), women: OR 1.74 (1.35–2.26)) and nT2D (men: OR 1.77 (1.40–2.27), women: OR 2.38 (1.81–3.18)). Subcutaneous abdominal adipose tissue showed an inverse relationship with nT2D in women (OR 0.63 (0.45–0.88)). Conclusions: Liver fat was associated with iIGT but not with iIFG, whereas visceral adiposity was associated with both. Liver fat and visceral adiposity were associated with nT2D, whereas subcutaneous adiposity showed an inverse relationship with nT2D in women.

Introduction: We previously demonstrated in an animal model that steatosis, in the absence of fibrosis, induces a significant rise in portal pressure, indicating substantial changes in liver hemodynamics. As assessment of portal pressure is an invasive procedure, non-invasive parameters are needed to identify patients at risk. Aims: To study the portal pressure in nonalcoholic fatty liver disease patients and to identify factors that are possibly related to steatosis-induced changes in liver hemodynamics. Materials and methods: Patients presenting with a problem of overweight or obesity, and in whom non-invasive investigations showed signs of liver involvement, were proposed for transjugular hepatic vein catheterization and liver biopsy. The biopsy was scored according to the Nonalcoholic Steatohepatitis Clinical Research Network Scoring System. Results: A total of 50 consecutive patients were studied. Their mean age was 47.9±1.8 years; 31 (62%) were female. Hepatic venous pressure gradient was normal in 36 (72%) and elevated in 14 (28%) patients. The degree of steatosis was the only histological parameter that differed significantly between the two groups (P=0.016), and was a predictor of the presence of portal hypertension (PHT) in regression analysis (P=0.010). Comparing normal versus portal hypertensive patients, waist circumference (117±2 versus 128±4 cm, P=0.005), waist–hip ratio (0.96±0.06 versus 1.04±0.03, P=0.003), visceral fat (229±15 versus 292±35 cm2, P=0.022), fasting insulin (15.4±1.7 versus 21.8±2.4 μU ml−1, P=0.032), fasting c-peptide (1.22±0.06 versus 1.49±0.09 nmol l−1, P=0.035) and homeostasis model assessment–insulin resistance (HOMA IR) (3.28±0.29 versus 4.81±0.57, P=0.019) were significantly higher. Age, gender, liver enzymes, ferritin and high-sensitive C-reactive protein were not significantly different. In regression analysis, waist circumference (P=0.008) and HOMA IR (P=0.043) were independent predictors of PHT. Conclusions: Estimates of both visceral adiposity and IR are predictors for the presence of PHT, related to the degree of steatosis, and may help in identifying patients who are at risk of developing steatosis-related complications.

Objective: To investigate whether leukocyte count, fibrinogen, von Willebrand factor (vWF) and plasminogen activator inhibitor-1 activity (PAI-1) are increased in subjects with the metabolic syndrome as defined by the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) and the World Health Organisation (WHO). Design: Cross-sectional study. Subjects: A total of 520 overweight and obese subjects: 379 women and 141 men, visiting the weight management clinic of a University Hospital. Subjects and measurements: Waist circumference, triglycerides, HDL cholesterol, blood pressure and fasting glucose were determined, and the presence or absence of the metabolic syndrome according to the NCEP-ATPIII criteria was assessed. In 349 subjects, data on the waist-to-hip ratio (WHR) and albumin excretion rate were available and the WHO criteria were applied. Insulin resistance was defined using the HOMA-IR index. Results: Subjects with the metabolic syndrome according to the NCEP-ATPIII criteria had significantly higher levels of leukocyte count (P<0.001) and PAI-1 (P<0.001), while no significant differences were found for fibrinogen or vWF (P>0.05). Using the WHO criteria, similar results were found except for vWF, where higher levels were found in subjects with the metabolic syndrome. When subjects were classified according to the number of components of the metabolic syndrome, levels of leukocyte count, vWF and PAI-1 activity were significantly different (P<0.05). In logistic regression analysis PAI-1, gender and leukocyte count were independent determinants of the metabolic syndrome (P<0.001). Conclusion: Evidence for being a true component of the metabolic syndrome is strong for PAI-1, less for leukocyte count and weak for vWF and fibrinogen.

Objective: To study the relationship between elevated liver tests and high sensitive C-reactive protein (hs-CRP), as potential markers of liver inflammation and non-alcoholic steatohepatitis (NASH), with anthropometric and laboratory parameters in overweight patients, especially the relationship with visceral adipose tissue (VAT). Methods: Patients presenting to the obesity clinic were prospectively included. Detailed anthropometry, computed tomography (CT)-measured VAT, liver tests (aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT)) and hs-CRP were assessed, along with an extended series of biochemical parameters. Results: All 480 patients (gender distribution male (M)/female (F) (10/90%)) with complete data were included. Mean age was 39±13 years, mean BMI 34.5±6.0 kg m−2. In 37.3% of the patients one or more of the liver tests were elevated. VAT was positively related to AST (r=0.18, P<0.001), ALT (r=0.29, P<0.001), ALP (r=0.16, P<0.01) and GGT (r=0.39, P<0.001). Comparing subjects with high (VAT113 cm2) vs low (VAT<113 cm2) VAT levels, significant differences were noted for AST (26±12 vs 24±12 U l−1, P=0.003), ALT (37±21 vs 31±21 U l−1, P<0.001), ALP (76±20 vs 71±18 U l−1, P=0.008), GGT (33±20 vs 25±15 U l−1, P<0.001) and hs-CRP (0.62±0.43 vs 0.52±0.48 mg dl−1, P<0.001). After correction for BMI the difference in AST and ALP between the high vs low VAT group disappeared. The differences for ALT and GGT remained significant (P=0.008 and P<0.001 respectively). After correction for hs-CRP the four different liver tests remained significantly higher in the high VAT group. A stepwise multiple regression analysis revealed that every single liver test has his own most important determinant; VAT and hs-CRP for AST, insulin resistance calculated with homeostasis model assessment (HOMA-IR) and hs-CRP for ALT and ALP, and triglycerides and VAT for GGT. Conclusion: In overweight and obese patients, liver tests, especially ALT and GGT, are associated with visceral fat mass. After correction for BMI and hs-CRP, ALT and GGT are significantly higher in patients with increased VAT, thereby supporting evidence for a potential key role of VAT in the pathogenesis of non-alcoholic fatty liver disease (NAFLD).