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Purpose Variability in cytochrome P450 3A4 (CYP3A4) metabolism is mainly caused by non-genetic factors, hence providing a need for accurate phenotype biomarkers. Although 4β-hydroxycholesterol (4βOHC) is a promising endogenous CYP3A4 biomarker, additional investigations are required to evaluate its ability to predict CYP3A4 activity. This study investigated the correlations between 4βOHC concentrations and hepatic and intestinal CYP3A4 protein expression and ex vivo microsomal activity in paired liver and jejunum samples, as well as in vivo CYP3A4 phenotyping (midazolam) in patients with a wide body weight range. Methods The patients (n = 96; 78 with obesity and 18 normal or overweight individuals) were included from the COCKTAIL-study (NCT02386917). Plasma samples for analysis of 4βOHC and midazolam concentrations, and liver (n = 56) and jejunal (n = 38) biopsies were obtained. The biopsies for determination of CYP3A4 protein concentration and microsomal activity were obtained during gastric bypass or cholecystectomy. In vivo CYP3A4 phenotyping was performed using semi-simultaneous oral (1.5 mg) and intravenous (1.0 mg) midazolam. Results 4βOHC concentrations were positively correlated with hepatic microsomal CYP3A4 activity (ρ = 0.53, p ρ = 0.30, p = 0.027), but not with intestinal CYP3A4 concentrations (ρ = 0.18, p = 0.28) or intestinal microsomal CYP3A4 activity (ρ = 0.15, p = 0.53). 4βOHC concentrations correlated weakly with midazolam absolute bioavailability (ρ = − 0.23, p = 0.027) and apparent oral clearance (ρ = 0.28, p = 0.008), but not with systemic clearance (ρ = − 0.03, p = 0.81). Conclusion These findings suggest that 4βOHC concentrations reflect hepatic, but not intestinal, CYP3A4 activity. Further studies should investigate the potential value of 4βOHC as an endogenous biomarker for individual dose requirements of intravenously administered CYP3A4 substrate drugs. Trial registration Clinical.Trials.gov identifier: NCT02386917.

Background Weight loss improves fatty liver disease. No randomized trial has compared the effects of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) on liver fat content and fibrosis. Objective To compare the 1-year effects of SG and RYGB on hepatic steatosis and fibrosis. Design Single-center, randomized, controlled trial (Oseberg [ObesitySurgery in Tonsberg]). (ClinicalTrials.gov: NCT01778738). Setting Tertiary care obesity center in Norway. Participants 100 patients (65% female; mean age, 47.5 years; mean body mass index, 42 kg/m2) with type 2 diabetes mellitus (T2DM). Intervention From January 2013 to February 2018, patients were randomly assigned (1:1 ratio) to SG or RYGB. Measurements The primary outcome was remission of T2DM (previously published). Predefined secondary outcomes in the present study were hepatic steatosis and fibrosis assessed by magnetic resonance imaging (liver fat fraction), enhanced liver fibrosis (ELF) test, noninvasive indices, and liver enzymes. Results Liver fat fraction declined similarly after SG (-19.7% [95% CI, -22.5% to -16.9%]) and RYGB (-21.5% [CI, -24.3% to -18.6%]) from surgery to 1-year follow-up, and almost all patients (SG, 94%; RYGB, 100%) had no or low-grade steatosis at 1 year. The ELF score category remained stable in 77% of patients, but 18% experienced worsening of fibrosis at 1 year, with no substantial between-group difference. Limitations Single-center study, short follow-up time, and lack of power for secondary outcomes. Conclusion With an almost complete clearance of liver fat 1 year after surgery, RYGB and SG were both highly effective in reducing hepatic steatosis. Bariatric surgery had less influence on degree of fibrosis in the short term, but assessment of long-term progression is warranted. Primary funding source Vestfold Hospital Trust and the South-Eastern Norway Regional Health Authority.

Introduction Rosuvastatin pharmacokinetics is mainly dependent on the activity of hepatic uptake transporter OATP1B1. In this study, we aimed to investigate and disentangle the effect of Roux-en-Y gastric bypass (RYGB) and weight loss on oral clearance (CL/F) of rosuvastatin as a measure of OATP1B1-activity. Methods Patients with severe obesity preparing for RYGB (n = 40) or diet-induced weight loss (n = 40) were included and followed for 2 years, with four 24-hour pharmacokinetic investigations. Both groups underwent a 3-week low-energy diet (LED; < 1200 kcal/day), followed by RYGB or a 6-week very-low-energy diet (VLED; < 800 kcal/day). Results A total of 80 patients were included in the RYGB group (40 patients) and diet-group (40 patients). The weight loss was similar between the groups following LED and RYGB. The LED induced a similar (mean [95% CI]) decrease in CL/F in both intervention groups (RYGB: 16% [0, 31], diet: 23% [8, 38]), but neither induced VLED resulted in any further changes in CL/F. At Year 2, CL/F had increased by 21% from baseline in the RYGB group, while it was unaltered in the diet group. Patients expressing the reduced function SLCO1B1 variants (c.521TC/CC) showed similar changes in CL/F over time compared with patients expressing the wild-type variant. Conclusions Neither body weight, weight loss nor RYGB per se seem to affect OATP1B1 activity to a clinically relevant degree. Overall, the observed changes in rosuvastatin pharmacokinetics were minor, and unlikely to be of clinical relevance.

Obesity is associated with comorbidities of which pharmacological treatment is needed. Physiological changes associated with obesity may influence the pharmacokinetics of drugs, but the effect of body weight on drug metabolism capacity remains uncertain. The aim of this study was to investigate ex vivo activities of hepatic drug metabolizing CYP enzymes in patients covering a wide range of body weight. Liver biopsies from 36 individuals with a body mass index (BMI) ranging from 18 to 63 kg/m2 were obtained. Individual hepatic microsomes were prepared and activities of CYP3A, CYP2B6, CYP2C8, CYP2D6, CYP2C9, CYP2C19 and CYP1A2 were determined. The unbound intrinsic clearance (CLint,u) values for CYP3A correlated negatively with body weight (r = −0.43, p < 0.01), waist circumference (r = −0.47, p < 0.01), hip circumference (r = −0.51, p < 0.01), fat percent (r = −0.41, p < 0.05), fat mass (r = −0.48, p < 0.01) and BMI (r = −0.46, p < 0.01). Linear regression analysis showed that CLint,u values for CYP3A decreased with 5% with each 10% increase in body weight (r2 = 0.12, β = −0.558, p < 0.05). There were no correlations between body weight measures and CLint,u values for the other CYP enzymes investigated. These results indicate reduced hepatic metabolizing capacity of CYP3A substrates in patients with increasing body weight.

Purpose Understanding patients’ reasons for having bariatric surgery and their expectation on surgery outcomes is important to provide the best clinical practice and reduce unrealistic expectations. It is unknown if reasons and expectations differ between countries. We aimed to investigate the reasons for seeking bariatric surgery and expectations of surgical outcomes among patients in five European countries. Methods In total, 250 women accepted for bariatric surgery were recruited: 50 women each from Finland, Germany, Norway, Sweden, and the Netherlands. Participants ranked 14 reasons for seeking surgery, and reported the three primary reasons. They also reported expectations on weight loss and impact of surgery vs. lifestyle on weight loss outcomes. Results Mean age and body mass index were 42.9 ± 11.5 years and 45.1 ± 6.2 kg/m2, respectively. Weight loss and improved co-morbidity were ranked as the most important reasons. Participants expected to lose between 70.8 and 94.3% of their excessive weight. The expected impact of surgery as a driver of weight loss was higher in Germany and the Netherlands compared to in Finland, Norway, and Sweden where participants expected lifestyle changes to also have an impact. Conclusion Weight loss and improved co-morbidities were the main reasons for undergoing bariatric surgery. Expectations on weight loss were generally very high, but expectations of surgery vs. lifestyle as the main driver of weight loss differed between countries. While some patients understand the importance of lifestyle change and maintenance of a healthy lifestyle after surgery in order to obtain a successful weight loss, other may need additional counselling. Graphical Abstract

Type 2 diabetes (T2DM) is associated with gastroesophageal reflux disease (GERD) in the general population, but the relationship between these conditions in candidates for bariatric surgery is uncertain. We compared the prevalence of GERD and the association between GERD symptoms and esophagitis among bariatric candidates with and without T2DM. Cross-sectional study of baseline data from the Oseberg study in Norway. Both groups underwent gastroduodenoscopy and completed validated questionnaires: Gastrointestinal Symptom Rating Scale and Gastroesophageal Reflux Disease Questionnaire. Participants with T2DM underwent 24-h pH-metry. A total of 124 patients with T2DM, 81 women, mean (SD) age 48.6 (9.4) years and BMI 42.3 (5.5) kg/m2, and 64 patients without T2DM, 46 women, age 43.0 (11.0) years and BMI 43.0 (5.0) kg/m2, were included. The proportions of patients reporting GERD-symptoms were low (

Aim: Roux-en-Y gastric bypass (RYGB) may influence drug disposition due to surgery-induced gastrointestinal alterations and/or subsequent weight loss. The objective was to compare short- and long-term effects of RYGB and diet on the metabolic ratios of paraxanthine/caffeine (cytochrome P450 [CYP] 1A2 activity), 5-hydroxyomeprazole/omeprazole (CYP2C19 activity) and losartan/losartan carboxylic acid (CYP2C9 activity), and cross-sectionally compare these CYP-activities with normal-to-overweight controls. Methods: This trial included patients with severe obesity preparing for RYGB (n = 40) or diet-induced (n = 41) weight loss, and controls (n = 18). Both weight loss groups underwent a 3-week low-energy diet (

Prediction of type 2 diabetes (T2DM) remission is an important part of risk-benefit assessment before bariatric surgery.Advanced-DiaRem (Ad-DiaRem) and ABCD diabetes remission scores for sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) were calculated using baseline data. Differences in model discrimination using area under the curve of receiver operating curve (AUC-ROC) and model calibration were tested for complete remission (HbA1c ≤ 6.0% without antidiabetic medications) in the two groups. Optimal cutoff scores were calculated using the Youden index.We randomized 109 patients to either SG or RYGB. With one patient lost to follow-up in each group, the scores were calculated for 54 patients in the SG group and 53 patients in the RYGB group. Both models showed moderate predictive power without any significant difference between the groups: AUC-ROCs (95% CI) for the Ad-DiaRem score (SG versus RYGB) were 0.872 (0.780-0.964) versus 0.843 (0.733-0.954), p = 0.69, and for the ABCD score 0.849 (0.752-0.946) versus 0.750 (0.580-0.920), p = 0.32, respectively. Using optimal cutoff points derived from the whole study population, the actual proportion of diabetes remission was significantly higher than predicted for both the Ad-DiaRem and ABCD scores in the RYGB group. Diabetes duration and glycated haemoglobin predicted diabetes remission in the entire Oseberg population.Both the Ad-DiaRem and ABCD scores showed moderate ability to discriminate between those who achieved remission of T2DM and those who did not after SG and RYGB. Larger studies are needed for the identification of procedure-specific optimal cutoffs. Trial Registration ClinicalTrials.gov Identifier: NCT01778738.

Summary Anatomical changes in the gastrointestinal tract and subsequent weight loss may influence drug disposition and thus drug dosing following bariatric surgery. This review systematically examines the effects of bariatric surgery on drug pharmacokinetics, focusing especially on the mechanisms involved in restricting oral bioavailability. Studies with a longitudinal before‐after design investigating the pharmacokinetics of at least one drug were reviewed. The need for dose adjustment following bariatric surgery was examined, as well as the potential for extrapolation to other drugs subjected to coinciding pharmacokinetic mechanisms. A total of 22 original articles and 32 different drugs were assessed. The majority of available data is based on Roux‐en‐Y gastric bypass (RYGBP) (18 of 22 studies), and hence, the overall interpretation is more or less limited to RYGBP. In the case of the majority of studied drugs, an increased absorption rate was observed early after RYGBP. The effect on systemic exposure allows for a low degree of extrapolation, including between drugs subjected to the same major metabolic and transporter pathways. On the basis of current understanding, predicting the pharmacokinetic change for a specific drug following RYGBP is challenging. Close monitoring of each individual drug is therefore recommended in the early postsurgical phase. Future studies should focus on the long‐term effects of bariatric surgery on drug disposition, and they should also aim to disentangle the effects of the surgery itself and the subsequent weight loss.

Background: Roux-en-Y gastric bypass is associated with increased risk of bone fractures. Malabsorptive procedures may be associated with secondary hyperparathyroidism and detrimental effects on bone health. We aimed to compare the effects of standard and distal gastric bypass on bone turnover markers 2 years after surgery. Methods: Patients with body mass index (BMI) 50–60kg/m2 (n=113) were randomized to standard or distal gastric bypass,105 patients (95%) completed 2-year follow-up. Serum C-terminal telopeptide of type I collagen (CTX-1), procollagen type I Npropeptide (PINP), and bone-derived alkaline phosphatase (BALP) was measured at baseline and up to 2 years after surgery. ANCOVA and linear mixed models were used to compare groups. Results: The levels of bone turnover markers increased significantly in both groups, with no statistically significant difference betweengroups.Two years after standard and distal gastric bypass mean (SD) CTX-1 were 0.81 (0.32) and 0.83 (0.31) μg/L (p= 0.38), mean PINP was 77.6 (23.2) and 77.7 (29.3) μg/L (p=0.42), and BALP 47.9 (21.9) vs. 50.7 (19.6) μg/L (p=0.38), respectively. Multiple linear regression analyses showed that PINP and BALP correlated positively (p=0.01 and p

It remains uncertain whether pharmacokinetic changes following Roux‐en‐Y gastric bypass (RYGB) can be attributed to surgery‐induced gastrointestinal alterations per se and/or the subsequent weight loss. The aim was to compare short‐ and long‐term effects of RYGB and calorie restriction on CYP3A‐activity, and cross‐sectionally compare CYP3A‐activity with normal weight to overweight controls using midazolam as probe drug. This three‐armed controlled trial included patients with severe obesity preparing for RYGB (n = 41) or diet‐induced (n = 41) weight‐loss, and controls (n = 18). Both weight‐loss groups underwent a 3‐week low‐energy‐diet (

There is limited evidence for the effectiveness of bariatric surgery in adolescents, and the associated complications. The main objective of the 4XL study was to clarify whether laparoscopic Roux-en-Y gastric bypass (LGBP) combined with lifestyle intervention is a safe and effective treatment method.Data were retrieved from an ongoing non-randomised intervention study of adolescents with morbid obesity that is comparing the effects of gastric bypass combined with lifestyle intervention versus lifestyle intervention alone.Altogether 39 patients (64 % girls) treated with a gastric bypass, and 96 patients (57 % girls) treated with lifestyle intervention were examined prior to the start of treatment and one year later. The average age at inclusion (SD) was 16.7 (1.0) years vs. 15.6 (1.3) years, and average BMI was 45.6 (4.4) vs. 43.3 (4.1) kg/m2 in the two groups. Average (95 % CI) percentage weight loss was 30 % (27 %-33 %) after surgery versus weight gain of 1 % (-1 % to 3 %) in the control group. The difference between the groups was 31 % (95 % CI 27 %-34 %, p0.001). Cardiometabolic risk factors improved only after surgery. After gastric bypass, two early (6 weeks) minor complications were recorded. One year after surgery, 4 (10 %), 8 (21 %) and 4 (10 %) of patients had anaemia, iron deficiency or low vitamin B12 levels respectively, and 20 of 33 patients (61 %) had low two-hour blood glucose (2.8 mmol/l) after oral glucose tolerance testing.The results support previous studies showing that gastric bypass is associated with significant weight loss in adolescent patients with morbid obesity. The 4XL study is currently too small and the follow-up time too short to allow the risk of long-term complications to be assessed.

We examined complaints submitted to the Norwegian System of Patient Injury Compensation (NPE) following bariatric surgery, including the background for the complaint, the proportion of patients whose complaints were upheld, and the characteristics of complaints that were upheld.All complaints relating to bariatric surgery performed in the period 2012-18 were reviewed and categorised according to symptoms, findings and events relevant to the outcome of the complaint. Anonymous summaries from the experts' statements were reviewed and categorised according to year of decision, gender, age, basis for compensation or rejection, and whether the intervention was carried out in the public or private health service.Forty-four (26 %) of a total of 171 applications for patient injury compensation were upheld. These applications represented 25 patients who had surgery in the public health service (19 % upheld) and 19 patients who were operated on in the private health service (51 % upheld). The single most common reason for a complaint being upheld (n = 18) was lack of indication for bariatric surgery.More post-bariatric surgery complaints were upheld for lack of indication than for surgical errors. Proper patient selection, good preoperative preparation, good information and shared decision-making are important factors for achieving the best possible bariatric surgery outcome. An interdisciplinary team that monitors patients over time can help ensure the quality of the entire treatment chain.

The Oseberg study demonstrated a higher one year remission rate of type 2 diabetes after Roux-en-Y gastric bypass (RYGB) than after sleeve gastrectomy (SG). To explore mechanisms for the superiority of RYGB we assessed changes in glucose, C-peptide and incretin hormones after a 25 g OGTT and an IVGTT and calculated Disposition Indexes (DI) of beta cell function (DIIVGTT and DIOGTT). We used linear mixed models for repeated measures. Patients randomized to either RYGB (n=54) or SG (n=55), had a mean (SD) age of 48 (10) years, BMI 42.3 (5.3) kg/m², HbA1c 66 (18) mmol/mol, and 72 (66%) were women. OGTT and IVGTT were performed in 97% and 91% of patients respectively. At one year, the OGTT-derived glucose levels at 60-120 minutes were significantly lower after RYGB than after SG (all p Disclosure F. Fatima: Other Relationship; Self; South-Eastren Reagional Health Authority Norway. J. Hjelmesæth: Advisory Panel; Self; Novo Nordisk A/S. K.I. Birkeland: None. H.L. Gulseth: None. J.K. Hertel: None. M. Svanevik: None. R. Sandbu: None. B. Hartmann: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. D. Hofsø: None.

BACKGROUND We examined complaints submitted to the Norwegian System of Patient Injury Compensation (NPE) following bariatric surgery, including the background for the complaint, the proportion of patients whose complaints were upheld, and the characteristics of complaints that were upheld. MATERIAL AND METHOD All complaints relating to bariatric surgery performed in the period 2012-18 were reviewed and categorised according to symptoms, findings and events relevant to the outcome of the complaint. Anonymous summaries from the experts' statements were reviewed and categorised according to year of decision, gender, age, basis for compensation or rejection, and whether the intervention was carried out in the public or private health service. RESULTS Forty-four (26 %) of a total of 171 applications for patient injury compensation were upheld. These applications represented 25 patients who had surgery in the public health service (19 % upheld) and 19 patients who were operated on in the private health service (51 % upheld). The single most common reason for a complaint being upheld (n = 18) was lack of indication for bariatric surgery. INTERPRETATION More post-bariatric surgery complaints were upheld for lack of indication than for surgical errors. Proper patient selection, good preoperative preparation, good information and shared decision-making are important factors for achieving the best possible bariatric surgery outcome. An interdisciplinary team that monitors patients over time can help ensure the quality of the entire treatment chain.

BACKGROUND There is limited evidence for the effectiveness of bariatric surgery in adolescents, and the associated complications. The main objective of the 4XL study was to clarify whether laparoscopic Roux-en-Y gastric bypass (LGBP) combined with lifestyle intervention is a safe and effective treatment method. MATERIAL AND METHOD Data were retrieved from an ongoing non-randomised intervention study of adolescents with morbid obesity that is comparing the effects of gastric bypass combined with lifestyle intervention versus lifestyle intervention alone. RESULTS Altogether 39 patients (64 % girls) treated with a gastric bypass, and 96 patients (57 % girls) treated with lifestyle intervention were examined prior to the start of treatment and one year later. The average age at inclusion (SD) was 16.7 (1.0) years vs. 15.6 (1.3) years, and average BMI was 45.6 (4.4) vs. 43.3 (4.1) kg/m2 in the two groups. Average (95 % CI) percentage weight loss was 30 % (27 %-33 %) after surgery versus weight gain of 1 % (-1 % to 3 %) in the control group. The difference between the groups was 31 % (95 % CI 27 %-34 %, p

The preferred surgical procedure for treating morbid obesity is debated. Patient-reported outcome measures (PROMs) are relevant for evaluation of the optimal bariatric procedure. A total of 113 patients with BMI from 50 to 60 were randomly assigned to standard (n = 57) or distal (n = 56) Roux-en-Y gastric bypass (RYGB). Validated PROMS questionnaires were completed at baseline and 2 years after surgery. Data were analyzed using mixed models for repeated measures and the results are expressed as estimated means and mean changes. Obesity-related quality of life improved significantly after both procedures, without significant between-group differences (− 0.4 (95% CI = − 8.4, 7.2) points, p = 0.88, ES = 0.06). Both groups had significant reductions in the number of weight-related symptoms and symptom distress score, with a mean group difference (95% CI) of 1.4 (− 0.3, 3.3) symptoms and 5.0 (2.9. 12.8) symptom distress score points. There were no between-group differences for uncontrolled eating (22.0 (17.2–26.7) vs. 28.9 (23.3–34.5) points), cognitive restraint (57.4 (52.0–62.7) vs. 62.1 (57.9–66.2) points), and emotional eating (26.8 (20.5–33.1) vs. 32.6 (25.5–39.7) points). The prevalence of anxiety was 33% after standard and 25% after distal RYGB (p = 0.53), and for depression 12 and 9%, respectively (p = 0.76). There were no statistically significant differences between standard and distal RYGB 2 years post surgery regarding weight loss, obesity-related quality of life, weight-related symptoms, anxiety, depression, or eating behavior. Clinical Trials.gov number NCT00821197

IntroductionBariatric surgery is increasingly recognised as an effective treatment option for subjects with type 2 diabetes and obesity; however, there is no conclusive evidence on the superiority of Roux-en-Y gastric bypass or sleeve gastrectomy. The Oseberg study was designed to compare the effects of gastric bypass and sleeve gastrectomy on remission of type 2 diabetes and β-cell function.Methods and analysisSingle-centre, randomised, triple-blinded, two-armed superiority trial carried out at the Morbid Obesity Centre at Vestfold Hospital Trust in Norway. Eligible patients with type 2 diabetes and obesity were randomly allocated in a 1:1 ratio to either gastric bypass or sleeve gastrectomy. The primary outcome measures are (1) the proportion of participants with complete remission of type 2 diabetes (HbA1c≤6.0% in the absence of blood glucose-lowering pharmacologic therapy) and (2) β-cell function expressed by the disposition index (calculated using the frequently sampled intravenous glucose tolerance test with minimal model analysis) 1 year after surgery.Ethics and disseminationThe protocol of the current study was reviewed and approved by the regional ethics committee on 12 September 2012 (ref: 2012/1427/REK sør-øst B). The results will be disseminated to academic and health professional audiences and the public via publications in international peer-reviewed journals and conferences. Participants will receive a summary of the main findings.Trial registration numberNCT01778738;Pre-results.

Background For patients with obesity and type 2 diabetes, weight loss improves insulin sensitivity and β-cell function, and can induce remission of diabetes. The comparative efficacy of various bariatric procedures for the remission of type 2 diabetes has not been fully elucidated. We aimed to compare the effects of the two most common bariatric procedures, gastric bypass and sleeve gastrectomy, on remission of diabetes and β-cell function. Methods We conducted a single-centre, triple-blind, randomised trial at Vestfold Hospital Trust (Tønsberg, Norway), in which patients (aged ≥18 years) with type 2 diabetes and obesity were randomly assigned (1:1) to receive gastric bypass or sleeve gastrectomy (the Oseberg study). Randomisation was performed with a computerised random number generator and a block size of 10. Treatment allocation was masked from participants, study personnel, and outcome assessors and was concealed with sealed opaque envelopes. Surgeons used identical skin incisions during both surgeries and were not involved in patient follow-up. The primary clinical outcome was the proportion of participants with complete remission of type 2 diabetes (HbA 1c of ≤6·0% [42 mmol/mol] without the use of glucose-lowering medication) at 1 year after surgery. The primary physiological outcome was disposition index (a measure of β-cell function) at 1 year after surgery, as assessed by an intravenous glucose tolerance test. Primary outcomes were analysed in the intention-to-treat and per-protocol populations. This trial is ongoing and closed to recruitment, and is registered with ClinicalTrials.gov, NCT01778738. Findings Between Oct 15, 2012, and Sept 1, 2017, 1305 patients who were preparing for bariatric surgery were screened, of whom 319 consecutive patients with type 2 diabetes were assessed for eligibility. 109 patients were enrolled and randomly assigned to gastric bypass (n=54) or sleeve gastrectomy (n=55). 107 (98%) of 109 patients completed 1-year follow-up, with one patient in each group withdrawing after surgery (per-protocol population). In the intention-to-treat population, diabetes remission rates were higher in the gastric bypass group than in the sleeve gastrectomy group (risk difference 27% [95% CI 10 to 44]; relative risk [RR] 1·57 [1·14 to 2·16], p=0·0054); results were similar in the per-protocol population (risk difference 27% [95% CI 10 to 45]; RR 1·57 [1·14 to 2·15], p=0·0036). In the intention-to-treat population, disposition index increased in both groups (between-group difference 55 [–111 to 220], p=0·52); results were similar in the per-protocol population (between-group difference 21 [–214 to 256], p=0.86). In the gastric bypass group, ten of 54 participants had early complications and 17 of 53 had late side-effects. In the sleeve gastrectomy group, eight of 55 participants had early complications and 22 of 54 had late side-effects. No deaths occurred in either group. Interpretation Gastric bypass was found to be superior to sleeve gastrectomy for remission of type 2 diabetes at 1 year after surgery, and the two procedures had a similar beneficial effect on β-cell function. The use of gastric bypass as the preferred bariatric procedure for patients with obesity and type 2 diabetes could improve diabetes care and reduce related societal costs.

To assess if altered bone turnover following bariatric surgery is related to metabolic consequences of the surgical procedure or weight loss. We evaluated serum markers reflecting bone turnover and metabolic pathways at baseline and after 1-year in a controlled non-randomized clinical trial comparing Roux-en-Y gastric bypass surgery (n = 74) with lifestyle intervention (n = 63) on obesity-related comorbidities. The decrease in body mass index (BMI) was larger in the surgery (-14.0 kg/m(2)) compared to lifestyle (-3.7 kg/m(2)). Markedly increased bone turnover was observed following surgery compared to lifestyle intervention and was correlated with change in BMI. Stepwise multivariable regression analysis revealed that group (β = 0.31, p

Importance The association of bariatric surgery and specialized medical obesity treatment with beneficial and detrimental outcomes remains uncertain. Objective To compare changes in obesity-related comorbidities in patients with severe obesity (body mass index ≥40 or ≥35 and at least 1 comorbidity) undergoing bariatric surgery or specialized medical treatment. Design, Setting, and Participants Cohort study with baseline data of exposures from November 2005 through July 2010 and follow-up data from 2006 until death or through December 2015 at a tertiary care outpatient center, Vestfold Hospital Trust, Norway. Consecutive treatment-seeking adult patients (n = 2109) with severe obesity assessed (221 patients excluded and 1888 patients included). Exposures Bariatric surgery (n = 932, 92% gastric bypass) or specialized medical treatment (n = 956) including individual or group-based lifestyle intervention programs. Main Outcomes and Measures Primary outcomes included remission and new onset of hypertension based on drugs dispensed according to the Norwegian Prescription Database. Prespecified secondary outcomes included changes in comorbidities. Adverse events included complications retrieved from the Norwegian Patient Registry and a local laboratory database. Results Among 1888 patients included in the study, the mean (SD) age was 43.5 (12.3) years (1249 women [66%]; mean [SD] baseline BMI, 44.2 [6.1]; 100% completed follow-up at a median of 6.5 years [range, 0.2-10.1]). Surgically treated patients had a greater likelihood of remission and lesser likelihood for new onset of hypertension (remission: absolute risk [AR], 31.9% vs 12.4%); risk difference [RD], 19.5% [95% CI, 15.8%-23.2%], relative risk [RR], 2.1 [95% CI, 2.0-2.2]; new onset: AR, 3.5% vs 12.2%, RD, 8.7% [95% CI, 6.7%-10.7%], RR, 0.4 [95% CI, 0.3-0.5]; greater likelihood of diabetes remission: AR, 57.5% vs 14.8%; RD, 42.7% [95% CI, 35.8%-49.7%], RR, 3.9 [95% CI, 2.8-5.4]; greater risk of new-onset depression: AR, 8.9% vs 6.5%; RD, 2.4% [95% CI, 1.3%-3.5%], RR, 1.5 [95% CI, 1.4-1.7]; and treatment with opioids: AR, 19.4% vs 15.8%, RD, 3.6% [95% CI, 2.3%-4.9%], RR, 1.3 [95% CI, 1.2-1.4]). Surgical patients had a greater risk for undergoing at least 1 additional gastrointestinal surgical procedure (AR, 31.3% vs 15.5%; RD, 15.8% [95% CI, 13.1%-18.5%]; RR, 2.0 [95% CI, 1.7-2.4]). The proportion of patients with low ferritin levels was significantly greater in the surgical group (26% vs 12%, P Conclusions and Relevance Among patients with severe obesity followed up for a median of 6.5 years, bariatric surgery compared with medical treatment was associated with a clinically important increased risk for complications, as well as lower risks of obesity-related comorbidities. The risk for complications should be considered in the decision-making process.

IntroductionRoux-en-Y gastric bypass (GBP) is associated with changes in cardiometabolic risk factors and bioavailability of drugs, but whether these changes are induced by calorie restriction, the weight loss or surgery per se, remains uncertain. The COCKTAIL study was designed to disentangle the short-term (6 weeks) metabolic and pharmacokinetic effects of GBP and a very low energy diet (VLED) by inducing a similar weight loss in the two groups.Methods and analysisThis open, non-randomised, three-armed, single-centre study is performed at a tertiary care centre in Norway. It aims to compare the short-term (6 weeks) and long-term (2 years) effects of GBP and VLED on, first, bioavailability and pharmacokinetics (24 hours) of probe drugs and biomarkers and, second, their effects on metabolism, cardiometabolic risk factors and biomarkers. The primary outcomes will be measured as changes in: (1) all six probe drugs by absolute bioavailability area under the curve (AUCoral/AUCiv) of midazolam (CYP3A4 probe), systemic exposure (AUCoral) of digoxin and rosuvastatin and drug:metabolite ratios for omeprazole, losartan and caffeine, levels of endogenous CYP3A biomarkers and genotypic variation, changes in the expression and activity data of the drug-metabolising, drug transport and drug regulatory proteins in biopsies from various organs and (2) body composition, cardiometabolic risk factors and metabolic biomarkers.Ethics and disseminationThe COCKTAIL protocol was reviewed and approved by the Regional Committee for Medical and Health Research Ethics (Ref: 2013/2379/REK sørøst A). The results will be disseminated to academic and health professional audiences and the public via presentations at conferences, publications in peer-reviewed journals and press releases and provided to all participants.Trial registration numberNCT02386917.

BACKGROUND Massive weight loss after bariatric surgery often results in excess skin, which can lead to stigma due to appearance and pronounced physical and psychological impairments. This review considers the evidence base for post-bariatric plastic surgery and the treatment options that are available. METHOD The article is based on a literature search in PubMed with the keywords «bariatric surgery» AND «plastic surgery», in addition to the authors' experience with a large number of patients. RESULTS Body contouring surgery after massive weight loss is offered primarily for the treatment of troublesome skin conditions. The surgery can help to improve quality of life and functional status. However, there is little scientific evidence regarding indications for surgery, choice of surgical techniques and risk of complications, and the surgeon's own opinions and clinical experience often play a major role. Many plastic surgeons limit body contouring surgery to those with BMI < 28 kg/m². However, most patients who have undergone bariatric surgery have BMI ≥ 30 kg/m², and requests for body contouring surgery for these individuals are often denied, except when there are compelling medical grounds. INTERPRETATION Plastic surgery can lead to improved functioning and increased quality of life. The evidence base with respect to indications, treatment methods and outcomes should be strengthened through well-planned prospective studies and a patient registry. There is a particular need for documentation of treatment outcomes in the large group of patients with BMI ≥ 30 kg/m².

Objective To compare the long-term effects of Roux-en-Y gastric bypass (GBS) and intensive lifestyle intervention (ILI) on aortic stiffness. Methods Nonrandomized clinical trial. Aortic stiffness was assessed by carotid-femoral pulse wave velocity (cfPWV) using high-fidelity applanation tonometry. Results A total of 159 treatment-seeking morbidly obese patients were included, 82 (54 females) in the GBS-group and 77 (48 females) in the ILI-group. Participants in the GBS-group were younger (42.0 ± 9.9 vs. 46.4 ± 10.5 years), heavier (BMI 45.7 ± 5.3 vs. 42.0 ± 4.9 kg/m2), and had lower systolic pressure (137 ± 19 vs. 145 ± 18 mm Hg) and pulse pressure (57 ± 16 vs. 65 ± 17 mm Hg), all P ≤ 0.006. Mean (SD) cfPWV at baseline was 8.6 ± 1.7 m/s in the GBS-group and 8.6 ± 1.9 m/s in the ILI-group, P = 0.959. At follow-up, mean (95% CI) weight loss was larger in the GBS-group than in the ILI-group −43.3 (−46.0 to −40.7) vs. −12.1 (−14.6 to −9.6) kg, P

Background The effect of bariatric surgery on weight loss and improvement of co-morbidities is no longer doubted. However, little attention has been given to the treatment goals from the patient's point of view (patient expectations). The objective of this study was to examine patients' expectations of bariatric surgery and identify gender differences. Methods Bariatric patients were asked to complete a questionnaire. Statistical analysis was performed using chi-square, Pearson correlation coefficient, and Wilcoxon rank sum test. Results Overall, 248 patients participated in this study (69.4% females). The male patients (45.2 yr, SD±11.1) were significantly older than the female (41.8 yr, SD±12.0; P = .04) and suffered significantly more often from diabetes, hypertension, hypercholesterolemia, and sleep apnea. One hundred thirty patients (52.4%) expected to lose at least 45 kg and 39 patients (15.7%)>70 kg. The mean expected excess weight loss was 71.8%. Females expected significantly more often that surgery alone would induce weight loss ( P = .03). "Improved co-morbidity" was by far the highest ranked parameter. Conclusion The male bariatric surgery patients were older and suffered from more co-morbidities. Most of the patients had unrealistic weight loss goals and overestimated the effect of the surgical intervention. However, for both female and male patients, "improved co-morbidity" was the most important issue.

Few studies have compared the effect of surgical and conservative weight loss strategies on obstructive sleep apnea (OSA). We hypothesized that Roux-en-Y gastric bypass (RYGB) would be more effective than intensive lifestyle intervention (ILI) at reducing the prevalence and severity of OSA (apnea-hypopnea-index [AHI] ≥ 5 events/hour).A total of 133 morbidly obese subjects (93 females) were treated with either a 1-year ILI-program (n = 59) or RYGB (n = 74) and underwent repeated sleep recordings with a portable somnograph (Embletta).Participants had a mean (SD) age of 44.7(10.8) years, BMI 45.1(5.7) kg/m(2), and AHI 17.1(21.4) events/hour. Eighty-four patients (63%) had OSA. The average weight loss was 8% in the ILI-group and 30% in the RYGB-group (p0.001). The mean (95%CI) AHI reduced in both treatment groups, although significantly more in the RYGB-group (AHI change -6.0 [ILI] vs -13.1 [RYGB]), between group difference 7.2 (1.3, 13.0), p = 0.017. Twenty-nine RYGB-patients (66%) had remission of OSA, compared to 16 ILI-patients (40%), p = 0.028. At follow-up, after adjusting for age, gender, and baseline AHI, the RYGB-patients had significantly lower adjusted odds for OSA than the ILI-patients-OR (95% CI) 0.33 (0.14, 0.81), p = 0.015. After further adjustment for BMI change, treatment group difference was no longer statistically significant-OR (95% CI) 1.31 (0.32, 5.35), p = 0.709.Our study demonstrates that RYGB was more effective than ILI at reducing the prevalence and severity of OSA. However, our analysis also suggests that weight loss, rather than the surgical procedure per se, explains the beneficial effects.

Individual variability in expression and function of organic anion-transporting polypeptide 1B1 (OATP1B1), multidrug resistance protein 1 (MDR1), and/or cytochrome P450 3A4 (CYP3A4) may impact the clinical response of many drugs. We investigated the correlation between expression of these proteins and pharmacokinetics of atorvastatin, a substrate of all three, in 21 obese patients with paired biopsies from liver and intestinal segments. The patients were also screened for the SLCO1B1 c.521T→C variant alleles. Approximately 30% (r(2) = 0.28) of the variation in oral clearance (CL/F) of atorvastatin was explained by hepatic OATP1B1 protein expression (P = 0.041). Patients carrying the SLCO1B1 c.521C variant allele (homozygous, n = 4; heterozygous, n = 2) exhibited 45% lower CL/F of atorvastatin than the c.521TT carriers (P = 0.067). No association between hepatic and intestinal expression of MDR1 or CYP3A4 and atorvastatin pharmacokinetics was found (P > 0.149). In conclusion, this study suggests that OATP1B1 phenotype is more important than CYP3A4 and MDR1 phenotypes for the individual pharmacokinetic variability of atorvastatin.

Up to one-third of patients undergoing bariatric surgery have a body mass index (BMI) of more than 50. Following standard gastric bypass, many of these patients still have a BMI greater than 40 after peak weight loss.To assess the efficacy and safety of standard gastric bypass vs distal gastric bypass in patients with a BMI of 50 to 60.Double-blind, randomized clinical parallel-group trial at 2 tertiary care centers in Norway (Oslo University Hospital and Vestfold Hospital Trust) between May 2011 and April 2013. The study included 113 patients with a BMI of 50 to 60 aged 20 to 60 years. The 2-year follow-up was completed in May 2015.Standard gastric bypass (alimentary limb, 150 cm) and distal gastric bypass (common channel, 150 cm), both with a biliopancreatic limb of 50 cm and a gastric pouch of about 25 mL.Primary outcome was the change in BMI from baseline until 2 years after surgery. Secondary outcomes were cardiometabolic risk factors, nutritional outcomes, adverse events, gastrointestinal symptoms, and health-related quality of life.At baseline, the mean age of the patients was 40 years (95% CI, 38-41 years), 65% were women, mean BMI was 53.5 (95% CI, 52.9-54.0), and mean weight was 158.8 kg (95% CI, 155.3-162.3 kg). The mean reduction in BMI was 17.8 (95% CI, 16.9-18.6) after standard gastric bypass and 17.2 (95% CI, 16.3-18.0) after distal gastric bypass, and the mean between-group difference was 0.6 (95% CI, -0.6 to 1.8; P = .32). Reductions in mean levels of total and low-density lipoprotein cholesterol were greater after distal gastric bypass than standard gastric bypass, and between-group differences were 19 mg/dL (95% CI, 11-27 mg/dL ) and 28 mg/dL (95% CI, 21 to 34 mg/dL), respectively (P .001 for both). Reductions in fasting glucose levels and hemoglobin A1c were greater after distal gastric bypass. Secondary hyperparathyroidism and loose stools were more frequent after distal gastric bypass. The number of adverse events and changes in health-related quality of life did not differ between the groups. Importantly, 1 patient developed liver failure and 2 patients developed protein-caloric malnutrition treated by elongation of the common channel following distal gastric bypass.Distal gastric bypass was not associated with a greater BMI reduction than standard gastric bypass 2 years after surgery. However, we observed different changes in cardiometabolic risk factors and nutritional markers between the groups.Clinicaltrials.gov Identifier: NCT00821197.

Background The King’s Obesity Staging Criteria (KOSC) comprises of a four-graded set of health related domains. We aimed to examine whether, according to KOSC, patients undergoing bariatric surgery differed from those opting for conservative treatment. Methods We graded 2142 consecutive patients with morbid obesity attending our centre from 2005-10 into the following KOSC domains: airway/apnoea, body mass index (BMI), cardiovascular risk (CV-risk), diabetes mellitus, economic complications, functional limitations, gonadal dysfunction, and perceived health status/body image. Both patients and physicians agreed upon treatment choice through a shared decision making process. Results A total of 1329 (62%) patients opted for lifestyle intervention and 813 (37%) for bariatric surgery as their first treatment choice. The patients treated with bariatric surgery were younger (42 vs. 44 years, p

Background The number of bariatric surgical procedures in Norway is increasing. Patients who undergo bariatric surgery may experience surgical, medical and nutritional complications. Follow-up of these patients is therefore important. Methods The article is based on non-systematic literature searches in PubMed and on the clinical experience of the authors. Results Bariatric surgery induces significant and sustained weight loss and improves obesity-related disorders. Gastric bypass is the most commonly performed bariatric procedure in Norway. This procedure is associated with a 30-day mortality of below 0.5 %, while severe complications occur in approximately 5 % of patients. Late complications include internal herniation, intestinal ulcers and gallbladder disease. After surgery all patients are given iron, vitamin D/calcium and vitamin B12 supplements to prevent vitamin and mineral deficiencies. Gastrointestinal symptoms and postprandial hypoglycaemia after surgery can be improved by dietary modifications, and the need for anti-diabetic and blood pressure lowering medications is reduced. Dose adjustment of other medications may also be necessary. Pregnancy is not recommended during the first year after bariatric surgery. Many patients need plastic surgery after the operation. Interpretation Complications after bariatric surgery may manifest in the long term. Regular follow-up is required. General practitioners should be responsible for follow-up in the long term, and should be familiar with common and serious complications as well as normal symptomatology after bariatric surgery.

ObjectiveWeight reduction improves several obesity-related health conditions. We aimed to compare the effect of bariatric surgery and comprehensive lifestyle intervention on type 2 diabetes and obesity-related cardiovascular risk factors.DesignOne-year controlled clinical trial (ClinicalTrials.gov identifier NCT00273104).MethodsMorbidly obese subjects (19–66 years, mean (s.d.) body mass index 45.1 kg/m2(5.6), 103 women) were treated with either Roux-en-Y gastric bypass surgery (n=80) or intensive lifestyle intervention at a rehabilitation centre (n=66). The dropout rate within both groups was 5%.ResultsAmong the 76 completers in the surgery group and the 63 completers in the lifestyle group, mean (s.d.) 1-year weight loss was 30% (8) and 8% (9) respectively. Beneficial effects on glucose metabolism, blood pressure, lipids and low-grade inflammation were observed in both groups. Remission rates of type 2 diabetes and hypertension were significantly higher in the surgery group than the lifestyle intervention group; 70 vs 33%,P=0.027, and 49 vs 23%,P=0.016. The improvements in glycaemic control and blood pressure were mediated by weight reduction. The surgery group experienced a significantly greater reduction in the prevalence of metabolic syndrome, albuminuria and electrocardiographic left ventricular hypertrophy than the lifestyle group. Gastrointestinal symptoms and symptomatic postprandial hypoglycaemia developed more frequently after gastric bypass surgery than after lifestyle intervention. There were no deaths.ConclusionsType 2 diabetes and obesity-related cardiovascular risk factors were improved after both treatment strategies. However, the improvements were greatest in those patients treated with gastric bypass surgery.

Background Bariatric surgery particularly benefits patients with obesity-related comorbidities such as type 2 diabetes and obstructive sleep apnea. We aimed to examine whether the variables that influence treatment choice differ between morbidly obese patients undergoing bariatric surgery and those opting for conservative treatments. Methods A total of 505 consecutive morbidly obese patients (72% women; mean (SD) age 42 (12) years) who attended our tertiary care center between December 2005 and February 2007 were examined by a multidisciplinary team and offered surgical or conservative treatment. The chi-square test, independent samples t test, and multiple logistic regression were used in the statistical analyses. Results A total of 249 (49%) patients underwent bariatric surgery. When compared to the conservative group of patients, the surgery group was characterized by a significantly higher mean (SD) BMI (46.5(6.2) vs. 43.2(5.5) kg/m2, p 50 kg/m2 had between 3 (OR = 3.0; 95% CI 1.9–4.9, p

Massive weight loss after bariatric surgery often results in excess skin, which can lead to stigma due to appearance and pronounced physical and psychological impairments. This review considers the evidence base for post-bariatric plastic surgery and the treatment options that are available.The article is based on a literature search in PubMed with the keywords «bariatric surgery» AND «plastic surgery», in addition to the authors' experience with a large number of patients.Body contouring surgery after massive weight loss is offered primarily for the treatment of troublesome skin conditions. The surgery can help to improve quality of life and functional status. However, there is little scientific evidence regarding indications for surgery, choice of surgical techniques and risk of complications, and the surgeon's own opinions and clinical experience often play a major role. Many plastic surgeons limit body contouring surgery to those with BMI28 kg/m². However, most patients who have undergone bariatric surgery have BMI ≥ 30 kg/m², and requests for body contouring surgery for these individuals are often denied, except when there are compelling medical grounds.Plastic surgery can lead to improved functioning and increased quality of life. The evidence base with respect to indications, treatment methods and outcomes should be strengthened through well-planned prospective studies and a patient registry. There is a particular need for documentation of treatment outcomes in the large group of patients with BMI ≥ 30 kg/m².

About 80% of patients with type 2 diabetes are classified as overweight. However, only about 1/3 of severely obese subjects have type 2 diabetes. This indicates that several se- verely obese individuals may possess certain characteristics that protect them against type 2 diabetes. We therefore hypothesized that this apparent paradox could be related to funda- mental differences in skeletal muscle lipid handling. Energy metabolism and metabolic flexi- bility were examined in human myotubes derived from severely obese subjects without (BMI 44 ± 7 kg/m 2 ) and with type 2 diabetes (BMI 43 ± 6 kg/m 2 ). Lower insulin sensitivity was observed in myotubes from severely obese subjects with type 2 diabetes. Lipolysis rate was higher, and oleic acid accumulation, triacylglycerol content, and fatty acid adaptability were lower in myotubes from severely obese subjects with type 2 diabetes compared to se- verely obese non-diabetic subjects. There were no differences in lipid distribution and mRNA and protein expression of the lipases HSL and ATGL, the lipase cofactor CGI-58, or the lipid droplet proteins PLIN2 and PLIN3. Glucose and oleic acid oxidation were also simi- lar in cells from the two groups. In conclusion, myotubes established from severely obese donors with established type 2 diabetes had lower ability for lipid accumulation and higher li- polysis rate than myotubes from severely obese donors without diabetes. This indicates that a difference in intramyocellular lipid turnover might be fundamental in evolving type 2 diabetes.

Background For all surgical procedures, a surgeons’ learning curve can be anticipated during which complication rates are increased. The aims of this study were to evaluate individual learning curves for a group of surgeons performing laparoscopic fundoplication and to evaluate if the Procedicus MIST-simulator (Mentice Inc., Goteborg, Sweden) accurately predicts surgical performance. Methods Twelve Nordic centers participated, each contributing with a “master” and a “pupil” surgeon. The pupils were tested in the simulator and thereafter performed their first 20 supervised operations. All procedures were videotaped and evaluated by 3 independent reviewers. Results A significant decrease in operative time ( P P = 0.12) toward improved score were seen during the series. The master significantly affected the pupil’s score ( P =0.0137). The simulator-test showed no correlation with the operative score. Conclusions Individual learning curves varied, and the teacher was shown to be the most important factor influencing the pupil’s performance score. The correlation between assessed performance and patient outcome will be further investigated.

Background Well conducted, comparative trials of laparoscopic versus open antireflux surgery with an adequate patient enrolment are few and they do not demonstrate obvious advantages for the laparoscopic approach except for a marginal gain in shorter hospital stay. The aim of this study was to compare the effectiveness of laparoscopic and open procedures. Methods Two unselected groups of 230 patients were identified through a register of all inpatient public care in Sweden. Outcomes of laparoscopic and open antireflux surgery were compared using a disease-specific questionnaire 4 years after operation. Results Failure and dissatisfaction were significantly more common in the laparoscopy group than among patients having conventional open surgery. Treatment failure rates were 29·0 and 14·6 per cent respectively (P = 0·004). Dissatisfaction rates were 15·0 and 7·0 per cent respectively (P = 0·005). There was no other questionnaire item for which the proportion of failures differed significantly between the two groups. Conclusion This study does not support the presumption that laparoscopic antireflux surgery is to be preferred to the open procedure. It is strongly recommended that a randomized controlled trial be conducted.