Gastric Bypass Versus Sleeve Gastrectomy in Type 2 Diabetes: Effects on Hepatic Steatosis and Fibrosis : A Randomized Controlled Trial.

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 Tønsberg]). (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.

Short- and long-term effects of body weight, calorie restriction and gastric bypass on CYP1A2, CYP2C19 and CYP2C9 activity.

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 (<1200 kcal/day, weeks 0-3) followed by a 6-week very-low-energy diet or RYGB (both <800 kcal/day, weeks 3-9). Follow-up time was 2 years, with four pharmacokinetic investigations. RESULTS: Mean ± SD weight loss from baseline was similar in the RYGB-group (13 ± 2.4%) and the diet group (10.5 ± 3.9%) at week 9, but differed at year 2 (RYGB -30 ± 6.9%, diet -3.1 ± 6.3%). From weeks 0 to 3, mean (95% confidence interval [CI]) CYP2C19 activity similarly increased in both groups (RYGB 43% [16, 55], diet 48% [22, 60]). Mean CYP2C19 activity increased by 30% (2.6, 43) after RYGB (weeks 3-9), but not in the diet-group (between-group difference -0.30 [-0.63, 0.03]). CYP2C19 activity remained elevated in the RYGB group at year 2. Baseline CYP2C19 activity was 2.7-fold higher in controls compared with patients with obesity, whereas no difference was observed in CYP1A2 and CYP2C9 activities. CONCLUSION: Our findings suggest that CYP2C19 activity is lower in patients with obesity and increases following weight loss. This may be clinically relevant for drug dosing. No clinically significant effect on CYP1A2 and CYP2C9 activities was observed.

Correlations between 4ß-hydroxycholesterol and hepatic and intestinal CYP3A4: protein expression, microsomal ex vivo activity, and in vivo activity in patients with a wide body weight range.

PURPOSE: Variability in cytochrome P450 3A4 (CYP3A4) metabolism is mainly caused by non-genetic factors, hence providing a need for accurate phenotype biomarkers. Although 4ß-hydroxycholesterol (4ßOHC) is a promising endogenous CYP3A4 biomarker, additional investigations are required to evaluate its ability to predict CYP3A4 activity. This study investigated the correlations between 4ßOHC 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 4ßOHC 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: 4ßOHC concentrations were positively correlated with hepatic microsomal CYP3A4 activity (ρ = 0.53, p < 0.001), and hepatic CYP3A4 concentrations (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). 4ßOHC 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 4ßOHC concentrations reflect hepatic, but not intestinal, CYP3A4 activity. Further studies should investigate the potential value of 4ßOHC as an endogenous biomarker for individual dose requirements of intravenously administered CYP3A4 substrate drugs. TRIAL REGISTRATION: Clinical. TRIALS: gov identifier: NCT02386917.

Patient complaints following bariatric surgery 2012-18. / Pasientklager etter vektreduserende kirurgi 2012­18.

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.

Laparoscopic gastric bypass versus lifestyle intervention for adolescents with morbid obesity. / Laparoskopisk gastrisk bypassoperasjon versus livsstilsbehandling av unge med sykelig overvekt.

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<0.001). 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. INTERPRETATION: 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.

Association of Bariatric Surgery vs Medical Obesity Treatment With Long-term Medical Complications and Obesity-Related Comorbidities.

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 < .001). 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.

Plastic surgery after bariatric surgery.

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 surgery¼ AND «plastic surgery¼, 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.

Oral Drug Dosing After Gastric Bypass and Diet-Induced Weight Loss: Simpler Than We Think? Lessons Learned From the COCKTAIL Study.

This article summarizes the lessons learned from the COCKTAIL study: an open, three-armed, single-center study including patients with obesity scheduled for treatment with Roux-en-Y gastric bypass (RYGB) or nonsurgical calorie restriction, and a normal- to overweight control group. The clinical implications of the results from multiple peer-reviewed articles describing the effects of RYGB, severe caloric restriction, weight loss, and type 2 diabetes on the in vivo activity and protein expression of drug-metabolizing enzymes (cytochrome P450 (CYP) 1A2, 2C9, 2C19, and 3A) and transporters (DMETs; organic anion-transporting polypeptide (OATP) 1B1 and P-glycoprotein (P-gp)) are discussed in the perspective of three clinically relevant questions: (1) How should clinicians get the dose right in patients after RYGB? (2) Will drug disposition in patients with obesity be normalized after successful weight loss? (3) Are dose adjustments needed according to obesity and diabetes status? Overall, RYGB seems to have a lower impact on drug disposition than previously assumed, but clinicians should pay close attention to drugs with a narrow therapeutic range or where a high maximum drug concentration may be problematic. Whether obesity-related alterations of DMETs normalize with substantial weight loss depends on the DMET in question. Obesity and diabetes downregulate the in vivo activity of CYP2C19 and CYP3A (only obesity) but whether substrate drugs should be dose adjusted is also dependent on other factors that influence clearance, that is, liver blood flow and protein binding. Finally, we recommend frequent and individualized follow-up due to high inter- and intraindividual variability in these patients, particularly following RYGB.

Digoxin Pharmacokinetics in Patients with Obesity Before and After a Gastric Bypass or a Strict Diet Compared with Normal Weight Individuals.

BACKGROUND AND OBJECTIVE: Several drugs on the market are substrates for P-glycoprotein (P-gp), an efflux transporter highly expressed in barrier tissues such as the intestine. Body weight, weight loss, and a Roux-en-Y gastric bypass (RYGB) may influence P-gp expression and activity, leading to variability in the drug response. The objective of this study was therefore to investigate digoxin pharmacokinetics as a measure of the P-gp phenotype in patients with obesity before and after weight loss induced by an RYGB or a strict diet and in normal weight individuals. METHODS: This study included patients with severe obesity preparing for an RYGB (n = 40) or diet-induced weight loss (n = 40) and mainly normal weight individuals scheduled for a cholecystectomy (n = 18). Both weight loss groups underwent a 3-week low-energy diet (<1200 kcal/day) followed by an additional 6 weeks of <800 kcal/day induced by an RYGB (performed at week 3) or a very-low-energy diet. Follow-up time was 2 years, with four digoxin pharmacokinetic investigations at weeks 0, 3, and 9, and year 2. Hepatic and jejunal P-gp levels were determined in biopsies obtained from the patients undergoing surgery. RESULTS: The RYGB group and the diet group had a comparable weight loss in the first 9 weeks (13 ± 2.3% and 11 ± 3.6%, respectively). During this period, we observed a minor increase (16%) in the digoxin area under the concentration-time curve from zero to infinity in both groups: RYGB: 2.7 µg h/L [95% confidence interval (CI) 0.67, 4.7], diet: 2.5 µg h/L [95% CI 0.49, 4.4]. In the RYGB group, we also observed that the time to reach maximum concentration decreased after surgery: from 1.0 ± 0.33 hours at week 3 to 0.77 ± 0.08 hours at week 9 (-0.26 hours [95% CI -0.47, -0.05]), corresponding to a 25% reduction. Area under the concentration-time curve from zero to infinity did not change long term (week 0 to year 2) in either the RYGB (1.1 µg h/L [-0.94, 3.2]) or the diet group (0.94 µg h/L [-1.2, 3.0]), despite a considerable difference in weight loss from baseline (RYGB: 30 ± 7%, diet: 3 ± 6%). At baseline, the area under the concentration-time curve from zero to infinity was -5.5 µg h/L [95% CI -8.5, -2.5] (-26%) lower in patients with obesity (RYGB plus diet) than in normal weight individuals scheduled for a cholecystectomy. Further, patients undergoing an RYGB had a 0.05 fmol/µg [95% CI 0.00, 0.10] (29%) higher hepatic P-gp level than the normal weight individuals. CONCLUSIONS: Changes in digoxin pharmacokinetics following weight loss induced by a pre-operative low-energy diet and an RYGB or a strict diet (a low-energy diet plus a very-low-energy diet) were minor and unlikely to be clinically relevant. The lower systemic exposure of digoxin in patients with obesity suggests that these patients may have increased biliary excretion of digoxin possibly owing to a higher expression of P-gp in the liver.

Gastric Bypass vs Diet and Cardiovascular Risk Factors: A Nonrandomized Controlled Trial.

Importance: Roux-en-Y gastric bypass (RYGB) is associated with reduced cardiovascular (CV) risk factors, morbidity, and mortality. Whether these effects are specifically induced by the surgical procedure or the weight loss is unclear. Objective: To compare 6-week changes in CV risk factors in patients with obesity undergoing matching caloric restriction and weight loss by RYGB or a very low-energy diet (VLED). Design, Setting, and Participants: This nonrandomized controlled study (Impact of Body Weight, Low Calorie Diet, and Gastric Bypass on Drug Bioavailability, Cardiovascular Risk Factors, and Metabolic Biomarkers [COCKTAIL]) was conducted at a tertiary care obesity center in Norway. Participants were individuals with severe obesity preparing for RYGB or a VLED. Recruitment began February 26, 2015; the first patient visit was on March 18, 2015, and the last patient visit (9-week follow-up) was on August 9, 2017. Data were analyzed from April 30, 2021, through June 29, 2023. Interventions: VLED alone for 6 weeks or VLED for 6 weeks after RYGB; both interventions were preceded by 3-week LED. Main Outcomes and Measures: Between-group comparisons of 6-week changes in CV risk factors. Results: Among 78 patients included in the analyses, the mean (SD) age was 47.5 (9.7) years; 51 (65%) were women, and 27 (35%) were men. Except for a slightly higher mean (SD) body mass index of 44.5 (6.2) in the RYGB group (n = 41) vs 41.9 (5.4) in the VLED group (n = 37), baseline demographic and clinical characteristics were similar between groups. Major atherogenic blood lipids (low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein B, lipoprotein[a]) were reduced after RYGB in comparison with VLED despite a similar fat mass loss. Mean between-group differences were -17.7 mg/dL (95% CI, -27.9 to -7.5), -17.4 mg/dL (95% CI, -29.8 to -5.0) mg/dL, -9.94 mg/dL (95% CI, -15.75 to -4.14), and geometric mean ratio was 0.55 U/L (95% CI, 0.42 to 0.72), respectively. Changes in glycemic control and blood pressure were similar between groups. Conclusions and Relevance: This study found that clinically meaningful reductions in major atherogenic blood lipids were demonstrated after RYGB, indicating that RYGB may reduce CV risk independent of weight loss. Trial Registration: ClinicalTrials.gov Identifier: NCT02386917.

Dietary changes in obese patients undergoing gastric bypass or lifestyle intervention: a clinical trial.

We compared changes in the dietary patterns of morbidly obese patients undergoing either laparoscopic gastric bypass surgery or a comprehensive lifestyle intervention programme. The present 1-year non-randomised controlled trial included fifty-four patients in the lifestyle group and seventy-two in the surgery group. Dietary intake was assessed by a validated FFQ. ANCOVA was used to adjust for between-group differences in sex, age, baseline BMI and baseline values of the dependent variables. Intakes of food groups and nutrients did not differ significantly between the intervention groups at baseline. At 1-year follow-up, the lifestyle group had a significantly higher daily intake of fruits and vegetables (561 (sd 198) v. 441 (sd 213) g, P= 0·002), whole grains (63 (sd 24) v. 49 (sd 16) g, P< 0·001) and fibre (28 (sd 6) v. 22 (sd 6) g, P< 0·001) than the surgery group and a lower percentage of total energy intake of saturated fat (12 (sd 3) v. 14 (sd 3) %, P< 0·001). The intake of red meat declined significantly within both groups, vegetables and fish intake were reduced significantly in the surgery group and added sugar was reduced significantly in the lifestyle group. The lifestyle patients improved their dietary patterns significantly (compared with the surgery group), increasing their intake of vegetables, whole grains and fibre and reducing their percentage intake of saturated fat (ANCOVA, all P< 0·001). In conclusion, lifestyle intervention was associated with more favourable dietary 1-year changes than gastric bypass surgery in morbidly obese patients, as measured by intake of vegetables, whole grains, fibre and saturated fat.

Health related quality of life after gastric bypass or intensive lifestyle intervention: a controlled clinical study.

BACKGROUND: There is little robust evidence relating to changes in health related quality of life (HRQL) in morbidly obese patients following a multidisciplinary non-surgical weight loss program or laparoscopic Roux-en-Y Gastric Bypass (RYGB). The aim of the present study was to describe and compare changes in five dimensions of HRQL in morbidly obese subjects. In addition, we wanted to assess the clinical relevance of the changes in HRQL between and within these two groups after one year. We hypothesized that RYGB would be associated with larger improvements in HRQL than a part residential intensive lifestyle-intervention program (ILI) with morbidly obese subjects. METHODS: A total of 139 morbidly obese patients chose treatment with RYGB (n=76) or ILI (n=63). The ILI comprised four stays (seven weeks) at a specialized rehabilitation center over one year. The daily schedule was divided between physical activity, psychosocially-oriented interventions, and motivational approaches. No special diet or weight-loss drugs were prescribed. The participants completed three HRQL-questionnaires before treatment and 1 year thereafter. Both linear regression and ANCOVA were used to analyze differences between weight loss and treatment for five dimensions of HRQL (physical, mental, emotional, symptoms and symptom distress) controlling for baseline HRQL, age, age of onset of obesity, BMI, and physical activity. Clinical relevance was assessed by effect size (ES) where ES<.49 was considered small, between .50-.79 as moderate, and ES>.80 as large. RESULTS: The adjusted between group mean difference (95% CI) was 8.6 (4.6,12.6) points (ES=.83) for the physical dimension, 5.4 (1.5-9.3) points (ES=.50) for the mental dimension, 25.2 (15.0-35.4) points (ES=1.06) for the emotional dimension, 8.7 (1.8-15.4) points (ES=.37) for the measured symptom distress, and 2.5 for (.6,4.5) fewer symptoms (ES=.56), all in favor of RYGB. Within-group changes in HRQOL in the RYGB group were large for all dimensions of HRQL. Within the ILI group, changes in the emotional dimension, symptom reduction and symptom distress were moderate. Linear regression analyses of weight loss on HRQL change showed a standardized beta-coefficient of -.430 (p<.001) on the physical dimension, -.288 (p=.004) on the mental dimension, -.432 (p<.001) on the emotional dimension, .287 (p=.008) on number of symptoms, and .274 (p=.009) on reduction of symptom pressure. CONCLUSIONS: Morbidly obese participants undergoing RYGB and ILI had improved HRQL after 1 year. The weaker response of ILI on HRQL, compared to RYGB, may be explained by the difference in weight loss following the two treatments. TRIAL REGISTRATION: Clinical Trials.gov number NCT00273104.

Long-term effects of gastric bypass and duodenal switch on systemic exposure of atorvastatin.

BACKGROUND: A previous study of 22 patients undergoing either gastric bypass or duodenal switch showed increased systemic exposure of atorvastatin acid 3-8 weeks after surgery in the majority of patients. This study aimed to investigate the long-term effects on systemic exposure of atorvastatin acid in the same group of patients. METHODS: An 8-h pharmacokinetic investigation was performed a median of 27 months (range 21-45 months) after surgery. Systemic exposure was measured as the area under the plasma concentration versus the time curve from 0 to 8 h postdose (AUC0-8). Linear mixed models with AUC0-8 as the dependent variable were implemented to assess the effect of time, surgical procedure, and body mass index (BMI) as explanatory variables. RESULTS: The study enrolled 20 patients. The systemic exposure of atorvastatin acid changed significantly over time (p = 0.001), albeit there was substantial variation between subjects. The effect of time was attenuated but remained significant after adjustment for surgical procedure and BMI (p = 0.048). The initial AUC0-8 increase seen in the majority of patients 3-8 weeks after surgery was normalized long term, with 7 of the 12 gastric bypass patients and 6 of the 8 duodenal switch patients showing decreased AUC0-8 compared with preoperative values. CONCLUSIONS: The systemic exposure of atorvastatin showed a significant change over time after bariatric surgery, albeit with large inter- and intraindividual variations. The findings indicate that patients using atorvastatin or drugs with similar pharmacokinetic properties should be monitored closely for both therapeutic effects and adverse events the first years after gastric bypass and duodenal switch.

Neither Gastric Bypass Surgery Nor Diet-Induced Weight-Loss Affect OATP1B1 Activity as Measured by Rosuvastatin Oral Clearance.

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.

Patient-reported outcomes, weight loss, and remission of type 2 diabetes 3 years after gastric bypass and sleeve gastrectomy (Oseberg); a single-centre, randomised controlled trial.

BACKGROUND: Little is known about the comparative effects of various bariatric procedures on patient-reported outcomes. We aimed to compare 3-year effects of gastric bypass and sleeve gastrectomy on patient-reported outcome measures in patients with obesity and type 2 diabetes. METHODS: The Oseberg trial was a single-centre, parallel-group, randomised trial at Vestfold Hospital Trust, a public tertiary obesity centre in Tønsberg, Norway. Eligible patients were aged 18 years or older with previously verified BMI 35·0 kg/m2 or greater. Diabetes was diagnosed if glycated haemoglobin was at least 6·5% (48 mmol/mol) or by their use of anti-diabetic medications with glycated haemoglobin at least 6·1% (43 mmol/mol). Eligible patients were randomly assigned (1:1) to gastric bypass or sleeve gastrectomy. All patients received identical preoperative and postoperative treatment. Randomisation was done with a computerised random number generator and a block size of ten. Study personnel, patients, and the primary outcome assessor were blinded to allocations for 1 year. The prespecified secondary outcomes reported here were 3-year changes in several clinically important patient-reported outcomes, weight loss, and diabetes remission. Analyses were done in the intention to treat population. This trial is ongoing, closed to recruitment and is registered with ClinicalTrials.gov, NCT01778738. FINDINGS: Between Oct 15, 2012 and Sept 1, 2017, 319 consecutive patients with type 2 diabetes scheduled for bariatric surgery were assessed for eligibility. 101 patients were not eligible (29 did not have type 2 diabetes according to inclusion criteria and 72 other exclusion criteria) and 93 declined to participate. 109 patients were enrolled and randomly assigned to sleeve gastrectomy (n=55) or gastric bypass (n=54). 72 (66%) of 109 patients were female and 37 (34%) were male. 104 (95%) of patients were White. 16 patients were lost to follow up and 93 (85%) patients completed the 3-year follow-up. Three additional patients were contacted by phone for registration of comorbidities Compared with sleeve gastrectomy, gastric bypass was associated with a greater improvement in weight-related quality of life (between group difference 9·4, 95% CI 3·3 to 15·5), less reflux symptoms (0·54, 0·17 to -0·90), greater total bodyweight loss (8% difference, 25% vs 17%), and a higher probability of diabetes remission (67% vs 33%, risk ratio 2·00; 95% CI 1·27 to 3·14). Five patients reported postprandial hypoglycaemia in the third year after gastric bypass versus none after sleeve-gastrectomy (p=0·059). Symptoms of abdominal pain, indigestion, diarrhoea, dumping syndrome, depression, binge eating, and appetitive drive did not differ between groups. INTERPRETATION: At 3 years, gastric bypass was superior to sleeve gastrectomy in patients with type 2 diabetes and obesity regarding weight related quality of life, reflux symptoms, weight loss, and remission of diabetes, while symptoms of abdominal pain, indigestion, diarrhoea, dumping, depression and binge eating did not differ between groups. This new patient-reported knowledge can be used in the shared decision-making process to inform patients about similarities and differences between expected outcomes after the two surgical procedures. FUNDING: Morbid Obesity Centre, Vestfold Hospital Trust. TRANSLATION: For the Norwegian translation of the abstract see Supplementary Materials section.

Validation of Ad-DiaRem and ABCD Diabetes Remission Prediction Scores at 1-Year After Roux-en-Y Gastric Bypass and Sleeve Gastrectomy in the Randomized Controlled Oseberg Trial.

BACKGROUND: Prediction of type 2 diabetes (T2DM) remission is an important part of risk-benefit assessment before bariatric surgery. STUDY DESIGN: 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. RESULTS: 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. CONCLUSION: 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.

Women's Reasons to Seek Bariatric Surgery and Their Expectations on the Surgery Outcome - a Multicenter Study from Five European Countries.

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.

Gastrointestinal Hormones and ß-Cell Function After Gastric Bypass and Sleeve Gastrectomy: A Randomized Controlled Trial (Oseberg).

CONTEXT: Whether Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) differentially affect postprandial gastrointestinal hormones and ß-cell function in type 2 diabetes remains unclear. OBJECTIVE: We aimed to compare gastrointestinal hormones and ß-cell function, assessed by an oral glucose tolerance test (OGTT) 5 weeks and 1 year after surgery, hypothesizing higher glucagon-like peptide-1 (GLP-1) levels and greater ß-cell response to glucose after RYGB than after SG. METHODS: This study was a randomized, triple-blind, single-center trial at a tertiary care center in Norway. The primary outcomes were diabetes remission and IVGTT-derived ß-cell function. Participants with obesity and type 2 diabetes were allocated (1:1) to RYGB or SG. We measured gastrointestinal hormone profiles and insulin secretion as ß-cell glucose sensitivity (ß-GS) derived from 180-minute OGTTs. RESULTS: Participants were 106 patients (67% women), mean (SD) age 48 (10) years. Diabetes remission rates at 1 year were higher after RYGB than after SG (77% vs 48%; P = 0.002). Incremental area under the curve (iAUC0-180) GLP-1 and ß-GS increased more after RYGB than after SG, with 1-year between-group difference 1173 pmol/L*min (95% CI, 569-1776; P = 0.0010) and 0.45 pmol/kg/min/mmol (95% CI, 0.15-0.75; P = 0.0032), respectively. After surgery, fasting and postprandial ghrelin levels were higher and decremental AUC0-180 ghrelin, iAUC0-180 glucose-dependent insulinotropic polypeptide, and iAUC0-60 glucagon were greater after RYGB than after SG. Diabetes remission at 1 year was associated with higher ß-GS and higher GLP-1 secretion. CONCLUSION: RYGB was associated with greater improvement in ß-cell function and higher postprandial GLP-1 levels than SG.

Impact of type 2 diabetes on in vivo activities and protein expressions of cytochrome P450 in patients with obesity.

Previous studies have not accounted for the close link between type 2 diabetes mellitus (T2DM) and obesity when investigating the impact of T2DM on cytochrome P450 (CYP) activities. The aim was to investigate the effect of T2DM on in vivo activities and protein expressions of CYP2C19, CYP3A, CYP1A2, and CYP2C9 in patients with obesity. A total of 99 patients from the COCKTAIL study (NCT02386917) were included in this cross-sectional analysis; 29 with T2DM and obesity (T2DM-obesity), 53 with obesity without T2DM (obesity), and 17 controls without T2DM and obesity (controls). CYP activities were assessed after the administration of a cocktail of probe drugs including omeprazole (CYP2C19), midazolam (CYP3A), caffeine (CYP1A2), and losartan (CYP2C9). Jejunal and liver biopsies were also obtained to determine protein concentrations of the respective CYPs. CYP2C19 activity and jejunal CYP2C19 concentration were 63% (-0.39 [95% CI: -0.82, -0.09]) and 40% (-0.09 fmol/µg protein [95% CI: -0.18, -0.003]) lower in T2DM-obesity compared with the obesity group, respectively. By contrast, there were no differences in the in vivo activities and protein concentrations of CYP3A, CYP1A2, and CYP2C9. Multivariable regression analyses also indicated that T2DM was associated with interindividual variability in CYP2C19 activity, but not CYP3A, CYP1A2, and CYP2C9 activities. The findings indicate that T2DM has a significant downregulating impact on CYP2C19 activity, but not on CYP3A, CYP1A2, and CYP2C9 activities and protein concentrations in patients with obesity. Hence, the effect of T2DM seems to be isoform-specific.