- Email: [email protected]
Preoperative assessment of gut hormones does not correlate to weight loss after Roux-en-Y gastric bypass surgery
Author's Accepted Manuscript
Preoperative assessment of gut hormones does not correlate to weight loss after Roux-en-Y gastric bypass surgery WerlingM , FändriksL , VincentRP , CrossGF , le RouxCW , OlbersT
www.elsevier.com/locate/buildenv
PII: DOI: Reference:
S1550-7289(14)00167-1 http://dx.doi.org/10.1016/j.soard.2014.04.018 SOARD1984
To appear in:
Surgery for Obesity and Related Diseases
Cite this article as: WerlingM , FändriksL , VincentRP , CrossGF , le RouxCW , OlbersT , Preoperative assessment of gut hormones does not correlate to weight loss after Roux-en-Y gastric bypass surgery, Surgery for Obesity and Related Diseases, http://dx. doi.org/10.1016/j.soard.2014.04.018 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Preoperative assessment of gut hormones does not correlate to weight loss after Roux-en-Y gastric bypass surgery
Werling M1, Fändriks L1, Vincent RP2, Cross GF2, le Roux CW1,3, Olbers T1
1
Department of Gastrosurgical Research and Education, Sahlgrenska Academy, University of
Gothenburg, Department of surgery, Sahlgrenska University Hospital/Sahlgrenska, Gothenburg, Sweden 2
Clinical Biochemistry, King’s College Hospital NHS Foundation Trust, London, UK
3
Diabetes Complications Research Centre, UCD Conway Institute, School of Medicine and
Medical Sciences, University College Dublin, Ireland
Corresponding author: Malin Werling, M.D., Ph.D. Department of Gastrosurgical Research and Education. Blå stråket 5, floor 1, Sahlgrenska University Hospital, 413 45 Gothenburg. [email protected], telephone +46738 268 751, fax +4631 411882.
Funding sources: This study received financial support by the Swedish Research Council (LF; grant no K2010-55X-21432-01-2), the University of Gothenburg (LF, MW) and Sahlgrenska University Hospital/ALF (LF), the Gothenburg Medical Association (MW), Ethicon Endosurgery (MW). CleR was supported by a Department of Health Clinician scientist award. Imperial College London receives support from an Integrative Mammalian Biology (IMB) Capacity Building Award, a FP7-HEALTH-2009-241592 EurOCHIP grant and a NIHR Biomedical Research Centre Funding Scheme. 1
MESH TERMS: Gastric bypass; Bariatric surgery; Obesity; Body weight change; Weight loss; Predictive factor; Predictive value of tests; Outcome assessment (Health care); Glucagon like peptide 1; GLP-1; Peptide YY; PYY; Gastrointestinal hormones.
SHORT TITLE: GLP-1 and PYY as weight outcome predictors ABSTRACT Background: Roux-en-Y gastric bypass (RYGB) surgery is an effective and frequently used surgical treatment for severe obesity. Postoperative weight loss varies markedly, but biomarkers to predict weight loss outcomes remain elusive. Levels of the satiety gut hormones glucagon like peptide-1 (GLP-1) and peptide YY (PYY) are attenuated in obese subjects but elevated after RYGB surgery. Objectives: We aimed to evaluate the preoperative response of GLP-1 and PYY to a standard meal as a predictor of weight loss after RYGB surgery. We hypothesized that weak satiety gut hormone responses preoperatively, would predict poor weight loss after RYGB surgery. Setting: Our study was conducted at Sahlgrenska University Hospital in Gothenburg Sweden. Methods: Preoperatively 43 subjects (F=25/M=18) had GLP-1 and PYY measured in the fasting state and at 30 min intervals over 180 minutes after a standard 400 kcal mixed meal. Weight loss was assessed at weight stability after surgery [mean 16.2 months (CI 15.5 to 16.9)]. Results: BMI (Body Mass Index) decreased from 44.0 kg/m2 (CI 42.2-45.7) before surgery to 30.3 kg/m2 (CI 28.4- 32.2) after surgery (p<0.001). Preoperative GLP-1 and PYY response to food intake; as delta value between fasting and maximum as well as total response during 180 minutes, did not correlate to total weight loss (GLP-1; rho=0.060 and rho=-0.089, PYY; rho=-
2
0.03 and rho=-0.022 respectively) or to excess weight loss % (GLP-1; rho=0.051 and rho=0.064, PYY; rho=-0.1 and rho=-0.088 respectively). Conclusion: Preoperative responses of GLP-1 and PYY to a 400 kcal mixed meal does not correlate to postoperative weight loss after RYGB surgery for morbid obesity.
KEY WORDS/MESH TERMS: Gastric bypass; Bariatric surgery; Obesity; Body weight change; Weight loss; Predictive factor; Predictive value of tests; Outcome assessment (Health care); Glucagon like peptide 1; GLP-1; Peptide YY; PYY; Gastrointestinal hormones.
BACKGROUND
For a majority of morbidly obese patients Roux-en-Y gastric bypass (RYGB) is an excellent treatment which induces substantial and sustained weight loss as well as improvements in obesity associated diseases like type 2 diabetes, hyperlipidaemia, hypertension, sleep apnoea, reduced quality of life and musculo-skeletal problems. (1-6) Bariatric surgery is relatively expensive and not without risks. Some patients only achieve moderate weight loss after RYGB, despite having the same complication risks due to surgery as those with substantially more weight loss. In order to avoid unnecessary surgery, accurate prediction of weight loss after intervention would be of value. However, there are currently no preoperative and easily available biomarkers which can accurately predict weight loss after surgery. (4, 5, 7-10)
In our study we evaluated whether satiety gut hormones before surgery could serve as biomarkers of weight loss after surgery. Glucagon like peptide-1 (GLP-1) and peptide YY (PYY) promote satiety and are excreted in response to food intake from mucosal endocrine Lcells in the small intestine and in the colon. (11-15) Obese subjects have attenuated satiety and a 3
reduced GLP-1 and PYY response in comparison to lean subjects. (16-18) Meal responses of GLP-1 and PYY are enhanced in patients after RYGB (11, 19-24) and those patients with the most weight loss also appear to have the best response of GLP-1 and PYY after a meal. (20, 21)
We hypothesized that weak satiety gut hormone responses preoperatively, would predict poor weight loss after RYGB surgery. Morbidly obese patients scheduled for surgery were examined for fasting GLP-1 and PYY and their postprandial responses to a standard meal. The individual preoperative results were analyzed in relation to stable postoperative weight 16 months after surgery.
METHODS
Ethics and patients This prospective cohort study was approved by the local ethics committee of the University of Gothenburg (Ref 583-07) and was conducted according to the principles of the Helsinki declaration. All patients gave written informed consent.
Forty-three consecutive patients were recruited between 2008 and 2009 at Sahlgrenska University hospital, Gothenburg, Sweden. Inclusion criterion for surgery at the clinic were BMI >35 kg/m2 with well controlled co morbidities, i.e. diabetes type 2 and hypertension, or BMI > 40 kg/m2 and age between 18 and 60 years. Demographics are shown in table 1.
Twelve patients out of the 43 included were on medication. Six patients were on antidepressant medication (Citalopram, Escitalopram), eight were on antihypertensive 4
medication (Metoprolol, Felodipin, Enalapril), four were on medication for high blood lipids (Simvastatinum, Atorvastatinum) and two patients were on thyroid hormone replacement medication (Levothyroxine).
Surgery was performed laparoscopically as previously described with an antecolic-antegastric Roux-en-Y construction and a small gastric pouch (10–20 mL). The gastro-enteroanastomosis was constructed with a 45-mm straight stapler and supplementary hand suturing. The length of the Roux-limb was approximately 100 cm and the biliopancreatic limb was short. (25) All patients completed routine follow up visits at the hospital at 2, 6 and 12 months. No patient was prescribed weight loss medication after surgery.
Study assessments Preoperative study visit: Patients were investigated prior to commencing the preoperative low calorie diet. Height was measured to the closest 0.5 cm and weight was measured to the closest 0.1 kg both preoperatively and at study visit after surgery. Patients arrived for a preoperative standard meal test at 07:30 after an overnight fast from 21:00 the evening before. A 400 kcal standard mixed semi liquid meal (8 energy % protein, 36 energy % carbohydrate and 56 energy % fat) was consumed. Blood samples were collected in fasting and at subsequent 30 minutes intervals for 180 minutes. GLP 1 and PYY were analyzed in duplicates using a well validated in-house radioimmunoassay. (17, 26) Postoperative study visit: Body weight usually stabilises one year postoperatively and at least one month weight stability was demanded in order to be eligible for study assessment. After the clinical routine follow up at 12 months postoperatively the patients were contacted on a monthly basis and when they reported one month weight stability they were invited for
5
body weight assessment at the laboratory, in mean 16.2 (CI 15.5 to 16.9) months after surgery.
Data analysis and statistics Data are presented as means with confidence intervals. Data used for correlation analysis to weight change were: 1./hormonal concentrations in the fasting state, 2./ delta value between fasting and maximum postprandial concentration, 3./ total response during 180 minutes after food intake represented by the area under the curve (AUC)) and 4./ net change from fasting value during 180 minutes after food intake (the AUC above fasting value). The trapetzoid rule was used to calculate AUC. The data was examined for normal distribution by Shapiro-Wilk’s and Kolmogorovs-Smirnov’s test. Data was also assessed for skewness and kurtosis. As data were not normal distributed non-parametric tests were used during analysis. Wilcoxon signedrank test was used to compare BMI before and after surgery. Correlations were calculated by Spearman’s rank correlation test. The conventional p<0.05 was used as statistical rejection criterion. A sample size of 42 subjects and a limit of statistical rejection criterion at p<0.05 gave a power of 90%.
RESULTS
Twenty-five women and 18 men with an age of 44 years (41 to 46.9) had a preoperative BMI of 44 kg/m2 (42.2 to 45.7) as shown in Table 1. GLP-1 responses increased by 52 % and PYY increased by 20 % above fasting set point after food intake as shown in Table 2.
6
At follow up 16.2 months (15.5 to 16.9) after surgery BMI had decreased to 30.3 kg/m2 (28.4 to 32.2) (p<0.001) with a weight loss of 13.7 kg/m2 (12.3 to 15). Total weight loss was 31.2 % (28.1 to 34.2) and corresponding excess weight loss was 76 % (67.2 to 84.8), with twelve of 43 patients (28 %) having a BMI above 35 kg/m2. One patient (2.3 %) lost less than 10 % total bodyweight and six patients (14 %) lost less than 20 %. In relation to excess weight loss: one patient (2.3 %) had an excess weight loss lower than 25 % and eight patients (18.6 %) had an excess weight loss under 50 %. Preoperative BMI predicted postoperative BMI, (rho=0.688, p<0.001) and are shown in Table 1.
There were no significant correlations between preoperative, postoperative or change in BMI or weight in relation to fasting or postprandial levels of GLP-1 and PYY as demonstrated in Table 3 as well as in Figure 2 and 3.
None of the patients had any serious peri- or postoperative complications requiring medical or surgical treatment. Five patients had undergone laparoscopic cholecystectomy due to gallstone symptomatology before their first visit in the study and another three underwent laparoscopical cholecystectomy after the RYGB. There were no significant differences regarding outcome of GLP-1, PYY, BMI or weight loss between patients with and without cholecystectomy.
DISCUSSION
We hypothesised that morbidly obese patients with the lowest satiety hormonal responses would have the poorest weight loss after RYGB surgery. However, the preoperative levels of 7
GLP-1 and PYY, both in the fasting state and as a response to a standard meal, were not predictive for weight loss in our setting.
Excess weight loss below 50 % is achieved in approximately 20 % of gastric bypass patients one and two years postoperatively, and in approximately 10 % ten years after surgery. (27-31) If patients that are destined to have minor weight loss could be identified preoperatively, then the discussion between clinician and patient around the risk benefit ratio of RYGB may be more informed, especially as similar weight loss may be achieved with intensive non-surgical treatment. (32, 33)
Previous predictors proposed including age, gender, body mass index (BMI), preoperative weight loss and genetically differences, appears to have limited value. (34-40) Psychosocial and behavioural factors including self-esteem, mental health, socio-economic status, health concerns, realistic expectations and compliance with follow up regimen affect postoperative weight loss, but these factors remain poor predictors at the individual level. (35, 38, 39, 41, 42) In addition, in collaboration with others we have examined change in gut microbiota (in manuscript) and blood levels of bile salts after RYGB surgery but have not been able to identify any relevant preoperative predictor of weight loss. (43)
Success in the treatment of morbid obesity has commonly been assessed as kilograms or % weight lost. However, while patients still expect significant weight loss, there is now a focus on resolution or prevention of co-morbidities. (1, 4, 5, 9) Weight loss of less than 10 % together with increased physical activity can be of significant metabolic benefit. (44) Thus even patients with less than 10 % weight loss after surgery could have benefit, but the same weight loss may also be achieved by non-surgical means. Improved quality of life correlates with the 8
magnitude of weight loss after surgery. (6, 45) Future research to identify outcome predictors can be expected to also target metabolic improvements. One example is the reduction in fasting insulin, which correlates with reduction in the incidence of diabetes. (5, 46) Accordingly there are many factors to take into account when discussing expectations at the preoperative consultation concerning treatment outcome from both the perspective of health professionals and patients.
Our study population is representative for RYGB patients as regards BMI before surgery, weight loss outcome, gender distribution and age. (4, 5, 9, 47, 48)
In contrast to previous publications, the GLP-1 and PYY responses in our cohort did not correlate to pre-operative BMI. (17, 18, 49-52) A possible explanation may be that previous studies included normal weight and overweight subjects, while we studied a morbidly obese group where variability in response may be different.
We used a mixed meal consisting of a high energy-% of fat and relatively low energy-% from carbohydrates and proteins compared to the general dietary recommendation. The same standard meal has previously been used in many studies and was selected as it suites most people’s taste preference and induces measurable response of GLP-1 and PYY. (11, 16, 20) Most patients reported the standard meal in our setting was experienced as a normal portion. A greater caloric content or a larger volume might have caused symptoms of discomfort, which could have confounded the test.
RYGB surgery was thought to work through simple mechanical restriction and caloric malabsorption through bypassing parts of the intestine. A more complex mechanistic 9
synergism has emerged during recent years including; decreased hunger, pronounced and earlier satiety, altered taste and food preferences and increased meal induced energy expenditure. (11, 20, 21, 23, 53-57)
The observation that postprandial responses of GLP-1 and PYY increase after food intake, following RYGB, may be one of several factors contributing to weight loss outcome. The individual variability in physiological systems and their relative importance as contributing factor for body weight control also add to complexity, possibly proving preoperative physiological testing for weight loss outcome challenging.
Limitations of this study include the number of patients studied. However, we consider the number probably sufficient as the results were unambiguous and there were no trends suggesting a type II error. We did not analyze GLP-1 or PYY at the postoperative visit as our study aimed at testing the prognostic value of the gut hormones if used before surgery, while the postoperative changes are well established. (11, 20, 22, 24, 58)
Conclusion
Preoperative assessment of the satiety hormones GLP-1 and PYY, both at fasting and in response to food intake, does not seem to predict the amount of weight loss after RYGB surgery. Predicting weight loss remains important for patients in considering the benefits and risks of bariatric surgery and further possible prognostic tools are to be evaluated.
10
FIGURE LEGENDS
Figure 1. Weight loss in body mass index (BMI) units in 43 gastric bypass patients in mean 16.2 months after surgery
Figure 2. Preoperative levels of GLP-1 and PYY as change from fasting to maximum value in relation to excess weight loss % and total weight loss % in 43 gastric bypass patients in mean 16.2 months after surgery
Figure 3. Preoperative levels of GLP-1 and PYY as total value during 180 minutes after food intake in relation to excess weight loss % and total weight loss % in 43 gastric bypass patients in mean 16.2 months after surgery
11
REFERENCES 1.
Sjostrom L, Peltonen M, Jacobson P, et al. Bariatric surgery and long-term
cardiovascular events. JAMA 2012;307:56-65. 2.
Carlsson LM, Peltonen M, Ahlin S, et al. Bariatric surgery and prevention of
type 2 diabetes in Swedish obese subjects. New Eng J Med 2012;367:695-704. 3.
Sjostrom L, Gummesson A, Sjostrom CD, et al. Effects of bariatric surgery on
cancer incidence in obese patients in Sweden (Swedish Obese Subjects Study): a prospective, controlled intervention trial. Lancet Oncol 2009;10:653-62. 4.
Sjostrom L, Narbro K, Sjostrom CD, et al. Effects of bariatric surgery on
mortality in Swedish obese subjects New Eng J Med 2007;357:741-52. 5.
Sjostrom L, Lindroos AK, Peltonen M, et al. Lifestyle, diabetes, and
cardiovascular risk factors 10 years after bariatric surgery. New Eng J Med 2004;351:268393. 6.
Karlsson J, Taft C, Ryden A, Sjostrom L, Sullivan M. Ten-year trends in health-
related quality of life after surgical and conventional treatment for severe obesity: the SOS intervention study. Int J Obes (Lond). 2007;31:1248-61. 7.
Gilbert EW, Wolfe BM. Bariatric surgery for the management of obesity: Plast
Reconstr Surg 2012;130:948-54. 8.
O'Brien PE. Bariatric surgery: mechanisms, indications and outcomes. J
Gastroenterol Hepatol 2010;25:1358-65. 9.
Buchwald H, Oien DM. Metabolic/bariatric surgery Worldwide 2008. Obes
Surg 2009;19:1605-11. 10.
O'Brien PE, McPhail T, Chaston TB, Dixon JB. Systematic review of medium-
term weight loss after bariatric operations. Obes Surg 2006;16:1032-40.
12
11.
le Roux CW, Aylwin SJ, Batterham RL, et al. Gut hormone profiles following
bariatric surgery favor an anorectic state, facilitate weight loss, and improve metabolic parameters. Ann Surg 2006;243:108-14. 12.
Small JCBSR. Gut hormones and the control of appetite. Trends Endocrinol
Metab 2004;15:259-63. 13.
Huda MS, Wilding JP, Pinkney JH. Gut peptides and the regulation of appetite.
Obes Rev 2006;7:163-82. 14.
Druce MBS. The regulation of appetite. Arch Dis Child 2006;91:183-7.
15.
Baynes KC, Dhillo WS, Bloom SR. Regulation of food intake by
gastrointestinal hormones. Curr Opin Gastroenterol 2006;22:626-31. 16.
le Roux CW, Batterham RL, Aylwin SJ, et al. Attenuated peptide YY release in
obese subjects is associated with reduced satiety. Endocrinology 2006;147:3-8. 17.
Batterham RL, Cohen MA, Ellis SM, et al. Inhibition of food intake in obese
subjects by peptide YY3-36. New Engl J Med 2003;349:941-8. 18.
Verdich C, Toubro S, Buemann B, Lysgard Madsen J, Juul Holst J, Astrup A.
The role of postprandial releases of insulin and incretin hormones in meal-induced satiety-effect of obesity and weight reduction. Int J Obes Relat Metab Disord 2001;25:1206-14. 19.
Laferrere B. Effect of gastric bypass surgery on the incretins. Diabetes Metab
2009;35:513-7. 20.
le Roux CW, Welbourn R, Werling M, et al. Gut hormones as mediators of
appetite and weight loss after Roux-en-Y gastric bypass. Ann Surg 2007;246:780-5. 21.
Dirksen C, Jorgensen NB, Bojsen-Moller KN, et al. Gut hormones, early
dumping and resting energy expenditure in patients with good and poor weight loss response after Roux-en-Y gastric bypass. Int J Obes (Lond). 2013;37:1452-9.
13
22.
Borg CM, le Roux CW, Ghatei MA, Bloom SR, Patel AG, Aylwin SJ.
Progressive rise in gut hormone levels after Roux-en-Y gastric bypass suggests gut adaptation and explains altered satiety. Brit J Surg 2006;93:210-5. 23.
Bose M, Machineni S, Olivan B, et al. Superior appetite hormone profile after
equivalent weight loss by gastric bypass compared to gastric banding. Obesity (Silver Spring). 2010;18:1085-91. 24.
Rubino F, Gagner M, Gentileschi Pet al. The early effect of the Roux-en-Y
gastric bypass on hormones involved in body weight regulation and glucose metabolism. Ann Surg 2004;240:236-42. 25.
Olbers T, Lonroth H, Fagevik-Olsen M, Lundell L. Laparoscopic gastric bypass:
development of technique, respiratory function, and long-term outcome. Obes Surg 2003;13:364-70. 26.
Kreymann B, Williams G, Ghatei MA, Bloom SR. Glucagon-like peptide-1 7-
36: a physiological incretin in man. Lancet 1987;2:1300-4. 27.
Nelson DW, Blair KS, Martin MJ. Analysis of obesity-related outcomes and
bariatric failure rates with the duodenal switch vs gastric bypass for morbid obesity. Arch Surg 2012;147:847-54. 28.
Valezi AC, de Almeida Menezes M, Mali J, Jr. Weight loss outcome after Roux-
en-Y gastric bypass: 10 years of follow-up. Obes Surg 2013;23:1290-3. 29.
Vijgen GH, Schouten R, Bouvy ND, Greve JW. Salvage banding for failed
Roux-en-Y gastric bypass. Surg Obes Relat Dis 2012;8:803-8. 30.
Ritz P, Caiazzo R, Becouarn G, et al. Early prediction of failure to lose weight
after obesity surgery. Surg Obes Relat Dis. 2013;9:118-21. 31.
Magro DO, Geloneze B, Delfini R, Pareja BC, Callejas F, Pareja JC. Long-term
weight regain after gastric bypass: a 5-year prospective study. Obes Surg 2008;18:648-51. 14
32.
Wadden TA, Neiberg RH, Wing RR, et al. Four-year weight losses in the Look
AHEAD study: factors associated with long-term success. Obesity (Silver Spring). 2011;19:1987-98. 33.
Yancy WS, Jr., Westman EC, McDuffie JR, et al. A randomized trial of a low-
carbohydrate diet vs orlistat plus a low-fat diet for weight loss. Arch Int Med 2010;170:13645. 34.
Contreras JE, Santander C, Court I, Bravo J. Correlation Between Age and
Weight Loss after Bariatric Surgery. Obes Surg 2013;23:1286-9 35.
El Chaar M, McDeavitt K, Richardson S, Gersin KS, Kuwada TS, Stefanidis D.
Does patient compliance with preoperative bariatric office visits affect postoperative excess weight loss? Surg Obes Relat Dis 2011;7:743-8. 36.
Livhits M, Mercado C, Yermilov I, et al. Does weight loss immediately before
bariatric surgery improve outcomes: a systematic review. Surg Obes Relat Dis 2009;5:713-21. 37.
Hatoum IJ, Greenawalt DM, Cotsapas C, Reitman ML, Daly MJ, Kaplan LM.
Heritability of the weight loss response to gastric bypass surgery. J Clin Endocrinol Metab 2011;96:E1630-3. 38.
Garcia Diaz E, Martin Folgueras T. Preoperative determinants of outcomes of
laparoscopic gastric bypass in the treatment of morbid obesity. Nutr Hosp 2011;26:851-5. 39.
Livhits M, Mercado C, Yermilov Iet al. Preoperative predictors of weight loss
following bariatric surgery: systematic review. Obes Surg 2012;22:70-89. 40.
Harnisch MC, Portenier DD, Pryor AD, Prince-Petersen R, Grant JP, DeMaria
EJ. Preoperative weight gain does not predict failure of weight loss or co-morbidity resolution of laparoscopic Roux-en-Y gastric bypass for morbid obesity. Surg Obes Relat Dis 2008;4:445-50.
15
41.
Gould JC, Beverstein G, Reinhardt S, Garren MJ. Impact of routine and long-
term follow-up on weight loss after laparoscopic gastric bypass. Surg Obes Relat Dis 2007;3:627-30; discussion 30. 42.
van Hout GC, Verschure SK, van Heck GL. Psychosocial predictors of success
following bariatric surgery. Obes Surg 2005;15:552-60. 43.
Werling M, Vincent RP, Cross GF, et al. Enhanced fasting and post-prandial
plasma bile acid responses after Roux-en-Y gastric bypass surgery. Scand J Gastroenterol 2013;48:1257-64. 44.
Penn L, White M, Lindstrom J, et al. Importance of weight loss maintenance and
risk prediction in the prevention of type 2 diabetes: analysis of European Diabetes Prevention Study RCT. PloS one 2013;8:e57143. 45.
Kral JG, LV, Sullivan MB. Assessment of quality of life before and after
surgery for severe obesity. Am J Clin Nutr. 1992;55(2 Suppl):611S-4S. 46.
Sjoholm K, Anveden A, Peltonen M, et al. Evaluation of current eligibility
criteria for bariatric surgery: diabetes prevention and risk factor changes in the Swedish obese subjects (SOS) study. Diabetes care 2013;36:1335-40. 47.
Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systematic
review and meta-analysis. JAMA 2004;292:1724-37. 48.
Picot J, Jones J, Colquitt JL, , et al. The clinical effectiveness and cost-
effectiveness of bariatric (weight loss) surgery for obesity: a systematic review and economic evaluation. Health Technol Assess 2009;13:1-190, 215-357, iii-iv. 49.
Chaudhri OB, Field BC, Bloom SR. Gastrointestinal satiety signals. Int J Obes
(Lond). 2008;32 Suppl 7:S28-31. 50.
Holst JJ. Incretin hormones and the satiation signal. Int J Obes (Lond).
2013;37:1161-8. 16
51.
Vilsboll T, Krarup T, Sonne J, et al. Incretin secretion in relation to meal size
and body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus. J Clin Endocrinol Metabol 2003;88:2706-13. 52.
Suzuki K, Jayasena CN, Bloom SR. Obesity and appetite control. Exp Diabetes
Res 2012;2012:824305. 53.
Miras AD, le Roux CW. Bariatric surgery and taste: novel mechanisms of
weight loss. Curr Opin Gastroenterol 2010;26:140-5. 54.
le Roux CW, Bueter M, Theis N, et al. Gastric bypass reduces fat intake and
preference. Am J Physiol Regul Integr Comp Physiol 2011;301:R1057-66. 55.
Bueter M, Lowenstein C, Olbers T, et al. Gastric bypass increases energy
expenditure in rats. Gastroenterology 2010;138:1845-53. 56.
Stylopoulos N, Hoppin AG, Kaplan LM. Roux-en-Y gastric bypass enhances
energy expenditure and extends lifespan in diet-induced obese rats. Obesity (Silver Spring). 2009;17:1839-47. 57.
Werling M, Olbers T, Fändriks L, et al. Increased Postprandial Energy
Expenditure May Explain Superior Long Term Weight Loss after Roux-en-Y Gastric Bypass Compared to Vertical Banded Gastroplasty. PLoS One 2013;8:e60280. 58.
Korner J, Inabnet W, Febres G, et al. Prospective study of gut hormone and
metabolic changes after adjustable gastric banding and Roux-en-Y gastric bypass. Int J Obes (Lond). 2009;33:786-95.
17
Table 1
Table 1. Demographics and BMI before and at weight stability after gastric bypass surgery. n (Females/Males) Age at surgery [years] Visit two [months after surgery]
43 (25/18) 44 (41 to 46.9) 16.2 (15.5 to 16.9)
Preop BMI [kg/m2]
44 (42.2 to 45.7)
Postop BMI [kg/m2]
30.3 (28.4 to 32.2)
BMI loss [units] Total weight loss [%] Excess weight loss [%]
13.7 (12.3 to 15) 31.2 (28.1 to 34.2) 76 (67.2 to 84.8)
Data are presented as means and confidence intervals within brackets. BMI; Body Mass Index, n; number of subjects included.
Table 2
Table 2. Levels of GLP 1 and PYY in fasting and calculated during 180 minutes after standard meal. GLP 1
PYY
[pmol/L] Fasting Maximum Delta fasting to maximum AUC AUC above fasting
77.8 (69.3 to 86.3) 118 (104.4 to 131.6) 40.2 (29.7 to 50.7) 15055.7 (14432.2 to 17679.1) 2053.6 (1033.9 to 3073.3)
[pmol/L] Fasting Maximum Delta fasting to maximum AUC AUC above fasting
24.4 (20.3 to 28.5) 29.2 (25.9 to 32.5) 4.3 (0.9 to 7.7) 4205 (3780.6 to 4629.5) "-187.1 (-787.5 to 413.4)"
Data are presented as means and confidence intervals within brackets. GLP-1; Glucagon-like peptide 1, PYY; Peptide YY, AUC; area under the curve.
Table 3
0.119 0.040 0.027 0.073 "-0.092
PYY; [pmol/L] Fasting Maximum Delta fasting to maximum AUC AUC above fasting 0.447 0.799 0.863 0.642 0.559
0.805 0.498 0.469 0.694 0.346
p
0.112 0.142 0.062 0.082 "-0.123
0.121 0.059 "-0.075 0.058 "-0.161
rho
p
0.475 0.362 0.693 0.600 0.431
0.438 0.708 0.631 0.712 0.302
[kg/m ]
2
Postoperative BMI 2
"-0.057 "-0.096 0.042 0.017 0.175
"-0.089 "-0.118 0.055 "-0.088 0.091
rho
0.716 0.541 0.791 0.916 0.262
0.571 0.449 0.726 0.577 0.562
p
[units; kg/m ]
BMI loss
"-0.081 "-0.142 "-0.030 "-0.022 0.154
"-0.119 "-0.131 0.060 "-0.089 0.141
rho
[%]
GLP-1; Glucagon-like peptide 1, PYY; Peptide YY, BMI; Body Mass Index, AUC; area under the curve.
0.606 0.363 0.849 0.890 0.323
0.446 0.401 0.703 0.571 0.366
p
Total weight loss
Spearman's rank correlation test are used for analysis. p<0.05 is used as rejection criterion. Number of subjects included=43.
0.093 "-0.106 "-0.113 "-0.062 "-0.147
GLP 1; [pmol/L] Fasting Maximum Delta fasting to maximum AUC AUC above fasting
rho
[kg/m ]
2
Preoperative BMI
"-0.081 "-0.186 "-0.100 "-0.088 0.106
"-0.131 "-0.098 0.051 "-0.064 0.172
rho
[%]
0.606 0.233 0.524 0.574 0.501
0.404 0.533 0.744 0.685 0.269
p
Excess weight loss
Table 3. GLP-1 and PYY as fasting value and as response during 180 minutes to food intake in relation to BMI before and 16.2 months after gastric bypass surgery.
Figure 1
Figure 2
Figure 3
Preoperative assessment of gut hormones does not correlate to weight loss after Roux-en-Y gastric bypass surgery WerlingM , FändriksL , VincentRP , CrossGF , le RouxCW , OlbersT
www.elsevier.com/locate/buildenv
PII: DOI: Reference:
S1550-7289(14)00167-1 http://dx.doi.org/10.1016/j.soard.2014.04.018 SOARD1984
To appear in:
Surgery for Obesity and Related Diseases
Cite this article as: WerlingM , FändriksL , VincentRP , CrossGF , le RouxCW , OlbersT , Preoperative assessment of gut hormones does not correlate to weight loss after Roux-en-Y gastric bypass surgery, Surgery for Obesity and Related Diseases, http://dx. doi.org/10.1016/j.soard.2014.04.018 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Preoperative assessment of gut hormones does not correlate to weight loss after Roux-en-Y gastric bypass surgery
Werling M1, Fändriks L1, Vincent RP2, Cross GF2, le Roux CW1,3, Olbers T1
1
Department of Gastrosurgical Research and Education, Sahlgrenska Academy, University of
Gothenburg, Department of surgery, Sahlgrenska University Hospital/Sahlgrenska, Gothenburg, Sweden 2
Clinical Biochemistry, King’s College Hospital NHS Foundation Trust, London, UK
3
Diabetes Complications Research Centre, UCD Conway Institute, School of Medicine and
Medical Sciences, University College Dublin, Ireland
Corresponding author: Malin Werling, M.D., Ph.D. Department of Gastrosurgical Research and Education. Blå stråket 5, floor 1, Sahlgrenska University Hospital, 413 45 Gothenburg. [email protected], telephone +46738 268 751, fax +4631 411882.
Funding sources: This study received financial support by the Swedish Research Council (LF; grant no K2010-55X-21432-01-2), the University of Gothenburg (LF, MW) and Sahlgrenska University Hospital/ALF (LF), the Gothenburg Medical Association (MW), Ethicon Endosurgery (MW). CleR was supported by a Department of Health Clinician scientist award. Imperial College London receives support from an Integrative Mammalian Biology (IMB) Capacity Building Award, a FP7-HEALTH-2009-241592 EurOCHIP grant and a NIHR Biomedical Research Centre Funding Scheme. 1
MESH TERMS: Gastric bypass; Bariatric surgery; Obesity; Body weight change; Weight loss; Predictive factor; Predictive value of tests; Outcome assessment (Health care); Glucagon like peptide 1; GLP-1; Peptide YY; PYY; Gastrointestinal hormones.
SHORT TITLE: GLP-1 and PYY as weight outcome predictors ABSTRACT Background: Roux-en-Y gastric bypass (RYGB) surgery is an effective and frequently used surgical treatment for severe obesity. Postoperative weight loss varies markedly, but biomarkers to predict weight loss outcomes remain elusive. Levels of the satiety gut hormones glucagon like peptide-1 (GLP-1) and peptide YY (PYY) are attenuated in obese subjects but elevated after RYGB surgery. Objectives: We aimed to evaluate the preoperative response of GLP-1 and PYY to a standard meal as a predictor of weight loss after RYGB surgery. We hypothesized that weak satiety gut hormone responses preoperatively, would predict poor weight loss after RYGB surgery. Setting: Our study was conducted at Sahlgrenska University Hospital in Gothenburg Sweden. Methods: Preoperatively 43 subjects (F=25/M=18) had GLP-1 and PYY measured in the fasting state and at 30 min intervals over 180 minutes after a standard 400 kcal mixed meal. Weight loss was assessed at weight stability after surgery [mean 16.2 months (CI 15.5 to 16.9)]. Results: BMI (Body Mass Index) decreased from 44.0 kg/m2 (CI 42.2-45.7) before surgery to 30.3 kg/m2 (CI 28.4- 32.2) after surgery (p<0.001). Preoperative GLP-1 and PYY response to food intake; as delta value between fasting and maximum as well as total response during 180 minutes, did not correlate to total weight loss (GLP-1; rho=0.060 and rho=-0.089, PYY; rho=-
2
0.03 and rho=-0.022 respectively) or to excess weight loss % (GLP-1; rho=0.051 and rho=0.064, PYY; rho=-0.1 and rho=-0.088 respectively). Conclusion: Preoperative responses of GLP-1 and PYY to a 400 kcal mixed meal does not correlate to postoperative weight loss after RYGB surgery for morbid obesity.
KEY WORDS/MESH TERMS: Gastric bypass; Bariatric surgery; Obesity; Body weight change; Weight loss; Predictive factor; Predictive value of tests; Outcome assessment (Health care); Glucagon like peptide 1; GLP-1; Peptide YY; PYY; Gastrointestinal hormones.
BACKGROUND
For a majority of morbidly obese patients Roux-en-Y gastric bypass (RYGB) is an excellent treatment which induces substantial and sustained weight loss as well as improvements in obesity associated diseases like type 2 diabetes, hyperlipidaemia, hypertension, sleep apnoea, reduced quality of life and musculo-skeletal problems. (1-6) Bariatric surgery is relatively expensive and not without risks. Some patients only achieve moderate weight loss after RYGB, despite having the same complication risks due to surgery as those with substantially more weight loss. In order to avoid unnecessary surgery, accurate prediction of weight loss after intervention would be of value. However, there are currently no preoperative and easily available biomarkers which can accurately predict weight loss after surgery. (4, 5, 7-10)
In our study we evaluated whether satiety gut hormones before surgery could serve as biomarkers of weight loss after surgery. Glucagon like peptide-1 (GLP-1) and peptide YY (PYY) promote satiety and are excreted in response to food intake from mucosal endocrine Lcells in the small intestine and in the colon. (11-15) Obese subjects have attenuated satiety and a 3
reduced GLP-1 and PYY response in comparison to lean subjects. (16-18) Meal responses of GLP-1 and PYY are enhanced in patients after RYGB (11, 19-24) and those patients with the most weight loss also appear to have the best response of GLP-1 and PYY after a meal. (20, 21)
We hypothesized that weak satiety gut hormone responses preoperatively, would predict poor weight loss after RYGB surgery. Morbidly obese patients scheduled for surgery were examined for fasting GLP-1 and PYY and their postprandial responses to a standard meal. The individual preoperative results were analyzed in relation to stable postoperative weight 16 months after surgery.
METHODS
Ethics and patients This prospective cohort study was approved by the local ethics committee of the University of Gothenburg (Ref 583-07) and was conducted according to the principles of the Helsinki declaration. All patients gave written informed consent.
Forty-three consecutive patients were recruited between 2008 and 2009 at Sahlgrenska University hospital, Gothenburg, Sweden. Inclusion criterion for surgery at the clinic were BMI >35 kg/m2 with well controlled co morbidities, i.e. diabetes type 2 and hypertension, or BMI > 40 kg/m2 and age between 18 and 60 years. Demographics are shown in table 1.
Twelve patients out of the 43 included were on medication. Six patients were on antidepressant medication (Citalopram, Escitalopram), eight were on antihypertensive 4
medication (Metoprolol, Felodipin, Enalapril), four were on medication for high blood lipids (Simvastatinum, Atorvastatinum) and two patients were on thyroid hormone replacement medication (Levothyroxine).
Surgery was performed laparoscopically as previously described with an antecolic-antegastric Roux-en-Y construction and a small gastric pouch (10–20 mL). The gastro-enteroanastomosis was constructed with a 45-mm straight stapler and supplementary hand suturing. The length of the Roux-limb was approximately 100 cm and the biliopancreatic limb was short. (25) All patients completed routine follow up visits at the hospital at 2, 6 and 12 months. No patient was prescribed weight loss medication after surgery.
Study assessments Preoperative study visit: Patients were investigated prior to commencing the preoperative low calorie diet. Height was measured to the closest 0.5 cm and weight was measured to the closest 0.1 kg both preoperatively and at study visit after surgery. Patients arrived for a preoperative standard meal test at 07:30 after an overnight fast from 21:00 the evening before. A 400 kcal standard mixed semi liquid meal (8 energy % protein, 36 energy % carbohydrate and 56 energy % fat) was consumed. Blood samples were collected in fasting and at subsequent 30 minutes intervals for 180 minutes. GLP 1 and PYY were analyzed in duplicates using a well validated in-house radioimmunoassay. (17, 26) Postoperative study visit: Body weight usually stabilises one year postoperatively and at least one month weight stability was demanded in order to be eligible for study assessment. After the clinical routine follow up at 12 months postoperatively the patients were contacted on a monthly basis and when they reported one month weight stability they were invited for
5
body weight assessment at the laboratory, in mean 16.2 (CI 15.5 to 16.9) months after surgery.
Data analysis and statistics Data are presented as means with confidence intervals. Data used for correlation analysis to weight change were: 1./hormonal concentrations in the fasting state, 2./ delta value between fasting and maximum postprandial concentration, 3./ total response during 180 minutes after food intake represented by the area under the curve (AUC)) and 4./ net change from fasting value during 180 minutes after food intake (the AUC above fasting value). The trapetzoid rule was used to calculate AUC. The data was examined for normal distribution by Shapiro-Wilk’s and Kolmogorovs-Smirnov’s test. Data was also assessed for skewness and kurtosis. As data were not normal distributed non-parametric tests were used during analysis. Wilcoxon signedrank test was used to compare BMI before and after surgery. Correlations were calculated by Spearman’s rank correlation test. The conventional p<0.05 was used as statistical rejection criterion. A sample size of 42 subjects and a limit of statistical rejection criterion at p<0.05 gave a power of 90%.
RESULTS
Twenty-five women and 18 men with an age of 44 years (41 to 46.9) had a preoperative BMI of 44 kg/m2 (42.2 to 45.7) as shown in Table 1. GLP-1 responses increased by 52 % and PYY increased by 20 % above fasting set point after food intake as shown in Table 2.
6
At follow up 16.2 months (15.5 to 16.9) after surgery BMI had decreased to 30.3 kg/m2 (28.4 to 32.2) (p<0.001) with a weight loss of 13.7 kg/m2 (12.3 to 15). Total weight loss was 31.2 % (28.1 to 34.2) and corresponding excess weight loss was 76 % (67.2 to 84.8), with twelve of 43 patients (28 %) having a BMI above 35 kg/m2. One patient (2.3 %) lost less than 10 % total bodyweight and six patients (14 %) lost less than 20 %. In relation to excess weight loss: one patient (2.3 %) had an excess weight loss lower than 25 % and eight patients (18.6 %) had an excess weight loss under 50 %. Preoperative BMI predicted postoperative BMI, (rho=0.688, p<0.001) and are shown in Table 1.
There were no significant correlations between preoperative, postoperative or change in BMI or weight in relation to fasting or postprandial levels of GLP-1 and PYY as demonstrated in Table 3 as well as in Figure 2 and 3.
None of the patients had any serious peri- or postoperative complications requiring medical or surgical treatment. Five patients had undergone laparoscopic cholecystectomy due to gallstone symptomatology before their first visit in the study and another three underwent laparoscopical cholecystectomy after the RYGB. There were no significant differences regarding outcome of GLP-1, PYY, BMI or weight loss between patients with and without cholecystectomy.
DISCUSSION
We hypothesised that morbidly obese patients with the lowest satiety hormonal responses would have the poorest weight loss after RYGB surgery. However, the preoperative levels of 7
GLP-1 and PYY, both in the fasting state and as a response to a standard meal, were not predictive for weight loss in our setting.
Excess weight loss below 50 % is achieved in approximately 20 % of gastric bypass patients one and two years postoperatively, and in approximately 10 % ten years after surgery. (27-31) If patients that are destined to have minor weight loss could be identified preoperatively, then the discussion between clinician and patient around the risk benefit ratio of RYGB may be more informed, especially as similar weight loss may be achieved with intensive non-surgical treatment. (32, 33)
Previous predictors proposed including age, gender, body mass index (BMI), preoperative weight loss and genetically differences, appears to have limited value. (34-40) Psychosocial and behavioural factors including self-esteem, mental health, socio-economic status, health concerns, realistic expectations and compliance with follow up regimen affect postoperative weight loss, but these factors remain poor predictors at the individual level. (35, 38, 39, 41, 42) In addition, in collaboration with others we have examined change in gut microbiota (in manuscript) and blood levels of bile salts after RYGB surgery but have not been able to identify any relevant preoperative predictor of weight loss. (43)
Success in the treatment of morbid obesity has commonly been assessed as kilograms or % weight lost. However, while patients still expect significant weight loss, there is now a focus on resolution or prevention of co-morbidities. (1, 4, 5, 9) Weight loss of less than 10 % together with increased physical activity can be of significant metabolic benefit. (44) Thus even patients with less than 10 % weight loss after surgery could have benefit, but the same weight loss may also be achieved by non-surgical means. Improved quality of life correlates with the 8
magnitude of weight loss after surgery. (6, 45) Future research to identify outcome predictors can be expected to also target metabolic improvements. One example is the reduction in fasting insulin, which correlates with reduction in the incidence of diabetes. (5, 46) Accordingly there are many factors to take into account when discussing expectations at the preoperative consultation concerning treatment outcome from both the perspective of health professionals and patients.
Our study population is representative for RYGB patients as regards BMI before surgery, weight loss outcome, gender distribution and age. (4, 5, 9, 47, 48)
In contrast to previous publications, the GLP-1 and PYY responses in our cohort did not correlate to pre-operative BMI. (17, 18, 49-52) A possible explanation may be that previous studies included normal weight and overweight subjects, while we studied a morbidly obese group where variability in response may be different.
We used a mixed meal consisting of a high energy-% of fat and relatively low energy-% from carbohydrates and proteins compared to the general dietary recommendation. The same standard meal has previously been used in many studies and was selected as it suites most people’s taste preference and induces measurable response of GLP-1 and PYY. (11, 16, 20) Most patients reported the standard meal in our setting was experienced as a normal portion. A greater caloric content or a larger volume might have caused symptoms of discomfort, which could have confounded the test.
RYGB surgery was thought to work through simple mechanical restriction and caloric malabsorption through bypassing parts of the intestine. A more complex mechanistic 9
synergism has emerged during recent years including; decreased hunger, pronounced and earlier satiety, altered taste and food preferences and increased meal induced energy expenditure. (11, 20, 21, 23, 53-57)
The observation that postprandial responses of GLP-1 and PYY increase after food intake, following RYGB, may be one of several factors contributing to weight loss outcome. The individual variability in physiological systems and their relative importance as contributing factor for body weight control also add to complexity, possibly proving preoperative physiological testing for weight loss outcome challenging.
Limitations of this study include the number of patients studied. However, we consider the number probably sufficient as the results were unambiguous and there were no trends suggesting a type II error. We did not analyze GLP-1 or PYY at the postoperative visit as our study aimed at testing the prognostic value of the gut hormones if used before surgery, while the postoperative changes are well established. (11, 20, 22, 24, 58)
Conclusion
Preoperative assessment of the satiety hormones GLP-1 and PYY, both at fasting and in response to food intake, does not seem to predict the amount of weight loss after RYGB surgery. Predicting weight loss remains important for patients in considering the benefits and risks of bariatric surgery and further possible prognostic tools are to be evaluated.
10
FIGURE LEGENDS
Figure 1. Weight loss in body mass index (BMI) units in 43 gastric bypass patients in mean 16.2 months after surgery
Figure 2. Preoperative levels of GLP-1 and PYY as change from fasting to maximum value in relation to excess weight loss % and total weight loss % in 43 gastric bypass patients in mean 16.2 months after surgery
Figure 3. Preoperative levels of GLP-1 and PYY as total value during 180 minutes after food intake in relation to excess weight loss % and total weight loss % in 43 gastric bypass patients in mean 16.2 months after surgery
11
REFERENCES 1.
Sjostrom L, Peltonen M, Jacobson P, et al. Bariatric surgery and long-term
cardiovascular events. JAMA 2012;307:56-65. 2.
Carlsson LM, Peltonen M, Ahlin S, et al. Bariatric surgery and prevention of
type 2 diabetes in Swedish obese subjects. New Eng J Med 2012;367:695-704. 3.
Sjostrom L, Gummesson A, Sjostrom CD, et al. Effects of bariatric surgery on
cancer incidence in obese patients in Sweden (Swedish Obese Subjects Study): a prospective, controlled intervention trial. Lancet Oncol 2009;10:653-62. 4.
Sjostrom L, Narbro K, Sjostrom CD, et al. Effects of bariatric surgery on
mortality in Swedish obese subjects New Eng J Med 2007;357:741-52. 5.
Sjostrom L, Lindroos AK, Peltonen M, et al. Lifestyle, diabetes, and
cardiovascular risk factors 10 years after bariatric surgery. New Eng J Med 2004;351:268393. 6.
Karlsson J, Taft C, Ryden A, Sjostrom L, Sullivan M. Ten-year trends in health-
related quality of life after surgical and conventional treatment for severe obesity: the SOS intervention study. Int J Obes (Lond). 2007;31:1248-61. 7.
Gilbert EW, Wolfe BM. Bariatric surgery for the management of obesity: Plast
Reconstr Surg 2012;130:948-54. 8.
O'Brien PE. Bariatric surgery: mechanisms, indications and outcomes. J
Gastroenterol Hepatol 2010;25:1358-65. 9.
Buchwald H, Oien DM. Metabolic/bariatric surgery Worldwide 2008. Obes
Surg 2009;19:1605-11. 10.
O'Brien PE, McPhail T, Chaston TB, Dixon JB. Systematic review of medium-
term weight loss after bariatric operations. Obes Surg 2006;16:1032-40.
12
11.
le Roux CW, Aylwin SJ, Batterham RL, et al. Gut hormone profiles following
bariatric surgery favor an anorectic state, facilitate weight loss, and improve metabolic parameters. Ann Surg 2006;243:108-14. 12.
Small JCBSR. Gut hormones and the control of appetite. Trends Endocrinol
Metab 2004;15:259-63. 13.
Huda MS, Wilding JP, Pinkney JH. Gut peptides and the regulation of appetite.
Obes Rev 2006;7:163-82. 14.
Druce MBS. The regulation of appetite. Arch Dis Child 2006;91:183-7.
15.
Baynes KC, Dhillo WS, Bloom SR. Regulation of food intake by
gastrointestinal hormones. Curr Opin Gastroenterol 2006;22:626-31. 16.
le Roux CW, Batterham RL, Aylwin SJ, et al. Attenuated peptide YY release in
obese subjects is associated with reduced satiety. Endocrinology 2006;147:3-8. 17.
Batterham RL, Cohen MA, Ellis SM, et al. Inhibition of food intake in obese
subjects by peptide YY3-36. New Engl J Med 2003;349:941-8. 18.
Verdich C, Toubro S, Buemann B, Lysgard Madsen J, Juul Holst J, Astrup A.
The role of postprandial releases of insulin and incretin hormones in meal-induced satiety-effect of obesity and weight reduction. Int J Obes Relat Metab Disord 2001;25:1206-14. 19.
Laferrere B. Effect of gastric bypass surgery on the incretins. Diabetes Metab
2009;35:513-7. 20.
le Roux CW, Welbourn R, Werling M, et al. Gut hormones as mediators of
appetite and weight loss after Roux-en-Y gastric bypass. Ann Surg 2007;246:780-5. 21.
Dirksen C, Jorgensen NB, Bojsen-Moller KN, et al. Gut hormones, early
dumping and resting energy expenditure in patients with good and poor weight loss response after Roux-en-Y gastric bypass. Int J Obes (Lond). 2013;37:1452-9.
13
22.
Borg CM, le Roux CW, Ghatei MA, Bloom SR, Patel AG, Aylwin SJ.
Progressive rise in gut hormone levels after Roux-en-Y gastric bypass suggests gut adaptation and explains altered satiety. Brit J Surg 2006;93:210-5. 23.
Bose M, Machineni S, Olivan B, et al. Superior appetite hormone profile after
equivalent weight loss by gastric bypass compared to gastric banding. Obesity (Silver Spring). 2010;18:1085-91. 24.
Rubino F, Gagner M, Gentileschi Pet al. The early effect of the Roux-en-Y
gastric bypass on hormones involved in body weight regulation and glucose metabolism. Ann Surg 2004;240:236-42. 25.
Olbers T, Lonroth H, Fagevik-Olsen M, Lundell L. Laparoscopic gastric bypass:
development of technique, respiratory function, and long-term outcome. Obes Surg 2003;13:364-70. 26.
Kreymann B, Williams G, Ghatei MA, Bloom SR. Glucagon-like peptide-1 7-
36: a physiological incretin in man. Lancet 1987;2:1300-4. 27.
Nelson DW, Blair KS, Martin MJ. Analysis of obesity-related outcomes and
bariatric failure rates with the duodenal switch vs gastric bypass for morbid obesity. Arch Surg 2012;147:847-54. 28.
Valezi AC, de Almeida Menezes M, Mali J, Jr. Weight loss outcome after Roux-
en-Y gastric bypass: 10 years of follow-up. Obes Surg 2013;23:1290-3. 29.
Vijgen GH, Schouten R, Bouvy ND, Greve JW. Salvage banding for failed
Roux-en-Y gastric bypass. Surg Obes Relat Dis 2012;8:803-8. 30.
Ritz P, Caiazzo R, Becouarn G, et al. Early prediction of failure to lose weight
after obesity surgery. Surg Obes Relat Dis. 2013;9:118-21. 31.
Magro DO, Geloneze B, Delfini R, Pareja BC, Callejas F, Pareja JC. Long-term
weight regain after gastric bypass: a 5-year prospective study. Obes Surg 2008;18:648-51. 14
32.
Wadden TA, Neiberg RH, Wing RR, et al. Four-year weight losses in the Look
AHEAD study: factors associated with long-term success. Obesity (Silver Spring). 2011;19:1987-98. 33.
Yancy WS, Jr., Westman EC, McDuffie JR, et al. A randomized trial of a low-
carbohydrate diet vs orlistat plus a low-fat diet for weight loss. Arch Int Med 2010;170:13645. 34.
Contreras JE, Santander C, Court I, Bravo J. Correlation Between Age and
Weight Loss after Bariatric Surgery. Obes Surg 2013;23:1286-9 35.
El Chaar M, McDeavitt K, Richardson S, Gersin KS, Kuwada TS, Stefanidis D.
Does patient compliance with preoperative bariatric office visits affect postoperative excess weight loss? Surg Obes Relat Dis 2011;7:743-8. 36.
Livhits M, Mercado C, Yermilov I, et al. Does weight loss immediately before
bariatric surgery improve outcomes: a systematic review. Surg Obes Relat Dis 2009;5:713-21. 37.
Hatoum IJ, Greenawalt DM, Cotsapas C, Reitman ML, Daly MJ, Kaplan LM.
Heritability of the weight loss response to gastric bypass surgery. J Clin Endocrinol Metab 2011;96:E1630-3. 38.
Garcia Diaz E, Martin Folgueras T. Preoperative determinants of outcomes of
laparoscopic gastric bypass in the treatment of morbid obesity. Nutr Hosp 2011;26:851-5. 39.
Livhits M, Mercado C, Yermilov Iet al. Preoperative predictors of weight loss
following bariatric surgery: systematic review. Obes Surg 2012;22:70-89. 40.
Harnisch MC, Portenier DD, Pryor AD, Prince-Petersen R, Grant JP, DeMaria
EJ. Preoperative weight gain does not predict failure of weight loss or co-morbidity resolution of laparoscopic Roux-en-Y gastric bypass for morbid obesity. Surg Obes Relat Dis 2008;4:445-50.
15
41.
Gould JC, Beverstein G, Reinhardt S, Garren MJ. Impact of routine and long-
term follow-up on weight loss after laparoscopic gastric bypass. Surg Obes Relat Dis 2007;3:627-30; discussion 30. 42.
van Hout GC, Verschure SK, van Heck GL. Psychosocial predictors of success
following bariatric surgery. Obes Surg 2005;15:552-60. 43.
Werling M, Vincent RP, Cross GF, et al. Enhanced fasting and post-prandial
plasma bile acid responses after Roux-en-Y gastric bypass surgery. Scand J Gastroenterol 2013;48:1257-64. 44.
Penn L, White M, Lindstrom J, et al. Importance of weight loss maintenance and
risk prediction in the prevention of type 2 diabetes: analysis of European Diabetes Prevention Study RCT. PloS one 2013;8:e57143. 45.
Kral JG, LV, Sullivan MB. Assessment of quality of life before and after
surgery for severe obesity. Am J Clin Nutr. 1992;55(2 Suppl):611S-4S. 46.
Sjoholm K, Anveden A, Peltonen M, et al. Evaluation of current eligibility
criteria for bariatric surgery: diabetes prevention and risk factor changes in the Swedish obese subjects (SOS) study. Diabetes care 2013;36:1335-40. 47.
Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systematic
review and meta-analysis. JAMA 2004;292:1724-37. 48.
Picot J, Jones J, Colquitt JL, , et al. The clinical effectiveness and cost-
effectiveness of bariatric (weight loss) surgery for obesity: a systematic review and economic evaluation. Health Technol Assess 2009;13:1-190, 215-357, iii-iv. 49.
Chaudhri OB, Field BC, Bloom SR. Gastrointestinal satiety signals. Int J Obes
(Lond). 2008;32 Suppl 7:S28-31. 50.
Holst JJ. Incretin hormones and the satiation signal. Int J Obes (Lond).
2013;37:1161-8. 16
51.
Vilsboll T, Krarup T, Sonne J, et al. Incretin secretion in relation to meal size
and body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus. J Clin Endocrinol Metabol 2003;88:2706-13. 52.
Suzuki K, Jayasena CN, Bloom SR. Obesity and appetite control. Exp Diabetes
Res 2012;2012:824305. 53.
Miras AD, le Roux CW. Bariatric surgery and taste: novel mechanisms of
weight loss. Curr Opin Gastroenterol 2010;26:140-5. 54.
le Roux CW, Bueter M, Theis N, et al. Gastric bypass reduces fat intake and
preference. Am J Physiol Regul Integr Comp Physiol 2011;301:R1057-66. 55.
Bueter M, Lowenstein C, Olbers T, et al. Gastric bypass increases energy
expenditure in rats. Gastroenterology 2010;138:1845-53. 56.
Stylopoulos N, Hoppin AG, Kaplan LM. Roux-en-Y gastric bypass enhances
energy expenditure and extends lifespan in diet-induced obese rats. Obesity (Silver Spring). 2009;17:1839-47. 57.
Werling M, Olbers T, Fändriks L, et al. Increased Postprandial Energy
Expenditure May Explain Superior Long Term Weight Loss after Roux-en-Y Gastric Bypass Compared to Vertical Banded Gastroplasty. PLoS One 2013;8:e60280. 58.
Korner J, Inabnet W, Febres G, et al. Prospective study of gut hormone and
metabolic changes after adjustable gastric banding and Roux-en-Y gastric bypass. Int J Obes (Lond). 2009;33:786-95.
17
Table 1
Table 1. Demographics and BMI before and at weight stability after gastric bypass surgery. n (Females/Males) Age at surgery [years] Visit two [months after surgery]
43 (25/18) 44 (41 to 46.9) 16.2 (15.5 to 16.9)
Preop BMI [kg/m2]
44 (42.2 to 45.7)
Postop BMI [kg/m2]
30.3 (28.4 to 32.2)
BMI loss [units] Total weight loss [%] Excess weight loss [%]
13.7 (12.3 to 15) 31.2 (28.1 to 34.2) 76 (67.2 to 84.8)
Data are presented as means and confidence intervals within brackets. BMI; Body Mass Index, n; number of subjects included.
Table 2
Table 2. Levels of GLP 1 and PYY in fasting and calculated during 180 minutes after standard meal. GLP 1
PYY
[pmol/L] Fasting Maximum Delta fasting to maximum AUC AUC above fasting
77.8 (69.3 to 86.3) 118 (104.4 to 131.6) 40.2 (29.7 to 50.7) 15055.7 (14432.2 to 17679.1) 2053.6 (1033.9 to 3073.3)
[pmol/L] Fasting Maximum Delta fasting to maximum AUC AUC above fasting
24.4 (20.3 to 28.5) 29.2 (25.9 to 32.5) 4.3 (0.9 to 7.7) 4205 (3780.6 to 4629.5) "-187.1 (-787.5 to 413.4)"
Data are presented as means and confidence intervals within brackets. GLP-1; Glucagon-like peptide 1, PYY; Peptide YY, AUC; area under the curve.
Table 3
0.119 0.040 0.027 0.073 "-0.092
PYY; [pmol/L] Fasting Maximum Delta fasting to maximum AUC AUC above fasting 0.447 0.799 0.863 0.642 0.559
0.805 0.498 0.469 0.694 0.346
p
0.112 0.142 0.062 0.082 "-0.123
0.121 0.059 "-0.075 0.058 "-0.161
rho
p
0.475 0.362 0.693 0.600 0.431
0.438 0.708 0.631 0.712 0.302
[kg/m ]
2
Postoperative BMI 2
"-0.057 "-0.096 0.042 0.017 0.175
"-0.089 "-0.118 0.055 "-0.088 0.091
rho
0.716 0.541 0.791 0.916 0.262
0.571 0.449 0.726 0.577 0.562
p
[units; kg/m ]
BMI loss
"-0.081 "-0.142 "-0.030 "-0.022 0.154
"-0.119 "-0.131 0.060 "-0.089 0.141
rho
[%]
GLP-1; Glucagon-like peptide 1, PYY; Peptide YY, BMI; Body Mass Index, AUC; area under the curve.
0.606 0.363 0.849 0.890 0.323
0.446 0.401 0.703 0.571 0.366
p
Total weight loss
Spearman's rank correlation test are used for analysis. p<0.05 is used as rejection criterion. Number of subjects included=43.
0.093 "-0.106 "-0.113 "-0.062 "-0.147
GLP 1; [pmol/L] Fasting Maximum Delta fasting to maximum AUC AUC above fasting
rho
[kg/m ]
2
Preoperative BMI
"-0.081 "-0.186 "-0.100 "-0.088 0.106
"-0.131 "-0.098 0.051 "-0.064 0.172
rho
[%]
0.606 0.233 0.524 0.574 0.501
0.404 0.533 0.744 0.685 0.269
p
Excess weight loss
Table 3. GLP-1 and PYY as fasting value and as response during 180 minutes to food intake in relation to BMI before and 16.2 months after gastric bypass surgery.
Figure 1
Figure 2
Figure 3