Bariatric surgery and reduction in morbidity and mortality: experiences from the SOS study

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1 (2008) 32, S93 S97 & 2008 Macmillan Publishers Limited All rights reserved /08 $ REVIEW Bariatric surgery and reduction in morbidity and mortality: experiences from the SOS study L Sjöström Department of Body Composition and Metabolism, Sahlgrenska University Hospital, Göteborg, Sweden Obesity is associated with increased morbidity and mortality. Intentional weight loss results in improvement of cardiovascular risk factors, but most observational studies suggest that weight reduction is associated with increased overall and cardiovascular mortality. No prospective intervention studies on mortality have earlier been reported in obese subjects. The prospective, controlled Swedish Obese Subjects Study enrolled obese subjects who either underwent bariatric surgery (n ¼ 2010) or were allocated to a contemporaneously matched, conventionally treated obese control group (n ¼ 2037). This review sums up effects on morbidity and mortality over an average of 10 years. The mean weight change of the control group was less than ±2% over up to 15 years of weight recording. Maximum weight losses in the surgical subgroups were observed after 1 2 years. After 10 years, the weight losses from baseline were stabilized at 25, 16 and 14%, respectively. Bariatric surgery improved all traditional cardiovascular risk states except hypercholesterolemia over 10 years. There were 129 deaths in the control group compared with 101 in the surgery group. The unadjusted overall mortality was reduced by 23.7% (P ¼ ) in the surgery group (relative to controls), whereas the gender-, age- and risk factor-adjusted mortality reduction was 30.7% (P ¼ ). The most common causes of death were myocardial infarction (controls n ¼ 25, surgery n ¼ 13) and cancer (47/29). Bariatric surgery for severe obesity is associated with long-term weight loss, improved risk factors and decreased overall mortality. (2008) 32, S93 S97; doi: /ijo Keywords: bariatric surgery; controlled intervention trial; risk factors; mortality Introduction The majority of large and long-term epidemiological studies indicate that obesity is associated with increased mortality. 1 7 Weight loss is known to be associated with improvement of intermediate risk factors for disease, 8 suggesting that weight loss would also reduce mortality. Although four retrospective, bariatric cohort studies have indicated that this may be the case, 9 12 the prospective, controlled, interventional studies showing that weight loss is in fact reducing mortality have been lacking. To date, most observational epidemiologic studies have indicated that overall and cardiovascular mortality is increased after weight loss, 13 even in subjects who were obese at baseline This discrepancy regarding the effects of weight loss on risk factors as compared with mortality has been related to certain limitations inherent in observational studies, particularly the inability of such studies to distinguish intentional from unintentional weight loss. Thus, the observed weight loss might be the consequence of conditions that lead to death rather than the cause of increased mortality. Correspondence: Professor L Sjöström, Department of Body Composition and Metabolism, Sahlgrenska University Hospital, Goteborg, Sweden. lars.sjostrom@medfak.gu.se To ascertain the effects of intentional weight loss on mortality, controlled, prospective interventional trials are needed. In the Swedish Obese Subjects (SOS) trial, we used bariatric surgery to achieve weight loss, as such treatment was and still is the only technique available with proven ability to produce large weight losses over prolonged periods of time. The primary aim of SOS was to examine if intentional weight loss induced by bariatric surgery is associated with lower mortality as compared with conventional treatment in contemporaneously matched, obese controls. Several secondary aims, related to the effects of bariatric surgery on diabetes and other morbidities, risk factors, health-related quality of life and health economics, were also defined. Finally, we planned to study the genetics of obesity. Discussion Study design and baseline description The ongoing SOS project consists of four substudies: The SOS matching (or registry) study (n ¼ 6905). From this cross-sectional study patients were recruited to the SOS intervention study.

2 S94 The SOS intervention study. The intervention study consists of one surgical group (n ¼ 2010) and one obese control group (n ¼ 2037). The follow-up time will be 20 years. The SOS reference study (n ¼ 1135), which is a small crosssectional study on randomly selected subjects from the general population examined contemporaneously with and in the same way as subjects in the matching and intervention trials. The SOS sib-pair study is a cross-sectional study consisting of 160 body mass index (BMI)-discordant sib pairs and their families. SOS matching and intervention studies. The SOS 8,17,18 intervention trial is an ongoing, prospective, matched, surgical interventional trial involving 4047 obese subjects. Patients were recruited for 13.4 years between 1 September 1987 and 31 January The follow-up is currently (February 2008) ranging from 6 to 20 years. As a result of recruitment campaigns, subjects sent standardized application forms to the SOS secretariat, and 6905 completed a matching examination (the Matching study). Among the potential subjects examined, 2010 eligible subjects desiring surgery constituted the surgical group, and, based on data from the matching examination, a contemporaneously matched control group (n ¼ 2037) was created. The matching program used 18 matching variables, and the matching could not be influenced by the investigators. 17 A base-line examination for the surgical subjects and their matched controls was undertaken 4 weeks before bariatric surgery. The intervention began on the day of surgery for surgically treated subjects and their matched controls. Individual dates of all subsequent examinations and questionnaires (0.5, 1, 2, 3, 4, 6, 8, 10, 15 and 20 years) for surgically treated and control subjects were calculated based on the date of operation. Inclusion criteria for the interventional study were age years and BMI (weight kg/(height m) 2 )of34 or more for men and 38 or more for women. Exclusion criteria, described elsewhere, 17 were minimal and were aimed at obtaining an operable surgical group. Identical inclusion and exclusion criteria were used for the two treatment groups. The surgically treated subjects underwent nonadjustable or adjustable banding (n ¼ 376), vertical-banded gastroplasty (n ¼ 1369) or gastric bypass (n ¼ 265) operations. 19 The obese, contemporaneously matched controls received the customary non-surgical obesity treatment for their given center of registration. No attempt was made to standardize the conventional treatment, which ranged from sophisticated lifestyle intervention and behavior modification to, in many practices, no treatment whatsoever. The SOS reference study. The SOS reference study is a crosssectional study of randomly selected individuals. The main purpose of the study was to create a reference sample to obese SOS subjects in genetic association studies and in comparative analyses of clinical conditions (see below). Between August 1994 and December 1999, that is, during the period when the major part of patients were included in the SOS intervention study, 524 men and 611 women were included in the SOS reference study. Body composition and biochemical characteristics of the SOS reference study have been published and will not be further discussed in this review. The SOS sib-pair study. This study consists of 160 BMIdiscordant (X10 BMI units) sib pairs and their families, in total 750 subjects. Genome-wide association studies are ongoing using expression data from adipose tissue as one of many phenotypes. This study will not be further discussed here. Follow-up rates In the publication on overall mortality, 18 the vital status was known for all initial study participants except three: two who had requested to be deleted from the SOS database and one who had left the study and later obtained a secret social security number. The follow-up rate with respect to vital status on the date of analysis was thus 99.93%. In the intervention study, the participation rates of still living subjects at the 2-, 10- and 15-year examinations ranged between 66 and 94%. The participation rate was 100% at the baseline examination. Baseline characteristics in the SOS intervention study The matching procedure created two largely comparable groups, although the surgically treated subjects were on average 2.3 kg heavier (119.2 vs kg, Po0.001), 1.3 years younger (46.1 vs 47.4 years, Po0.001) and were smoking more frequently (27.9 vs 20.2%, Po0.001) than the controls. 18 The higher body weight of the surgery group was associated with higher values in several anthropometric measurements and in some biochemical variables. 18 Weight changes in SOS Figure 1 shows the weight changes for up to 15 years from baseline for control and surgery subgroups. 18 The number of observations decreased over time, mainly owing to the 13-year-long recruitment period but also due to dropout from examinations. In the control group, average weight change remained within ±2% over the observation period. In the three surgical subgroups, weight loss was maximal after 1 2 years (gastric bypass 32±8%; vertical-banded gastroplasty 25±9%; and banding 20±10%, mean±s.d.). Weight increase was seen in all surgical subgroups in the following years, but the relapse curves leveled off after 8 10 years (Figure 1). After 10 years, the weight losses were 25±11% (gastric bypass), 16±11% (vertical-banded

3 S95 Figure 1 Mean percent weight change during the 15 first study years of the SOS intervention trial in the control group and the three surgical subgroups. I bars denote 95% confidence intervals. From Sjöström et al. 18 with permission. gastroplasty) and 14±14% (banding) compared with the baseline weight. After 15 years, the corresponding weight losses were 27±12, 18±11 and 13±14%, respectively. Effects of weight loss on risk factors Two- and 10-year risk factor changes observed in the SOS trial were published in 2004 (Figures 2 and 3). 8 As illustrated in Figures 2 and 3, the 2- and 10-year recovery rates from diabetes, hypertriglyceridemia, low levels of high-density lipoprotein cholesterol, hypertension and hyperuricemia were more favorable in the surgery group than in the control group, whereas recovery from hypercholesterolemia did not differ between the groups. The surgery group had lower 2- and 10-year incidence rates of diabetes, hypertriglyceridemia and hyperuricemia than the control group, whereas differences between groups in the incidence of hypercholesterolemia and hypertension were not detectable. Effects of bariatric surgery on overall mortality The effect of bariatric surgery on overall mortality in SOS was recently published. 18 Figure 4 depicts the cumulative overall mortality over up to 16 years. Surgery was associated with an unadjusted hazard ratio (HR) of 0.76 relative to conventional treatment of the obese controls (95% confidence interval , P ¼ 0.04). Over the follow-up period, 129 subjects (6.3%) died in the control group and 101 (5.0%) in the surgery group. The adjusted HR for the treatment (surgery relative to controls) was similar when based on matching information (HR ¼ 0.73, P ¼ 0.02) and on baseline information (HR ¼ 0.71, P ¼ 0.01), although the two models did not use exactly the same variables. 18 In both models, the strongest predictors were age and smoking, whereas the strongest univariate predictors of mortality were plasma triglycerides and blood glucose. There were 53 cardiovascular deaths in the control group and 43 in the surgery group. 18 The most common cardiovascular

4 S96 Figure 2 Incidence of diabetes, lipid disturbances, hypertension and hyperuricemia over 2- and 10-year periods among surgically treated subjects and their obese controls in the SOS intervention study. Data are for subjects who completed 2 and 10 years of the study. The bars and the percentage values above the bars show unadjusted values for incidence. I bars represent the corresponding 95% confidence intervals (CIs). Below each panel, the odds ratios, 95% CI for the odds ratios and P-values have been adjusted for gender, age, and body mass index at the time of inclusion in the intervention study. From Sjöström et al. 8 with permission. Figure 3 Recovery from diabetes, lipid disturbances, hypertension and hyperuricemia over 2- and 10-year periods among surgically treated subjects and their obese controls in the SOS intervention study. Data are for subjects who completed 2 and 10 years of the study. The bars and the percentage values above the bars show unadjusted recovery rates. I bars represent the corresponding 95% confidence intervals. Below each panel, the odds ratios, 95% CI for the odds ratios and P-values have been adjusted for gender, age and body mass index at the time of inclusion in the intervention study. From Sjöström et al. 8 with permission. causes of death were myocardial infarction, sudden death and cerebrovascular damage. Cancer was the most common cause of non-cardiovascular death. Lack of power made it impossible to estimate the risk reduction for specific causes of death. Effects of bariatric surgery on the incidence of MI, stroke and cancer Preliminary calculations indicate that the incidence rates of fatal plus non-fatal myocardial infarction and cancer are more favorable in the SOS surgery group than in the obese control group obtaining non-surgical treatment, while no significant differences between the two groups could be detected regarding the incidence of stroke. Surgical complications in SOS Five of the 2010 subjects who underwent surgery (0.25%) died postoperatively (within 90 days). 18 As reported elsewhere for 1164 patients, individuals (13.0%) had 193 postoperative complications (bleeding 0.5%, thrombosis and embolism 0.8%, wound complications 1.8%, deep infections 2.1%, pulmonary complications 6.1%, other complications 4.8%). In 26 patients (2.2%), the postoperative complications were serious enough to require reoperation. The frequency of reoperations and/or conversions (excluding operations due to postoperative complications) among 1338 subjects followed for at least 10 years in November 2005 was 31, 21 and 17% for those obtaining banding, vertical-banded gastroplasty and gastric bypass, respectively. 18

5 Figure 4 Unadjusted cumulative mortality over 16 years among surgically treated subjects and their obese controls in the SOS intervention study. The hazard ratio for subjects who underwent bariatric surgery, as compared with control subjects, was 0.76 (95% CI: ; P ¼ 0.04), with 129 deaths in the control group and 101 in the surgery group. The statistical calculations were performed on all observations, that is, up to 18 years of observation at the time of database analysis. From Sjöström et al. 18 with permission. Summary and conclusion Surgery is the only treatment for obesity resulting, on average, in more than 15% weight loss over 10 years. This treatment has dramatic positive effects on most cardiovascular risk factors over a 10-year period. It has excellent effects on established type 2 diabetes and prevents the development of new cases of this disease. Finally, bariatric surgery is associated with a significant reduction of mortality. Thus, bariatric surgery is a favorable option in the treatment of severe obesity. Conflict of interest SOS has obtained research grants from Roche, AZ, Sanofi and Ethicon. The author has obtained lecture and consulting fees from AZ, Biovitrum, J&J, Merck, Novo, Roche, Sanofi and Ethicon. References 1 Freedman DM, Ron E, Ballard-Barbash R, Doody MM, Linet MS. Body mass index and all-cause mortality in a nationwide US cohort. Int J Obes (London) 2006; 30: van Dam RM, Willett WC, Manson JE, Hu FB. The relationship between overweight in adolescence and premature death in women. Ann Intern Med 2006; 145: Price GM, Uauy R, Breeze E, Bulpitt CJ, Fletcher AE. Weight, shape, and mortality risk in older persons: elevated waist-hip ratio, not high body mass index, is associated with a greater risk of death. Am J Clin Nutr 2006; 84: Jee SH, Sull JW, Park J, Lee SY, Ohrr H, Guallar E et al. Body-mass index and mortality in Korean men and women. 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