Systematic Review of Bariatric Surgery LITERATURE REVIEW REPORT

Transcription

1 Systematic Review of Bariatric Surgery LITERATURE REVIEW REPORT

2 TABLE OF CONTENTS. Executive summary Burden of obesity Definition of obesity Obesity epidemiology Incidence of obesity Prevalence of obesity Patient impact Co-morbid conditions associated with obesity Impact of obesity and diabetes on patients lives Healthcare and economic impact of obesity Cost of treating obesity Cost of treating obesity-related co morbid conditions Impact on productivity Unmet needs in obesity management Benefits of improved obesity management Bariatric surgery Overview of bariatric surgery Types of procedures in bariatric surgery Open and laparoscopic approaches in bariatric surgery Bariatric surgery versus standard medical management Comparison of medical care and bariatric surgery Effect of bariatric surgery on comorbidities Impact of intervention on diabetes Impact of bariatric surgery on comorbidities Comparison of effectiveness for bariatric surgery procedures Treatment schemes and guidelines Economics of bariatric surgery Cost of bariatric surgery Cost savings following bariatric surgery Quality of life and societal benefit Cost effectiveness of bariatric surgery Return on investment Health technology assessment Outcomes after bariatric surgery Surgeon-related outcomes Impact of bariatric surgery on hospitals Impact of bariatric surgery on employers and payers Concluding remarks References Systematic Review of Bariatric Surgery: Literature Review Report

3 LIST OF FIGURES Figure 1-1 Change in country age-standardized BMI of males between 1980 and Figure 1-2 Change in country age-standardized BMI of females between 1980 and Figure 1-3 Prevalence of obesity by country Figure 1-4 Trends in the prevalence of obesity in males by country from 1980 to Figure 1-5 Trends in the prevalence of obesity in females by country from 1980 to Figure 1-6 Faster increases in extreme obesity compared with obesity over the last decade in the United States Figure 1-7 Prevalence of obesity in the United States in by gender and ethnicity Figure 1-8 Prevalence of obesity in US adults aged 20 years of age by gender Figure 1-9 Prevalence of type 2 diabetes by country Figure 1-10 Relative risk of co-morbid conditions due to obesity compared with normal body weight Figure 1-11 Weight gain is associated with an increase in obstructive sleep apnea symptomatology as measured by the apnea-hypoxia index Figure 1-12 Average number of missed days due to injury by weight status Figure 1-13 Percentage of a country s healthcare expenditure attributed to obesity Figure 1-14 Trends in hospitalizations and costs for patients aged 2 19 years, in whom obesity was secondary diagnosis Figure 1-15 Percentage of healthcare expenditure attributed to diabetes in 2010 by country Figure 1-16 Percentage of GDP lost to obesity by country Figure 1-17 Changes in mean waist circumference over the course of the Look AHEAD trial Figure 2-1 Restrictive procedures for bariatric surgery Figure 2-2 Bariatric procedures that reduce weight through restricting the absorption of nutrients Figure 2-3 Change in the makeup of bariatric surgery in the US between 2008 and Figure 2-4 Increase in laparoscopic bariatric surgery from 1998 to Figure 2-5 Weight loss is faster and greater after bariatric surgery compared with lifestyle intervention.. 40 Figure 2-6 Weight change after bariatric surgery is significantly improved compared with medical care.. 40 Figure 2-7 Bariatric surgery results in reduced longterm patient mortality Figure 2-8 Surgery results in higher weight loss than lifestyle interventions Figure 2-9 Roux-en-Y gastric bypass results in significant reduction of glycated hemoglobin and systolic blood pressure at 12 months Figure 2-10 Change in markers of diabetes over time after bariatric surgery Figure 2-11 Rate of diabetes resolution by bariatric procedure Figure 2-12 Remission of sleep apnea after bariatric surgery Figure 2-13 Roux-en-Y gastric bypass has fewer failures than gastric banding Figure 2-14 Figure 2-15 Enhanced recovery after surgery, a protocol to optimize patient outcomes from bariatric surgery The use of standardized procedures reduces morbidity (A) and mortality (B) compared with general practice Figure 2-16 Significant reduction in medical claims after bariatric surgery Figure 2-17 Reduction in claims for prescription medication following bariatric surgery in France Systematic Review of Bariatric Surgery: Literature Review Report

4 Figure 2-18 Incidence of obesity-associated co-morbid conditions developed within the 3-year follow up period in subjects who underwent bariatric surgery and subjects denied bariatric surgery Figure 2-19 Roux-en-Y gastric bypass results in greater quality of life improvement Figure 2-20 Time taken in months to recoup initial cost of bariatric surgery Figure 2-21 Figure 2-22 Shorter surgery time for laparoscopic Roux-en-Y gastric bypass is associated with fewer patient complications Time savings can be achieved through optimization of high-volume bariatric surgery procedures Figure 2-23 Projected 5-year gains from bariatric surgery in Class II and Class III obese subjects Systematic Review of Bariatric Surgery: Literature Review Report

5 LIST OF TABLES Table 1-1 International classification of adult underweight, overweight and obesity according to BMI... 8 Table 1-2 Table 1-3 Change in BMI from 2008 to 2009 among US adults aged 18 years in the Behavioral Risk Factor Surveillance System Prevalence of co-morbid conditions by age in obese populations relative to normal body weight individuals Table 1-4 Comparison of mean health related quality of life scores among children in the US Table 1-5 Impact of diabetes on work disability, retirement and death among French gas and electricity employees aged years Table 1-6 Healthcare costs in Australia in increased with increased BMI Table 1-7 Table 1-8 Increase in BMI between and and increased healthcare costs in Australia Volume and impact of obesity-related hospital admissions in in patients aged 2 19 years Table 1-9 Breakdown of annual costs per patient in Brazil in 2007 (n = 1,000) Table 1-10 Costs of complications of type 2 diabetes in Australia Table 1-11 Increased BMI is associated with increased government subsidies in Australia Table 1-12 Annual indirect costs associated with type 2 diabetes in the UK in Table 2-1 Comparison of complications after open or laparoscopic bariatric surgery Table 2-2 Table 2-3 Randomized controlled trials assessing bariatric surgery in the treatment of obesity and obesity-related co-morbid conditions Meta-analyses of bariatric surgery in the treatment of obesity and obesity-related co-morbid conditions Table 2-4 Prevalence of co-morbid conditions pre- and post-surgery by procedure Table 2-5 Guidelines for the management of overweight and obesity Table 2-6 Mean cost and cost contributors to bariatric surgery in the US in Table 2-7 Cost-effectiveness of bariatric surgery in different settings Table 2-8 Costs of covering bariatric surgery are minimal Table 2-9 Health technology assessment of bariatric surgery Table 2-10 Improved patient outcomes after laparoscopic compared with open bariatric surgery Systematic Review of Bariatric Surgery: Literature Review Report

6 EXECUTIVE SUMMARY Obesity epidemiology and burden The World Health Organization (WHO) describes obesity as an escalating global epidemic. 1 Obesity is a major cause and contributor to mortality and the WHO estimated that in 2008 there were 500 million people worldwide who met the criteria for obesity. 2 The condition is also a key risk factor for a number of comorbid conditions, such as type 2 diabetes, that are associated with an elevated risk of morbidity and/or mortality. Compared with normalweight individuals, obese patients visit their physician more often, incur 46% higher inpatient costs and have an 80% increase in spending on prescription drugs. 3 It has been estimated that 20.6% of US healthcare expenditure is attributed to obesity or obesityassociated co-morbid conditions. 4 Clinical effectiveness of bariatric surgery versus medical management Lifestyle and nutrition management is often the first intervention recommended for weight loss. The impact of lifestyle intervention is, however, transient and patients often regain weight. 5-7 The large-scale Look AHEAD trial, in which 5,145 obese patients with type 2 diabetes were randomized to either lifestyle intervention or support and education was stopped early after a futility analysis indicated that there was no difference between the groups. 5 In terms of weight loss, sustained weight loss and resolution of comorbid conditions bariatric surgery has demonstrated superiority to lifestyle intervention in a number of clinical trials Although the extent of weight loss is procedure specific, 13 it is often in the range of kg for bariatric surgery compared with 2 5 kg following lifestyle intervention. 10, 14 Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy are generally reported to provide a good balance between weight loss (being more effective than adjustable gastric banding (AGB) and vertical banded gastroplasty) and surgical safety (being associated with fewer complications compared with biliopancreatic diversion). 13, 15 For all bariatric procedures laparoscopic surgery reduces complications and improves outcomes compared with open surgery There is evidence that undergoing bariatric surgery can protect patients from development of further co-morbid conditions. Compared with obese patients that were denied bariatric surgery, patients that received bariatric surgery had significantly lower 3-year incidence of hypertension (0.9% vs. ~42%), obstructive sleep apnea (OSA, 0.4% vs. ~34%) and type 2 diabetes (0.9% vs. ~9%). 20 Furthermore, remission of type 2 diabetes often occurs in over 70% of patients. 21, 22 In the study by Lakadawala et al., glycated hemoglobin (HbA1c) decreased from 8% pre-bariatric surgery to approximately 6% at 3 months postsurgery, an improvement that was maintained at 5-year follow up. 23 Similarly, improvement or resolution of hypertension, OSA, cardiovascular diseases and kidney disease, amongst others, have been documented after clinical studies of 14, bariatric surgery. Health economics Increased weight loss is associated with increased quality of life (QoL), 27 and the study of Romy et al. found that RYGB induced larger and faster improvements in QoL compared with AGB. 28 Although the initial costs of bariatric surgery are high relative to the cost of lifestyle intervention, bariatric surgery is associated with increased weight loss, QoL and downstream savings from reduced medication and healthcare resource use. In Europe bariatric surgery has often proved to be dominant compared with 6 Systematic Review of Bariatric Surgery: Literature Review Report

7 lifestyle intervention in cost-effectiveness analyses. 29, 30 In the US, bariatric procedures were estimated to be cost effective, with a cost per quality-adjusted life year (QALY) gained of USD 1,400 to USD 18,543, 31, 32 much lower than the Medicare threshold (USD 50,000) for payment to ESRD patients. 33 Furthermore, the time required to recoup the costs of bariatric surgery is decreasing and was recently estimated to be months. 34 After this time, downstream savings following bariatric surgery result in a benefit to society and the annual return to payers over 5 years has been estimated at 28.8%. 34 Furthermore, health benefits following bariatric surgery return patients to work, reduce sick leave and increase productivity. Productivity following bariatric surgery was estimated to increase by approximately 57% in 35, 36 Spain and be worth USD 9.9 billion in the US. Conclusions As a weight loss procedure, the benefits of bariatric surgery are dominant to those of lifestyle intervention and pharmaceutical management. It has the additional benefits of reducing risk factors for and leading to remission of co morbid conditions. Furthermore, the initial cost of bariatric surgery can be recovered within 2 years through reduced patient reliance on medication, fewer physician visits, increased employment and increased workplace productivity. 7 Systematic Review of Bariatric Surgery: Literature Review Report

8 1.0 BURDEN OF OBESITY 1.1 DEFINITION OF OBESITY Body Mass Index (BMI) is a simple index of weight-for-height and is probably the most commonly used measure to classify overweight and obesity in adults. BMI (Equation 1) is calculated by dividing the individual s weight (in kilograms) by the square of their height (in meters). For ease of application, BMI values are generally treated as age- and gender-independent. Within different populations, however, the same BMI might not correspond to the same degree of body fat because of variations in body proportions between races. 37 Equation 1 BMI = Weight (kg) Height 2 (m) Many studies, as discussed in detail in later sections, have linked a BMI outside the normal range to health risk factors. In general, individuals of normal weight have a BMI between 18.5 and 25 kg/m 2. Underweight individuals have a BMI < 18.5 kg/m 2, while overweight and obese are defined by a BMI 25 and 30 kg/m 2, respectively (Table 1-1). 37, 38 Although these definitions are commonly used throughout the literature, studies indicating that BMI is not independent of height, gender and race have led to a growing debate on alternative measures to define a target body weight 37, 39, 40 or composition. Table 1-1 International classification of adult underweight, overweight and obesity according to BMI Classification BMI (kg/mg 2 ) Underweight < Severe thinness < Principle cut-offs Moderate thinness Mild thinness OBESITY EPIDEMIOLOGY Additional cut-offs Normal body weight Overweight Pre-obese Obese Class I Class II Class III Source: World Health Organization The World Health Organization (WHO) describes obesity as an escalating global epidemic. 1 The WHO estimated that in 2008 there were 500 million people worldwide, 11% of adults aged > 20 years, who met the criteria for obesity. 2 Furthermore, overweight or obesity is estimated to cause the deaths of approximately 2.8 million adults each year. 2 In specific cases, the reasons for individuals becoming obese might be difficult to determine. Although obesity derives when an individual s energy intake is higher than their energy expenditure, 41 it is also associated with environmental, genetic and behavioural factors. For the United States of America (US), Kant et al. showed that as the quantity and energy density of food consumed increased so did the prevalence of obesity. 42 In England, the rise in car ownership and time spent watching television closely parallel 8 Systematic Review of Bariatric Surgery: Literature Review Report

9 the increase in obesity prevalence. 41 For every extra hour of television watched by adolescents (12 17 years), the prevalence of obesity increased by 2%. 43 In Arab and Asian countries, increased urbanization has been associated with an increase in obesity. 44, 45 The prevalence of obesity in children in rural, southwestern Saudi Arabia (4%) is notably lower than the equivalent rates in cities: Ha il (34%) and Riyadh (22%). 44 Income also seems important, and in Egypt it was reported that poorer people have a lower prevalence of obesity (3%) compared to 10% in those who are more affluent. 44 The opposite trend is evident in the US, where a study of 3,139 counties found that obesity prevalence in counties with poverty rates > 35% was 145% higher than in more affluent counties. 46 Although obesity is generally classified using the BMI, central adiposity (often measured via waist circumference) is also a marker of obesity and is associated with metabolic syndrome in Asian populations. 45 Compared with matched, white controls, Asians and in particular south Asians have higher central adiposity at a given body weight. 45 The International Diabetes Federation (IDF) criteria for metabolic syndrome recommends use of ethnic specific thresholds for waist circumference, specifically 90 cm in men and 80 cm in women of Asian origin (excluding the Japanese). 45 In the International Day for the Evaluation of Abdominal Obesity (IDEA) study that used these criteria, 47 the prevalence of obesity in men and women were 58% and 78% in south Asia, 38%, and 51% in East Asia and 38% and 51% in South East Asia. 45 The equivalent values for Europeans, using thresholds of 94 cm for men and 80 cm for women, were 58% and 67%, respectively. 45 It is considered that the higher central adiposity in Asians may be linked to the higher prevalence of diabetes and cardiovascular disease in Asian populations. 45 Genetics studies have shown that mutations in leptin (LEP), leptin receptor (LEPR), melanocortin-4 receptor (MC4R), or proopiomelanocortin (POMC) are responsible for rare forms of monogenic obesity. 41 The α-ketoglutaratedependent dioxygenase protein, also known as Fat mass and obesity-associated protein, is associated with an increased risk of both obesity and type 2 diabetes. 41 Social factors also play a role. An analysis of 32 years of Framingham Heart Study data ( ) demonstrated that if an individual s friend became obese, that individual s risk of becoming obese increased by 57% Incidence of obesity Through the analysis of health surveys and epidemiological studies that included 9.1 million respondents over 960 country-years, it was found that the worldwide mean BMI increased by 0.4 kg/m 2 per decade (95% confidence interval (CI): ) in men and 0.5 kg/m 2 per decade (95% CI: ) in women in the 28 year interval from 1980 to Mean BMI reached 33.9 kg/m 2 for men and 35.0 kg/m 2 for women in Nauru (Oceania). 49 The lowest mean BMIs were observed in Democratic Republic of the Congo for men (19.9 kg/m 2 ) and in Bangladesh (20.5 kg/m 2 ) for women. 49 Worldwide in 2008 the authors estimated that 1.46 billion adults ( billion) had a BMI 25 kg/m From 1980 to 2008, male BMI increased in all except eight countries (Figure 1-1). 49 Nauru and the Cook Islands both had an increase in BMI of over 2 kg/m 2 per decade. 49 In countries defined as high income, male BMI increased the most in the US (1.1 kg/m² per decade, p > 0.999), UK (1.0 kg/ m² per decade, p > 0.999) and Australia (0.9 kg/m² per decade, p > 0.999). 49 The lowest increases male in BMI were found in Brunei, Switzerland, Italy, and France, with increases ranging kg/m² per decade. 49 The largest rise in female BMI per decade was also observed in Oceania (1.8 kg/m² per decade, p > 0.999), which was followed by Latin America (Southern and Central) with an 9 Systematic Review of Bariatric Surgery: Literature Review Report

10 Figure 1-1 Change in country age-standardized BMI of males between 1980 and 2008 Source: Finucane et al. 49 The probability that the change in BMI is true is (A), (B), (C), or <0.75 (D). The highest points on the Y-axis derive from Oceania (dark blue triangles), indicating that this region had the largest increase in BMI between 1980 and Although there is also relatively high variation within these data (located on the far right of the X-axis), the finding is significant (P < 0.025). Figure 1-2 Change in country age-standardized BMI of females between 1980 and 2008 Source: Finucane et al. 49 The probability that the change in BMI is true is (A), (B), (C), or < 0.75 (D). The highest points on the Y-axis derive from Oceania (dark blue triangles), indicating that this region had the largest increase in BMI between 1980 and Although there is also relatively high variation within these data (located on the far right of the X-axis), the finding is significant (P < 0.025). Compared with males (Figure 1-1), females were more likely to have a reduction in BMI (below 0.0 on the Y-axis) over this time period. In particular, this was true in central (light blue cross) and eastern (light blue triangle) Europe. 10 Systematic Review of Bariatric Surgery: Literature Review Report

11 Table 1-2 Change in BMI from 2008 to 2009 among US adults aged 18 years in the Behavioral Risk Factor Surveillance System 2008 BMI (kg/m2) 2009 BMI (kg/m2) % (1.37) 35.8% (1.37) 1.6% (0.32) 0.5% (0.13) 0.02% (0.02) % (0.05) 88.8% (0.19) 9.5% (0.18) 0.7% (0.06) 0.04% (0.01) % (0.01) 9.0% (0.17) 83.4% (0.22) 7.5% (0.16) 0.1% (0.03) % (0.02) 1.2% (0.07) 16.7% (0.26) 79.3% (0.29) 2.7% (0.13) % (0.08) 0.3% (0.04) 2.4% (0.22) 29.6% (0.71) 67.6% (0.72) Source: Pan et al. 50 Values are provided as the % (standard error) of each BMI class (sum of rows equals 100) increase in BMI of kg/m² per decade (Figure 1-2). 49 In the US, the incidences of obesity (BMI 30 kg/m 2 ) and morbid obesity (BMI 40 kg/m 2 ) in 2009 were 4% and 0.7% per year, respectively. 50 Amongst individuals of normal weight (BMI kg/m 2 ) in 2008, 9.5% became overweight in 2009, while 0.7% became obese and 0.4% morbidly obese. Only 1.2% of obese individuals in 2008 transitioned to a normal body weight in The transition probabilities between health states in this study are detailed in Table 1-2. Assessing the 5-year transition period from adolescent to young adult, Gordon-Larsen et al. found that 12.7% (95% CI: %) of adolescents became obese, 9.4% (95% CI: %) remained obese and 1.6% (95% CI: %) lost sufficient weight to transition from obese to non-obese. 51 The authors noted that the obesity incidence was especially high in non-hispanic black females, of whom 18.4% (95% CI: %) became obese and 16.1% (95% CI: %) remained obese. 51 At baseline in 1996, females had a lower incidence of obesity (10.6%) compared with males (11.3%), but over the subsequent 5 years were more likely to become obese and less likely to transition from obese to non-obese. 51 In the study by Pan et al., it was noted that women, young adults, and those who did not participate in any leisure time physical activity had a significantly increased incidence of both obesity and morbid obesity. 50 The authors used multivariate analysis that accounted for BMI at study baseline and identified that the incidences of both obesity and morbid obesity decreased significantly as the level of education increased (Table 1-2) Prevalence of obesity The WHO reported in their 2013 obesity factsheet that global prevalence of obesity has almost doubled since Stevens et al. calculated that in 1980 the worldwide prevalence of obesity was 6.4% (95% CI: %) and that in 2008 it had risen to 12.0% (95%CI: %). 52 The increase in obesity prevalence is speeding up, with 50% of the increase reported by Stevens et al. occurring in the 8 years from 2000 to When agestandardized obesity was considered, the authors found that the prevalence of overweight (BMI > 25) increased from 24.6% (95% CI: %) in 1980 to 34.4% (95% CI: %) in The prevalence of obesity in males was under 1% in Bangladesh, Democratic Republic of the Congo, and Ethiopia, and was highest in Nauru at 67.9% ( %). 52 Female obesity was also most prevalent in Nauru (74.8%, 95% CI: %), and was least prevalent in Bangladesh at 1.4% (95% CI: %). 52 In 2008 in Europe, the prevalence of obesity in males ranged from 4.0% to 28.3%, while the obesity prevalence in females ranged from 6.2% to 36.5%. 53 There was significant inter-country variation, with prevalence rates in Central, Eastern, and Southern Europe being higher than those in Western and Northern Europe. In the UK, the obesity rate has risen by approximately 11 Systematic Review of Bariatric Surgery: Literature Review Report

12 Figure 1-3 Prevalence of obesity by country Source: Stevens et al. 52 and Squires 55. *OECD health data for Australia are from OECD data was not available for all countries. one percentage point per year since the mid- 1990s, and by 2009 about 57% of UK adults were overweight while almost half of whom (absolute 25%, relative 44%) were classified as obese. 54 That 25% of UK adults are classified as obese is in agreement with the findings of Stevens et al., who calculated that 25.7% of UK adult males and 27.6% of UK adult females were obese in Similar values for the prevalence of obesity in the UK were published by Squires after analysis of Organisation for Economic Co-operation and Development (OECD) Health Data from The OECD data were also in general agreement with the calculations by Stevens et al. for Australia, Canada, and the US. For France, Germany and Sweden, however, the OECD data provided a lower estimate of obesity prevalence. In both studies, it is clear that the prevalence of obesity is higher in the US than in other developed nations (Figure 1-3), with approximately one in every three people having a BMI 30 kg/m Country trends in obesity prevalence Although the actual obesity prevalence level varies by country, longitudinal country trends for both males (Figure 1-4) and females (Figure 1-5) mirror the observed increase in global obesity. 52 Analysis of data provided by Stevens et al. showed that the largest increase in obesity propensity between 1980 and 2008 was found in Brazilian males, a 395% increase from 3.2% in 1980 to 15.8% in Of countries with data presented here, Kuwait had the highest prevalence in both 1980 and 2008 for both males and females. The prevalence of obesity in Kuwaiti males increased 197% over the period , whereas the increase in prevalence in Kuwaiti females was 82%. Between 2000 and 2005, Cremieux et al. found that the prevalence of obesity in the US increased by 24%. 56 This value is in approximate agreement with the increase in obesity propensity as calculated from the data of Stevens et al., whereby the increase in obesity propensity between 2000 and 2005 was 18% and 20% for males and females, respectively. The prevalence of obesity is expected to rise to 45 52% by Systematic Review of Bariatric Surgery: Literature Review Report

13 Figure 1-4 Trends in the prevalence of obesity in males by country from 1980 to 2008 Source: Stevens et al. 52 Figure 1-5 Trends in the prevalence of obesity in females by country from 1980 to 2008 Source: Stevens et al Increasing prevalence of morbid obesity Cremieux et al. identified that, compared with obesity (BMI 30 kg/m 2 ), there was a more rapid rise in the prevalence of morbid obesity (BMI > 40 kg/m 2 ), which increased 50%, and the prevalence of extreme obesity (BMI > 50 kg/m 2 ), which increased by 75%, between 2000 and Sturm and Hattori found that in 2010 over 6.6% of the US population had a BMI > 40 kg/m 2, which corresponds to 15.5 million adults. 57 In agreement with the study of Cremieux et al., the authors found that the prevalence of morbid obesity and 13 Systematic Review of Bariatric Surgery: Literature Review Report

14 Figure 1-6 Faster increases in extreme obesity compared with obesity over the last decade in the United States Source: Sturm and Hattori 57 the prevalence of extreme obesity were both increasing faster than the prevalence of obesity (Figure 1-6). 57 In Spain, the prevalence of obesity increased by 6% between 2004 and 2007, and the increase in the prevalence of morbid obesity was much higher at 40%. 58 Likewise, in Korea the prevalence of severe obesity (BMI 30 kg/m 2 ) was increasing faster than the prevalence of obesity (BMI 25 kg/m 2 ): 61.8% versus 15.7% between 1998 and Prevalence of obesity by gender Multiple studies have found that the prevalence of obesity in the US is higher amongst females than amongst males. 3, 52 In a study that examined obesity prevalence by both gender and ethnicity, the overall prevalence of obesity in the US in was estimated at 32%, with non-hispanic black women being the group with the highest prevalence at 46% (Figure 1-7). 3 This is aligned with the finding that the incidence of obesity is Figure 1-7 Prevalence of obesity in the United States in by gender and ethnicity Source: Wang et al Systematic Review of Bariatric Surgery: Literature Review Report

15 Figure 1-8 Prevalence of obesity in US adults aged 20 years of age by gender 60, 61 Source: Flegal et al. also much higher in non-hispanic black females compared with other ethnic groups. 51 In recent years, however, there has been a more pronounced increase in the prevalence of obesity in US males compared with US females. Flegal et al. reported that since the percentage of US adults classified as obese (BMI 30) has risen from 27.5% and 33.4% in males and females, respectively, to 35.5% and 36.3% in (Figure 1-8). 60, 61 These figures corresponds to 29.1% and 8.7% increases in the prevalence of obesity in males and females, respectively, in the US during this 10-year period Risk of diabetes The International Diabetes Federation (IDF) reported that for every 1 kg increase in body weight the risk of diabetes increased by 4.5%. 62 Investigating the role of body fat on non-insulin dependent diabetes, Carey et al. found a strong association between abdominal fat (r 2 = 0.79) and insulin sensitivity in a sample of 22 healthy females. 63 Not only were higher levels of abdominal fat associated with a decrease in insulin sensitivity, they were also linked to other risk factors including increased fasting non-esterified fatty acids, lipid oxidation, and hepatic glucose output. 63 The authors found that peripheral body fat was also associated with insulin sensitivity (r 2 = 0.44), but the association was not as strong as with abdominal fat. 63 This work demonstrates that abdominal fat may be a key marker for risk of type 2 diabetes, whereby 79% of the variance in insulin sensitivity in healthy women is explained through abdominal adiposity. In an analysis of obesity-related co-morbid conditions, it was found that being obese increased the risk of type 2 diabetes 6.7-fold in males and 12.4-fold in females. 64 There is, however, a paucity of recently published data on the incidence of type 2 diabetes, and the IDF has highlighted the urgent need for reliable data in this area. 62 Of particular importance, is the incidence rate in the young, which is expected to increase in parallel with rising levels of obesity and physical inactivity in childhood in many countries. 62 Type 2 diabetes, as well as two pre-diabetes conditions: impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), is increasingly common in obese children and adolescents. Compared with approximately 3% a decade ago, type 2 diabetes now accounts for 45% of newly diagnosed diabetes cases in adolescents Systematic Review of Bariatric Surgery: Literature Review Report

16 Figure 1-9 Prevalence of type 2 diabetes by country India Australia (2011) 3.8% Brazil (1997) 5.6% Canada (2009) 5.6% China (2009) 7.4% France (2007) 4.6% Germany (2011) 8.2% (2006) 10.1% Japan (2006) 5.5% Spain (2009) 7.3% UK (2011) 4.3% US (2008) 9.0% Sources: 67, 68, Year of data collection is provided in parentheses for each country The prevalence of type 2 diabetes in the US is approximately 9% 66, and is higher than in many other developed nations (Figure 1-9). The UK was found to have a prevalence rate of 4.3%, less than half that of the US, with prevalence varying by region, ranging from 3.8% in Northern Ireland to 5.5% in England. 67 Assessing adults (18 59 years) and elderly (60+ years) inhabitants of Bambuí, Brazil, Passos et al., found the prevalence of type 2 diabetes in 2005 to be 2.3% and 14.6% in adult and elderly people, respectively. 68 A 2011 study in Bauru (São Paulo state) references a 9.7% prevalence rate for type 2 diabetes. 69 In 2012, Li et al. published the results of a 2009 survey on type 2 diabetes that was conducted in randomly selected adults aged years in Shanghai. 70 The prevalence of diagnosed and undiagnosed type 2 diabetes was found to be 7.4% and 5.2%, respectively, with the prevalences higher among men than women and in urban compared to rural areas. Projections from the IDF published in 2012 indicate that the global prevalence of diabetes in the adult population (20 79 years) will grow from 8.3% in 2011 to 9.9% in 2030, 62 a relative increase of almost 20%. In the US, data from the Centers for Disease Control and Prevention (CDC) indicated that there was a total of approximately 1.6 million new cases of diabetes (type 1 and type 2 combined) diagnosed in people aged 20 years in 2007 (annual population incidence circa 0.52%). 77 The US incidence of adult onset diabetes (aged 18 years) increased during the four years from 2004 to 2008; increasing from 8.3 to 8.4 cases per 1000 males and from 6.8 to 8.1 cases per 1000 females. 77 A subgroup analysis demonstrated, however, that although the overall incidence has increased, the change in incidence varied considerably according to gender, ethnic group and socio-economic status, with the greatest increases seen in low education sub-groups. 78 In a number of studies, authors have indicated that the global increase in diabetes prevalence, in particular type 2 diabetes, is the consequence of an aging and increasing population. 79, 80 The IDF also cited an unhealthy diet, overweight/obesity, and sedentary lifestyles as the main reasons for the increasing prevalence of type 2 diabetes. 62 A burden of disease study by Mathers and Loncar reported that by 2030 diabetes will be the eleventh leading cause of reduced disability-adjusted life expectancy (DALE) globally. 81 However, owing to the association between increased diabetes 16 Systematic Review of Bariatric Surgery: Literature Review Report

17 prevalence and a number of features associated with epidemiologic transition including changes in diet, increased urbanization and an increasingly sedentary lifestyle, DALE projections vary according to income. In high income countries, diabetes is projected to be the fifth leading cause of reduced DALE by 2030, whereas in middle-income countries diabetes is projected to be the tenth leading cause. The findings of Mathers and Loncar are echoed by those of Lopez et al., who assessed both the global and regional burden of disease and risk factors in PATIENT IMPACT Co-morbid conditions associated with obesity Obesity is a key risk factor for a number of conditions that are associated with an elevated risk of morbidity and/or mortality. In China, a 15- year study of 220,000 men reported that mortality from stroke and coronary heart disease (CHD) increased by 50% for each 5 kg/m 2 increase in BMI. 83 As well as the direct clinical implications, the increase in co-morbid conditions often results in increased pharmacy costs for treatments and increased healthcare resource utilization; areas that are discussed in Section 1.4. Commentators have indicated that the increasing prevalence both of obesity and of diabetes, in particular type 2 diabetes, may both be linked to unhealthy diet and sedentary lifestyles (see Section ). In 2009, the relationship between overweight or obesity and comorbid conditions was examined via a meta-analysis. 64 From evaluation of 89 published studies, Guh et al. identified evidence of 18 obesity-related comorbid conditions that met inclusion criteria. Associations between being overweight and the incidence of type 2 diabetes, pancreatic and prostate cancer, all cardiovascular (CV) diseases apart from congestive heart failure (CHF), asthma, gallbladder disease, osteoarthritis and chronic back pain were significant. 64 The greatest increase in the risk of incidence in overweight individuals was found for type 2 diabetes in females, with a relative risk (RR) of 3.92 (95% CI: ). 64 The RR of type 2 diabetes in females was further increased by being classified as obese, RR = (95% CI: ). This means that, compared with females of normal body weight, obese females are 12.4 times more likely to be diagnosed with type 2 diabetes. For obese males, the risk increases 3.9 times (Figure 1-10). Furthermore, and unlike being overweight, there was a significant increase in the risk of heart failure for both males and females associated with being obese. 64 In all but one cases, being obese increased the risk of comorbid conditions relative to being overweight; the exception was the RR of prostate cancer, which was 1.14 in overweight males and 1.05 in obese males. 64 Although not included in the analysis by Guh et al., the development of obstructive sleep apnea (OSA) has also been strongly linked to obesity. The prevalence of OSA within the obese population has been placed at about 40%, and approximately 70% of patients with OSA are obese. 84, 85 In 2002, Young et al. reported that the OR for an AHI of 15 was +2.4 for every 10 kg/m 2 increase in BMI. 85 Earlier, the Longitudinal Study of Moderate Weight Change and Sleep-Disordered Breathing had demonstrated that an increase in weight was linked to an increase in the apnea-hypoxia index (AHI), while weight loss was associated with a decrease in symptoms (Figure 1-11). 86 From the patient perspective, it also important to recognize that OSA impacts negatively on sleep and can result in reduced motivation and increased incidence of depression. 87 Furthermore, and given the association between obesity and type 2 diabetes, it is perhaps valuable to note that patients with OSA have higher fasting blood glucose, insulin, and 17 Systematic Review of Bariatric Surgery: Literature Review Report

18 Figure 1-10 Relative risk of co-morbid conditions due to obesity compared with normal body weight Relative risk T2D Osteo CRC HTN CHF CAD Stroke Asthma Co-morbid condition Source: Guh et al. 64. T2D: type 2 diabetes; Osteo: osteoarthritis; CRC: colorectal cancer; HTN: hypertension; CHF: chronic heart failure; CAD: coronary artery disease. Error bars indicate the 95% confidence interval around the calculated relative risk. HbA1c compared with weight matched controls without OSA. 88 As demonstrated in Figure 1-10, being obese increases the risk of many co-morbid conditions including type 2 diabetes, hypertension and chronic heart failure (CHF). In other studies, Figure 1-11 Weight gain is associated with an increase in obstructive sleep apnea symptomatology as measured by the apnea-hypoxia index Source: Peppard et al. 86 AHI: Apnea hypoxia index the relationship between increasing body weight and risk factors has been examined. King and Wofford reported in 2000 that being obese raised the risk of being diagnosed with hypertension by a factor of three. 89 Examining data from the Framingham Heart Study, the authors found that for every gain of 10 Lbs (4.5 kgs) in body weight, systolic blood pressure (SBP) increased by 4.5 mm Hg. 89 Data from the Nurses Health Study found that women gaining weight increased the risk of hypertension. An increase of kg increased the risk of hypertension by 29%, whereas larger increases in risk of 74% and 500% were identified for weight gains of kg and 25 kg, respectively, after the age of 18 years. 90 Weight gain in children has also been shown to increase the risk of hypertension. Analysis of data from the Bogalusa Heart Study indicated that overweight children (aged 5 17 years) were 4.5 times more likely to have elevated SBP compared with children of normal body weight. 91 Analyzing the third National Health and Nutrition Examination Survey (NHANES), Must et al. found that an increasing level of obesity was associated with increased prevalence of high blood pressure, type 18 Systematic Review of Bariatric Surgery: Literature Review Report

19 Table 1-3 Prevalence of co-morbid conditions by age in obese populations relative to normal body weight individuals Co-morbid condition Male obesity Female obesity Class I Class II Class III Class I Class II Class III Type 2 diabetes, relative prevalence (95% confidence interval) < 55 years 55 years ( ) 2.56 ( ) 7.95 ( ) 4.23 ( ) Gall bladder disease, relative prevalence (95% confidence interval) < 55 years 55 years 4.08 ( ) 1.82 ( ) 6.84 ( ) 1.37 ( ) Coronary heart disease, relative prevalence (95% confidence interval) All ages 1.59 ( ) 1.14 ( ) High blood pressure, relative prevalence (95% confidence interval) < 55 years 55 years 2.52 ( ) 1.35 ( ) 4.50 ( ) 1.47 ( ) ( ) 3.44 ( ) ( ) 1.45 ( ) 2.22 ( ) 4.60 ( ) 1.66 ( ) 2.49 ( ) 2.19 ( ) 2.56 ( ) 2.02 ( ) 1.58 ( ) 3.22 ( ) 1.24 ( ) ( ) 3.24 ( ) 4.33 ( ) 2.29 ( ) 1.74 ( ) 3.90 ( ) 1.42 ( ) ( ) 5.76 ( ) 5.20 ( ) 3.04 ( ) 2.98 ( ) 5.45 ( ) 1.41 ( ) Source: Must et al. 92 Relative prevalence as compared with the reference category of normal body weight individuals with a BMI of kg/m 2 2 diabetes, gall bladder disease and CHD in both males and females (Table 1-3). 92 Individuals with class III obesity were over twice as likely to have CHD compared with controls. With respect to CHF, the study by Shaper et al. demonstrated that for every 1 kg/m 2 increase in BMI above a BMI of 22 kg/m 2 resulted in a 10% increase in the rate of coronary events. 93 Wang et al. reported that for every 5 unit increase in BMI, men are at a 24% and 52% increased risk of colon cancer and esophageal cancer, respectively. 3 In women, every 5 unit increase in BMI increased the risk of endometrial cancer, gall bladder cancer, and postmenopausal breast cancer increases 59%, 59% and 12%, respectively. 3 The metaanalysis of Guh et al. reported that obese individuals were at increased risk of all cancer types evaluated, with the exception of esophageal cancer in obese women. 64 For example, the risk of colorectal cancer was approximately doubled in obese males and obese females. Obesity-related co-morbid conditions may increase the risk of development of further comorbidities. In one study, the presence of diabetes approximately doubled the risk of CHD in men and quadrupled the risk among women. 94 Similarly, the incidence of stroke in patients with type 2 diabetes was found to be more than three times that in the general population. Of concern for the future, is that the offspring of overweight or obese parents are more likely to become obese themselves compared with the offspring of two parents who had normal body weight. The offspring obesity prevalence with two normal-weight parents was 2.3%, this increased to 4.9% with two overweight parents, 21.7% with two obese parents, and 35.3% with two severely obese parents Systematic Review of Bariatric Surgery: Literature Review Report

20 1.3.2 Impact of obesity and diabetes on patients lives Quality of life A large scale study assessed health-related quality of life (QoL) in a cohort of 1,187 apparently healthy individuals (mean age 57 ± 7 years), of whom 24% were of normal weight, 49% overweight, 20% obese and 7% severely obese. 96 Among females, all physical components of QoL decreased in an approximately linear manner as BMI increased. In males, however, this linear trend was only observed in a subset physical functioning scales. 96 A recent meta-analysis has shown that being overweight or obese is associated with a significant decrease in QoL as determined by criteria for physical functioning. The evaluation by UlHaq et al. concluded that being overweight reduced QoL (as scored on the SF36 algorithm, scale 0 100) by 1.40 points (95% CI: 1.82 to 0.98). 97 The impact of being obese was more detrimental to QoL, reducing scores by 3.73 points on average (95% CI: 5.54 to 1.92), while class III obesity reduced scores by 9.72 points (95% CI: ). 97 The detrimental effect on QoL might not derive purely from obesity, and a number of studies have demonstrated that obesity-related comorbid conditions also influence patient QoL. In Brazil, diabetes was found to account for 5.1% of all disability adjusted life years (DALYs). 98 In this study, the impact of diabetes was higher amongst women (6%) than amongst men (4.4%). 98 Schunk et al. analyzed five Germany-specific QoL studies that compared individuals with type 2 diabetes to individuals not diagnosed with type 2 diabetes. The authors noted that type 2 diabetes had a negative impact on QoL, compared with controls that did not have type 2 diabetes, the derived regression model estimated that the physical components of QoL were significantly reduced by the presence of type 2 diabetes. 99 In agreement with the Brazilbased study of Oliveira et al., the authors also reported that the impact on QoL was greater among females. From pooled study data, prior to regression analysis, the physical functioning QoL (100 point scale) of females was reduced from 45.4 (controls) to 40.1 (type 2 diabetes), a difference of 5.3 points. 99 For males, the respective values were 47.0 and 42.2, resulting in a type 2 diabetes driven reduction of 4.8 points. 99 Similar findings were published by Garner et al., who found that females (from their mid-sixties onwards) with class I obesity had a significant reduction in their QoL. 38 A significant and clinically important reduction in QoL was identified in females with class II or class III obesity throughout the 8-year study. 38 Boodai and Reilly analyzed a paired sample of 98 obese and 98 heavy (but not obese) adolescents in Kuwait. In line with other studies, the authors reported that QoL as measured by physical functioning was significantly decreased in obese patients (P = 0.007); psychosocial scores were lower in obese patients but did not differ significantly between the groups Psychological status In the US, in contrast to the findings from Kuwait of Boodai and Reilly, overweight, obese and extremely obese children were found to have significantly worse psychosocial QoL, which included dissatisfaction with physical appearance, compared with normal weight children (Table 1-4). 101 Regression analysis indicated that the impact of obesity on QoL scores was greater in Latinos ( 1.4) and Blacks ( 2.15) compared with Whites (baseline). 101 Obese patients often report difficulties in psychosocial functioning and quality of life. Summarizing the literature on this subject, Sarwer et al. reported that between 25% and 30% of patients presenting for bariatric surgery report elevated symptoms of depression. 102 The 20 Systematic Review of Bariatric Surgery: Literature Review Report

21 meta-analysis by Ul-Haq et al. also assessed the psychological impact of overweight and obesity. Overweight patients did not differ significantly from controls when the quality of mental health was assessed; however, the presence of class III obesity did significantly reduce mental health scores (mean 1.75, 95% CI: 3.33 to 0.16). 97 In Germany, only females with type 2 diabetes exhibited lower scores for mental components of QoL when compared with controls. 99 The mean MCS-12 score (100 point scale) of females with type 2 diabetes was 48.8, significantly below that of female controls (51.4), males with type 2 diabetes (52.9) and male controls (53.6) Absenteeism Obesity results in increased absenteeism, which in turn reduces productivity and tax revenue (see Section 1.4). As early as 1990, it was estimated that 50 million work days each year were lost in the US due to obesity. 103 Given the increasing prevalence of obesity, this value may be much higher today. A survey of 10,825 employees in 1998 found that employees classified as obese were more than twice to have high-level absenteeism ( 7 absences due to illness in the past 6 months) than employees of normal weight. 104 In 2011, Ewing et al. reported that, in the year before bariatric surgery, obese workers missed over 10 times more days of work than workers of normal weight. 35 The average US worker loses 3.0 days/year of productivity due to illness or injury; obese patients in this study missed, on average, 33 (± 10) days of work in the year before surgery. 35 Given the eligibility criteria for bariatric surgery, it is possible that these patients represent a more severe subgroup of obesity. It was reported by Finkelstein and Brown that, compared with workers of normal body weight, obese workers miss an extra 5.1 days of work per year (P < 0.01). 105 A 2007 evaluation of the Medical Expenditure Panel Survey (years 2000 to 2004) concluded that the probability of missing work, number of days missed, and the Table 1-4 Comparison of mean health related quality of life scores among children in the US QoL Measure (range) Total QoL (0 100) Physical QoL (0 100) Psychosocial QoL (0 100) Normal weight 1 (n=2363) Overweight (n=847) Obese (n=571) Extremely obese (n=620) (0.143) (0.006) (<0.001) (0.205) (0.491) (0.003) (0.143) (0.001) (<0.001) Emotional QoL (0 100) (0.028) (0.035) (0.015) Social QoL (0 100) School QoL (0 100) Global self-worth (4 24) Physical appearance (4 24) Body satisfaction (0 2) Overall health status (0 4) (0.325) (0.001) (<0.001) (0.459) (0.079) (0.234) (0.019) (0.002) (<0.001) (<0.001) (<0.001) (<0.001) (<0.001) 1.25 (<0.001) 0.89 (<0.001) (0.039) 1.74 (<0.001) 1.51 (<0.001) Source: Wallander et al Mean data are shown with the p-value relative to normal body weight children in parentheses. 1) p-value calculated against normal weight children 21 Systematic Review of Bariatric Surgery: Literature Review Report