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NATURE REVIEWS | ENDOCRINOLOGY VOLUME 11 | AUGUST 2015 | 465

Department of Endocrinology & Nutrition, CIBEROBN, Clínica Universidad de Navarra, University of Navarra, IdiSNA, Avda. Pío XII 36, 31008 Pamplona, Spain. [email protected]

Bariatric and metabolic surgery: a shift in eligibility and success criteriaGema Frühbeck

Abstract | The obesity epidemic, combined with the lack of available and effective treatments for morbid obesity, is a scientific and public health priority. Worldwide, bariatric and metabolic surgeries are increasingly being performed to effectively aid weight loss in patients with severe obesity, as well as because of the favourable metabolic effects of the procedures. The positive effects of bariatric surgery, especially with respect to improvements in type 2 diabetes mellitus, have expanded the eligibility criteria for metabolic surgery to patients with diabetes mellitus and a BMI of 30–35 kg/m2. However, the limitations of BMI, both in the diagnosis and follow-up of patients, need to be considered, particularly for determining the actual adiposity and fat distribution of the patients following weight loss. Understanding the characteristics shared by bariatric and metabolic surgeries, as well as their differential aspects and outcomes, is required to enhance patient benefits and operative achievements. For a holistic approach that focuses on the multifactorial effects of bariatric and metabolic surgery to be possible, a paradigm shift that goes beyond the pure semantics is needed. Such a shift could lead to profound clinical implications for eligibility criteria and the definition of success of the surgical approach.

Frühbeck, G. Nat. Rev. Endocrinol. 11, 465–477 (2015); published online 9 June 2015; doi:10.1038/nrendo.2015.84

IntroductionObesity is a major public health challenge; it is wide-spread, highly prevalent and has clinical implications with potential negative effects on almost every organ system, as well as being a psychosocial and economic burden.1–5 Morbid obesity, in particular, is a rapidly growing segment of the obesity epidemic; the detrimen-tal effects of obesity can be especially prevalent in these patients,6 taxing not only individuals, but health-care systems and society at large.

This Review aims to provide an accurate and bal-anced conceptual analysis of the current body of evi-dence related to the outcomes of bariatric and metabolic surgery. This analysis provides insight into the identifica-tion and improved understanding of the specific patho-physiological conditions changed by the interventions and of the surgery-induced effects. The clinical implica-tions of a paradigm shift in the eligibility criteria for bari-atric and metabolic surgery, as well as in the definition of success for these procedures, are explored.

Surgical proceduresStrictly speaking, the term ‘bariatric surgery’ is applied to all surgical procedures that aim to reduce excess weight. Candidates for bariatric interventions currently include patients with morbid obesity (BMI >40.0 kg/m2) or those with a BMI >35.0 kg/m2 who also have impor tant comorbidities, such as type 2 diabetes mellitus (T2DM), hypertension or obstructive sleep apnoea (OSA).7 The

type of bariatric procedure performed depends on the patient characteristics and the surgeon’s preferences. Traditionally, operations are classified as restrictive, malabsorptive or mixed procedures. However, the mechanisms of action of bariatric surgery are com-plex and involve multiple neuroendocrine signals that exert effects at the central nervous system as well as in peripheral organs. Restrictive techniques (for example, adjustable gastric banding [AGB], vertical banded gastro plasty [VBG], gastric plication or sleeve gastrec-tomy) decrease the size of the stomach, which triggers satiety with smaller volumes of food than before surgery. Malabsorptive procedures (for example, duodenal–jejunal bypass or jejuno–ileal bypass) bypass segments of the bowel, thereby causing a certain degree of macro-nutrient malabsorption that can be variable and tran-sient.8 The mixed interventions combine restriction and malabsorption (for example, Roux-en-Y gastric bypass [RYGB] and biliopancreatic diversion with or without duodenal switch). Furthermore, bariatric surgery results in durable glycaemic control compared with intensive medical therapy.9,10 Bariatric surgery also improves the metabolic status of patients, ameliorating hypertension and improving the blood lipid profile, thus decreasing cardiovascular risk.11

Conceptually aligned with the positive weight- independent outcomes on T2DM remission, the term ‘metabolic surgery’ or ‘diabetes surgery’ was coined to describe bariatric surgery in patients with less severe obesity than those who are traditionally eligible for bari-atric surgery. Consequently, an important expansion

Competing interestsThe author declares no competing interests.

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of bariatric surgical inclusion criteria has taken place to include these patients. These gastrointestinal inter-ventions (such as sleeve gastrectomy and RYGB) are currently also recognized as ‘metabolic’ procedures with pathophysiological effects that go beyond simple weight loss.12,13 The increased use of metabolic surgery will have epidemiological implications as although the rates of complications of diabetes mellitus have declined since 1990, a large burden of disease persists as a result of the continued rise in the prevalence of T2DM, which is increasing alongside (and as a result of) the obesity epidemic.1,14,15 The accompanying end-organ damage is the major cause of morbidity and mortality in these patients.16 However, a paradoxical situation is being faced in which the high prevalence of obesity and its comor-bidities collides with a scenario where clear opportunities for diagnosis and effective treatment are being missed.17

Current treatments for weight loss with diet, exercise and lifestyle modification have a high failure rate.18 It has taken many years to acknowledge the effectiveness of surgery for the treatment of obesity and its comorbidi-ties.19–21 Over the past decade, the number of bariatric and metabolic interventions performed worldwide has more than doubled, with bariatric surgery reportedly being the most cost-effective therapy for sustained weight loss in patients with morbid obesity.22,23 Rigorous evaluation of the evidence has led to the release of offi-cial guidelines and recommendations for the appropri-ate selection of candidates for either bariatric surgery or metabolic surgery.7,24 Eligibility criteria are mainly based on BMI cut-off points and the focus has been predomi-nantly on quantitative reductions of weight and glycae-mia following surgery. A further step is now needed, namely, to move away from the semantics of the con-cepts and to go deeper into the actual functional effects on overall health variables and the pathophysiologi-cal impact of the surgical approach. Such a step could promote a paradigm shift in eligibility criteria.

Classic effects of surgeryA BMI >35 kg/m² and a high abdominal circumfer-ence (waist circumference >102 cm for men and >88 cm for women) are known predictors of increased overall

Key points

■ Bariatric surgery has a proven role in achieving sustained weight loss, improving obesity-related comorbidities and reducing mortality

■ Bariatric surgery is considered to address mainly weight loss, whereas metabolic surgery focuses mainly on improving type 2 diabetes mellitus

■ Bariatric and metabolic surgery cannot be viewed as dichotomic procedures, as most of the clinical benefits of both approaches have a multifactorial origin derived from a combination of effects

■ Detailed patient phenotyping shows that the BMI cut-off points for determining eligibility for surgery are blurred when considering total adiposity and fat distribution, as BMI often does not tally with these factors

■ Changes in eligibility and follow-up criteria that move away from a merely BMI-centric view for indicating bariatric or metabolic surgery should be pursued

■ A more functional, individualized and holistic approach with extensive evaluation of comorbidities will yield improved patient selection that does not have a ‘weight-centric’ focus

mortality and decreased life expectancy.2,6,25 This increased risk is the result of obesity being associ ated with an augmented risk of cardiovascular diseases (CVD), including hypertension, stroke, coronary heart dis ease, dyslipidaemia and atherosclerosis, as well as T2DM.2,6,25 Rigorous studies and registries of bariatric sur gery that were initiated almost three decades ago enable detailed follow-up analysis of the diverse sur-gical procedures used to achieve both weight loss and improvements in comorbidities.11,19,20,26–40

The nonrandomized, prospective, controlled Swedish Obese Subjects (SOS) study was the first long-term trial to provide information on the effects of bariatric surgery on the incidence of objective end points.11,21,41,42 The study started in 1987 and enrolled individuals with obesity (BMI ≥34 kg/m2 in men and ≥38 kg/m2 in women) who were undergoing bariatric surgery (n = 2,010; 19% banding, 69% VBG and 12% RYGB). The surgically treated patients were matched to conventionally treated control patients with obesity (n = 2,037). The SOS study was the first study to demonstrate long-term weight loss, improvements in risk factors for comorbidities and a reduction in overall mortality.11,21,41–44 In patients who underwent surgery, the maximum weight loss was gener-ally reached after 1–2 years, with stabilization of weight loss from baseline at 25% and 14% below the baseline weight for RYGB and AGB, respectively after 10 years.21 Whereas the SOS study mainly included restrictive sur-gical procedures (88%), the Longitudinal Assessment of Bariatric Surgery (LABS) study45 largely included mixed surgical procedures. The LABS study is a multicentre observational cohort study that was initiated in 2006 in the USA and included 2,458 adults undergoing bari-atric surgery for the first time (70.7% RYGB, 24.8% AGB and 4.5% other procedures).45 Percentages of weight loss from baseline of 31.5% and 15.9% for RYGB and AGB, respective ly, were observed after 3 years.

Figure 1 summarizes the major effects of the key long-term studies10,20,27,31,42,45–49 that illustrate the variability in outcomes depending on the type of surgery performed. Restrictive interventions generally have a smaller effect than mixed techniques on weight loss, hypertension, dyslipidaemia and T2DM (Figure 1). On average, bari-atric surgery can achieve a sustained weight loss of up to 40%, which leads to important benefits for hyper-tension, dyslipidaemia and T2DM in a huge proportion of patients, as illustrated in Figure 1. These outcomes translate into a 72% reduction in the risk of CVD at 5 years and a reduction in mortality (adjusted for sex, age and risk factors) of 30.7% at 10 years.21,27,43 The most common causes of death in the control and surgical groups were myo cardial infarction and cancer.42 In com-parison with usual care (that is, lifestyle modification), bariatric surgery was associated with a reduced number of total first time (fatal or nonfatal) cardio vascular events (myocardial infarction or stroke, whichever occurred first) and cardiovascular deaths.11 Interestingly, bari-atric surgery was also associated with a reduction in the incidence of myocardial infarction in patients with obesity and T2DM, whilst no effect was observed on

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the incidence of stroke. Of note, the effect of surgery in reducing the incidence of myo cardial infarction was strongest in patients with high baseline fasting levels of triglycerides and total cholesterol, with BMI not being related to the surgical outcome.33

In the LABS trial, dyslipidaemia resolved in 61.9% of patients who underwent RYGB and 27.1% of patients who received AGB, with remission of hypertension in 38.2% (RYGB) and 17.4% (AGB) of patients.45 At 3 years, partial remission of T2DM was observed in 67.5% and 28.6% of patients undergoing RYGB and AGB, respec-tively. At 3 years after surgery, the incidence of T2DM was 0.9% after RYGB and 3.2% after AGB. In the SOS study, after 15 years, T2DM developed in 28.4 cases per 1,000 person-years in the control group versus 6.8 cases per 1,000 person-years in the bariatric-surgery group.50 The remission rate of T2DM in the SOS study was increased several-fold at 2 years and 10 years and was

considerably influenced by the presence or absence of impaired fasting glucose levels but not by BMI.21 Whereas basal hyper insulinaemia and/or hyperglycaemia pre-dicted favour able outcomes, high baseline BMI did not, which suggests that the current BMI-based se lection criter ia for bariatric surgery are not optimal.44,50,51

Obesity also seems to be associated with several other serious health problems, ranging from nonalcoholic fatty liver disease, osteoarthritis, OSA and other respiratory alterations to gastrointestinal disorders, renal problems, infertility and cancer, with bariatric surgery reportedly exhibiting favourable effects on all of them.6,52–60 As a result of these favourable outcomes, bariatric surgery can induce notable reductions in mortality from CVD, T2DM and cancer.10,42,45–49 Moreover, bariatric surgery is reportedly more effective than nonsurgical treatment in terms of weight loss, T2DM remission and attenuation of cardiovascular risk factors.10,19,21,23,32,61,62 Interestingly, bariatric surgery is associated with a reduced incidence of cancer in women with obesity but not in men with obesity.21,43 The underlying mechanisms of the cancer-protective role of surgery most probably relate to the metabolic effects of surgery, including increased insulin sensitivity, improvements in the metabolic syndrome and decreased inflammation and oxidative stress in combina-tion with the beneficial effects on gut hormones, levels of estrogen and related compounds, levels of adipokines, immunometabolism and cellular energetics.63–65

Temporal patterns of improvementOne of the most illuminating aspects of bariatric opera-tions is that the favourable modulation of comorbidities does not take place uniformly or gradually for all comor-bidities, thereby highlighting the involvement of both weight-dependent and weight-independent effects. Most cardiovascular risk factors and mechanically-related comorbidities (such as respiratory alterations, ortho-paedic problems and gastro-oesophageal reflux disease [GERD]) ameliorate slowly and mainly in parallel with weight loss. By contrast, T2DM tends to improve rapidly and soon after surgery, even before major reductions in body weight occur (Figure 1). Patients who have under-gone RYGB have lower fasting glycaemia after 2 years than individuals receiving intensive medical therapy,32 with similar findings being observed in patients who underwent sleeve gastrectomy.10,19 RYGB and bilio-pancreatic diversion with or without duodenal switch produce larger improvements in T2DM than AGB;20,27 however, careful and regular follow-up of gastric band-ing can yield similarly positive amelioration.29,66 In fact, gastric banding does not induce statistically signifi-cant changes in levels of incretins or gut hormones, with improvements in glycaemia, insulin secretion and insulin resistance being directly related to weight loss.39,67 Bariatric operations, especially those incorporating duo-denal exclusion, can improve insulin sensitivity twofold to threefold within days after surgery, which implicates mechanisms independent of weight loss that involve the modulation of intrinsic gut hormones via the gastro–entero–insular axis.68–70 In this respect, it is important

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Nature Reviews | EndocrinologyFigure 1 | Summary of the effects (expressed as mean data for efficacy and 95% confidence intervals) of the main bariatric surgery procedures on weight loss (reported as excess and mean weight loss) and principal comorbidities (hypertension, hyperlipidaemia and T2DM) at 3–5 years.10,19,21,23,27,31,32,61,62 The last column on the right indicates the temporal pattern of the effects on T2DM. Abbreviations: AGB, adjustable gastric banding; BPD-DS, biliopancreatic diversion with or without duodenal switch; RYGB, Roux-en-Y gastric bypass; SG, sleeve gastrectomy; T2DM, type 2 diabetes mellitus.

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to bear in mind the plausible multifactorial nature of the decrease in insulin resistance induced by surgery (Box 1).

RYGB improves pancreatic β-cell function at 2 years, whereas sleeve gastrectomy does not.9 Although basal plasma concentrations of insulin are reduced after RYGB, an exaggerated postprandial response is obser-ved71,72 within days of the surgery, which is associ-ated with a rise in levels of glucagon-like peptide 1 (GLP-1).39,67 Similar results are seen after sleeve gastrec-tomy, although to a smaller extent, in the rise in levels of GLP-1 and peptide YY, reductions in fasting levels of insulin and increases in insulin sensitivity.73 In spite of the precocious effects of bariatric surgery on T2DM, 50% of the patients who experience early remission relapse.21,41 Nonetheless, more patients in the surgical group than in the control group experience remission of T2DM after 15 years, which indicates that bariatric surgery has a preventive effect on the progression from impaired glucose tolerance to T2DM.50

In the SOS study, the cardiovascular parameters that remained favourable at 10 years after surgery were T2DM, circulating levels of triglycerides, uric acid levels and diastolic blood pressure, whereas levels of HDL cholesterol and systolic blood pressure were only improved during the first 2 years after surgery, before returning to preoperative levels.43 In fact, reductions in blood pressure were observed in 73.2% of patients who were actively losing weight after bariatric surgery and, thus, were in negative energy balance.20,27,74 The under-lying mechanisms are multifactorial and relate to weight loss, reduced systemic inflammation, increased urinary sodium loss and restoration of metabolic homeostasis.39 Consequently, blood pressure might often increase back to preoperative levels during the weight regain or even the weight maintenance phase.11,41,42 RYGB resulted in a greater reduction in total cholesterol and LDL cho-lesterol after 1 year than sleeve gastrectomy.20,27,39 This difference might be the result of changes in serum levels of bile acids, which alters cholesterol metabolism via transcriptional regulation.75

Psychosocial factors are important predictors of out-come in terms of physical and mental health.76,77 Chronic pain, depression and OSA were consistently associated with reduced health-related quality of life (HRQL). Importantly, weight reductions to achieve minimal clinically important differences for most HRQL instru-ments (such as the Impact of Weight on Quality of Life [IWQOL]-Lite survey consisting of 31 items describing

five domains [physical function, self-esteem, sexual life, public distress and work]) after surgery are mark-edly higher (the IWQOL-Lite total score was reached for 49% of medically treated patients and 76% of sur-gically treated patients)] than the conventionally con-sidered threshold of 5–10%.78 Thus, surgical, but not medical, treatment consistently led to clinically impor-tant improvements in HRQL over 2 years.78 As expected, bariatric surgery exerted profound effects on HRQL with net gains compared with baseline being observed after 10 years.79 This finding alone justifies surgical treatment of patients with severe obesity.80 The surgi-cal group showed considerably improved outcomes in current health perceptions, social interaction, psycho-social functioning and depression, whereas no dif-ferences were found for overall mood and anxiety.79 Interest ingly, the improvements and deteriorations in HRQL over time were associated with the magnitude of weight loss or regain during the observational period, except for anxiety. Peak improvements in the surgical group co incided with the first year of weight loss and the weight regain phase was accompanied by a gradual decline in HRQL. RYGB was superior to an intensive lifestyle intervention consisting of a 1-year cognitive approach programme aimed at inducing weight loss of at least 10% via motivation to increase physical activity and to normalize eating habits regarding improvements in HRQL, which is probably due to the greater weight loss following surgery than with lifestyle changes.81

Unexpectedly, an increase in alcohol dependence has been observed after RYGB and VBG. An increased risk of alcohol abuse diagnoses, excessive alcohol consump-tion and alcohol problems were observed in patients who underwent AGB compared with control individuals.82,83 Importantly, patients who undergo bariatric surgery reportedly exhibit higher rates of suicide than the general population,29,47,61 which highlights the need for health-care professionals to be aware of these possibilities to encourage early detection and treatment.

Unravelling the main effectsThe benefits of bariatric interventions undoubtedly result from a variety of anatomical, neurological, endo-crine and metabolic effects. Three main pillars of action should be considered in relation to the temporal pattern of response elicited by surgery in ameliorating obesity and its comorbidities. These pillars encompass weight-loss-independent, weight-loss-dependent and adiposity-dependent effects.

Weight-loss-independent effectsThe quick, almost immediate favourable effect of surgery on T2DM84,85 shows that weight-loss-independent mechanisms in the control of glucose metabolism are occurring from the very beginning. This observation is supported by the finding that procedures involving an anatomical-physiological rearrangement of the gastro-intestinal tract have a superior effect on T2DM remission compared with restrictive techniques.27 Interestingly, duodenal exclusion alone is reportedly sufficient to

Box 1 | Effects of bariatric surgery on insulin resistance

■ Fasting, caloric restriction ■ Weight loss ■ Vagal stimulation ■ Reduced adiposity ■ Decreased inflammation ■ Gut microbiota changes ■ Other hepatoportal signals ■ Intestinal gluconeogenesis ■ Bile metabolism ■ Gastrointestinal hormones

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reduce fasting blood levels of glucose in patients with T2DM independently of weight loss.68,69,86–89 This finding is further backed by experimental models of lean animals with T2DM, such as nonobese diabetic Goto-Kakizaki rats.90–92 Thus, signals originating in the proximal small intestine seem to exert a direct effect on the physiological regulation of glucose homeostasis.

T2DM can start to improve in the first few days after surgery (before weight loss has occurred), which indi-cates that an important part of this effect depends on gut hormones and neuroendocrine changes that are ini-tiated soon after surgery and independently of BMI.84,85 However, it is also true that the degree of weight loss (which partly depends on the relationship between BMI before and after surgery) is a predictor of whether a patient will experience remission of T2DM. Similarly, long-term weight gain is a determinant of T2DM recur-rence. Of note, T2DM remission seems to be a function of the severity of the disease at baseline, particularly preser-vation of the capacity of islets to respond to a stimu-lation to produce more insulin.93 At the same time, the amount and trajectory of weight loss, as well as remission of T2DM, is hugely variable.45 These findings illustrate that some individuals are able to maintain T2DM remis-sion in the long-term even if they regain the lost weight (probably those in whom the gut-dependent effects are dominant), whereas in others, T2DM recurrence takes place when weight regain occurs (patients in whom the gut-dependent effects disappear and are lost with the potential refunctionalization of the gastro intestinal tract over time). This variability in both weight change and improvements in comorbidities probably relies on the potentially variable degree to which the different mechanisms of action operate in different individuals. These findings underscore the complexity and multiple factors that influence T2DM remission or resolution and am elioration of insulin resistance.

Weight-loss-dependent effectsThe weight-loss-dependent effects of bariatric surgery are mainly evident in the psychosocial sphere and the mechanical comorbidities tightly related to the effects of excess body weight, such as GERD, OSA and other respiratory alterations as well as osteoarthritis and joint problems. Bariatric surgery considerably improves psycho logical and cognitive characteristics of individu-als with symptoms that are mostly the result of increased body weight, which thus improve with weight loss.94 The prevalence of GERD in individuals with morbid obesity is as high as 45%, with obesity increasing the risk of GERD becoming symptomatic, erosive oesophagitis and oesophageal adenocarcinoma.95 Markers of visceral and general obesity are independent determinants of oesophageal inflammation, which correlates with endo-scopic findings and symptoms of GERD. Bariatric pro-cedures improve GERD—the greater the excess weight loss (EWL), the greater the improvement in GERD score.96 In the majority of individuals with morbid obesity, bariatric surgery also improves or resolves OSA.94 Factors that predispose patients to OSA include a

small upper airway lumen, unstable respiratory control, a low arousal threshold, small lung volume and dysfunc-tional dilator muscles in the upper airway.57 In addition to the mechanical weight-dependent effects, the surgi-cal approach also exerts a metabolic weight- independent effect that results in improved insulin resistance and systemic inflammation, which decreases cardiovascular risk.94 Concurrently, cardiorespiratory complications such as hypoxaemia, pulmonary hypertension, hyper-capnia, and even OSA-associated atrial fibrillation, might also be improved.56,94

In the SOS study, patients undergoing surgery exhib-ited less severe OSA, reduced inflammatory activity and enhanced cardiac function compared with weight-stable control individuals with obesity.97 Of note, after controlling for BMI, the apnoea–hypopnoea index remained independently associated with high levels of proinflammatory adipokines, left ventricular mass, left atrial area, pulmonary artery pressure and the E/Ea ratio (a ratio of early diastolic mitral flow velocity to early diastolic tissue velocity). The heterogeneity between studies, together with poor follow-up measures, means that whether the weighted mean decrease in BMI and OSA severity (measur ed by the apnoea–hypopnoea index) varies between surgical and nonsurgical treat-ment of obesity, as well as between bariatric and meta-bolic surgery, cannot be determined. Further research is required to quantify the multisystem effects and mecha-nisms under lying re solution of OSA elicited specifically by metabolic surgery.

Obesity has been identified as an independent and modifiable risk factor for osteoarthritis and joint prob-lems.55 Weight loss decreases the risk of incident knee osteo arthritis, ameliorates symptoms in established dis-ease, improves function and reduces disease progres sion. These improvements are based on the biomechanical relationship between increased loads on articular carti-lage, subsequent wear and cartilage breakdown.55 How-ever, osteoarthritis also has a multifactorial aeti ology with its systemic effects being related to the ad ipokine profile and metainflammation.55

Adiposity-dependent actionsDuring surgically-induced weight loss, it should not be taken for granted that adiposity will improve with total body weight loss. In fact, EWL, BMI and adipos-ity have quite diverse trajectories over time (Figure 2).98 While a dramatic EWL takes place during the first few months (generally until the end of the first year after surgery), the decrease in BMI and body fat follows a less steep trajec tory.98 Moreover, the decline in BMI is not parallel ed by the decrease in adiposity. Particularly during the first month, the marked decrease in body weight corres ponds to the fat-free mass (FFM), with a low effect on total adiposity (Figure 2). Of note, even if a BMI in the range of overweight or normal weight is reached, it does not necessarily mean that body fat has decreased to normal limits (Figure 2). BMI neither dis-criminates between fat mass and FFM, nor distinguishes between body shape and fat distribution. Thus, during

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surgery-induced weight loss, particular consideration should be given to the fat mass to FFM ratio regarding the contribution of FFM to physiological functioning, pathology and well-being.

Interestingly, left ventricular volume, stroke volume and cardiac output are primarily associated with FFM, whereas blood pressure, heart rate and variables reflect-ing cardiac dysfunction tend to be related to total body fat and visceral adiposity.99,100 Moreover, FFM can be used to predict the diameter of the carotid artery lumen, while visceral adiposity has emerged as the main deter-minant of premature carotid artery atherosclerosis.101 As skeletal muscle is the body’s largest glucose buffering system, a conserved large muscle mass promotes insulin sensitivity and protects against the metabolic syn-drome.102–104 Moreover, FFM, but not fat mass or BMI, is positively associated with self-determined meal size and daily energy intake in humans.105,106 Thus, a rapid weight loss mainly at the expense of FFM entails the subse quent loss of protective muscle strength and its metabo lic bene fits on the regulation of energy homeo stasis.103,107 In addition, in the long term, adiposity rebounds more easily after bariatric surgery than does BMI, even in patients who have maintained the weight loss.107,108 This feature is particularly important in relation to the adipose tissue secretion profile for proinflammatory and prothrombotic factors that will return to increased cir-culating concentrations, thereby reversing the beneficial effects attained via the decrease in adipokines after the surgery-induced reduction in adiposity.109–112

Taken together, these findings might explain why some cardiovascular comorbidities re-emerge after surgery (such as hypertension11,41,42 and hypercholes-terolaemia42,43) and the lack of a reduced incidence of

cancer in male patients with obesity.21,43 Interestingly, the incidence of cancer and cancer-related death occurs in a setting that provides a unique adipose tissue micro-environment with concomitant systemic endocrine alterations that favour both tumour initiation and pro-gression.53,65 Low-grade chronic inflammation, dysregu-lation of growth signalling pathways, hyperinsulinaemia and hypoxia associated with increased adiposity are widely accepted as important factors that link obesity and cancer patho genesis.64,65 White adipose tissue con-stitutes a relevant source of growth factors, adipokines and stromal progenitor cells.113 Given that adipose tissue surrounds organs with a high predisposition to become malignant (for example, the prostate or the colon), recruit ment of stromal progenitor cells to the tumour micro environment favours the formation of supportive tumour stroma. Excess adiposity modifies the expression profile of adipose tissue genes to ultimately foster growth of fat mass via an upregu lation of genes related to cellular activity (increased cell proliferation or differentiation, cell cycle activation and inhibition of apoptosis) and mild immuno inflammatory processes (reduced immuno-surveillance).53 Adipocytes and infiltrating immune cells secrete pro inflammatory adipo kines and cytokines, growth factors, metalloproteinases, and reactive oxygen species, which can induce DNA damage and chromo-somal instability, thereby favouring carcinogenesis.114 Conversely, growing tumour cells frequently extend beyond the primary organ in which they developed towards surrounding fat depots, thereby contributing to tumour progression and meta stasis. Taken together, the rebounding of adipose tissue several years after under-going bariatric surgery might explain the lack of reduced incidence of cancer in some patients.

Beyond the semanticsThe recognition that the benefits of bariatric surgery extend well beyond weight loss provided the clinical rationale for the emergence of metabolic surgery. This type of surgery is primarily intended to treat T2DM and is offered to patients with obesity who have a lower BMI than those who are eligible for bariatric surgery (Figure 3a), which implies that a new model of care is being developed that is distinct from traditional bari atric sur gery.115,116 Although patients undergoing metabolic sur gery tend to have a lower BMI than those undergo-ing bariatric surgery, body composition does not differ much between both patient groups.117 The two groups have similarly high total and visceral adiposity, and thus associated cardiometabolic comorbidities, which blurs the strict BMI-centric cut-off limits (Figure 3b). In fact, even individuals with class I obesity (BMI 30.0– 34.9 kg/m2) usually exhibit increased total and intra- abdominal adipose depots that are similar to those of patients with morbid obesity (BMI 40.0–44.9 kg/m2) which partly explains the pattern of co morbidities observed in these patients.118

Importantly, bariatric surgery entails not only weight-reducing effects but also metabolic improvements. Thus, the dichotomy between strictly using the terminology

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Figure 2 | Short, medium and long-term trajectories of EWL, BMI and total adiposity following bariatric surgery. EWL, BMI and adiposity exhibit diverse trajectories over time.98 While a dramatic EWL takes place during the first few months after surgery, the decrease in BMI and body fat follows a less steep trajectory. The figure further illustrates that the rapid decline in BMI is not paralleled by the decrease in adiposity, in particular during the first month. Moreover, even if a BMI in the range of overweight or normal weight is reached after several years, body fat percentage does not necessarily decrease to normal limits (normal limits are 10–20% in men and 20–30% in women). Abbreviation: EWL, excess weight loss.

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of bariatric surgery for weight-reduction procedures and metabolic surgery for techniques aimed at improv-ing T2DM and other metabolic derangements does not match the actual practicalities of clinical care and therapeutic effects. When offering surgery to treat meta-bolic diseases or T2DM rather than simply as a weight-reduction therapy, clinicians need to consider that most of these patients have levels of dysfunctional adipose tissue similar to those of patients with morbid obesity.117 Moreover, weight and fat loss is also generally reported among patients undergoing metabolic surgery,13 which makes it difficult, if not impossible, to determine the relative contribution of gastrointestinal alterations in anatomy and physiology from weight loss itself.

Interestingly, so far both surgical approaches differ in their stated therapeutic goals. Offering the same surgi-cal interventions to treat diabetes mellitus and metabo-lic dis eases as for weight-reduction purposes reportedly changes demographical and clinical characteristics of sur gical candidates.13 In general, more men undergo metabolic surgery than bariatric surgery and patients who undergo metabolic surgery are usually older than those undergoing bariatric surgery (Figure 4).13,115 Although patients undergoing metabolic surgery have a lower BMI than patients undergoing bariatric surgery, they have more T2DM (in terms of both frequency and severity, with increased HbA1c levels and percentage of insulin use), hypertension, dyslipidaemia and other CVD.13,115 Similarly, patients with a BMI <35.0 kg/m2 without relevant metabolic alterations (below the tra-ditional cut-off point for bariatric surgery)119 can have osteoarthritis and joint problems, which can increase the difficulties of losing weight by conventional means; therefore, bariatric surgery could be a useful and effec-tive approach to alleviate the pain and functional impairment of these conditions. In addition to their involvement in the mechanical, weight-dependent effects of bariatric surgery, adipokines also have a critical role in the pathophysiologic features of osteoarthritis.55 Thus, patients with orthopaedic problems and who are not eligible for bariatric surgery would also benefit from the metabolic aspects of the surgical approach that are related to inflammation. These reflections should have relevant implications in clinical care to support the con-sideration of bariatric–metabolic surgery as an effective therapeutic tool for a wider spectrum of patients than traditionally thought. Thus, the strict application of semantics ob viates the broader pathophysiological cir-cumstances of the variety of existing patients, thereby limiting the selection of the best candidates who would benefit the most from the multifactorial effects of the surgical approach.

Implications of a paradigm shiftWhen the SOS study was started in 1987, no official eligi-bility criteria for bariatric surgery existed, which led to the inclusion of both eligible and noneligible patients according to current guidelines. Interestingly, no differ-ence in treatment effect with respect to mortality, CVD, T2DM or cancer prevention was found when patients

Metabolicsurgery

Bariatricsurgery


BMI 30–35 kg/m2 BMI 35 kg/m2 BMI ≥35–40 kg/m2

Metabolicsurgery

Bariatricsurgery

a

b

Dysfunctional adiposity

Figure 3 | The separation of bariatric and metabolic surgery. a | The strict separation of bariatric and metabolic surgery based on current BMI eligibility criteria. b | In reality, the separation is blurred by the common feature of actual body fat content characterized by a high degree of dysfunctional adiposity. Dashed lines indicate the overlap between metabolic surgery and bariatric surgery.


Age (years)

BMI (kg/m2)

Body fat (%)

Other CVD (%)

Dyslipidaemia(%)

Hypertension(%)

T2DM(%)

Sex(% of females)

Bariatric surgery Metabolic surgery

0

20

40

60

80

Figure 4 | Radial plot comparing the main clinical characteristics of patients undergoing bariatric and metabolic surgery. Offering surgery to treat metabolic disease or diabetes mellitus rather than as a mere weight-reduction therapy impinges on the demographical and clinical characteristics of surgical candidates.13,115 In general, more men undergo metabolic surgery than undergo bariatric surgery. Patients undergoing metabolic surgery have a lower BMI, as well as a higher incidence of T2DM, hypertension, dyslipidaemia and other CVD than patients undergoing bariatric surgery, but have a similar body adiposity. Abbreviations: CVD, cardiovascular diseases; T2DM, type 2 diabetes mellitus.

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were stratified by BMI.21,51 Analyses from the past 5 years have investigated whether the long-term effects of bari-atric surgery on the incidence of T2DM and changes in cardiovascular risk factors differed between patients who did or did not meet the current eligibility criteria.21,51 Results showed that after 15 years of follow-up, bariatric surgery reduced the incidence of T2DM by 73% in eligi-ble patients but also by 67% in noneligible patients. The number needed to treat to prevent one event of T2DM over 15 years was low in both groups, which reflects the strong effect of the surgical treatment. Improvements in body weight, lipid profiles and blood pressure, as well as levels of glucose and insulin, were statistically significant not only in the eligible group but also in the noneligible group after 10 years of follow-up.11,33,42,50,120 These find-ings prove that patients not considered eligible by current criteria benefited from bariatric surgery via a reduced risk of comorbidities or early death. Furthermore, non-eligible candidates with high adiposity exhibit increased circulating concentrations of triglycerides, uric acid, C-reactive protein, HbA1c and hepatic enzymes, together with decreased insulin sensitivity.117 This finding pro-vides evidence that the beneficial effects of surgery can in fact be achieved in patients with excess adiposity who are currently not eligible to undergo surgery because their BMI is not high enough. Thus, BMI-based eligi-bility criteria are not optimal and a more functional cri-terion (such as high adiposity) would be better suited for patient selection.

During the past 5 years, the eligibility criteria have been extended, which suggests that the surgical approach is advisable in patients with a BMI <35 kg/m2 and inade-quately controlled T2DM.121,122 Moreover, it has been proposed that metabolic surgery might also be use ful in patients with T2DM who have class I obesity or even in patients with T2DM who do not have obesity.24 By contrast, no recommendations are given for individuals without T2DM who have a BMI <35 kg/m2. Individu-als who are not obese according to their BMI can have increased adiposity accompanied by a raised cardio-metabolic risk factor profile.118,123 Thus, this high-risk sub population should also be considered as candidates for the surgical approach when conventional treatment has failed in order to improve the risk factor profile and prevent the development of comorbidities. Accordingly, bariatric and metabolic surgery cannot be viewed as dichotomic procedures, as in both procedures most of the clinical benefits have a multifactorial origin derived from a combination of mechanisms124 (for example, Box 1 in relation to insulin resistance improvement). These findings underscore the importance of a personal-ized approach for the indication of the surgical treatment and follow-up, instead of adopting a simplistic, unilateral approach that tries to explain multifactorial effects via a unidimensional perspective.

Obesity is a multifactorial disease associated with a variety of comorbidities that together with the lack of effectiveness in its conventional management highlights the need for more-tailored approaches. Despite the large body of evidence supporting the existence of obesity

subtypes,125 no detailed specific diagnostic protocols or more-tailored treatment strategies have been developed. The identification of the complex interactions contrib-uting to an increased caloric intake, decreased energy expenditure or a combination of both124 requires the development of finely designed protocols that identify the diversity of each component via classification of indi-viduals into subpopulations that differ in their suscepti-bility to develop the disease as well as in their response to a specific treatment.

Eligibility criteriaIs the continuing reliance on BMI limiting clinical pro-gress in obesity management? The inadequacy of BMI as a primary criterion for surgical selection resonates with the WHO definition of obesity as the degree of excess weight that is associated with “abnormal or excessive fat accumulation that may impair health”.126 Should we persist with BMI when more accurate measures of adiposity and fat distribution are currently available?127 The advantages arising from accurate assessment of adiposity and other functional determinations should be evident in management and research, which could result in improved understanding of the underlying aetiology of obesity and its pathophysiological and social consequences. In the current era of personal-ized medicine, working in the obesity clinic resembles being frozen in time. The potential for research findings to improve medical practice is evident in some areas, particularly in cancer, where patients receive a precise diagnosis based on the specific characteristics of their tumour that enables tailored treatments.128 By contrast, patients with obesity are lumped into one category, based primarily on their BMI, which does not convey a complete and realist ic reflection of the patient’s true health situation.39,129

Paradoxically, patients with obesity who are in the same BMI category can have quite diverse levels of health and risk factors, as well as experiencing different effects of obesity on quality of life.125 In fact, specific patients with class I obesity might have a comorbidity burden similar to, or even greater than, patients with more severe obesity according to their BMI.24 The denial of a surgical therapeutic approach to a patient with class I obesity with a considerable obesity-related health burden in whom conventional treatment has failed to achieve weight loss and/or metabolic control simply on the basis of the BMI level should be revised.24 The clinical justification of such a decision should be based on a more dynamic, compre-hensive and functional evaluation of the patient’s current global health and on a more reliable prediction of future morbidity and mortality. In this sense, a clear disconnect exists between the wealth of scientific advances in obesity research and the incorporation of this information into the clinic. This disconnect might result in opportunities being missed to understand, diagnose and treat obesity with increased precision, and to make better use of knowledge and resources to inform health-care decisions than is currently the case. The implications of a mentality change in this field would be substantial. The validation

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and application of scoring systems or algorithms that quantify the actual and future health burden induced by obesity in the individual patient would represent an important tool for precise phenotyping beyond BMI as well as for guiding therapeutic approaches.

In this context, it is worthwhile exploring the Edmonton Obesity Staging System (EOSS), a five-point ordinal classification (stage 0–4), that considers comor-bidity and functional status.130,131 This system assesses obesity drivers, complications and barriers to manage-ment using a framework that addresses the mental, mechanical, metabolic and monetary aspects of obesity development and weight management to determine how healthy a patient is.130,131 In a public-funded health-care system, with limited access and resources, prioritizing patients with the greatest need is prudent. Prioritiz-ing patients with the highest EOSS scores for bariatric surgery will identify individuals with obesity who have the greatest risk of death, as EOSS is reportedly a better predictor of mortality than BMI grading.131 However, it is debatable whether these patients are the ones who will benefit the most from the surgical approach.132 On the one hand, a high EOSS staging score suggests the patient will have an increased risk of death from anaes-thesia when undergoing surgical procedures. On the other hand, increased severity of some comorbidities related to high EOSS scores might result in a reduced likelihood of improvements occurring once end-organ damage or established end-stage disabilities have been reached. Thus, prioritizing patients with high rather than low EOSS scores might mean that an opportunity to use bariatric surgery as a more-preventative measure in patients who could really attain full recovery is missed. Moreover, due to the lack of knowledge on the natural history of the diverse obesity subtypes, it is challenging to identify which patients will indeed progress to higher EOSS stages and which patients will remain stable.

Although the EOSS has certain advantages, it is not a completely objective system and it does not discriminate between patients who have different numbers of comor-bidities (a patient with one comorbid condition is staged at the same level as a patient with four or five comor-bidities, when the pathophysiological circumstances are obviously quite different). Although the EOSS might be a useful tool to redefine indications for bariatric or metabolic surgery in patients with severe obesity, further research is needed to determine its cost-effectiveness, optimal ways of incorporation into clinical practice and improved quantification of objectivity. Moreover, other important aspects in the development of comorbidities, such as body composition and fat distribution, should also be considered. When health outcomes are reported, the criteria for the initial diagnosis of each comor bidity should be explicitly stated and be in accordance with accepted standards. Changes in these criteria with weight loss should be fully reported. Standardized evaluation of comorbidities and outcomes, including a uniform acceptance of the definition and terminology of each disease state and specific biomarkers to be used, should be universally applied for surgical referral and follow-up.

Patients in high-risk groups might be managed more aggressively than those in low-risk groups with regular screening, which could improve the accuracy of prog-noses and the identification of at-risk individuals who could benefit from early intervention.

More robust, proactive approaches are urgently needed. The challenge ahead lies in orienting our goals away from a ‘weight-centric’ approach towards a more functional holistic approach with extensive evaluation of comorbidities. Thus, detailed phenotyping of key features (such as body composition, fat distribution and immunometabolism, hunger and satiety, energy homeostasis, metabolic flexibility, sleep patterns, stress factors and environmental cues) would yield much more personalized approaches than focusing on BMI. In addition, obesity is a known risk factor for infertil-ity in women.133 Nearly 50% of patients undergoing bariatric surgery are women of reproductive age, with fertility in obese women improving after surgical inter-ventions.134,135 Thus, addressing the reproductive health of women should also be considered as an indication for bariatric surgery in patients in whom infertility might be related to increased adiposity and its subse-quent hyper insulinaemia, hyperleptinaemia and result-ant hyperandrogenism. Clarifying the long-term effects of the surgical interventions on these features should be pursued.

In addition to focusing on biological changes, con-certed action, including behavioural, psychological, soci-etal and legislative interventions, should be considered to maximize the effectiveness of surgery as a whole to affect the largely unmet needs of obesity management.136

Definition of successThe way weight change is expressed in clinical trials of weight management, as well as in the physician’s office, is an important topic.137 In most cases, weight loss is expressed as kg (pounds in some countries) or as a percent of baseline weight. One problem with this approach is that heavier people tend to lose more weight than less-heavy people and thus might seem to be more successful over short periods of time. EWL was intro-duced to complement the use of actual weight loss as it provides an improved estimate of the amount of weight loss that has been achieved relative to a defined goal. The use of EWL as a standard metric for reporting the efficacy of behavioural, medical and surgical weight-loss treatments has the advantage of unifying different ways of reporting results. This unification enabled the compa rison of studies of different treatment modalities in different populations of patients with differing start-ing weights and BMIs. EWL can also be used to increase the motivation of individual patients.

Criticism of the validity of percentage EWL reflects its original derivation,137 as it is determined not from the ideal weight of a patient at a BMI of 25 kg/m2, but from a set of ideal weight charts known as the Metropolitan Life Insurance scales, which were generated by the Metropolitan Life Insurance Company in 1943 and revised in 1983.138 Another drawback to using EWL is

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that the more obese a patient is, the less likely they are to achieve a 100% reduction.137 This is the case inde-pendent of how ‘normal weight’ is defined. As one of the main targets of any weight loss programme is loss of excess fat, the amount of body fat should be deter-mined directly. Similarly, work towards a definition of success that examines pathophysiological components of unhealthy adiposity associated with all-cause mortal-ity would be useful, as would the potential addition of factors that might even identify subclinical disease or metabolic frailty. These components include common carotid artery intima–media thickness, coronary artery calcium, markers of endothelial dysfunction, inflamma-tion and fatty liver disease. Functional tests such as bra-chial artery macrovascular flow-mediated vasodilation and microvascular reactive hyperaemia might provide more dynamic and clinically relevant information than simple weight, BMI and EWL change.

Physicians should be hesitant to rely only on BMI, as it might not be an accurate representation of the meta-bolic profile and could disguise an increased risk of CVD. Furthermore, the role of the diverse procedures relative to rigorously defined end points of heart failure, athero-thrombotic state, hepatic, pancreatic and renal function should be assessed, with its systematic application aiding inter-study comparisons. Moreover, the dependence of some obesity-related metabolic comorbidities on stress-related psychological disorders highlights important functional interactions between energy balance and brain stress integration.139 The existence of largely overlapping neural circuits that regulate metabolism, energy balance, reproductive performance and stress control indicate that relevant functional interactions exist between energy homeostasis and stress integration.60,139,140

In light of this important interrelation, the reduction of metabolic neuroendocrine signals that optimize the regulation of stress should be taken as a signal that the sur gery has had a positive effect. In some cases, even just halting the progressive trend towards an increase in weight and adiposity, together with its often subsequent clustering of mechanical, metabolic and psychosocial comorbidities, should be considered a success. Moreover, focusing on the salient personal investment made in undergoing surgery and the profound changes that trans-late to improved mood and self-esteem, together with a marked reduction in hedonic thoughts and psycho-social circumstances, might also be considered a success in some patients. Whilst weight change constitutes a relevant outcome of interest, changes in body compo-sition, HRQL and health-care costs are also important

and merit equal consideration. A composite measure that includes all relevant outcomes would be ideal. However, with so many inter-related variables, developing the optimal composite is not an easy task. Thus, realistic expectations should be set on an individual basis with the patient, and success evaluated in a personalized frame of reference.

ConclusionsObesity touches upon all medical specialties and pro-foundly impinges on quality of life; thus, obesity has important clinical, workplace and personal costs for those directly affected and has effects that reach further into society as a whole. Although a fundamental need for preventing excess weight is universally acknowledged, the medical, psychosocial and economic consequences of the current obesity epidemic require the widespread application of effective treatments and interventions. Mounting evidence shows that surgical approaches carried out by experienced multidisciplinary teams are useful to effectively and safely treat obesity. However, the body of knowledge gained so far is not being fully applied for a more dynamic and rational selection and follow-up of patients. An integrated holistic approach will undoubt-edly yield more successful, less invasive and safer inter-ventions to strengthen the physician’s armamentarium against obesity and its plentiful comorbidities.

Review criteria

A search for original articles and reviews published between 1987 and 2014 focusing on outcomes after bariatric and metabolic surgery was performed in PubMed and MEDLINE using the following search terms (or combination of terms): “bariatric surgery”, “metabolic surgery”, “obesity”, “diabetes”, “comorbidity or comorbidities”, “outcome”, “mortality”, “metabolic syndrome”, “impaired glucose tolerance”, “dyslipidaemia”, “hypertension”, “cardiovascular disease”, “coronary heart disease”, “stroke”, “myocardial infarction”, “cancer”, “body composition”, “fertility” and “quality of life”. Only English-language, full-text articles were included. Additional articles that were identified from the bibliographies of the retrieved articles were also used, as well as selected very recent references from 2015. Articles in journals with explicit policies governing conflicts of interest, and stringent peer-review processes were favoured. Data from larger replicated studies with longer periods of observation when possible were systematically chosen to be presented. More weight was given to randomized controlled trials, prospective case–control studies, meta-analyses and systematic reviews.

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AcknowledgementsThe author would like to acknowledge the support of Fondo de Investigación Sanitaria-FEDER (FIS PI12/00515) from the Spanish Instituto de Salud Carlos III. CIBER de Fisiopatología de la Obesidad y Nutrición (CIBERobn) is an initiative of the Instituto de Salud Carlos III, Spain.

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