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Metabolic Changes Following Bariatric SurgeryAli Tavakkoli, MD, and Robert N. Cooney, MD

METABOLIC CONSEQUENCES OF OBESITY

Obesity is an excess accumulation of body fat, and is commonly defined as a body mass index (BMI) of more than 30. Although BMI is easy to calculate, assessing obesity based on BMI has several limita-tions. For example, athletic individuals may have an elevated BMI because of increased muscle mass instead of excess fat. Although one can calculate body fat and define obesity as percentage body fat more than 32% in women and more than 25% in men, these calculations are difficult. More importantly, neither BMI nor percentage of body fat definitions of obesity provides any information on the regional distribution of excess body fat. This is important because the meta-bolic consequences of obesity are influenced by both the amount and the distribution of body fat. Abdominal or visceral obesity leads to a chronic inflammatory state caused in part by the release of free fatty acids and cytokines from adipose tissue. Visceral obesity is associated with increased risk of insulin resistance, hyperlipidemia, hyperten-sion, cardiovascular disease (CVD), and stroke. This pattern is also referred to as android obesity and is more commonly seen in men. The gynecoid pattern of obesity is characterized by an excess accu-mulation of subcutaneous fat in the gluteal and buttock areas, more commonly seen in women, and is less frequently associated with adverse metabolic effects. The importance of central obesity is high-lighted in populations who, despite relatively low BMI, have high levels of visceral obesity (e.g., Asians) and are prone to adverse effects of obesity at a lower BMI.

Although the obesity epidemic in the United States is well docu-mented, affecting 36% of the adult population and nearly 20% of children, the problem is an international one, with many Western countries reporting similar rates. The highest rate of obesity is observed in Samoa, where it affects 75% of adults. The global epi-demic of obesity is multifactorial and has genetic, environmental, and epigenetic roots. The recent exposure of humans to an environ-ment with excess cheap food is thought to have led to an imbalance between caloric intake and energy expenditure, resulting in patho-logic excess fat deposition. The risk of reaching this detrimental state of fat accumulation in our current environment is modulated by genetic risk factors, diet, exercise, and lifestyle.

Although adipose tissue was originally thought to be a relatively quiescent accumulation of stored calories, more recent studies indi-cate adipose tissue to be metabolically and hormonally active. In severe obesity, excess lipid accumulates in these metabolically active adipocytes, and in hepatocytes and muscle cells. Excess accumulation of nutrients and fat within these cells leads to increased secretion of adipocyte-derived peptides (e.g., leptin, adiponectin, resistin) and cytokines (e.g., tumor necrosing factor–α [TNF-α], interleukin-6 [IL-6]) collectively referred to as adipokines. The paracrine and endocrine actions of these adipokines contribute to a state of chronic low-grade inflammation, which in turn interferes with many physi-ologic cellular processes (such as insulin signaling) and leads to the metabolic derangements seen in obesity (such as insulin resistance and type 2 diabetes).

The obesity-induced inflammatory state adversely affects most organ systems in the body and contributes to a shortened life expec-tancy. Each 5-unit increase in BMI is associated with a 30% increase in all cause mortality, with BMIs of more than 40 associated with a reduced life expectancy of 8 years. Obese individuals have a poor quality of life with increased risk of many life-threatening conditions, including: cancers, heart disease, type 2 diabetes, hypertension, stroke, hyperlipidemia, and sleep apnea. The prevalence of these comorbidities often increases with the severity of obesity (Table 1). This is most evident with type 2 diabetes. At age 18 years, women with a BMI of 30 to 35 have a 54.6% lifetime risk of development of diabetes, which is increased to 74.4% for those with BMI of more than 35.

Although modest weight loss (5% to 10% excess weight) can lead to reductions in the risk of these chronic diseases, nonsurgical weight loss is often unsuccessful or short lived in 90% to 95% of patients. As a result, bariatric surgery has become the standard of care in the treatment of medically complicated or morbid obesity. A variety of weight loss operations are in common practice.

METABOLIC IMPROVEMENTS AFTER WEIGHT LOSS SURGERY

Weight Loss

The term excess body weight loss (EBWL), calculated with the actual and ideal body weight, is commonly used to describe weight loss. Not surprisingly, the degree of EBWL varies between procedures. The mean EBWL is 70% to 80% for biliopancreatic diversion (BPD) with or without duodenal switch, 60% to 70% for Roux-en-Y gastric bypass (RYGB), 50% to 60% for sleeve gastrectomy (SG), and 40% to 45% for laparoscopic adjustable gastric banding (LAGB) at 2 years. In general, procedures with higher weight loss are also associated with increased short-term and long-term complications. The balance between the desired weight loss and surgical risk influences the patient when choosing an operation and the surgeon when offering the procedure.

The mechanisms underlying the weight loss are multifactorial and vary by procedure. The proposed mechanisms for postsurgical weight loss are summarized in Table 2. Of critical importance are long-term changes in appetite and hunger after surgery. In contrast, nonsurgical weight loss leads to increased hunger and reduced energy expendi-ture, which presumably contribute to the ultimate failure of dieting in achieving long-term weight reduction. Weight loss surgery pre-vents such physiologic responses and maintains hunger control despite limited calorie intake.

Long-term follow-up studies such as the Swedish Obesity Study show significant long-term weight loss in surgical patients compared with control subjects, with up to 20 years of follow-up. The durability of postsurgical weight loss is a concern for patients and clinicians. Definition of successful weight loss for bariatric surgery varies depending on the procedure but for RYGB is described as losing and maintaining 50% or more EBWL. Most patients regain some weight after reaching their nadir weight, with pathologic weight regain (>20% of the maximal weight loss) reported in 15% to 20% of patients. This observation highlights the fact that bariatric surgery is not a replacement for long-term lifestyle changes that are needed to help maintain weight loss. A commitment to changes in diet and exercise are critical for long-term success. The importance of such changes and the need for regular postoperative follow-up examina-tion with the bariatric team should be discussed with patients before surgery.

678 Metabolic changes Following bariatric surgery

TABLE 1: Risks of cardiovascular and metabolic disorders with obesity

Life expectancy 30% increase in mortality rate for each 5-unit increase in BMI.In patients with BMI > 40, life expectancy is reduced by 8 years.

Hypertension 5-fold risk of hypertension in obese individuals.85% of patients with hypertension have a BMI > 25.

Cardiovascular disease A 9% increase in cardiovascular mortality rate with each unit increase in BMI.

Type 2 diabetes Men with BMI ≥ 35 have 42-fold increase in risk of diabetes compared with men with BMI < 23.74% lifetime risk of type 2 diabetes if BMI > 35.

BMI, Body mass index.

TABLE 2: Proposed mechanisms for weight loss after bariatric procedures

Physical restriction of food intake

Although a common belief, especially in case of LAGB, little data support this. Food transit through the stomach is only minimally altered after LAGB, and the supraband compartment is empty of food within 1-2 min after ingestion. BPD has a large gastric reservoir and yet leads to best weight loss results.

Malabsorption Although a degree of this occurs after BPD, little malabsorption is seen after LAGB, SG, or RYGB as measured with stool calorimetry and nitrogen balance.

Decreased hunger signals and reduced food intake

This is true for all bariatric procedures and the result of hormonal changes along the gut-brain axis after surgery.

Increased energy expenditure and diet induced thermogenesis

Although this has been documented in rodents, little data support this in humans.

Changes in food preference Changes in food preference have been documented and are related in part to alterations in reward and taste and concerns about physiologic implications of ingestion of certain foods that may lead to dysphagia or dumping syndrome.

Changes in gut microbiota Animal studies show a role for intestinal microbacteria in obesity and diabetes. Definitive human data are currently lacking, but this is an area of significant scientific interest.

BPD, Biliopancreatic diversion; LAGB, laparoscopic adjustable gastric band; RYGB, Roux-en-Y gastric bypass; SG, sleeve gastrectomy.

Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is present in more than 70% of individuals with a BMI of more than 35 and represents a spectrum of disease characterized initially by the accumulation of liver fat (steatosis), which if severe, causes inflammation and nonal-coholic steatohepatitis (NASH) and later fibrosis or cirrhosis. Hepatic steatosis and NASH, markers of central adiposity, are thought to be important in the pathogenesis of obesity-related metabolic disorders, often referred to as the metabolic syndrome (visceral adiposity, insulin resistance, hyperinsulinemia, hypertension, hyperlipidemia). NASH is a leading cause of cirrhosis in the United States and one of the main indications for liver transplantation. Therefore, resolution of NASH-related hepatic injury is an important endpoint in bariatric and metabolic surgery. Studies have shown weight loss operations lead to a near universal improvement in the severity of hepatic ste-atosis, inflammation, and fibrosis. A few cases of worsening fibrosis and inflammation have been reported, although in most cases, this is transient and is thought to be related to the rate of postoperative weight loss. Although all bariatric procedures lead to improvements in the severity of liver injury, a recent study showed patients who underwent RYGB had significantly greater improvement in grade of liver disease compared with those who underwent restrictive-only procedures (SG and LAGB; 95% vs 66%) as a direct result of better weight loss seen after RYGB.

Lipid Profiles

Dyslipidemia is seen in up to 50% of patients who undergo bariatric surgery, with more than 70% experiencing an improvement or reso-lution of this comorbidity within 2 years of surgery. Surgery leads to reductions in total cholesterol and low-density lipoprotein (LDL) and also increases high-density lipoprotein (HDL) levels. Variation is found in the remission rate of dyslipidemia between the common bariatric procedures, and better results are achieved with the more malabsorptive operations, with BPD leading the way with a 90% remission/improvement rate. In a recent study that compared SG and RYGB, gastric bypass led to a reduction in cholesterol and LDL and an increase in HDL, and the SG only increased HDL without altering LDL levels. Both operations result in a significant reduction in tri-glyceride levels.

Hypertension

Hypertension is common in obesity and rises in prevalence with increasing weight. The odds ratio for hypertension is 1.7 for indi-viduals who are overweight compared with those of normal weight and is 2.6 for BMI 30 to 34.9, 3.7 for BMI 35 to 39.9, and 4.8 for BMI 40 or more. Elevated blood pressure is seen in up to 50% of patients who undergo bariatric surgery, with 60% to 70% documenting an

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to continue to climb. New pharmacologic therapies (glucagon-like peptide-1 [GLP-1] analogues and dipeptidyl peptidase-IV [DDP-IV] inhibitors) have been disappointing, and most patients with diabetes do not reach the therapeutic goals set by the American Diabetic Association and other endocrine societies (glycosylated hemoglobin [HbA1c], <7%). These trends and the remarkably rapid improvement in diabetes seen after bariatric interventions have pushed surgery to the forefront of the diabetes treatment and created the field of meta-bolic surgery, defined as the operative manipulation of a normal organ or organ system to achieve a biologic result for a potential health gain.

The observation that alterations in gastrointestinal anatomy can lead to diabetes resolution was noted more than 50 years ago, and improvements in glycemic control after weight loss operations have been well documented for the past 20 years. Several large studies and meta-analyses have confirmed that all bariatric procedures lead to significant improvements in glucose control and diabetes remission, although success rates vary between the different operations with RYGB and BPD offering the best chance of disease remission (Table 3). Although improvements in glycemic control are expected after any form of weight loss (surgical or diet-induced), studies have confirmed weight-independent effects on diabetes after RYGB and BPD.

Three randomized studies have now confirmed that LAGB, RYGB, SG, and BPD lead to better diabetes control than intensive medial therapy. In the study that compared LAGB with medical therapy, surgery led to a diabetes remission rate of 73% versus 13% for the medical arm at 2 years. The improved outcomes in the surgical arm were linked to improved weight loss. Mingrone and colleagues com-pared medial therapy with RYGB or BPD and showed that at 2 years diabetes remission (defined by fasting glucose <100 mg/dL and HbA1c <6.5% in the absence of pharmacologic therapy) was seen in 0 in the medical arm compared with 75% in RYGB and 95% for BPD. Interestingly, weight loss did not predict glycemic improvement after these procedures. Schauer and associates compared medical therapy with RYGB or SG and showed that after 12 months of follow-up, diabetes remission (defined as HbA1c <6% with or without medica-tions) was 12% in the medical group versus 42% in the RYGB and 37% in the SG arms.

These data have prompted many of the diabetes societies to alter their treatment guidelines for management of type 2 diabetes and recommend surgery in patients with poorly controlled diabetes and BMI of more than 35. The International Diabetes Federation, an umbrella organization that represents many national societies, in their 2011 position statement went one step further, recommending that patients with BMI of more than 30 and diabetes that is poorly controlled with medication should also be considered for surgery.

Although the antidiabetic effects of LAGB are directly linked to weight loss, the studies point to a weight-independent effect for RYGB and BPD. This topic has received significant scientific attention over the last few years with many proposed mechanisms (Table 4). Although many hormones have been investigated to help elucidate the mechanisms of weight-independent effect of RYGB on glucose homeostasis, GLP-1 has emerged as a likely explanation, with several

improvement or remission after weight loss surgery. Improvements in blood pressure are also linked to weight loss, and the remission rates vary between the bariatric procedures.

A meta-analysis of several studies showed improvement in hyper-tension in 58% of patients undergoing LAGB. These improvements were less evident when gastric banding was studied in randomized fashion with control arms. In a small Australian study of obese adolescents randomized to LAGB, systolic blood pressure (BP) was reduced by 12.5 mm Hg compared with baseline values; however, this was not significant when compared with the control group. The Swedish Obesity Study, a study cohort that consisted mainly of adjustable or vertical banding, also showed no significant improve-ment in hypertension at 10 years after surgery compared with control subjects, although a modest improvement was seen at the 2-year time point.

For patients who undergo RYGB, hypertension has been shown to improve or resolve in 60% to 70% of cases compared with baseline, an observation that has been further confirmed in a nonrandomized study. A European study of patients undergoing RYGB or intensive medical therapy showed the rate of hypertension remission was 49% for the surgical group versus 23% for the medical therapy group. BPD has also been shown to resolve hypertension in 60% to 80% of patients.

Cardiovascular Risk and Mortality

CVD remains the leading cause of mortality in the United States. Several risk scores have been developed to calculate an individual’s risk of having a cardiovascular event and are widely used to help guide strategies for primary prevention. Of these risk scores, the Framingham risk score (FRS) is most commonly used. This risk score is calculated on the basis of age, gender, and smoking status and cholesterol, HDL, and systolic blood pressure. These parameters are all improved after bariatric surgery; therefore, it is not surprising that weight loss procedures have been shown to reduce FRS and the 10-year risk of a cardiac event by 40%. Serum and laboratory risk predictors, such as creactive protein (CRP), have also been shown to decline after surgery by about 60%.

Two large cohort studies have shown the reductions in risk factors also translate to reductions in mortality rate. In a large cohort study from Utah, at a mean follow-up of 7.1 years, cardiovascular mortality rate was decreased by 56% compared with control groups. Similar improvements in cardiovascular mortality have also been reported in the Swedish Obesity Study.

Type 2 Diabetes

Of all metabolic changes after bariatric surgery, none have been as impressive as the improvements in glucose homeostasis. Type 2 dia-betes has reached epidemic proportions in the United States, and despite significant investments in preventive measures, the rate is set

TABLE 3: Weight changes and metabolic improvements 2 years after bariatric procedures

Weight loss Lipid improvement Hypertension T2D improvement

BPD 70%-80% 90% 80% 90%

RYGB 60%-70% 60%-70% 60% 80%

SG 50%-60% 50%-60% 60% 70%-80%

LAGB 40%-45% 60% 58% 50%-60%

BPD, Biliopancreatic diversion; LAGB, laparoscopic adjustable gastric band; RYGB, Roux-en-Y gastric bypass; SG, sleeve gastrectomy; T2D, type 2 diabetes.

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surgery, the immense interest to lower the BMI threshold for patients with diabetes who are interested in surgical intervention is not sur-prising. The proposal has been to lower the BMI to 30, with this number lowered to 27 for those of Asian ethnic origin, where adverse metabolic effects are seen at a lower BMI.

Several small studies have confirmed the safety of bariatric pro-cedures in this patient population, although long-term data are lacking. There is also no consensus as to the best surgical procedure for this patient population. In a randomized study from Taiwan that involved patients with diabetes with a BMI of 25 to 34, RYGB was shown to be more effective than SG in achieving diabetes remission (93% vs 47%). The mean postoperative BMI was 22.8 for RYGB and 24.4 for SG, both within normal weight range.

Data, however, have suggested that our current surgical interven-tions are less effective in achieving glycemic control in patients with diabetes and low BMI. Other studies have documented cases of dia-betes recurrence in patients after bariatric procedures, including RYGB. A few cases of pancreatic β-cell hypertrophy (nesidioblastosis) that lead to hypoglycemic episodes and necessitated pancreatic resec-tion have also been documented. These observations have been cited as reasons for caution in declaring surgery the treatment of choice for the low-BMI and diabetes group and highlight the need for more studies to confirm success, safety, and durability of surgical proce-dures in patients with low BMI.

Alternative Surgical Procedures

Surgical steps in the rearrangements of gastrointestinal anatomy are thought to be critical to the metabolic success of most bariatric surgi-cal procedures. These include (1) isolation of duodenum and proxi-mal bowel from nutrient exposure and (2) earlier exposure of distal bowel and ileum to undigested food (see Table 4). Some surgical groups have worked on developing alternative novel procedures that achieve one or both of the previous goals and could have therapeutic value in patients with diabetes and low BMI. Of these procedures, duodenal-jejunal bypass and ileal interposition with or without sleeve gastrectomy have received the most attention and have been tested in human subjects with good early results. These procedures are, however, complex, and whether they offer any advantages in terms of effectiveness, durability, or safety over the more standard procedures, such as RYGB, is not clear.

studies showing increased postprandial levels after RYGB and BPD. GLP-1, an incretin hormone, leads to enhanced insulin secretion and satiety. However, it likely is not the only contributing factor; isolation of the proximal bowel from nutrient exposure also appears to play a critical role by altering nutrient sensing. Alterations in vagal signaling have been identified as a potential mechanism that leads to the meta-bolic benefit of surgery.

Although more work is needed to help understand the mecha-nism of diabetes improvement after RYGB and other weight loss operations, we have entered an era of metabolic surgery where surgi-cal outcomes are assessed by improvements in diabetes and cardio-vascular risk factors.

METABOLIC SURGERY AND FUTURE DIRECTIONS

The slow progress in finding effective new medical therapy for type 2 diabetes, the increasing prevalence of the disease, and increasing data that confirm effectiveness of bariatric surgery in diabetes remis-sion have been the impetus behind recommendations to lower the BMI threshold for surgical intervention in patients with diabetes to 30, and possibly below. An intense interest also exists in understand-ing the scientific mechanisms that underlie the antidiabetic effects of these procedures to help develop less invasive alternatives that can replicate the metabolic benefits of these procedures. Alternative sur-gical procedures have been tested, and significant investment has been seen in developing endoluminal devices for treatment of diabe-tes, heralding with it the emerging field of “interventional diabetology.”

Surgery in Patients With Diabetes and Low Body Mass Index

The 1991 National Institutes of Health (NIH) consensus statement recommends bariatric surgery in patients with BMI of more than 35 and type 2 diabetes. Although most patients with type 2 diabetes are overweight or obese, around 70% have a BMI of less than 35 and fail to qualify for surgical intervention on the basis of BMI. They struggle with their chronic disease, which is often poorly controlled with medications alone. Considering the impressive results of bariatric

TABLE 4: Proposed mechanisms for anti-diabetic effects of RYGB and other similar procedures

Restriction and acute decrease in food intake after surgery

Unlikely. Food intake is reduced after many GI surgeries where patients are kept nothing by mouth. Most of these surgeries, however, lead to a state of insulin resistance rather than sensitivity.

Malabsorption Unlikely. No evidence that RYGB leads to enough nutrient malabsorption to account for the rapid improvement in diabetes.

Changes in postprandial incretin response

Postprandial GLP-1 levels are increased after these surgeries, leading to enhanced insulin release. This is likely from earlier delivery of food to the distal small bowel where GLP-1 is primarily secreted.

Isolation of proximal bowel from nutrient flow

Evidence points to a role for proximal bowel in sensing nutrient availability and quality. Isolation of this region of the intestine from nutrient exposure can lead to alterations in nutrient absorption and glucose homeostasis. This idea is behind some of the metabolic devices currently in development.

Intestinal gluconeogenesis Rodent studies have suggested that ability of proximal bowel to generate glucose and release it to the portal circulation leads to changes in hepatic insulin sensitivity and glucose homeostasis. Human studies are lacking.

Changes in circulating bile acids Human and animal studies have shown increased circulating bile acid levels in patients after RYGB and linked this to improved glucose homeostasis.

GI, Gastrointestinal; GLP, glucagon-like peptide; RYGB, Roux-en-Y gastric bypass.

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are marketed as metabolic devices with a primary indication for diabetes management and not weight loss.

S u g g e S t e d R e a d i n g S

Dixon JB, le Roux CW, Rubino F, et al: Bariatric surgery for type 2 diabetes, Lancet 379(9833):2300–2311, 2012.

Dixon JB, Zimmet P, Alberti KG, et al: International Diabetes Federation Taskforce on Epidemiology and Prevention: Bariatric surgery: an IDF statement for obese type 2 diabetes, Surg Obes Relat Dis 7(4):433–447, 2011.

Mingrone G, Panunzi S, De Gaetano A, et al: Bariatric surgery versus conven-tional medical therapy for type 2 diabetes, N Engl J Med 366(17):1577–1585, 2012.

Schauer PR, Kashyap SR, Wolski K, et al: Bariatric surgery versus intensive medical therapy in obese patients with diabetes, N Engl J Med 366(17):1567–1576, 2012.

Sjöström L, Peltonen M, Jacobson P, et al: Bariatric surgery and long-term cardiovascular events, JAMA 307(1):56–65, 2012.

Endoluminal Devices and the Interventional Diabetologist

With the recognition that gastrointestinal manipulation can lead to improvements in glycemic control, several endoluminal devices are in development to replicate the metabolic success of bariatric surgery without the need for an invasive procedure. Many such devices are in various stages of development, and a few have received regulatory approval in Europe or Australia; none have as of yet received approval in the United States. This is, however, likely to change in the near future. Their induction will herald an era when diabetes management will not be only handled by the endocrinologists but also by surgeons who will help manage obese diabetes with surgery and by advanced interventional endoscopists (interventional diabetologists) who will deploy endoluminal devices to manage patients with poorly con-trolled diabetes who do not qualify for surgery or wish to avoid it.

The devices in development can be broadly divided in to three groups, as summarized in Table 5. Of these, many achieve modest weight loss and with it an improvement in diabetes; a few however,

TABLE 5: Broad categories of endoluminal devices in development for weight and diabetes

Device category Mechanism of action Examples

Restrictive devices This category includes devices that change gastric volume or shape or modulate transit to induce earlier and prolonged satiety. Most of these devices are placed for a short period of time and lead to modest weight loss.

Intragastric balloons (e.g., BIB, Allergan, Irvine, Calif)

Barrier devices These devices prevent nutrient contact with the proximal gut, in effect reproducing elements of RYGB. The devices are marketed as metabolic devices. They are designed for temporary placement and, although they have shown promising results, do not have the long-term effect of surgery.

Duodenal-jejunal bypass liner (e.g., EndoBarrier, GI Dynamics, Lexington, Mass)

Neuromodulators These devices involve a generator that sends signals via laparoscopically placed electrodes to targeted organs, which can be stomach, intestine, or nerves. Signals can be stimulatory or inhibitory. Although device placement involves a surgical procedure, it is less risky than traditional bariatric procedures.

Gastric stimulators (e.g., Tantalus system, Metacure, Raleigh, NC)

Vagal blockers (e.g., VBLOC, Enteromedics, St. Paul, Minn)

RYGB, Roux-en-Y gastric bypass.