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Published May 2016

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NOTE: Part 1 is originally published with the lipid association.

Prepared by Harold Bays, M.D., F.T.O.S., F.A.C.C., F.A.C.E., F.N.L.A., Shanu N. Kothari, M.D., F.A.C.S., F.A.S.M.B.S., Dan E. Azagury, M.D., Ninh T. Nguyen, M.D., F.A.C.S., F.A.S.M.B.S., Terry A. Jacobson, M.D., F.A.C.P., F.N.L.A., Carl Orringer, M,D., Deborah B. Horn, D.O., M.P.H., Diplomate A.B.O.M., John M. Morton, M.D., M.P.H., F.A.C.S., F.A.S.M.B.S., Eric C. Westman, M.D., M.H.S., Diplomate A.B.O.M., Peter H. Jones, M.D., F.N.L.A., David E. Cohen, M.D., Ph.D., Wendy Scinta, M.D., M.S., Craig Primack, M.D., F.A.C.P., F.A.A.P., Diplomate A.B.O.M.

Abstract: Bariatric procedures generally improve dyslipidemia, sometimes substantially so. Bariatric procedures also improve other major cardiovascular risk factors. This 2-part Scientific Statement examines the lipid effects of bariatric procedures and reflects contributions from authors representing the American Society for Metabolic and Bariatric Surgery (ASMBS), the National Lipid Association (NLA), and the Obesity Medicine Association (OMA). Part 1 was published in the Journal of Clinical Lipidology, and reviewed the impact of bariatric procedures upon adipose tissue endocrine and immune factors, adipose tissue lipid metabolism, as well as the lipid effects of bariatric procedures relative to bile acids and intestinal microbiota. This Part 2 reviews: (1) the importance of nutrients (fats, carbohydrates, and proteins) and their absorption on lipid levels; (2) the effects of bariatric procedures on gut hormones and lipid levels; (3) the effects of bariatric procedures on nonlipid cardiovascular disease (CVD) risk factors; (4) the effects of bariatric procedures on lipid levels; (5) effects of bariatric procedures on CVD; and finally, (6) the potential lipid effects of vitamin, mineral, and trace element deficiencies, that may occur after bariatric procedures. (Surg Obes Relat Dis 2016;12:468–495.) (r) 2016 American Society for Metabolic and Bariatric Surgery. All rights reserved.

Bariatric procedures generally improve dyslipidemia, sometimes substantially so. Part 1 of this 2-part scientific statement provided an overview of: (1) adipose tissue, cholesterol metabolism, and lipids; (2) bariatric procedures, cholesterol metabolism, and lipids; (3) endocrine factors relevant to lipid influx, synthesis, metabolism, and efflux; (4) immune factors relevant to lipid influx, synthesis, metabolism, and efflux; (5) bariatric procedures, bile acid metabolism, and lipids; and (6) bariatric procedures, intestinal microbiota, and lipids, with specific emphasis on how the alterations in the microbiome by bariatric procedures influence obesity, bile acids, and inflammation, which in turn may all affect lipid levels.

Part 2 of this scientific statement reviews: (1) the importance of nutrients (fats, carbohydrates, and proteins) and their absorption on lipid levels; (2) the effects of bariatric procedures on gut hormones and lipid levels; (3) the effects of bariatric procedures on nonlipid cardiovascular disease (CVD) risk factors; (4) the effects of bariatric procedures on lipid levels; (5) effects of bariatric procedures on CVD; and finally (6) the potential lipid effects of vitamin, mineral, and trace element deficiencies that may occur after bariatric procedures.

Bariatric procedures, intestinal nutrient metabolism, and lipids

General nutritional considerations

Bariatric procedures may affect gut hormones, which are important for nutrient digestion and metabolism, which in turn may affect lipid levels. Both the quantity and quality of foods (e.g., fats, carbohydrates, proteins, vitamins, minerals, trace elements, and other chemical compounds) can influence adipocyte and adipose tissue function. Metabolic diseases (including dyslipidemia) [1–3] are affected by bariatric procedures.

Fats are organic compounds that include cholesterol (see Part 1 of this Scientific Statement) and triglycerides. Triglycerides are composed of 3 fatty acids attached to a glycerol backbone, which may be saturated (no double bonds) or unsaturated (1 or more double bonds). The fatty acid components of triglycerides are mostly 4–28 carbons long. In adipose tissue, stored triglycerides usually have fatty acid components 12–24 carbons long and 0–6 double bonds. The fatty acids perhaps most easily mobilized from adipocytes by hormone-sensitive lipase are fatty acids that are shorter and more unsaturated (e.g., highly mobilized fatty acids include 16–20 carbon fatty acids with 4–5 double bonds; weakly mobilized fatty acids include 20–24 carbon fatty acids with 0–1 double bond) [4]. Dietary fats are energy-dense foods, with fat generating 9 calories per gram, carbohydrates 4 calories per gram, proteins 4 calories per gram, and alcohol 7 calories per gram. After undergoing emulsification by bile secreted by the liver and gallbladder, most dietary fats are absorbed in the small intestine.

Carbohydrates are chain or ring structures composed of 1 carbon per 2 hydrogens per 1 oxygen and include: (1) simple sugars often utilized for short-term cellular energy (i.e., monosaccharides such as glucose, fructose, and galactose, as well as disaccharides such as sucrose, maltose, and lactose); (2) complex carbohydrates for intermediate energy storage (i.e., plant starches composed of long polymers of glucose molecules with bond attachments in the same direction, and animal glycogen composed of polymers of glucose molecules with branching structure); and (3) polysaccharide cellulose composed of long polymers of glucose molecules with bond alternating in opposite directions, which provides structural support for plant cell walls and which represent “dietary fiber.” After enzymatic digestion of complex carbohydrates beginning in the mouth, and after further metabolism occurring in the small intestine, simple sugars are absorbed in the small intestine. In humans, dietary fiber usually passes through the intestine without significant digestion. As noted in Part 1 of this Scientific Statement, certain bacteria microbiota (e.g., phyla Firmicutes) can at least partially digest fibers into short chain fatty acids, which may be absorbed by the intestine, thus enhancing body energy/calorie absorption [5].

Proteins are linear chain compounds, folded into a tertiary or quarternary structure composed of nitrogen-containing amino acids. After undergoing digestion in the stomach by gastric juices, proteins are absorbed in the small intestine as amino acids. Different proteins may differ in their effects on adipocyte function and insulin secretion [1].

Dietary quantity can affect lipid blood levels [2,3,6,7]. Especially in patients with dyslipidemia caused by adiposo- pathic consequences of obesity, fat weight loss may be the most important factor in improving dyslipidemia, relative to the types of nutrients consumed. At least within the first year or so, regarding food quality: (1) Restricting saturated fats and transfats may reduce low-density lipoprotein (LDL) cholesterol levels; (2) restricting carbohydrates (especially carbohydrates with high glycemic index and load) may reduce triglyceride and increase high-density lipoprotein (HDL) cholesterol levels; and (3) if substituted for simple carbohydrates and saturated/transfats, increasing the proportion of protein food intake may: (a) improve adipocyte and adipose tissue function, (b) increase satiety and promote thermo- genesis, (c) preserve muscle mass, particularly in older individuals, (d) favorably affect metabolic parameters, and (e) improve dyslipidemia [1,3,8,9]. To the extent bariatric procedures alter the quantity and quality of intestinal nutrient absorption [10], then alterations in macronutrients and micronutrients may affect lipid levels. Therefore, to better understand how bariatric procedures might affect metabolic disease such as dyslipidemia, it is important to understand nutrient metabolism. Part 1 of this Scientific Statement provided details regarding the clinical relevance of enzymes, systemic hormones, inflammation mediators, and other factors relative to adipocyte and adipose tissue function, and the effect of bariatric surgery on these factors with respect to dyslipidemia. The following background discussion on nutrient digestion and metabolism in this Part 2 specifically focuses on the effects of bariatric procedures on gut hormones (Fig. 1; Table 1) [3,11–53] and how affected gut hormones may influence lipid blood levels.

Intestinal fat metabolism

More than 90% of consumed fats are triglycerides. Upon entering the small intestine, dietary fats stimulate duodenal cholecystokinin release (Fig. 1; Table 1) [3,11–53], facilitating bile release from the gallbladder and liver, as well as lipase, cholesteryl esterase, and phospholipase release from the pancreas. After triglycerides undergo emulsification by bile salts, pancreatic and intestinal lipases hydrolyze the triglycerides. Digested triglycerides are absorbed into the small intestine as free fatty acids and monoglycerides in the duodenum, with a small fraction absorbed as free glycerol and diglycerides. Once absorbed in intestinal cells, free fatty acids and glycerol are re-esterified into triglycerides and then packaged with re-esterified cholesterol into apoB48-containing chylomicrons. Chylomicrons enter mesenteric lymph vessels and eventually are introduced into the circulation, where they bind to peripheral tissues such as membranes of hepatocytes, adipocytes, and myocytes. Increased hepatic delivery of triglyceride-containing saturated fatty acids or trans-fatty acids may result in hepatosteatosis, and increased very low density lipoprotein (VLDL) secretion, potentially resulting in hypertriglyceridemia [54]. It is unclear that hepatic delivery of monounsaturated fats increase hepatosteatosis or VLDL secretion. Polyunsaturated omega-3 fatty acids may actually decrease hepatosteatosis and may decrease hepatic VLDL secretion, reducing triglyceride levels [55].

During periods of fasting, when body tissue energy is needed, triglycerides stored in adipocytes undergo lipolysis by hormone-sensitive lipase, generating the release of free or nonesterified fatty acids in to the circulation, which are complexed and carried by plasma proteins (i.e., albumin). Free fatty acids are the major secretory product of adipose tissue. Once these circulating free fatty acids are delivered to tissues such as muscle and liver, they may become activated in the intracellular cytosol by binding to coenzyme A, wherein they are then transported to the mitochondria via carnitine, undergo β-oxidation, and ultimately generate acetyl-CoA. Acetyl-CoA enters the tricarboxlic acid cycle (i.e., citric acid cycle or Krebs cycle) to generate adenosine triphosphate, which is the intracellular transporter of chemical energy.

Two of the more sentinel lipases involved with fat metabolism include hormone-sensitive lipase and lipoprotein lipase. Hormone-sensitive lipase is an intracellular, rate-limiting enzyme highly expressed in adipocytes that hydrolyzes cholesteryl esters to free cholesterol and hydrolyses triglyceride esters into free fatty acids and diglycerides. Adipocyte triglyceride lipase also hydrolyzes triglycerides; adipocyte triglyceride lipase and hormone-sensitive lipase are responsible for more than 95% of triglyceride hydrolase activity in white adipose tissue [3]. Diglycerides are rapidly metabolized by diglyceride lipase to a monoglycerides, with the remaining fatty acid cleaved from the glycerol backbone by monoglyceride lipase. Hormone-sensitive lipase is the lipolytic enzyme most affected by hormones. Hormone-sensitive lipase is downregulated by insulin hormone, with hyperinsulinemia being anabolic in promoting triglyceride storage in adipocytes. Conversely, hypoinsulinemia increases hormone-sensitive lipase activity, catalyzing intracellular triglycerides into fatty acids. Hormone-sensitive lipase is also upregulated with catecholamines (i.e., β-adrenergic stimulation) and adrenocorticotropic hormone (ACTH). Increased stress responses via sympathetic nervous system and ACTH and decreased insulin levels are thus both catabolic in promoting triglyceride breakdown and, ultimately, facilitating adipose tissue release of fatty acids into the circulation.

Lipoprotein lipase is another important lipase enzyme that is produced and secreted by adipocytes into extracellular surroundings. Lipoprotein lipase serves to hydrolyze triglycerides found in circulating lipoproteins into glycerol and free fatty acids. Because adipocytes do not synthesize fatty acids, adipocytes rely on acquiring extracellular fatty acids generated by lipoprotein lipase interaction with lipoproteins for intra-adipocyte lipogenesis. In the postprandial state, lipoprotein lipase interacts with chylomicrons (as well as other triglyceride-rich lipoproteins, such as VLDL and intermediate-density lipoproteins [IDL]). In the fasting state, lipoprotein lipase mainly interacts with VLDL and other triglyceride-rich lipoproteins. Once extracellular triglycerides are hydrolyzed by lipoprotein lipase, free fatty acids undergo transport via fatty acid transport protein into adipocytes.

Fig. 1. Gastrointestinal hormones help regulate caloric balance, food digestion, and nutrient utilization. After fasting and before eating, gastrointestinal hormones may increase hunger (e.g., ghrelin and neuropeptide Y). After eating, gastrointestinal hormones may (1) decrease hunger/promote satiety (e.g., somatostatin, cholecystokinin, motilin, insulin, glucagon, pancreatic polypeptide, amylin, fibroblast grown factor 19, glucagon like peptide-1, oxyntomodulin, and peptide YY); (2) help manage digestion through slowing gastric motility/emptying (e.g., cholecystokinin, amylin, glucagon like peptide-1, oxyntomodulin, and peptide YY) (3) stimulate the release of digestive enzymes (e.g., gastrin, cholecystokinin, secretin); (4) have counter-regulatory functions in impairing digestive enzyme release (e.g., somatostatin, secretin, pancreatic polypeptide, glucagon like peptide 2, oxyntomodulin, peptide YY); and/or may assist with postabsorptive systemic nutrient management after digestion (e.g., somatostatin, insulin, glucagon, fibroblast growth factor 19). *Neuropeptide Y (NPY) is a member of the pancreatic polypeptide-peptide family, expressed at all levels of the gut. NPY is also produced in the brain, and is the most abundant neuropeptide in the brain, involved with appetite and pain sensation functions.

Afterward, free fatty acids undergo activation by CoA, which is an esterification process required for fatty acid oxidation, synthesis of triglycerides, or attachment to proteins. The 3-carbon glycerol for which the 3 activated fatty acids are attached in forming triglycerides originates from glucose or pyruvate. Thus, adipocytes must have access to both free fatty acids and glucose to store fatty acids as triglycerides. Through a number of enzymatic steps involving the formation of lysophatidic acid (one fatty acid), and then phosphatidic acid and diacylglycerol (both 2 fatty acids), glycerol-3-phosphate may ultimately be esterified with 3 fatty acids (often mixed in size) through the terminal enzymatic step involving diacylglycerol acyltransferase (DGAT). In addition to hormones (similar to hormone-sensitive lipase), lipoprotein lipase activity may also be affected by apolipoproteins and drugs. Although insulin may decrease hormone-sensitive lipase (limiting fatty acid release from adipocytes), insulin increases lipoprotein lipase activity, which reduces triglyceride blood levels. Apolipoprotein C-III (ApoC-III) is a small protein that resides on triglyceride-rich VLDL and chylomicron particles that inhibits lipoprotein lipase, impairs hepatic uptake of triglyceride-rich lipoproteins (e.g., lipoprotein remnants), contributes to insulin resistance, and generally promotes elevated triglyceride levels. Fibrates and omega-3 fatty acids are lipid-altering pharmacotherapies that reduce ApoC-III levels, increase lipoprotein lipase activity and thus lower triglyceride blood levels.

The hormone effects on hormone-sensitive lipase and lipoprotein lipase affect circulating free fatty acid levels. After meals, circulating free fatty acids are dramatically decreased (by 70%–90%), substantially as a result of increased insulin levels, which upregulate lipoprotein lipase and downregulate hormone-sensitive lipase, reducing triglyceride blood levels, increasing transport of fatty acids into fat cells, and “trapping” fatty acids in the form of intracellular triglycerides (because of reduced intracellular triglyceride lipase activity). During fasting, decreased insulin levels downregulate lipoprotein lipase and upregulate hormone-sensitive lipase, and increase the release of free fatty acids from adipocytes into the circulation. These circulating free fatty acids may undergo β-oxidation by muscle for energy or undergo hepatic β-oxidation, ketogenesis, lipogenesis, and gluconeogenesis. Prolonged fasting for longer than 7 days may markedly increase circulating free fatty acids, resulting in hepatosteatosis, ketosis, and insulin resistance and potentially a rise in triglyceride blood levels.

Especially if adipocytes have adiposopathic impairment of adipogenesis and function, then during times of positive caloric balance, free fatty acids not stored in adipocytes and may be shunted to other body tissues, such as the liver, muscle, and pancreas. This may result in "lipotoxicity," which is the dysfunction of body organs promoted by deposition of excessive free fatty acids and their products (e.g., ceramides and diacylglycerols). Lipotoxicity may result in hepatic and muscle insulin resistance, potential insulinopenia from the pancreas, and dysfunction of other body organs (e.g., the heart, vasculature, kidney). Patients with type 2 diabetes often have increased circulating fasting and postprandial free fatty acids compared with those without type 2 diabetes, and also often have increased insulin resistance and decreased pancreatic insulin release relative to glucose levels. In summary, elevated circulating free fatty acids may contribute to “lipotoxicity.” The levels of free fatty acids in the circulation can be attributable to: (1) postprandial or fasting state; (2) adipose tissue storage capacity; and (3) the degree by which other body organs either store free fatty acids as triglycerides or metabolize free fatty acids. The processes involved in intestinal fat metabolism are dependent on intestinal digestion and gut hormones. Table 1 describes bariatric procedure effects on gut hormones important for fat and lipid digestion, which may influence lipid levels [3,11–53].

Intestinal carbohydrate metabolism

Monosaccharides can be directly absorbed through the mouth mucosa (e.g., therapeutic use of oral glucose agents to treat hypoglycemia), whereas consumed plant starches and animal glycogen must undergo digestion from chewing and salivary gland amylase, which begins to hydrolyze these complex carbohydrates to more simple sugars. Once in the small intestine, chyme (the acidic gastric juices and partially digested food) promotes release of cholecystokinin by small intestine L-cells, causing the release of bile from the gallbladder, as well as digestive juices from the pancreas, which include: (1) lipase, cholesteryl esterase, and phospholipase for fat digestion; (2) trypsin, chymotrypsin, and carboxypolypeptidase for protein digestion; and (3) amylase, which further catalyzes the hydrolysis of complex carbohydrates (e.g., starches and glycogen, not cellulose) to more simple sugars (Fig. 1; Table 1) [3,11–53]. Afterward, monosaccharides (e.g., glucose, fructose, galactose) are mostly absorbed across the brush border of the small intestine by transporters, such as facilitative passive hexose glucose transporters (e.g., GLUT-2, GLUT-5, etc.) or active sodium-coupled glucose cotransporters (e.g., SGLT-1, etc.) [56]. The major circulatory hexose transporter found in adipocytes and muscle is GLUT-4, which is regulated by insulin. Once delivered to the liver or muscle, fructose and galactose are converted to glucose. Once glucose is phosphorylated, it may interact with uridine triphosphate to form uridine diphosphate glucose, which allows for linkage to other glucose and, ultimately, glycogen formation. Lipogenesis is limited in muscle. In the liver, if glycogen stores are replete, then an increased dietary consumption of carbohydrates may increase circulating insulin and glucose and, through SREBP-1–mediated increase in lipogenic gene expression, increase fat storage in the liver. In adipocytes, the increase in circulating insulin and glucose from consumption of carbohydrates may promote peroxisome proliferator activated receptor γ–mediated lipogenic gene expression. Although not clear that simple sugars differ in their potential adverse health effects when evaluated in the manner typically consumed, and at typical amounts in the human diet [57], fructose (such as from high-fructose corn syrup) is often described as especially promoting fatty liver, obesity, and insulin resistance [58]. The processes involved in carbohydrate metabolism are dependent on intestinal digestion and gut hormones. Table 1 describes bariatric procedures’ effects on gut hormones important for carbohydrate digestion, which may influence lipid levels [3,11–53].

Intestinal protein metabolism

Proteins are metabolized in the stomach by gastric acid (hydrochloric acid, potassium chloride, and sodium chloride) ecreted by stomach parietal cells, which breaks down proteins into amino acids. Other stomach epithelial lining cells produce gastric pepsin (most active at low pH), which breaks down collagen, the main structural protein found in animal connective tissue. Once in the small intestine, cholecystokinin-mediated release of trypsin, chymotrypsin, and carboxypolypeptidase (Fig. 1; Table 1) [3,11–53] from the pancreas continues to hydrolyze proteins into amino acids, which are then absorbed into circulation (Fig. 1; Table 1) [3,11–53]. Once delivered to the liver, surplus amino acids undergo deaminization and are converted into glucose via the alanine cycle. Nitrogen from the amine group of amino acids is converted to urea (e.g., urea cycle), which is excreted by the kidney. The carbon components of amino acids may also be converted to keto acids, giving rise to acetyl-CoA and generation of fatty acids for lipogenesis. The processes involved in intestinal protein metabolism are dependent on intestinal digestion and gut hormones. Table 1 describes bariatric procedures’ effects on gut hormones important for protein digestion, which may influence lipid levels [3,11–53].

Bariatric procedures and nonlipid atherosclerotic cardiovascular disease risk factors

Patients with obesity are at increased risk for cardiovascular disease [59]. Improvement in dyslipidemia is an important health benefit of bariatric procedures, helping to account for a reduction in CVD risk. However, bariatric procedures reduce multiple CVD risk factors [60]. Table 2 lists a number of CVD disorders caused by adiposopathy [61]. Table 3 describes the potential effects of bariatric procedures on atherosclerotic cardiovascular disease (ASCVD) risk factors, as well as adiposopathic markers that may contribute to metabolic disease, most of which are ASCVD risk factors [62–117].

Bariatric procedures and dyslipidemia

Lipids and atherosclerosis

An increase in atherogenic lipoprotein particle number is a root cause of atherosclerosis [118,119]. Lipoprotein concentration can be measured directly [120] or via the surrogate measure of apolipoprotein B (apoB), wherein 1 molecule of apoB resides on every atherogenic lipoprotein [120,121]. ApoB is thus a measure of the concentration of cholesterol-containing atherogenic lipoproteins such as LDL, VLDL, IDL, and VLDL remnants. The cholesterol carried by these atherogenic lipoproteins is termed atherogenic cholesterol, even as it is recognized that apoB–containing and cholesterol-containing lipoproteins themselves more precisely promote atherosclerosis [118,119].

Multiple epidemiologic studies have long supported the “cholesterol hypothesis.” An increase in atherogenic cholesterol increases ASCVD risk, and a decrease in atherogenic cholesterol reduces ASCVD risk [118]. The 2013 National Lipid Association Consensus Statement on the lipid effects of obesity noted that adipocytes and adipose tissue store the greatest amount of body lipids, including triglycerides and free cholesterol [3]. This Consensus Statement also acknowledged that adipocytes and adipose tissue have active endocrine and immune functions, whose disruption results in adiposopathy. Among the cellular findings of adiposopathy include adipocyte hypertrophy (potentially resulting in dysfunction of intracellular organelles such as mitochondria and endoplasmic reticula), growth of adipose tissue beyond its vascular supply (potentially contributing to adipocyte and adipose tissue hypoxia), increased number of adipose tissue immune cells (increasing the potential for proinflammatory responses, such as increased tumor necrosis factor, interleukin-6, and C-reactive protein), and ectopic fat deposition in nonadipose body organs (e.g., liver and muscle). If peripheral subcutaneous adipose tissue storage is limited, then positive caloric balance may also result in “energy over-flow” to other fat depots, such as visceral, pericardial, perivascular, and other periorgan fat. Thus, during positive caloric balance, the limitation in energy (i.e., fat) storage in peripheral subcutaneous tissue combined with an increase in fat deposition in other fat depots helps explain why visceral adiposity might be considered a surrogate marker for global fat dysfunction and why central obesity is a clinical marker of adiposopathy [7].

Adiposopathy (“adipose-opathy,” or “sick fat”) is defined as pathologic adipose tissue anatomic and functional disturbances promoted by positive caloric balance in genetically and environmentally susceptible individuals that results in adverse endocrine and immune responses, which in turn may promote metabolic diseases (e.g., dyslipemia, hyperglycemia, high blood pressure, etc.) and cardiovascular “Malabsorptive” surgical procedures are often described to represent “metabolic surgeries,” in that such procedures may alter gastrointestinal hormonal secretions and favorably influence intestinal bile acids, microbiota, and intestinal gluconeogenesis, which all may contribute to improvement in metabolic diseases, possibly independent of weight loss [65,124]. However, laparoscopic Roux-en-Y gastric bypass (sometimes considered “malabsorptive”) and sleeve gastrectomy (sometimes considered “restrictive”) may have similar degrees of weight loss and improved metabolic health outcomes (e.g., dyslipidemia, diabetes mellitus, high blood pressure) [125,126]. Given the similarities in weight loss and metabolic outcomes with the “malabsorptive” laparoscopic Roux-en-Y gastric bypass and the “restrictive” sleeve gas- trectomy bariatric procedures, all common bariatric procedures might best be considered “metabolic” surgical procedures. That is because the most consistent and unifying aspect of all of these common bariatric procedures is the reduction in body fat, which improves adipocyte and adipose tissue function, and which in turn improves metabolic disease [122]. Thus, the choice of the preferred bariatric procedures for metabolic diseases (including dyslipidemic patients with overweight or obesity) is best determined by the anticipated risks and benefits, expertise of the surgeon and affiliated facility, as well individual characteristics and preferences of the patient. Another consideration is comparative health metabolic outcomes (e.g., dyslipidemia, type 2 diabetes mellitus, hypertension) wherein gastric bypass (“malabsorptive”) may have improved long-term metabolic outcomes compared with gastric banding (“restrictive”) [63]. What may be less important in the bariatric procedure selection is the somewhat artificial and perhaps unhelpful “restrictive” versus “malabsorptive” label, at least with respect to comparisons of the expected weight loss and metabolic effects of laparoscopic Roux-en-Y gastric bypass versus sleeve gastrectomy.

Bariatric procedures and lipid effects

Table 4 describes the effects of various bariatric procedures on lipid parameters [81,107,127–149]. Some observations include the following:

  1. The greater the fat mass loss, the greater the improvement in dyslipidemia. According to the 2014 Cochrane Collaboration update on surgery for weight loss in adults [125], compared with nonsurgical interventions, bariatric surgery results in greater improvement in weight loss adverse health consequences, regardless of the type of procedures used. In general, weight loss is similar between Roux-en-Y gastric bypass and sleeve gastrectomy, with both promoting greater weight loss than adjustable gastric banding. For patients with very high body mass index, biliopancreatic diversion with or without duodenal switch may result in greater weight loss than Roux-en-Y gastric bypass. Many of the reports referenced in Table 4 [81,107,127–149] are consistent with the notion that the greater the fat mass loss, the greater the improvement in lipid (and other metabolic) parameters [150], as often occurs with the more “malabsorptive” procedures [151,152]. Table 4 [81,107,127–149] escribes the major lipid parameters most often reported as improved and includes reductions in LDL cholesterol, total cholesterol, and triglyceride levels, as well as (after 6 mo or so), increases in HDL cholesterol.

  2. Data regarding the lipid effects of biliopancreatic diversion/duodenal switch are less reported than with laparoscopic gastric banding, Roux-en-Y gastric bypass, and sleeve gastrectomy, probably because it is a less common bariatric procedure.

  3. Bariatric procedures allow for a decrease in the use of drugs for treatment of dyslipidemia [127,153], as well as a decrease in drugs used for treatment of diabetes mellitus and blood pressure, compared with medical therapy for obesity [154,155]. Thus, not only are bariatric surgeries superior to medical management in improving metabolic parameters among patients with obesity, but bariatric procedures often allow for less polypharmacy postoperatively. This may allow for both improved lipid levels and reduced lipid-altering drug therapies [156].

  4. HDL cholesterol may decrease during active weight loss (particularly the first 6 mo after bariatric surgery) and then may ultimately increase above baseline. The potential for an initial reduction in HDL cholesterol levels during active weight loss is a well-known phenomenon in clinical lipidology, occurring not only with bariatric procedures, but also some weight management pharmacotherapies, as well as nutritional weight loss—especially with fat-restricted nutritional intervention [3]. As per Part 1 of this Scientific Statement, human trials suggest that within the first 6 months during rapid weight loss with bariatric surgery, both HDL and apoE decrease. The initial drop in HDL cholesterol levels may reflect the gradual qualitative switch of HDL from apoE-containing to more functional apoAI-containing HDL particles [128,157,158].


One of the primary, if not the primary, lipid treatment target is non-HDL cholesterol, which includes the cholesterol carried by all atherogenic lipoproteins (e.g., the cholesterol carried by low-density lipoproteins, intermediate-density lipoproteins, very low density lipoproteins, VLDL remnants, chylomicrons, chylomicron remnants, and lipoprotein [a]) [118]. Non-HDL cholesterol is a calculation of total cholesterol minus the cholesterol carried by HDL particles (i.e., total cholesterol – HDL cholesterol). Likely because of its inclusive nature, non-HDL cholesterol is a better predictor of ASCVD risk than LDL cholesterol. Furthermore, changes in non-HDL cholesterol with dyslipidemia treatment are more strongly associated with reduced ASCVD risk than with on-treatment LDL cholesterol levels [119]. Yet despite its primary importance regarding diagnosis and treatment of dyslipidemia, non-HDL cholesterol is rarely reported in bariatric procedure clinical trials.

Similarly, an integral contributor to atherosclerosis is incorporation of atherogenic lipoproteins within the subendothelia, which promotes the inflammatory process potentially leading to ASCVD events (see Part 1 of this Scientific Statement). Given that 1 molecule of apoB resides on every atherogenic lipoprotein, apoB can be considered a surrogate for atherogenic lipoprotein particles. Diagnostically, whenever discordance exists between LDL cholesterol and either LDL particles or apoB, the latter 2 lipid parameter are superior in predicting ASCVD risk [119]. That is why apoB is sometimes considered a treatment target, with assigned treatment goals, by various interna- tional lipid guidelines [118,159,160]. Despite the central role of apoB and LDL particle numbers to atherosclerosis, these parameters are rarely reported in bariatric procedure clinical trials.

Yet another lipid parameter with scarce reporting is remnant lipoproteins. Increased triglyceride-rich lipoproteins are potentially transformed into lipoprotein remnants. Remnant particles may become incorporated into arterial subendothelia. Although remnant lipoproteins are much larger than LDL, and thus may have less potential to cross the endothelium, each remnant particle contains about 40 times more cholesterol compared with low-density lipoproteins. Thus, remnant lipoproteins are important contributors to atherosclerosis, and postprandial dyslipidemia is an important ASCVD risk factor [161,162]. Some literature supports that bariatric surgery improves both fasting and postprandial lipid levels, possibly because of impaired intestinal cholesterol absorption and improved insulin sensitivity, which might enhance postprandial clearance of triglyceride-rich lipoproteins [129,163,164]. However, given the high prevalence of hypertriglycemia in the population, the importance of remnant lipoproteins in the process of atherosclerosis, and the potential of bariatric procedures to improve clearance of triglyceride-rich lipoproteins and remnant lipoproteins, the amount of data regarding the effects of bariatric procedures on remnant lipoproteins could be more robust.

Finally, 2 other lipid parameters scarcely reported in trials of bariatric procedures include lipoprotein a (Lp[a]) and LDL particle size. Lp(a) is a lipoprotein similar to LDL and consists of an LDL molecule attached to a second protein, apo (a). Apo (a) has a structure similar to plasminogen. Although elevated Lp(a) is a risk factor for ASCVD, nutritional intervention or increased physical activity is not known to decrease its levels. Therefore, it is not surprising that on the rare instances Lp(a) was reported in bariatric procedure clinical trials, Lp(a) levels were not changed. The other lipid parameter scarcely reported is LDL particle size. Presumably, the smaller the LDL particle size (as often occurs in patients with adiposopathy, glucose intolerance, diabetes mellitus, and metabolic syndrome), the greater the potential to enter the arterial subendothelial wall. Furthermore, smaller LDL particles may have less affinity to LDL receptors, increasing their persistence in the circulation and exposure to the arterial endothelia. Smaller LDL particles are more easily oxidized upon interactions with subendothelial macrophages. However, although lipoprotein particle size may have diagnostic value, little evidence supports lipoprotein particle size as a treatment target or a clinically useful postintervention metric [119,120,165].

Bariatric procedures and atherosclerotic cardiovascular disease

Historical importance of intestinal procedures in validating the cholesterol hypothesis: Program on Surgical Control of the Hyperlipidemias (POSCH)

At least since the 1960s, intestinal surgery (i.e., ileal bypass) was employed as a way to reduce hyperlipidemia [166]. One of the first classic clinical trials to test the “cholesterol hypothesis” was the Program on Surgical Control of the Hyperlipidemias (POSCH), which was a randomized, secondary intervention trial among patients with prior myocardial infarction, evaluating the combination of nutritional intervention and partial ileal bypass (PIB) [167]. In this study of 838 participants, an interim analysis revealed that 396 (196 control and 200 surgical patients) had complete 5-year lipoprotein results [168]. Compared with control patients, the PIB group had a 24% reduction in total cholesterol and a 38% reduction in LDL cholesterol. Also compared with the control group, although triglyceride and VLDL cholesterol levels were higher, the PIB group had significantly lower apolipoprotein B-100 levels (reflecting an overall reduction of atherogenic lipoprotein particle number), as well as consistently higher HDL cholesterol and apolipoprotein A-I and HDL-2 levels. It was noted these lipoprotein changes were greater than reported from previous trials of dietary or pharmacologic intervention, which at the time included clinical trial results of bile acid resins [169]. Based on these lipoprotein effects of this intestinal surgery, the hypothesized predictive outcome was that PIB would demonstrate a reduction in ASCVD morbidity and mortality. After a mean follow-up of 9.7 years, the PIB group had a statistically significant mean weight loss of 5.3 kg (weight in the control group was not reported) [170]. Compared with the control group, PIB was found to produce sustained improvement in lipid levels, as well as a statistically significant 35% reduction in the combined endpoints of death as a result of coronary heart disease and confirmed nonfatal myocardial infarction, as well as a statistically significant reduction in coronary artery bypass grafting and reduction in angiographic atherosclerotic lesion progression. PIB also resulted in a reduction in overall mortality (estimated 149 deaths per 1000 in the control group versus 116 per 1000 in the PIB group), although this did not achieve statistical significance. Overall, this sentinel trial of an intestinal surgical procedure provided “strong evidence supporting the beneficial effects of lipid modification in the reduction of atherosclerosis progression” [170].

Bariatric procedures, cardiovascular disease risk factors, cardiovascular disease outcomes, and overall mortality

Regarding cardiovascular disease risk factors, current bariatric surgical procedures for the purpose of weight loss have shown a consistent reduction in cardiovascular risk factors. Most studies of bariatric procedures report improvement in lipid levels (Table 4) [81,107,127–149], as well as improvement in glucose levels, blood pressure, endothelial function, C-reactive protein, and ASCVD risk scores, such as the Framingham risk score [60]. In a systematic review of cardiovascular risk factors [171], bariatric surgery improved hyperlipidemia in 65% of patients, as well as improved diabetes mellitus in 73% and hypertension in 63% of patients. Echocardiographic data after bariatric surgery indicated significant improvements in left ventricular mass and function [171].

Regarding cardiovascular events, in a meta-analysis of clinical trials comparing bariatric surgery versus nonsurgical treatment, bariatric surgery patients had a statistically significant reduction in myocardial infarction (odds ratio = .54), stroke (odds ratio =1 .49), and composite ASDVD events (odds ratio = .54) and a 50% reduction in overall mortality [80].

Regarding deaths, the Swedish Obese Patients (SOS) study was the first large-scale, long-term, prospective, controlled trial to report the effects of bariatric surgery on the incidence of cardiovascular disease and overall mortality, as well as diabetes mellitus and cancer [172]. The SOS study evaluated 2010 patients with obesity who underwent bariatric surgery (gastric bypass [13%], banding [19%], and vertical banded gastroplasty [68%]), and compared the health outcomes to 2037 contemporaneously matched obese control patients receiving usual care. The age of participants was 37–60 years and body mass index (BMI) was Z34 kg/m2 in men and Z38 kg/m2 in women. Follow-up periods varied from 10 to 20 years. The mean changes in weight after 2, 10, 15, and 20 years were –23%, –17%, –16%, and –18% in the surgery group and 0%, 1%, –1%, and –1% in the control group, respectively. Compared with usual care, bariatric surgery produced a reduction in overall mortality (primary endpoint) and myocardial infarction, as well as decreased diabetes mellitus, stroke, and decreased cancer in women. In a 2- and 10-year follow-up publication, LDL cholesterol, non-HDL, apolipoprotein B, and lipoprotein particle number were not reported. However, although total cholesterol did not statistically change at 10 years, bariatric surgery did produce significant decreases in triglyceride and significant increases in HDL cholesterol levels [3,173].

Postbariatric deficiencies of vitamins, minerals, and trace elements, and their potential lipid effects

The main purpose of the gastrointestinal tract is to digest foodstuffs, absorb nutrients, and expel waste. The previous section described digestion of food, which is important in understanding the potential mechanisms of action of bariatric procedures. Also relevant is an understanding of vitamin, minerals, and trace element absorption, as well as the location of nutrient absorption. Vitamins are essential organic compounds that cannot be synthesized in the body. Vitamins are derived from plant and animal foods, and necessary for metabolic processes, such as serving as a nonprotein facilitator (coenzyme) for protein enzymes. Minerals (e.g., calcium, phosphorous, magnesium, potassium, and sodium) are nonorganic substances necessary for important biological processes (e.g., vital part of an enzyme). Trace elements (e.g., iron, cobalt, zinc, selenium, molybdenum, and iodine) are nonorganic substances required by the body for biological functions (e.g., vital part of an enzyme), but only in minute amounts. Regarding location of absorption, the stomach represents the location for substantial absorption of water and alcohol. The duodenum is especially important for absorption of fatty acids, amino acids, some minerals (e.g., iron and calcium, especially during calcium deficiency). Largely because of its length and location, the jejunum absorbs the greatest amount of fatty acids, simple sugars, and amino acids, as well as most minerals (e.g., calcium) and vitamins. The ileum is a location important for absorption of bile salts and vitamin B12, as well as some vitamins and minerals. Finally, the colon absorbs some water, sodium chloride, potassium, and intestinally derived vitamin K. Bariatric procedures often involve the manipulation of the location of gastrointestinal tract nutrient absorption, which may directly affect absorbed nutrient quantity and quality; both can affect lipid blood levels.

The American Association of Clinical Endocrinologists, the Obesity Society, and the American Society for Metabolic and Bariatric Surgery have issued guidelines toward the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient. This guideline includes a checklist of items to monitor (including vitamins and mineral assessments) based on the type of bariatric procedure (laparoscopic gastric banding, laproscopic sleeve gastrectomy, Roux-en-Y gastric bypass, and biliopancreatic diversion with duodenal switch) as well as the timing for such assessments [174]. In general, postprocedure micro- nutrient malabsorption deficiencies in vitamins, minerals, and trace elements are more common with bariatric procedures that involve intestinal resection, with relocation of intestinal connections. Thus, so-called malabsorptive procedures such as gastric bypass and biliopancreatic diversion/duodenal switch are reported to have a greater risk for postprocedure deficiencies in vitamins, minerals, and trace elements than laparoscopic adjustable gastric banding [175]. In general, although multivitamin supplementation is recommended for all bariatric procedures, laparoscopic adjustable gastric banding has among the lowest rate of postoperative micronutrient deficiency. Sleeve gastrectomy also has a low rate of postoperative micronutrient deficiency, although monitoring of selected vitamins, minerals, and trace elements are often performed. Roux-en-Y gastric bypass has a higher rate of postoperative micronutrient deficiency, and selected vitamins, minerals, and trace elements are routinely performed. Finally, biliopancreatic diversion/duodenal switch has among the highest rate of postoperative micronutrient deficiency, and selected vitamins, minerals, and trace elements are routinely performed. In the absence of signs or symptoms of deficiency, and in addition to complete blood cell count, general blood chemistries (including liver enzymes and glucose levels), and lipid profile, the vitamin, mineral, and trace element levels most commonly evaluated after bariatric surgery include thiamine, folate, vitamin B12, 25-hydroxyl-(OH)-vitamin D, parathyroid hormone, calcium, phosphorous, magnesium, iron, and ferritin, with most of these applicable in detecting potential causes of postoperative anemia. Post-operative dual-energy X-ray (DEXA) is also sometimes performed to assess bone mineral density and body composition.

Postbariatric procedure vitamin, mineral, and trace element deficiencies, and their effects on lipid levels, are described in Tables 5 [1,175–224] and 6 [1,111,175,181–184,225–244]. It is challenging to predict how bariatric procedures may affect lipid levels in patients with post-operative micronutrient malabsorption of vitamins, minerals, and trace elements from the intestine. That is because micronutrient deficiencies are often present before bariatric procedures (e.g., vitamin D), and because postoperatively, if 1 vitamin, mineral, or trace elements is deficient, then it is likely the underlying malabsorptive state is affecting other vitamins, minerals, and trace elements as well. Given that different vitamins, minerals, and trace elements may facilitate different effects on nutrient metabolism, via different effects on influx, efflux, anabolism, and catabolism, then the effect of multiple vitamin, mineral, and trace element deficiencies will likely have mixed biologic influences on determination of net lipid blood level (some deficiencies may increase lipid levels; others may decrease lipid levels). In cases of both micro and macronutrient malabsorption, diminished intestinal nutrient absorption may also substantially affect lipid blood levels. Table 7 describes replacement of select postoperative vitamin and mineraldeficiencies [1,245,246]. This may help explain why bariatric procedures may have varied postoperative effects on lipid blood levels, with lipid levels dependent on: (1) postbariatric procedure nutritional and physical activity, (2) caloric intake and other potential effects on macronutrients, (3) hormonal and metabolic effects of bariatric surgery, and (4) the degree by which micronutrient deficiencies are avoided or successfully treated.


Bariatric procedures improve multiple cardiovascular risk factors, including glucose metabolism, blood pressure, factors related to thrombosis, kidney function, adipocyte and adipose tissue function, inflammatory markers, and vascular markers. This helps explain why bariatric procedures may reduce ASCVD risk. Bariatric procedures also improve lipid levels, which is another potential contributor to reduced ASCVD risk. Principles that apply to bariatric procedures and lipid levels include the following: (1) The greater the fat mass loss, the greater the improvement in lipid parameters such as triglycerides and especially LDL cholesterol; (2) bariatric procedures allow for a decrease in the use of drug treatment for dyslipidemia; and (3) after bariatric procedures, HDL cholesterol may transiently decrease for the first 3–6 months after the procedure, which is usually followed by an increase in HDL cholesterol above the baseline value before the bariatric procedure. Finally, data are scarce regarding the effects of bariatric procedures on some of the lipid parameters of most interest to lipidologists, such as non-HDL cholesterol, apolipoprotein B, and lipoprotein particle number and remnant lipoproteins.


Harold Bays, M.D., is not a bariatric surgeon and has no industry disclosures regarding bariatric procedures. However, regarding other disclosures, in the past 12 months, Dr. Harold Bays’ research site has received research grants from Amarin, Amgen, Ardea, Arisaph, Catabasis, Cymabay, Eisai, Elcelyx, Eli Lilly, Esperion, Hanmi, Hisun, Hoffman LaRoche, Home Access, Janssen, Johnson and Johnson, Merck, Necktar, Novartis, Novo Nordisk, Omthera, Orexigen, Pfizer, Pronova, Regeneron, Sanofi, Takeda, and TIMI. In the past 12 months, Dr. Harold Bays has served as a consultant and/or speaker to Alnylam, Amarin, Amgen, Astra Zeneca, Eisai, Eli Lilly, Merck, Novartis, NovoNordisk, Regeneron, Sanofi and Takeda.

Peter Jones, M.D., reports being a consultant and scientific advisor to Merck, Amgen, Sanofi/Regeneron, and Chief Scientific Officer for the National Lipid Association.

Terry A. Jacobsen reports no disclosures.

David E. Cohen, M.D., Ph.D. is not a bariatric surgeon and has no industry disclosures regarding bariatric procedures. However, regarding other disclosures, in the ast 12 months, Dr. David Cohen has served as a consultant to Aegerion, Merck, Genzyme, Synageva, and Intercept.

Carl Orringer, M.D. reports no disclosures.

Shanu N. Kothari, M.D., Dan E. Azagury, M.D., John M. Morton, M.D., and Ninh Nguyen, M.D. report no disclosures.


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