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Metabolism 154.

Exploiting the Gut to Treat Obesity Soumitra Ghosh

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Newer Lipid Guidelines: Interpretation and Applications for Indians SN Narasingan

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Management of Dyslipidemia in India: What should be Our Approach in View of the Differing Guidelines

Santanu Guha, Sumanta Chatterjee

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Pharmacotherapy of Obesity Sachin Kumar Jain, Rati Singh, Ramesh Aggarwal, Ritika Sud

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Exploiting the Gut to Treat Obesity

ABSTRACT

The current obesity pandemic is due to interplay of genetic, epigenetic and environmental factors. It is now increasingly realised that the gut plays an important role in energy homeostasis; and impairment in its functioning results in obesity. Three major players from the gut gastrointestinal peptides, gut microbiota and bile acids are involved in energy homeostasis. Structural and functional changes of the above three have been observed in obesity. Thus, exploiting these pathophysiologic factors to develop the pharmacotherapeutic agents to correct the defect is the major cornerstone of obesity management.

INTRODUCTION

Obesity is global pandemic today, accelerating at an alarming speed. Between 1980 and 2014 the prevalence of obesity doubled. In 2014, according to the World Health Organization 1.9 billion adults were overweight, of which 600 million were obese1. In the same report, 41 million children under the age of 5 years were overweight or obese. According to the ICMR-INDIAB-3 study the predicted prevalence of generalised and abdominal obesity in India was 135 and 153 million respectively2.

This pandemic threatens to nullify all the achievements mankind has achieved so far in the field of medical science in the past centuries. For this pandemic to be contained and managed effectively we need to understand why obesity occurs.

Obesity is a very complex disease. Our current ‘obesogenic’ lifestyle definitely has a big role in precipitating this pandemic. However obesity arises from interplay of various factors including, but not limited to, genetic, epigenetic and environmental factors. Environmental influences can have effects from as early as intrauterine life continuing throughout the life-span of an individual.

Thus early life environment like mother’s health and disease, mode of delivery, mode of feeding, exposure to antibiotics and later life environment like diet and physical inactivity interact in a very diverse way to result in obesity. Environment has a major role in influencing genetic expression or epigenetics.

ROLE OF THE GUT IN ENERGY HOMEOSTASIS

Our Gut is Programmed to Increase Efficiency of Nutrient Extraction

Our gastrointestinal tract (the gut) is the only ‘natural and normal’ route through which we get calories and nutrients for our survival. From an evolutionary perspective the gut is programmed and modified in such a way so that maximum nutrient is extracted from

Soumitra Ghosh

the food we consume. This ‘effectiveness’ of the gut was necessary for survival when food supply was scarce and intermittent. But in today’s environment of excess and continuous food supply the adaptations made by the gut for survival becomes maladaptive. The gut does possess corrective mechanisms to prevent ‘energy overload’ by releasing peptide hormones that reduce appetite and decrease energy extraction from the food we consume.

However, these corrective mechanisms are non-functional in obesity, both as cause and effect of obesity.

Therefore ‘exploring’ and ‘exploiting’ the gut would be an ideal, scientific and effective way to manage obesity.

A lot of our understanding about the role of gut in the pathogenesis of obesity and thereby making it an ideal target for obesity management has emerged from the impressive weight loss seen with bariatric surgery.

Bariatric surgery is associated with a number of operative, post-operative and lifelong complications and thus can never remain the permanent treatment of morbid obesity.

But the understanding of the science of energy homeostasis from bariatric surgery remains the cornerstone for development of novel pharmacotherapeutic agents for the management of obesity.

Gut Peptides, Gut Microbiota and Bile Acids Play Major Role in Energy Homeostasis

The important players in the gut that have a role in energy homeostasis are i) gut hormones, ii) gut microbiota, and iii) bile acids. Their proper functioning results in good health and normal weight. But disturbance of these three important players singly or in combination can give rise to problems of either obesity or underweight. And thus, targeting these three becomes an important therapeutic tool for obesity.

GUT HORMONES: ROLE IN APPETITE AND WEIGHT HOMEOSTASIS

Hypothalamus integrates Energy Signals and Respond Accordingly

The body tries to maintain an intricate homeostasis of energy stores and thereby of weight. The hypothalamus plays the central role in this homeostasis by modifications of food intake, energy expenditure and energy allocation depending on signals it receives. The signals from the periphery especially from the gut and adipose tissues, tells the hypothalamus about the body’s energy reserve and the hypothalamus respond accordingly. The hypothalamus also receives supply from the cortical and mesolimbic areas which are influenced by emotions, behaviour and other factors.

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Long Term and Short Energy Signals Arise From Adipose Tissue and Gut Respectively

METABOLISM

Signals from the periphery to the hypothalamus are of 2 major types: long term and short term energy reserve signals3,4. The long term adiposity signals arise mainly from the white adipose tissue in the form of leptin.

Insulin is also a long-term adiposity signal. When body energy stores are increased leptin and insulin relay to the hypothalamus to decrease energy intake and increase energy expenditure3. Obesity is associated with both leptin and insulin resistance5.

Short term peripheral signals regarding meal initiation or termination arise from the gut in the form of hunger or satiety signals. These signals reach the hypothalamus, mainly at the arcuate nucleus (ARC) which is partially permeable to the blood brain barrier6. In the ARC there are two groups of neurons: appetite suppressing proopiomelanocortin (POMC) and appetite stimulating agouti-related peptide (AgRP) and neuropeptide Y (NPY) neurons7. These neurons project into the ventromedial and lateral areas of the hypothalamus involved respectively in satiety and hunger8.

Appetite is Modulated by Two Major Mechanisms: Homeostatic and Hedonic

Appetite is a complex issue and controlled by at least two mechanisms: homeostatic and hedonic mechanisms9.

The homeostatic mechanism described above depends on the body energy store and responds to correct any imbalances in it. Thus ghrelin is released from the stomach when energy stores are depleted, stimulating hunger and promoting consumption of food10. Contact with nutrients and distension of gut following eating, results in the release of a number of gastrointestinal peptides like glucagon-like peptide 1 (GLP-1), peptide YY (PYY), pancreatic polypeptide (PP), cholecystokinin (CCK) and oxyntomodulin (OXM) which delays gastric emptying and suppresses appetite by central and peripheral mechanisms11. The hedonic control of appetite is more complex and is under the control of the mesolimbic (reward) areas and others. This pathway is controlled by emotion, taste, texture, colour and smell of food. This pathway can continue to be active even when homeostatic mechanism has replenished energy stores. However the two mechanisms of appetite regulation are not exclusive of each other and frequently interact. Thus ghrelin, a hormone mainly acting via the homeostatic pathway also stimulates the hedonic pathway12.

Gut Signals are Impaired in Obesity: Aim of Treatment is to Replace the Defective Signals

Gut signals are impaired in obesity and bariatric surgery acts by correcting this defect to a certain extent.

Modulation of gut hormone levels by pharmacotherapy forms an important cornerstone of obesity treatment, without the risks of bariatric surgery.

As discussed above, important gut hormones involved in satiety are GLP-1, PYY, PP, CCK and OXM. GLP-1 is released from the L cells of the small intestine and colon

in response to nutrients like glucose, amino acids and fatty acids in the gut13. It promotes weight loss by central mechanisms and peripheral mechanisms. Centrally it acts directly on the hypothalamus causing an anorexigenic effect and peripherally it slows gastric emptying resulting in satiety. It also inhibits gastric acid secretion. It stimulates glucose dependent insulin secretion and inhibits glucagon secretion and therefore is a good anti-diabetic agent.

Obesity is associated with decreases in post-prandial GLP-1 levels. However obese individuals respond well to the anorexigenic effects of externally administered GLP-1 agonists14. Bariatric surgery has been shown to enhance post-prandial GLP-1 response15. Endogenous GLP-1 has a short half-life of around 5 minutes due to the effects of dipeptidyl peptidase-IV (DPP-IV) enzymes. Long acting analogues are already available for the treatment of diabetes. Liraglutide, a long acting GLP-1 analogue at a dose of 3mg subcutaneously daily has been approved by the USFDA for the treatment of obesity.

PYY is a 36 amino acid polypeptide secreted from the L cells of the intestine and belongs to the same family as PP. PYY3-36 is the more active form of the peptide and acts via the Y family of G-protein coupled receptors especially Y216. Similar to GLP-1 it decreases appetite and induces weight loss by peripheral and central mechanisms. Postprandial levels are low in obesity and levels of PYY3-36 rises following bariatric surgery17. Nasal sprays of PYY3-36 have shown modest weight loss in humans18. CCK, PP and OXM are other gastrointestinal peptides released in response to a meal and associated with weight loss by peripheral and central mechanisms. CCK released from the jejunum and duodenum was the first gut peptide known to affect appetite in humans19. CCK receptor antagonists have been studied in obese humans but the resultant weight loss was unsatisfactory20. PP is secreted mainly from the pancreas but also from L cells of the intestine and acts via the Y4 receptor in the hypothalamus21. OXM is released from the oxyntic cells of the stomach22. Like other gut peptides they cause weight loss by central and peripheral mechanisms and have also been found to increase energy expenditure23,24. All the gut peptides described above are low in obesity and rise to varying levels after metabolic surgery.

Ghrelin is the only gut peptide that stimulates appetite25.

It acts via its growth hormone secretagogue receptor in the hypothalamus and the brain. The expected fall in post-prandial ghrelin levels does not occur in obesity and hence hunger persists. In earlier studies bariatric surgery was shown to decrease ghrelin levels. However over the ensuing months after surgery, the ghrelin levels continue to rise reaching pre-operative levels months after surgery26. Ghrelin antagonists have been used in experimentally induced obesity in mice resulting in weight loss.

Following Roux-en-Y gastric bypass (RYGB), GLP-1 levels have been shown to rise by 10-fold a few days after surgery27. Levels of other gut peptides especially PYY and OXM increase after bariatric surgery. We have partially

exploited the gut peptides in the management of obesity, but more needs to be done. Liraglutide is already being used for the management of obesity. But a cocktail of gut peptides especially GLP-1, PYY and OXM could mimic many of the effects of RYGB on appetite, and could result in weight loss similar to bariatric surgery without the risks28.

Efficiency of Energy Extraction: Experimentally produced germ free mice are protected from diet induced obesity. Introduction of gut microbiota from conventionally raised mice to the germ free mice increased body weight by 60% in 2 weeks despite decrease in food consumption by 29% and increased activity by 27%36. The microbiota composition of the obese gut is different from the lean gut in both humans and mice. Firmicutes are higher and Bacteroidetes are lower in the obese and there is lesser bacterial diversity37,38. Successful and sustained weight loss in obese humans improved the Bacteroidetes/Firmicutes ratio38. Metagenomic studies have shown that the microbiota in the obese gut is enriched with genes coding for enzymes involved in digestion of indigestible polysaccharides39.

The gut microbiota increases the efficiency of energy extraction by the following mechanisms i) intestinal absorption of monosaccharides and short chain fatty acids (SCFA) after digestion of non-digestible polysaccharides by gut microbiota.

Among the SCFA propionate serves as a precursor for gluconeogenesis in the hepatocytes and acetate serves as a precursor of de novo lipogenesis in hepatocytes and adipocytes40; ii) suppression of fasting induced adipocyte factor (FIAF), which inhibits lipoprotein lipase (LPL). Inhibition of FIAF increases LPL activity. This promotes lipolysis of triglyceride in lipoproteins and facilitate greater fat storage in adipocytes41; iii) decrease activity of the AMPK which acts as a ‘fuel gauge’. AMPK plays an important role in maintaining body weight (by fuel utilisation) and preventing lipotoxicity42,43; iv) SCFA inhibits the release of PYY44 by acting on the G-protein coupled receptor 41 (Gpr41) in the enteroendocrine cell.

ii.

Release of Neurotransmitters: A number of neurotransmitters are produced by gut microbiota.

Important among them are SCFA, serotonin, dopamine, noradrenaline, acetylcholine and GABA45-49. SCFA can modulate secretion of serotonin and PYY50. SCFA like butyrate and propionate can cross the blood brain barrier and are major energy source for cellular metabolism, especially during brain development. They can also affect neurotransmitter synthesis in the CNS via regulation of tyrosine kinase gene activation51.

In mice models SCFA butyrate has been found to have anti-depressant effects52.

THE GUT MICROBIOTA: ROLE IN OBESITY PATHOGENESIS

The Size and Products of the Gut Microbiota is Impressive

The gut microbiota is composed of organisms that reside in our gut. The microbiota composition is variable between individuals but remains relatively stable in a single individual. It is composed of organisms that permanently reside in our gut and the organisms that temporarily pass through it. Initial colonization at birth may influence the permanent residents of the gut.

The stomach and duodenum harbour 103/ml with the numbers increasing to 1011-1012/ml at more distal tracts29.

There are at least 1000 different species of organisms, mainly anaerobes. The microbiota contains at least 100 times more genes than our own genome30. Bacteroidetes and Firmicutes account for more than 90% of all31. The volume of the gut microbiota is so impressive that it has an approximate weight of 1-2kg in an average size adult32 and an estimated 90% of all the cells in the human body is derived from microorganisms that reside in our body33,34.

Our understanding of the gut microbiota and microbiome has increased exponentially due to greater reliance on culture-independent techniques, especially genomic methods. This is possible because of large projects like the NIH sponsored Human Microbiome Project (http:// commonfund.nih.gov/hmp), the European-funded Metagenomics of the Human Intestinal Tract (http:// www.metahit.eu) consortium, and the International Human Microbiome Consortium (http://www.humanmicrobiome.org).

Gut Microbiota is a Virtual Endocrine Organ

The gut microbiota is a virtual complex endocrine organ. It satisfies all the definition of an organ because it collectively influences the functioning of the body and is responsive to secretions and signals from other organs of the host. It secretes a vast array of hormones and other neurotransmitters with the amount exceeding those secreted even by the brain35.

Gut Microbiota Increase Energy Extraction, Neurotransmitter Release and Modulate Bile Acids

The symbiotic role of the gut microbiota with the human host has been known for a long time. The microbiota is known to protect the host from other pathogens, synthesize vitamins, and digest indigestible polysaccharides. However, the gut microbiota is far more complex. In the context of obesity, the functions of the gut microbiota may be considered as follows i) efficiency of energy extraction, ii) release of neurotrasmitters that act on the enteric nervous system (ENS) and central nervous system (CNS), and iii) impact on bile acid metabolism.

iii. Impact on Bile Acid Metabolism: the microbiota can transform the primary bile acids to secondary bile acids. The effects of bile acids on metabolism will be discussed later.

Mode of Delivery, Mode of Feeding, Antibiotics and Mother’s Health Determine Initial Gut Colonization

The gut is sterile in the intrauterine life. The microbiota

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becomes established at the time of birth and therefore the mode of delivery determines the character of the microbiota. At 1-3 years of age adult-like microbiome is present53. Immediately after vaginal delivery infants have bacterial composition in the gut similar to those in mother’s faeces54. Infants delivered by caesarean section have microbiota derived from mother’s skin, air and nursing personnel55. Children born by vaginal delivery have greater diversity of the microbiota, higher number of Bacteroides fragilis, Bifidobacteria and lower Clostridium difficile compared to those born by caesarean section56,57. Breast fed children have higher Bifidobacteria, probably due to bifidobacterial growth factors in breast milk and have lower rates of colonization by E. Coli and Clostridium difficile56,58. Other factors that can adversely affect microbial composition in the infant are antibiotic use56 and maternal gut dysbiosis due to high fat diet, obesity and antibiotics. The composition of gut microbiota in early life determines the development of overweight and obesity in future. Bifidobacteria were higher in fecal samples of infants who remained normal weight at 7 years, whereas staphylococcus aureus was higher in fecal samples of infants who subsequently became overweight or obese at 7 years57.

High Fat Diet Can Induce Rapid Changes in the Gut Microbiota

Another very important fact is that diet can rapidly affect the microbiota. Results obtained from mouse models with humanised gut microbiome showed that gut microbiota can shift rapidly in a single day when highfat, high-sugar diet is consumed in contrast to low-fat, plant-based polysaccharide diet59. In experimental mice, high fat diet is associated with an increase in Firmicutes and Protobacteria, and a decrease in Bacteroidetes59. In humans, it has been shown that short term increases in nutrient load rapidly changes the gut microbiota in lean, but not in obese individuals, with increased Firmicutes and decreased Bacteroidetes, leading to increased energy harvest60. This suggests that the microbiota of the obese and lean respond differently to nutrient load.

Obese Gut Microbiota Promotes Greater Energy Extraction and Metabolic Endotoxinemia

As detailed above, the microbiota of the obese encode for genes that are efficient in energy extraction. A high fat diet contributes to ‘metabolic endotoxinemia’ by increasing lipopolysaccharides (LPS)61. LPS derived from the cellwall of gram negative bacteria are increased in obesity and this result in a low grade chronic inflammation. High fat diet changes the quality of the gut microbiota and can promote increase capillary permeability favouring LPS absorption62. In in vitro model of human colorectal adenocarcinoma cells formation of chylomicrons favoured the absorption of LPS63. All plasma lipoprotein class can bind LPS64. Thus dietary fat increases LPS absorption by at least 3 mechanisms: changes in composition of gut microbiota, increased chylomicron formation and increase capillary permeability. Bifidobacteria which is the prominent species in the lean gut do not degrade intestinal mucus glycoproteins as other

pathogenic bacteria, promoting a healthy gut that is less permeable, preventing LPS translocation65. The metabolic endotoxinemia results in low grade inflammation contributing to insulin resistance, adipocyte hypertrophy and β cell dysfunction66.

After bariatric surgery, especially after RYBG changes in the gut microbiota have been observed. The possible mechanisms could be anatomical rearrangement of the gut with rapid delivery of undigested nutrients to distal small gut, alterations in entero-hepatic bile flow, increase in pH with bacterial overgrowth, use of antibiotics and changes in food preference28.

Transfer of Microbiota from Obese to Lean or Vice Versa Can Induce Phenotypic Characteristics of the Donor

Are changes in the gut microbiota a cause or consequence of obesity? The probable answer is that it could be both.

Germ-free mice on receiving microbiota transplant from obese mice develop the obese phenotype67,39, whereas they lose weight on receiving microbiota from an animal who has lost weight following RYGB68. In genetically obese mice (ob/ob mice), there is a decrease in Bacteroidetes and increase in Firmicutes, suggesting that obesity by itself could determine the character of the gut microbiota69.

Modulation of Gut Microbiota: One Promising Aspect of Obesity Pharmacotherapy

It is therefore clear that the gut microbiota is altered in obesity and changes in the composition of the gut microbiota similar to a lean gut can bring about metabolic improvements. The therapeutic options that can be exploited for bringing out changes in the gut microbiota include the use of prebiotics, probiotics or both, antibiotics and gut microbial transplantation (GMT).

Probiotics are living non-pathogenic microbes that when consumed in appropriate amounts promote health.

Probiotics have been shown to decrease adipocyte size which is the strongest marker of insulin resistance.

Possible mechanisms include fecal excretion of neutral sterols and bile salts, decreased absorption of triglyceride, cholesterol and phospholipids and increased lipolysis70,71.

Studies using dahi supplemented with probiotic strains of Lactobacillus acidophilus and Lactobacillus casei have shown that this product can improve the stigmata of diabetes, i.e. hyperglycemia and hyperinsulinemia, in high-fructose induced rat models of diabetes72,73.

In another study administration of fermented milk containing Lactobacillus gasseri SBT2055 for 12 weeks lead to a significant reduction of abdominal visceral and subcutaneous fat areas by 4.6 and 3.3 % respectively as measured by computed tomography74. The human studies on probiotics are small scale and have short-term follow up. Larger and longer studies with different strains of microbiota will give more convincing results.

Prebiotics promote the growth of beneficial bacteria.

Prebiotics (oligosaccharides like galacto-oligosaccharides; the inulin derivatives like the fructo-oligosaccharides; and soluble fibers) are proposed to stimulate the growth of beneficial bacteria (i.e. Bifidobacteria and Lactobacilli) in

the gut, to generate fermentation products i.e. SCFAs with anti-inflammatory effects75, to reduce the appetite, and to mimic the pathogen binding sites that coat the surface of gastrointestinal epithelial cells inhibiting enteric pathogen adhesion and infection76.

Fecal transplantation or gut microbiota transplantation (GMT) refers to transfer of feces from a healthy donor to a recipient. It is already in use for the treatment of Clostridium difficile pseudomembranous colitis since 1950’s79. As discussed above transfer of gut microbiota from obese gut induces obese phenotype and lean microbiota induces lean phenotype in germ free mice.

GMT can actually be considered a probiotic treatment because what is being transferred is the organisms from healthy gut. In one study, GMT was done via a nasoduodenal tube in nine men with metabolic syndrome, whereas another nine men with metabolic syndrome received placebo80. Six weeks after GMT, treated subjects had an impressive 75% increase in insulin sensitivity.

Moreover, GMT was associated with favourable changes in the gut microbiota like greater bacterial diversity and a 2.5-fold increase in butyrate-producing bacteria80.

However, at this moment challenges to GMT exist. Some of the challenges are identification of healthy donor, mode of delivery and the psychological stress that could be associated with fecal transfer.

BILE ACIDS: METABOLIC EFFECTS

Modulation of Bile Flow and Content after Bariatric Surgery Confer Metabolic Benefits

Bile flow alteration following bariatric surgery contributes significantly to improvements in weight and correction of dysglycemia. In fact, many of the beneficial effects after bariatric surgery can be reproduced in rats by simply diverting bile from the common bile duct to the mid-distal jejunum via a catheter81. After RYGB fasting and postprandial concentrations of bile acids rise. Bariatric surgery could actually alter the expression of nuclear receptors of bile acids. Bile acids have multiple effects on metabolism.

It increases GLP-1 secretion by TGR5 receptor present on the L-cells82. It also increases the levels of other satiety hormones like PYY and CCK83,84. Bile acids have been known to suppress genes associated with lipogenesis85.

Acting via the FXR, bile acids have been shown to activate apo-CII and apoA-V expression which are co-activators of lipoprotein lipase. This inhibits serum triglyceride levels86. Bile acids may also contribute to changes in the gut microbiota following bariatric surgery. The results of

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CONCLUSION

In the course of evolution complex mechanisms have been developed by our gut to improve the efficiency of nutrient extraction. Pathways exist to keep the system in ‘check’ so that overnutrition does not occur. In the modern day ‘obesogenic’ environment, an intricate interplay of factors starting from intrauterine life and continuing in later life interferes with the proper functioning of the gut and results in obesity. The three important players in energy homeostasis for which we have a fair understanding are gut peptides, gut microbiota and bile acids. Obesity is associated with functional and/or structural alterations in the above three. Correction of these alterations can result in significant and sustained weight loss as shown by bariatric surgery. Bariatric surgery with its complications can never be the final treatment for obesity. The science of weight loss following bariatric surgery which manipulates the gut structurally and functionally has been understood to a large extent. We need to urgently develop pharmacotherapy to exploit the gut based on this understanding, so that the biggest epidemic to threaten mankind can be dealt with effectively and on time.

REFERENCES

1.

World Health Organization. Obesity (2015). http://www. who.int/topics/obesity/en/. Accessed 01 Sept 2016.

2. Rajendra Pradeepa et al. for the ICMR -INDIAB Collaborative Study Group. Prevalence of generalized & abdominal obesity in urban & rural India- the ICMRINDIAB study (Phase-I) [ICMR-INDIAB-3]. Indian J Med Res 2015; 142:139-150.

3.

Murphy KG, Bloom SR. Gut hormones in the control of appetite. Exp Physiol 2004; 89:507-516.

4. Hameed S, Dhillo WS, Bloom SR. Gut hormones and appetite control. Oral Dis 2009; 15:18-26.

5. Adam TC, Toledo-Corral et al. Insulin sensitivity as an independent predictor of fat mass gain in Hispanic adolescents. Diabetes Care 2009; 32:2114-2115.

6. Small CJ, Bloom SR. Gut hormones and the control of appetite. Trends Endocrinol Metab 2004; 15:259-263.

7. Williams G, Bing C et al. The hypothalamus and the control of energy homeostasis: different circuits, different purposes. Physiol Behav 2001; 74:683-701.

8.

Vettor R, Fabris R, Pagano C, Federspil G. Neuroendocrine regulation of eating behavior. J Endocrinol Invest 2002; 25:836-854.

9. Yu JH, Kim MS. Molecular mechanisms of appetite regulation. Diabetes Metab J 2012; 36: 391-398.

10. Woods SC, D’Alessio DA. Central control of body weight and appetite. J Clin Endocrinol Metab 2008; 93 (11 Suppl 1): S37-S50.

11. Chaudhri OB, Wynne K, Bloom SR. Can gut hormones control appetite and prevent obesity? Diabetes Care 2008; 31 (Suppl 2): S284-S289 12. Muller TD, Nogueiras R, et al. Ghrelin. Mol Metab 2015; 4:437-460.

CHAPTER 154

Antibiotic treatment reduces metabolic endotoxinemia and LPS levels in ob/ob mice resulting in improved metabolic profile66. However, the impact of antibiotics on metabolic health is variable. As discussed earlier, antibiotic use can cause obesity by changing the composition of the gut microbiota and by destruction of intestinal mucosa causing increased LPS absorption. In fact, farmers have used antibiotics for a long time in farm animals to increase fat mass and body weight. The possible explanation for increase in body weight are changes in the gut microbiota with resultant obesity77,78.

modification of bile acids and bile acid dynamics should be explored in greater detail, as this will guide novel pharmacotherapy for obesity.

METABOLISM

718

13. Herrmann C, Goke R et al. Glucagon-like peptide-1 and glucose-dependent insulin-releasing polypeptide plasma levels in response to nutrients. Digestion 1995; 56:117-126.

31. Hugenholtz P, Goebel BM et al. Impact of culture independent studies on the emerging phylogenetic view of bacterial diversity. J Bacteriol 1998; 180:4765-4774.

14. Verdich C, Toubro S et al. The role of postprandial releases of insulin and incretin hormones in meal-induced satietyeffect of obesity and weight reduction. Int J Obes Relat Metab Disord 2001; 25:1206-1214.

32. Forsythe P, Kunze WA. Voices from within: gut microbes and the CNS. Cell Mol Life Sci 2013; 70:55-69.

15. le Roux CW, Welbourn R et al. Gut hormones as mediators of appetite and weight loss after Roux-en-Y gastric bypass.

Ann Surg 2007; 246:780-785.

34. Qin J, Li R, Raes J, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010; 464:59-65.

16. Tatemoto K, Mutt V. Isolation of two novel candidate hormones using a chemical method for finding naturally occurring polypeptides. Nature 1980; 285:417-418.

17. Korner J, Bessler M et al. Effects of Roux-en-Y gastric bypass surgery on fasting and postprandial concentrations of plasma ghrelin, peptide YY, and insulin. J Clin Endocrinol Metab 2005; 90:359-365.

18. Gantz I, Erondu N et al. Efficacy and safety of intranasal peptide YY3-36 for weight reduction in obese adults. J Clin Endocrinol Metab 2007; 92:1754-1757.

19. Lieverse RJ, Jansen JB et al. Satiety effects of a physiological dose of cholecystokinin in humans. Gut 1995; 36:176-179.

20. Castillo EJ, Delgado-Aros S et al. Effect of oral CCK-1 agonist GI181771X on fasting and postprandial gastric functions in healthy volunteers. Am J Physiol Gastrointest Liver Physiol 2004; 287:G363-G369.

21. Neary NM, Small CJ et al. Peptide YY3-36 and glucagon-like peptide-17-36 inhibit food intake additively. Endocrinology 2005; 146:5120-5127.

22. Dubrasquet M, Bataille D et al. Oxyntomodulin (glucagon-37 or bioactive enteroglucagon): a potent inhibitor of pentagastrin-stimulated acid secretion in rats.

Biosci Rep 1982; 2:391-395.

23. Murphy KG, Dhillo WS et al. Gut peptides in the regulation of food intake and energy homeostasis. Endocr Rev 2006; 27: 719-727 24. Asakawa A, Inui A et al. Characterization of the effects of pancreatic polypeptide in the regulation of energy balance.

Gastroenterology 2003; 124:1325-1336.

25. Bailey AR, Von Englehardt N et al. Growth hormone secretagogue activation of the arcuate nucleus and brainstem occurs via a nonnoradrenergic pathway. J Neuroendocrinol 2000; 12:191-197.

26. Falken Y, Hellstrom PM eta al. Changes in glucose homeostasis after Roux-en-Y gastric bypass surgery for obesity at day three, two months, and one year after surgery: role of gut peptides. J Clin Endocrinol Metab 2011; 96:2227-35.

27. Jorgensen NB, Jacobsen SH et al. Acute and long-term effects of Roux-en-Y gastric bypass on glucose metabolism in subjects with type 2 diabetes and normal glucose tolerance. Am J Physiol Endocrinol Metab 2012; 303:E122-31.

28. Sten Madsbad, Carsten Dirksen et al. Mechanisms of changes in glucose metabolism and bodyweight after bariatric surgery. Lancet Diabetes Endocrinol 2014; 2:152–64.

29. Palmer C, Bik EM et al. Development of the human infant intestinal microbiota. PLoS Biol 2007; 5:e177.

30. Gill SR, Pop M, Deboy RT et a. Metagenomic analysis of thehumandistal gut microbiome. Science 2006; 312:13551359.

33. Arumugam M, Raes J, Pelletier E, et al. Enterotypes of the human gut microbiome. Nature 2011; 473:174-180.

35. Russell WR, Duncan SH et al. The gut microbial metabolome: modulation of cancer risk in obese individuals. Proc Nutr Soc 2013; 72:178-188 36. Backhed F, Ding H et al. Th e gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA 2004; 101:15718-23.

37. Ley RE, Backhed F et al. Obesity alters gut microbial ecology. Proc Natl Acad Sci USA 2005; 102:11070-5.

38. Ley RE, Turnbaugh PJ et al. Microbial ecology: human gut microbes associated with obesity. Nature 2006; 444:1022-3.

39. Turnbaugh PJ, Ley RE et al. An obesity-associated gut microbiome with increased capacity for energy harvest.

Nature 2006; 444:1027-31.

40. Bergman EN. Energy contributions of volatile fatty acids from the gastrointestinal tract in various species. Physiol Rev 1990; 70:567-590.

41. Backhed F, Ding H et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA 2004; 101:15718-15723.

42. Zhang H, DiBaise JK et al. Human gut microbiota in obesity and after gastric bypass. Proc Natl Acad Sci USA 2009; 106:2365-2370.

43. Duncan SH, Lobley GE et al. Human colonic microbiota associated with diet, obesity and weight loss. Int J Obes 2008; 32:1720-1724.

44. Backhed F, Manchester JK et al. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice.

Proc Natl Acad Sci USA 2007; 104:979-84.

45. Ozogul F, Kuley E et al. The function of lactic acid bacteria on biogenic amines production by food-borne pathogens in arginine decarboxylase broth. Food Sci Technol Res 2012; 18:795-804.

46. Tsavkelova EA, Botvinko IV et al. Detection of neurotransmitter amines in microorganisms with the use of high-performance liquid chromatography. Dokl Biochem 2000; 372:115-117.

47. Ozogul F. Production of biogenic amines by Morganella morganii, Klebsiella pneumoniae and Hafnia alvei using a rapid HPLC method. Eur Food Res Technol 2004; 219:465469.

48. Barrett E, Ross RP et al. Îł-Aminobutyric acid production by culturable bacteria from the human intestine. J Appl Microbiol 2012; 113:411-417.

49. Stanaszek PM, Snell JF et al. Isolation, extraction, and measurement of acetylcholine from Lactobacillus plantarum. Appl Environ Microbiol 1977; 34:237-239.

50. Evans JM, Morris LS et al. The gut microbiome: the role of a virtual organ in the endocrinology of the host. J Endocrinol 2013; 218:R37-R47.

51. DeCastro M, Nankova BB et al. Short chain fatty acids

regulate tyrosine hydroxylase gene expression through a cAMPdependent signaling pathway. Brain Res Mol Brain Res 2005; 142:28-38.

52. Schroeder FA, Lin CL et al. Antidepressant like effects of the histone deacetylase inhibitor, sodium butyrate, in the mouse. Biol Psychiatry 2007; 62:55–64.

53. Adlerberth I, Wold AE. Establishment of the gut microbiota in Western infants. Acta Paediatr 2009; 98:229-238.

54. Bettelheim KA, Breadon A et al. The origin of Oserotypes of Escherichia coli in babies after normal delivery. J Hyg (Lond) 1974; 72:67-70.

56. Penders J, Thijs C et al. Factors influencing the composition of the intestinal microbiota in early infancy. Pediatrics 2006; 118:511-521.

57. Kalliomaki M, Collado MC et al. Early differences in fecal microbiota composition in children may predict overweight. Am J Clin Nutr 2008; 87:534-8.

58. Coppa GV, Bruni S et al. The first prebiotics in humans: human milk oligosaccharides. J Clin Gastroenterol 2004; 38:S80-S83.

59. Turnbaugh PJ, Ridaura VK et al. The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci Transl Med 2009; 1:6ra14.

60. Jumpertz R, Le DS et al. Energy-balance studies reveal associations between gut microbes, caloric load, and nutrient absorption in humans. Am J Clin Nutr 2011; 94:5865.

61. Cani PD, Amar J et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007; 56:1761-72.

62. Brun P, Castagliuolo I et al. Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol 2007; 292:G518-25.

63. Ghoshal S, Witta J et al. Chylomicrons promote intestinal absorption of lipopolysaccharides. J Lipid Res 2009; 50:9097.

64. Levels JH, Abraham PR et al. Distribution and kinetics of lipoprotein-bound endotoxin. Infect Immun 2001; 69:28212828.

65. Caplan MS, Miller-Catchpole R et al. Bifidobacterial supplementation reduces the incidence of necrotizing enterocolitis in a neonatal rat model. Gastroenterology 1999; 117:577-583.

66. Cani PD, Amar J et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007; 56:1761-72.

67. Turnbaugh PJ, Bäckhed F et al. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe 2008; 3:213-223.

68. Liou AP, Paziuk M et al. Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity. Sci Transl Med 2013; 5:178ra141.

69. Ley RE, Bäckhed F et a. Obesity alters gut microbial ecology. Proc Natl Acad Sci USA 2005; 102:11070-11075

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71. Kadooka Y, Ogawa A et al. The probiotic Lactobacillus gasseri SBT2055 inhibits enlargement of visceral adipocytes and upregulation of serum soluble adhesion molecule (sICAM-1) in rats. Int Dairy J 2011; 21:623-627.

72. Yadav H, Jain S et al. Effect of dahi containing lactococcus lactis on the progression of diabetes induced by a highfructose diet in rats. Biosci Biotechnol Biochem 2006; 70:12558.

73. Yadav H, Jain S et al. Antidiabetic effect of probiotic dahi containing Lactobacillus acidophilus and Lactobacillus casei in high fructose fed rats. Nutrition 2007; 23:62-8.

74. Kadooka Y, Sato M et al. Regulation of abdominal adiposity by probiotics (Lactobacillus gasseri SBT2055) in adults with obese tendencies in a randomized controlled trial. Eur J Clin Nutr 2010; 64:636-43 doi:10.1038/ejcn.2010.19.

75. Watzl B, Girrbach S et al. Inulin, oligofructose and immunomodulation. Br J Nutr 2005; 93(Suppl 1):S49-S55.

76. Roberfroid M. Prebiotics: the concept revisited. J Nutr 2007; 137:830S-837S. 77. Gaskins HR, Collier CT et al. Antibiotics as growth promotants: mode of action. Anim Biotechnol 2002; 13:29-42.

78. Butaye P, Devriese et al. Antimicrobial growth promoters used in animal feed: effects of less well known antibiotics on gram-positive bacteria. Clin Microbiol Rev 2003; 6:175188.

79. Eiseman B, Silen W et al. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery 1958; 44:854-859.

80. Vrieze A, Van Nood E, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 2012; 143:913-916. e7.doi:10.1053/j.gastro.2012.06.031 81. Kohli R, Setchell KD et al. A surgical model in male obese rats uncovers protective effects of bile acids post-bariatric surgery. Endocrinology 2013; 154:2341-2351.

82. Mencarelli A, Renga B et al. Dissociation of intestinal and hepatic activities of FXR and LXRα supports metabolic effects of terminal ileum interposition in rodents. Diabetes 2013; 62:3384-93.

83. Pournaras DJ, Glicksman C et al. The role of bile after Roux-en-Y gastric bypass in promoting weight loss and improving glycaemic control. Endocrinology 2012; 153:36133619.

84. Werling M, Vincent RP et al. Enhanced fasting and postprandial plasma bile acid responses after Roux-en-Y gastric bypass surgery. Scand J Gastroenterol 2013; 48:1257-1264.

85. Repa JJ, Liang G et al. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXR alpha and LXR beta. Genes Dev 2000; 14:2819-2830.

86. Houten SM, Watanabe M et al. Endocrine functions of bile acids. EMBO J 2006; 25:1419-1425.

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55. Bezirtzoglou E. The intestinal microflora during the first weeks of life. Anaerobe 1997; 3:173-177.

70. Hamad EM, Sato M et al. Milk fermented by Lactobacillus gasseri SBT2055 influences adipocyte size via inhibition of dietary fat absorption in Zucker rats. Br J Nutr 2009; 101:716-724.

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155

Newer Lipid Guidelines: Interpretation and Applications for Indians SN Narasingan

ABSTRACT

There are number of guidelines and recommendations for managing cholesterol.American College of Cardiology [ACC] / American Heart Association [AHA] guidelines 2013 focussed on Atherosclerotic Cardiovascular risk and not on lipid goals. International Atherosclerosis Society [IAS] published global recommendations in the same year for the management of dyslipidemia. National Lipid Association [NLA] guidelines were published in 2014.Lipid Association of India [LAI]has released Expert Consensus Statement on Management of Dyslipidemia in Indians in 2016. European Guidelines on cardiovascular disease prevention in clinical practice was published in 2016..This chapter on Newer Lipid Guidelines : focuses on interpretation of these international guidelines including recommendations of LAI which may be applicable for Indians. Many aspects of lipid management targeting LDL- c and other lipoproteins are discussed in detail.

Indians have typical elevations of triglyceride with low levels of HDL-c and almost normal LDL- c levels.

Atherogenic dyslipidemia which is the characteristic feature of Metabolic syndrome [MetS] and diabetes is characterised by an increase in triglyceride levels with low HDL –c and increase in small dense LDL-c.In view of increasing prevalence of obesity, MetS and diabetes, there is a need for different approach in managing mixed dyslipidemia.Randomised Control Trials [RCTs] focussing on lipid lowering therapy have to be conducted for evidence and to develop guidelines for Indian patients.

Patient centric approach with evidence obtained from epidemiological / observational data on the prevalence and type of dyslipidemia was given importance in the recommendations of LAI which are highlighted in this chapter.

INTRODUCTION : WHY DO WE NEED GUIDELINES ?

Many times we get conflicting data in guidelines.

What is reasonable to do for overall approach to make sense of the totality of data ? What we should aspire to do at a population level is to standardise care and avoid inequalities. RCTs systematically test effects of an intervention on pre-specified outcomes in defined populations. Their use minimizes confounding. Their ability to generalize results to real-world patients may be limited due to exclusion criteria. Observational / Epidemiologic studies have world-wide in scope and may assess ASCVD risk across populations.Cohort studies :

evaluate mortality and morbidity within populations.

Guidelines are published based on robust evidence from RCTs, observational / epidemiological & cohort studies.

Experimental data are taken into account.

Atherosclerosis is a preventable disorder. Of all the lipoproteins, it is the LDL Cholesterol which plays a central role not only in the initiation of atherosclerosis but also in the progression of atherosclerosis ending in clinical cardiovascular events. Most robust evidence for the role played by LDL –C comes from RCT’s which had used statins. The evidence clearly shows that by reducing LDL –c, we get substantial reduction in CV morbidity & mortality. Many secondary prevention trials, primary prevention trials, and trials conducted in high risk groups, clearly demonstrated the important role of LDL-C reduction and the potency of statins in reducing the atherosclerotic cardiovascular risk.

NCEP ATP III Guidelines : Many guidelines were published by various academic bodies across the globe.

After the publication of National Cholesterol Education Program – Adult Treatment Panel - III [NCEP ATP III] Guidelines in the year 2001, we had also seen an updated recommendation from the same organisation in the year 2004. ACC/AHA recommendations on lipid lowering was released in the year 2006, mostly concurring with ATP III recommendations. Recommendations are : LDL-C Goals for High Risk Patients : < 100 mg/dl in patients with CHD or CHD risk equivalents including 10 years risk > 20 % and <70 mg/dl as option for very high risk patients. If it is not possible to attain LDL-C < 70 mg/dl because of a high baseline LDL-C, it is generally possible to achieve LDL-C reductions of >50% with more intensive LDL-C lowering therapy including drug combinations1. ATP III also recommended lowering of Non HDL -c as a secondary goal when Hypertriglyceridemia exceeds 200 mg/dl.

2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to reduce atherosclerotic cardiovascular risk in adults : Stone NJ, et al. 2013 ACC/AHA Blood Cholesterol Guideline circulation JACC, Nov 12, 2013.

Main focus on ASCVD risk reduction : 4 statin benefit groups in secondary and primary prevention are identified for high-intensity and moderate intensity statin therapy.

1.

Individuals with clinical ASCVD : [Seconday Prevention] Atherosclerotic CVD includes CHD,

Table 1: High & Moderate Intensity Statin Therapy High-Intensity Statin Therapy

Moderate-Intensity Statin Therapy

Daily dose lowers LDL-c on average, by approximately ≥50%

Daily dose lowers LDL-C on average, by approximately 30% to <50%

Atorvastatin (40)-80 mg

Atorvastatin 10 (20) mg

Rosuvastatin 20 (40) mg

Rosuvastatin (5) 10 mg Pravastatin 40 (80) mg Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40 mg bid Pitavastatin 2-4 mg

stroke, and PAD:High-intensity statin therapy should be used to achieve at least a 50% reduction in LDL - C unless otherwise contraindicated. For those older than 75 yrs, moderate dose statin may be used.

2.

4.

Individuals with primary elevations of LDL–C ≥190 mg/dL [Primary Prevention] High-intensity statin therapy should be used to achieve at least a 50% reduction in LDL -C unless otherwise contraindicated.3.Individuals between 40 and 75 years of age with diabetes & without clinical ASCVD with LDL-C 70-189 mg/dL : A moderateintensity statin- that lowers LDL-C 30% to 49%.

High-intensity statin is a reasonable choice if the patient also has a 10-year risk of ASCVD exceeding 7.5% Individuals without clinical ASCVD or diabetes who are 40 to 75 years of age with LDL-C 70-189 mg/dL and an estimated 10-year ASCVD risk of 7.5% or higher : A Moderate - or High-intensity statin therapy.

High & Moderate Intensity Statin Therapy : Ref Table 1 Statins and doses that are approved by the U.S.FDA but were not tested in the RCTs reviewed are listed in italics.

New perspective on LDL and / or Non HDL-C Treatment Goals : The expert panel included RCTs with robust evidence for framing guidelines and was unable to find RCT evidence to support continued use of specific LDLc and / or Non-HDL –c treatment targets. Global risk assessment for primary prevention is recommended by using new pooled cohort equations to estimate 10-year ASCVD risk by a new risk calculator. 7.5% risk threshold for primary prevention was selected based on analyses.

Some patients do not tolerate statins and may require treatment with lower doses. With few exceptions, use of lipid-modifying drugs other than statins is discouraged.

Only statins have data of CV protection.Non-statin lipid lowering drugs have no evidence of CV protection.

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Implementation of ACC / AHA Guidelines in clinical practice in India : Is this possible ?

These guidelines are intended for US population. It is very difficult to implement the same for Indians for the following reasons : Use of high dose statin may be difficult in patients with multiple co-morbidities & in Asian patients.Over estimation of CV risk by presently developed calculator was highlighted in the subsequent publications. There was no recommendation for LDL goal. This becomes difficult in Indian scenario. Asian subjects were not considered who have high TG and low HDL. MetS was totally neglected for recommendation in spite of an increasing prevalence in US. We have problems of overweight,Obesity and MetS with > 69 million people suffering from diabetes in India. Atherogenic dyslipidemia is the risk factor in MetS and in diabetes which was not addressed. Lower statin dose are frequently used in our population. Adequacy of statin therapy cannot be determined without measuring on treatment LDL. ACC/ AHA Guidelines2013 raised several questions that need to be answered.

Indian Scenario on Lipids and Lipoproteins

India Heart WATCH Study which evaluated for dyslipidemia prevalence in a population of 6400 subjects revealed higher TG levels with low HDL –c with normal or marginally elevated LDL –c levels.

High prevalence of Metabolic syndrome among urban subjects in India was highlighted in a multisite study2: 33.3% of men and 40.4% of women are having metabolic syndrome features with constellation of multiple risk factors.Atherogenic dyslipidemia was typically seen in this study.

ICMR – INDIAB Study 2014 : Prevalence of Dyslipidemia in urban and rural India was evaluated in this study.

Higher prevalence of TG [29.5%] with higher prevalence of low HDL [72.3%] and 13.9% subjects were seen with Hypercholesterolemia.

Non HDL-C is a better indicator of residual risk than LDL-C

Meta analysis of 62,154 statin-treated patients in 8 trials [4S, AFCAPS, LIPID, CARDS, TNT, IDEAL, SPARCL, JUPITER] published between 1994 and 2008 revealed the following: 1 SD increase in LDL-C, Apo B and Non HDL increase the risk of CV events by 13%, 14%, and 16% respectively indicating the strength of association with CVD is greater for non HDL-C than for LDL-C and ApoB 3 . People who had LDL levels < 100 mg/dl with Non-HDL level of > 130 mg/dl had hazard ratio of 1.32 indicating CV risk of 32% when compared to people who had uncontrolled LDL levels of > 100 mg/dl with Non HDL level of < 130mg/dl had hazard ratio of 1.02 indicating CV risk of 2%. Conclusion : Non HDL-C is associated with increased risk for future CV events, even if LDL is under control with statins.

CHAPTER 155

Simvastatin 20-40 mg

Measuring lipids during follow-up of drug-treated patients is done to assess adherence to treatment and not to see whether a specific LDL-C target has been achieved.

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AACE [American Association of Clinical Endocrinologists] Guidelines for management of Dyslipidemia and prevention of Atherosclerosis – 2012 : Calculate Non– HDL-C in patients with moderately elevated TG (200-500 mg/dL) with DM and/or established CHD.In patients with insulin resistance, AACE recommends evaluating Non – HDL-C to gain useful information on total atherogenic lipid burden4. AACE 2013 Diabetes Guidelines : Non HDL goal to be achieved with TG lowering therapy after achievement of desirable LDL-C level.5

METABOLISM

Role of Apo-B

Apo-B is the key atherogenic lipoprotein which is a more sensitive measure of risk than LDL-c.It provides information on LDL particle size which is difficult to measure directly. A recent analysis of the combined data set from the TNT and IDEAL studies showed that ontreatment level of apo-B was clearly superior to that of LDL-c as a predictor of CV events, but it was not superior to non - HDL-c6.

Role of Triglycerides

Prove IT-TIMI 22 trial conducted in ACS patients stressed the role of high triglyceride as a risk factor after reaching the LDL goal of 70mg/dl with high dose Atorvastatin 80 mg/day. People who had >200 mg/dl of triglyceride had higher CV risk of sudden cardiac death, fatal and nonfatal reinfarction in a 30 day follow up compared with people who had < 200 mg/dl of triglyceride. Clinicians need to focus on the residual risk contributed by high triglycerides.7 Meta-analysis of 5 landmark trials (ACCORD, BIP, FIELD, HHS, VAHIT) with 7389 patients with diabetes and or CVD, concluded that lowering TG in people who had elevated levels > 200mg/dl with PPAR alpha agonists-Fibrates reduced CV events by 25%. In different studies in the last 2-3 decades, TG reduction, with or without statin, has shown to cause significant risk reduction in patients with high TG and low HDL-C (Atherogenic Dyslipidemia)9.

Triglycerides can be measured in the non-fasting or fasting states. RCTs showing CV benefit of triglyceride reduction are scanty. Lowering triglycerides reduces the risk of CVD is still debated10. Saroglitazar, a novel lipid lowering drug which has both PPAR alpha and gamma agonistic activity has shown in clinical trials to lower triglycerides markedly in diabetics. This is a promising molecule which has been approved in India for managing diabetic dyslipidemia.

8

Role of HDL-C : Trials to raise HDL-C levels by using CETP Inhibitors like Torcetrapib,failed to show beneficial effects in spite of having a favorable HDL rise in number of studies. Therapeutic Lifestyle Changes, such as smoking cessation, weight loss,physical activity,moderate alcohol consumption,w-3 fatty acids have been found to show beneficial effects in increasing HDL. However, there is still lack of evidence that raising HDL reduces CV Risk.

HDL-C is not recommended as a target of therapy11.

Role of Lp(a): Lp(a) >50mg/dl independently predicts the presence of symptomatic & angiographic CAD. Primary

objective is to treat LDL and Non-HDL aggressively with high dose statin. Niacin is the only drug that lowers Lp(a). Novel Lipid lowering drugs like Apo B blockade

by AntiSense Oligonucleotide (ASO) [Mipomersen] MTP Inhibitor [Lomitapide] and PCSK9 inhibitors [Evolocumab] have shown reduction in Lp (a) with marked reduction of LDL – c. European Atherosclerosis Society recommends screening for elevated Lp(a) in those at moderately high or high ASCVD risk.

International Atherosclerosis Society : Global recommendations for the management of dyslipidemia:12 LDL –C and Non-HDL-C as target of Therapy : LDL is the major atherogenic lipoprotein and VLDL is an additional atherogenic lipoprotein. Non-HDL includes LDL + VLDL. LDL –C is the traditional primary target for clinical intervention and Non-HDL-C is also an appropriate target for clinical intervention based on huge body of evidence. Advantages of Non-HDL –C as Target : It does not require fasting for accurate measurement.Non HDL subsumes most cases of elevated triglycerides Growing evidence favor Non HDL has greater predictive power than LDL-C.Non –HDL is also considered equivalent to apo lipoprotein- B in predictive power.

Secondary Prevention : Achieving an optimal atherogenic cholesterol level : The optimal LDL-C in patients with established ASCVD is < 70 mg/dl or non-HDL-C of < 100 mg/dl. Most patients with ASCVD deserve maximal statin therapy when it is tolerated. To achieve an LDL-C < 70 mg/dl, some patients will require add on drugs to statins [i.e.ezetimibe and / or bile acid resins] Secondary Prevention : Patients with Hypertriglyceridemia :For those with high triglycerides, Nicotinic acid or a Fibrate are alternative add on drugs.However, risk reduction with combined drug therapy comparable to that with high-dose statins has not been documented in RCTs.Subgroup analysis of RCTs and atherosclerosis imaging provides some evidence of benefit of combined drug therapy.

National Lipid Association [NLA] recommendation for management of dyslipidemia11 : An elevated level of atherogenic cholesterol – cholesterol carried by apo B-containing lipoprotein particles (non-HDL-C and LDL-C) – is causally related to the development of atherosclerosis. Targets of Therapy : Atherogenic cholesterol (non-HDL-C and LDL-C) levels are the primary targets of therapy. Elevations in apo B-containing particles, and cholesterol carried by those particles, are considered a “ root cause” of atherosclerosis, and of primary importance for prevention. Non-HDL-C testing is universally available, requires no additional cost, and may be measured in the non-fasting state. An elevated triglyceride level is not a target of therapy per so, except when very high [severe]. Moderate or high-intensity statin therapy should be the first line agent.Starting with a moderate dose and titrating as necessary to achieve treatment goals is a reasonable approach. An alternate

drug : Bile Acid Sequestrant [BAS] Cholesterol absorption inhibitor like Ezetimibe,Fibrate and Niacin. These drugs may be considered in those with contraindications to statin.

What is needed for Indians ?

Non HDL-c (Non-High-Density lipoprotein Cholesterol)

Non-HDL-C, which is equal to total cholesterol –HDL-C and this includes all atherogenic lipoproteins.It is more accurate predictor of ASCVD risk, particularly in patients who have elevated TG (e.g. diabetes, obese persons, those with metabolic syndrome) and those already on statin therapy. LAI recommends non-HDL-C as a co-primary target, as important as LDL-C, for lipid lowering therapy.

Non-HDL-C level should be kept within 30mg/dL of LDL-C levels. Statins remain the first line agent for lipid lowering, regardless of whether LDL-C is the target for therapy or non-HDL-C.

Relevance of HighTG Levels

Elevated TG is associated with increased risk of ASCVD, independent of LDL-C levels. A combination of high TG and LDL-C imparts even greater risk. High TG is one of the components of atherogenic dyslipidemia.Keep TG<150 mg/dL, preferably <100mg/dL. In patients with elevated TG levels, rule out secondary causes of the same and intensify lifestyle modification, which can reduce TG by as much as 50%. Unless TG is very high (>500 mg/ dL), statin should be the first drug. Routine addition of a fibrate or another non-statin drug must be avoided. Only when TG is not sufficiently lowered with above measures, a non-statin drug should be added.

High Density Lipoprotein Cholesterol

Low HDL-C is an independent risk factor for ASCVD. It becomes even more relevant when LDL-C is not elevated.

Life style modification plays an important role in raising HDL-C. Among pharmacological agents, statins remain mainstay in the treatment of low HDL-C also. Although several other agents have been tried specifically for raising HDL-C, none of them has been shown to result in clinical benefit.

Usage of statins for Lipid Management

The clinical benefit of statins depends primarily on the extent of LDL-C reduction and not on the type of statin used. The type of the statin and dose to be used should be based on the degree of LDL-C reduction that is required to reach the target LDL-C in a given patient. Atleast moderate- or high intensity statin therapy is required to bring about a clinically meaningful reduction in LDL-C in most patients.

Lipid Association of India Expert Consensus Statement on Management of Dyslipidemia in Indians 2016 : Part 1 Journal of Association of Physicians of India [JAPI] Supplement copy March 2016,Vol : 64,Issue No.3.Visit www.lipid.net.in for full text

The ACC/AHA 2013 guidelines on the treatment of blood cholesterol to reduce ASCVD risk : A comparison with ESC/EAS guidelines for the management of dyslipidaemias 2011.13 Recommendations from LAI has been added apart from NLA & IAS for comparison.14 Ref. Tables 2, 3, 4 & 5

Low-Density Lipoprotein cholesterol

THE BAD : Comparison of International Guidelines

LDL-C should be the primary target for therapy. LDL-C lowering to a low level is essential to achieve the desired reduction in the risk of vascular disease. In those with elevated levels of ASCVD risk, lower LDL-C levels are

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ACC/AHA and ESC/EAS guidelines seek to lower LDL-C with statin therapy as their principal aim LAI also recommends the same. ACC/ AHA Guidelines : Treats risk alone with guidance only on treating ASCVD risk

CHAPTER 155

Number of guidelines were published with a focus on LDL lowering. We don’t have cholesterol management guidelines for Indians. We have a huge burden of CV disease in our country.CV deaths are increasing in alarming preportions. Young people are getting affected with CAD. This occurs one decade earlier when compared to western counterparts. Moreover CAD is diffuse with multi vessel involvement, predominantly affecting LAD. There is a need for development of risk calculator taking into account conventional risk factors and other risk factors which are peculiar to Indians. We are currently witnessing overweight, obesity, features of metabolic syndrome with insulin resistance. There is an increasing prevalence of diabetes which had crossed 69 million with features of atherogenic dyslipidemia in nearly 90% of diabetics. Hence we need individualised, patient centric approach to bring down the CV risk. We require separate guidelines to suit our patients. High dose statin are preferred for high risk and very high risk individuals, whereas moderate dose statin with uptitration to high dose may be the correct approach for Indian subjects. Indians respond quickly to moderate dose statin therapy and statin intolerance has been reported which needs to be tackled. We require LDL goals to have a good adherence for lifestyle modification and pharmacotherapy. If we are not able to reach the goal of LDL with high dose statin we may have to add Ezetemibe not only to reduce the LDL but also to reduce CV risk as has been highlighted in the recent studies. We require non statin drugs like Fibrates, Nicotinic acid, and omega 3 fatty acids to tackle high triglyceride levels in specific situations. At present we may not consider HDL as target of therapy. We need to pay more attention to non HDL which covers LDL and VLDL. Statins will play a major role in bringing down non HDL levels. Though we don’t have convincing data for marked CV risk reduction with TG lowering therapy, we are forced to continue the combination of drugs in view of predominant peculiar dyslipidemia in our population. Emphasis has to be given for therapeutic lifestyle changes which is a corner stone in the management of dyslipidemia not only in primary prevention but also in secondary prevention. It is appropriate to say that we need patient centric approach with our own recommendations/guidelines.

associated with better outcomes. LDL-C levels <50mg/dL is safe.

METABOLISM

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and discard the use of lipid targets It is simply fire and forget approach.Do not recommend additional lipidlowering therapies among those with high residual risk despite achievement of 50% reduction in LDL-C. ESC/ EAS Guidelines & LAI recommendations : Treats risk and more : Treats CVD risk, create a greater understanding of the role of LDL-C in CVD assessment (LDL-C monitoring). Individualized patient care approach : assessing other lipid-mediated factors “residual risk” :TG-rich lipoproteins remnants, HDL-C, Non-HDL-C & Apo B. Recommends LDL-C and other lipid measures for monitoring efficacy, compliance, assessing residual risk and allow a greater scope for modifying individual patient care by considering additional therapies if clinically warranted.

2016 ACC Expert Consensus Statement : This is a different compared to ACC/AHA Guidelines 2013. The statement

stressed the role of Non-statin therapies for LDL-C lowering in the management of ASCVD risk. Non HDL-C thresholds are included in high risk patients. Ezetimibe is preferred as the initial non statin therapy. Colesevelam has a modest hypoglycemic effect that may be of benefit in some diabetic patients with fasting triglycerides <300 mg/dl or in patients who are ezetimibe intolerant.

2016 European Guidelines on CVD prevention in clinical practice : Total CV risk should guide the intensity of the intervention. Non HDL –c is included as a target. Non statin therapy mainly Ezetimibe is recommended.

CONCLUSION

There is a need for absolute risk assessment in everyone and this is the best approach in managing Lipids. We need to assess the risk and then go with which ever is

Table 3: The Approach : Comparison of International Guidelines

Table 2: Comparison of International Guidelines Including recommendations of LAI ACC/ AHA

ESC/ EAS

NLA

IAS

LAI

Highlight the role of Lifestyle

√

√

√

√

√

Highlight the need to engage the patient as a partner

√

√

√

√

√

Highlight the role of lipid modification in the prevention of CVD

√

√

√

√

√

Highlight the need for risk assessment

√

In general use an absolute risk strategy

√

√

√

√

√

Risk categories easy to identify and agreed

√

√

√

√

√

Good summary of RCT data

√

√

√

√

√

ACC/ AHA

ESC/ EAS

Use doses seen in trials scenarios

√

√

√

√

√

Emphasis on higher intensity statins for established ASCVD

√

√

√

√

√

√

√

√

√

Plus TARGETS % Reductions

√

NLA IAS

LAI

√

Table 4: The Bad : Comparison of International Guidelines √

√

√

√ Targets

ACC/ AHA

ESC/ EAS

X

√

NLA IAS LAI √

√

√

Lower is better

X

√

√

√

√

Scope for other atherogenic lipids

X

√

√

√

√

Scope for other LLT

X

√

√

√

√

CKD as a high risk group

X

√

√

√

√

Table 5: The Uncertain : Comparison of International Guidelines ACC/AHA

ESC/EAS

NLA

IAS

?

?

?

LAI

What to do at the extremes of age

?

A new risk calculator

?

?

Reducing the primary

√

?

√

-

√

Reducing the primary prevention threshold [For Old]

X

?

-

-

?

What do our patients want

?

?

?

?

?

Promoting JBS 3 score

Prevention threshold [For Young]

greater i.e. a 50% LDL-C reduction or a target. In those at highest absolute risk we have to maximise the dose of the statin. We need to decide whether this is enough for this person’s level of risk or should we go lower ? Lower could be a greater percentage reduction in LDL-C or a target.

REFERENCES

1.

Grundy SM et al. Circulation. 2004;110:227–239. Smith SC Jr et al. Circulation 2006; 113:2363–2372.

2. Prakash Deedwania & Rajiv Gupta et al 2014 Diabetes & Metabolic Syndrome Clinical Research & Reviews Volume 8, Issue 3, July Sep 2014.Pages 156 – 161,ELSEVIER Boekholdt SM et al. JAMA 2012; 307:1302-1309

4.

Jellinger PS et al. Endocrine Practice 2012; 18 (Suppl 1):1-78.

5.

Endocrine Practice 2013; 19 (Suppl 2):1-48.

6. JAMA 2005; 294: 326-333, Circulation 2005; 112: 3375-3383 & National Lipid Association recommendation. Kastelein JJ, Van der steeg WA, Holme L, et al. Circulation 2008; 117:3002-3009.

8.

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Lee M et al. Atherosclerosis 2011; 217; 492–8.

9. N Engl J Med. 2010:363(7):692-4 Diabetes Care 32:493–498, 2009 10. Børge G Nordestgaard, Anette Varbo. Lancet 2014; 384: 626– 635 11. Terry A. Jacobson et al, National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 1 – executive summary*. Journal of Clinical Lipidology 2014; 8:473–488.

12. An International Atherosclerosis Society Position Paper 2013,Global Recommendations for the Management of Dyslipidemia [Full report] 13. Kausik K.Ray et al, European Heart Journal doi : 10.1093 / eurheartj / ehu 107.

14. Journal of Association of Physicians of India [JAPI] Supplement copy March 2016,Vol : 64 Issue No.3.

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3.

7. Fruchart JC, Sacks F, Hermans MP, et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Am J Cardiol 2008; 102(10 Suppl):1K-34K.

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Management of Dyslipidemia in India: What should be Our Approach in View of the Differing Guidelines Santanu Guha, Sumanta Chatterjee

SCOPE OF THE GUIDELINES

There are two major lipid guidelines- ESC and the ACC/ AHA guidelines. The major differences are- 1. The scope of ACC/AHA is limited to randomized trials only, which excludes a significant body of data and promotes essentially a statin centric approach only. 2. The abolition of low-density lipoprotein cholesterol (LDL-C) targets in favour of specific statin regimens producing a 30–50% reduction in LDL-C may confuse many physicians and may compromise medication adherence. 3. The absence of target LDL-C levels in very high-risk patients may discourage clinicians to consider the addition of lipid modification treatments and individualize patient care.

4. A reduction in the threshold for treatment in primary prevention will result in a greater number of patients being prescribed statin therapy, which is potentially good in young patients with high life time risk, but will result in a very large number of older patients offered therapy.

5. The mixed pool risk calculator used to asses CVD risk in the guidelines for primary prevention has not been fully evaluated1.6. ESC/EAS guidelines provide guidance on elevated triglycerides (TG) including the relevance of identifying and treating secondary causes, recommending pharmacological intervention, if fasting TGs are >2.3 mmol/L, using fibrates. The ACC AHA guidelines don’t recommend any other drugs beside statins and deals with risks rather than goals. 7. The guideline doesn’t adequately address the management of the group who cannot tolerate recommended statin doses. But both the guidelines ESC and ACC/AHA identifies LDL as the most important risk factor and both recommend behavioural and lifestyle modifications concurrent to drug therapy.

WHOM TO TREAT

Both sets of guidelines have categorised four major patient groups who would benefit from lipid modification therapy.

These include individuals with established CVD, diabetes mellitus, and familial hypercholesterolaemia. The fourth group contains those individuals not included in the first three, but who after undergoing global risk assessment (based on age, gender, smoking status, systolic blood pressure, total cholesterol and high-density lipoprotein cholesterol;HDL-C) seem to be at increased CVD risk.

The definition of ASCVD varies between guidelines as the ACC/AHA defines this as acute coronary syndromes, previous myocardial infarction, stable angina, prior coronary or other revascularization, ischaemic stroke or

transient ischaemic attack, and atherosclerotic peripheral arterial disease. In contrast, the ESC/EAS include all those mentioned in the ACC/AHA guidelines, but also include any pre-clinical evidence for atherosclerotic disease on the basis of any imaging modality. Importantly, the ACC/ AHA guidelines do not include chronic kidney disease (CKD), whereas the ESC/EAS guidelines consider those with CKD (as defined by a GFR ,60 mL/min/1.73 m2) as a very high-risk group who require lipid management with a target LDL-C of <1.8 mmol/L or a 50% reduction in LDL-C. The ESC/EAS guidelines also recognize that, while traditional risk factors are the basis of global risk assessment, there may be other factors such as elevated TG, social deprivation, central obesity, elevated lipoprotein (a), subclinical atherosclerosis, or family history of premature CVD which may further modify absolute risk.

The policy change that will have the largest impact on the healthcare system is the ACC/AHA statement that statin treatment is recommended for primary prevention in individuals with a 10-year ASCVD risk of 7.5% or higher when compared with previous guideline on the treatment of blood cholesterol recommendations that considered a substantially higher threshold for 10-year risk of fatal and non-fatal coronary heart disease (CHD).

The ACC/AHA 10-year threshold of 7.5% corresponds to a 2.5% risk for CVD death over 10 years in the SCORE model. In SCORE, those with a 10-year risk of fatal CVD of 2.5% are considered at moderate risk, and the ESC/ EAS recommendation is that an LDL-C of <3 mmol/L is achieved. Thus, while the ESC/EAS guidelines allows some scope by virtue of an LDL-C goal for lifestyle before medication are added, patients are more likely to receive medications under the new ACC/AHA guidelines. The consequence will be a greater expenditure to the public health budget.

The prescription of moderate to high intensity statins to persons having the 10 Yr ASCVD risk>7.5% will provide certain benefit of high dose statins but the impact of such a dose on tolerance in such a wide group is not clear. One important benefit of lowering the threshold for statin initiation in the primary prevention setting is that those young people with low short-term CVD risk but highlifetime risk will be initiated on statins earlier and will have a greater impact on the disease process. However practically all older individuals (>70 years) because of the

impact of age on 10-year ASCVD risk, will now be offered moderate- to high-intensity statins. As co-morbidities and tolerability of these agents becomes more of a concern in this age group, the potential for harm is much greater.

However, the guideline committee considered that there was lack of data on lifetime CVD risk, on long-term (i.e. >15 years) follow-up of treatments tested in RCTs, on long-term safety of statins, and on the effects of treatment initiation before the age of 40.

WHAT TO TREAT

The ACC/AHA guidelines discard the lipid targets as there is no RCT conducted based on such targets. While the ACC/AHA guidelines treat risk alone, the ESC/ EAS guidelines treat risk, create a greater understanding of the role of LDL-C in CVD risk assessment, and use LDL-C monitoring for measuring therapeutic efficacy and patient compliance. Furthermore, the ESC/EAS guidelines have given importance on the role of other lipid fractions such as TG-rich lipoproteins, remnants, and conditions associated with low HDL-C where LDL-C may not be as informative as non-HDL-C or apolipoprotein B (apoB), but for which there are clear data (Class IIa, Level B).

The ESC/EAS guidelines allow us to individualize patient care by potentially assessing other more appropriate factors driving lipid mediated so-called ‘residual risk’. For instance among patients with diabetes and low HDL-C, it is not uncommon to see an LDL-C level <1.8 mmol/L, but their non-HDL-C can be as high as 3.0 mmol/L thus above the 2.6 mmol/L target. In such situations which are now more common with the growing population of patients with diabetes or the metabolic syndrome, the ESC/EAS guideline allows greater flexibility to tailor individual care by using additional therapies to lower the non-HDL-C or apoB. In the ACC/AHA guidelines, those patients would not be considered for treatment optimization, but left to a trial-based regimen of high intensity statin with no additional consideration to residual risk.

HOW TO TREAT

The ACC/AHA guidelines essentially recommend either high intensity or moderate-intensity statin treatment.

Another practical problem of the recommendations regarding percentage reductions as treatment objectives instead of an on treatment LDL-C target is that the baseline LDL-C may not be known when the patient is already taking a low-dose statin. Hence percentage reductions may be quite complicated in settings such as primary care.

Another controversial issue in the ACC/AHA guidelines is the recommendation that physicians should consider decreasing the statin dose if LDL-C is <1.03 mmol/L on two occasions. This contradicts the genetic lifetime data on safety and the observational data from RCTs. Recent ESC 2016 guideline is a more elaborate and practical guide specially in our context given in Table 1.

HOW AND WHY INDIANS ARE DIFFERENT ?

In view of such conflicting strategies advocated in the accepted guidelines it would be reasonable to have individual assessment of every patient and accordingly plan for management. To treat our native patients it is important to understand the nature of metabolic and lipid derangements prevalent in our country. The Pooled Cohort Equation for calculating the estimated CV risk needs further validation in our population as the pattern of metabolic abnormalities seem to differ in this subset.

We need to develop our own risk calculator on the basis of large scale studies and apply those in future. South Asians are prone to develop CHD at a younger age, often before the age of 40 years in men.4 Compared with whites,

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The ESC/EAS guidelines place considerable weight to the measurement of LDL-C to determine future CVD risk and provide an algorithm which combines SCORE risk with measured LDL-C levels. This is of advantage as for general physicians it highlights the importance of screening for genetically elevated LDL-C levels. Additionally, LDL-C measurement is recommended for CVD risk assessment among those with established CVD, hypertension, smoking, type 2 diabetes, obesity, family history of premature CVD or familial hypercholesterolaemia, CKD, or chronic inflammatory disease. However new ACC/ AHA guidelines doesn’t mandate LDL-C measurement, if absolute risk is high enough to warrant statin therapy.

Thus adoption of the ESC/EAS guidelines will allow many more cases of undiagnosed familial hypercholesterolaemia to be identified which are much more common than the 1:500 that is generally perceived.

High-intensity statin treatment is defined as those regimens which reduce LDL-C by 50%. Of note, while atorvastatin 40, 80mg and rosuvastatin 20mg are endorsed as RCT outcomes tested high intensity statins, rosuvastatin 40mg is not, even though it is Food and Drug Administration (FDA) approved. Moderate-intensity statin treatment (assessed in outcomes studies) is defined as regimens which reduce LDL-C by 30–50% (atorvastatin 10 mg, simvastatin 20 or 40 mg, pravastatin 40 mg, fluvastatin 40 mg bd, rosuvastatin 10 mg), again note that atorvastatin 20 mg and rosuvastatin 5 are not included as those doses were not used in outcomes studies but are FDA approved doses. In these ACC/AHA recommendations, there is no mandated requirement to measure LDL-C levels or to attain a specific LDL-C goal as the recommendations draw on dosage of statin rather than specific LDL-C level attainment. However, they suggest that in high risk patients, therapy could be intensified, if 50% reduction in LDL-C is not achieved (50% being the proxy for response to high-intensity statins among adherent patients) at the doctor’s discretion. The 50% reduction does not seem to have a hard RCT evidence base which was claimed to be the sole criterion of the ACC/AHA guidelines. This is a marked divergence from existing ATP-III guidelines and other international guidelines which all recommend specific LDL-C goals. The remaining role of LDL-C measurements seems to be for monitoring adherence to lifestyle and medication, suggesting a fasting lipid panel at 4–12weeks and every 3–12 months thereafter. This seems a futile exercise, if the physician is not advised to consider residual risk or a specific target.

METABOLISM

728

Table 1: Treatment targets and Goals for Cardiovascular Disease Preventin Smoking

No exposure to tobacco in anby form

Diet

Healthy diet low in saturated fat with a focus on whole grain products, vegetables, fruit and fish

Physical activity

2.5 – 5 h moderately vigorous physical activity per week or 3060 min most days.

Body weight

BMI 20-25 kg/m2, waist circumference <94 cm (men) and <80 cm (women).

Blood pressue

<140 / 90 mmHg

Lipid LDL-C is the primary target

Very high-risk: LDL-C <1.8 mmol/L (70 mg/dL) or a reduction of at least 50% if the baseline is between 1.8 and 3.5 mmol/L (70 and 135 mg/dL).

High-risk: LDL-C <2.6 mmol/L (100 mg/dL) or a reduction of at least 50% if the baseline is between 2.6 and 5.2 mmol/L (100 and 200 mg/dL).

Low to moderate risk: LDL-C <3 mmol/L (115 mg/dL).

Non-HDL-C secondary targets are <2.6, 3.4 and 3.8 mmol/L (100, 130 and 145 mg/dL) for very high-, high- and moderate –risk subjects, respectively.

HDL-C: no target, but >1.0 mmol/L (40 mg/dL) in men and >1.2 mmol/L (48 mg/dL) in women indicates lower risk.

TG: no target but <1.7 mmol/L (150 mg/dL) indicates lower risk and higher levels indicate a need to look for other risk factors.

Diabetes

HbA1c: <7% (<8.6 mmol/L)

South Asians are more likely to have an anterior location of infarction.5 They are more likely to have significant left main, multivessel, and distal coronary artery disease.6 Numerous case-control studies documenting premature CHD in South Asians demonstrate similar or lower prevalence of traditional risk factors than with other populations. However unlike other traditional risk factors, the prevalence of diabetes mellitus is uniformly higher in South Asians.7 Compared with European populations, South Asians have increased abdominal visceral fat and greater insulin resistance at BMI levels that are traditionally considered “ideal” (<25 kg/m2).8 This body type, often termed “thin-fat phenotype” (muscle thin but body fat) is associated with an increased risk

of developing diabetes. A more appropriate estimate of visceral fat and insulin resistance in South Asians may be measurement of waist circumference.9 Hence we need to restratify our population and set up our own risk scores.

Although South Asians have levels of LDL cholesterol comparable to other populations, LDL particle size tends to be smaller10. Small LDL particles, are more atherogenic due to increased susceptibility to oxidation than larger particles. The serum triglyceride levels are highest in urban Asian Indians residing in India and migrant Asian Indians. Further, even the average serum triglyceride level of rural-based Asian Indians is higher than Caucasians.

A close association between Sst I polymorphism in the 3’ untranslated region of the apolipoproteinC3 (APOC3) gene and levels of plasma triglycerides (TG) had been reported in North India. Gupta et al (1997) showed that ~24% of the urban population of north India had low levels of HDL-cholesterol 11. HDL particle size, in addition to the actual level of HDL cholesterol, also appears to be an important predictor of CHD risk. South Asians not only have lower HDL levels but also have a higher concentration of small, less-protective HDL particles12. Asian Indian males have a higher prevalence of low HDL2b , which suggests impaired reverse cholesterol transport. Among the emerging risk factors, elevated lipoprotein(a), apolipoprotein B, homocysteine, plasminogen activator inhibitor-1, fibrinogen, and C-reactive protein (CRP) have considerable importance.

Lipoprotein(a), homocysteine, and plasminogen activator inhibitor-1 levels tend to be higher in South Asians than in white populations, although fibrinogen levels appear to be similar13. These factors support a prothrombotic milieu.

Microalbuminuria is recognized as an independent cardiovascular disease risk factor. Numerous studies have suggested that altered adipokine production or action may play a role in the heightened vascular risk observed in South Asian patients. Altered adipokines may explain why lean nondiabetic Asian Indians have decreased insulin sensitivity compared with others.

So Indians are many way different heterogenous population where atherogenic dyslipidemia prevails and that is why treatment schedule should be individualized here, approach should be extended beyond conventional stereotyped guidelines. For effective lipid lowering in Asian Indians, the following principles and interventions may be adopted: 1.

The therapeutic strategy likely to confer the greatest benefit to a South Asian individual is one of moderate weight loss through regular exercise and dietary restriction. Reduction of abdominal obesity through lifestyle measures can improve all components of the metabolic syndrome and likely delay the development of both diabetes and atherosclerosis.

Beyond lifestyle intervention, optimal management of risk factors to evidence-based targets is essential.

At present, there is no evidence to suggest that treatment targets should differ between ethnic

groups. Importantly, evidence-based treatments should be optimized in South Asians at risk, including the use of aspirin, lipid-lowering agents, blood pressure control, and renin-angiotensin inhibition.

It is advisable to increase intake of ω-3 polyunsaturated fatty acids in diets, particularly for the vegetarians which leads to effective lowering of serum triglyceride levels and increase HDLcholesterol levels.

3.

Statins are very effective in reducing LDLcholesterol levels. The newer statins (Atorvastatin and Rosuvastatin) reduce serum triglyceride levels by nearly 15-20% and also increase the LDL particle diameter14, but have relatively milder effect on HDL-cholesterol levels.

4.

Fibrates are more effective than statins in reducing serum triglyceride levels and increasing HDLcholesterol levels15 . Atherogenic dyslipidemia in Asian Indians may be well managed by the use of fibrates. Fibrates decrease TG levels by 20-50%, and increase HDL-C by 10-20%. They also reduce small, dense LDL particles by promoting a shift to larger, more buoyant particles which have higher binding affinity for the LDL receptor. Fibrates decrease fibrinogen levels and factor VЦ level, increase fibrinolysis ,decrease CRP & vascular inflammation , inhibit vascular smooth muscle proliferation and improves glucose tolerance. Subgroup analysis of FIELD and ACCORD trials showed that there was a possible benefit of fenofibrate in those with a triglyceride more than 204 and an HDL less than 34.

There were around 2014 patients in the FIELD trial who showed a CV event reduction of 27% while in the 941 patients of ACCORD trial there was a CV endpoint reduction of 31%.

Fibrate monotherapy was shown to reduce events in those with HDL-C concentrations less than 40 mg/dL in the VA-HIT trial (Veterans Affairs HDL Intervention Trial) and in those with triglyceride concentrations of 200 mg/dL or greater in the Bezafibrate Infarction Prevention trial. FIELD trial demonstrated a more certain preventive effect in patients with both triglyceride levels greater than 200 mg/dL and HDL-C levels less than 40 mg/dL.

Fibrates along with Simvastatin have shown a favourable trend in those diabetics with hypertriglyceridemia and low HDL in ACCORD Trial.

5.

Recent evidence indicates that combination of statins and fibrates is well tolerated 16. Adequate spacing of administration of both the drugs by several hours, gradual upward dose titration, and careful monitoring of liver function and creatine phosphokinase levels is essential to minimize adverse effects.

Fibrates and ω-3 polyunsatalso have antiinflammatory and anti atherogenic properties, and may be additionally useful in Indians who have high prevalence of subclinical inflammation although there is no hard evidence supporting their use.

7.

In IMPROVE-IT, the addition to statin therapy of a nonstatin agent, ezetimibe, which reduces the absorption of cholesterol from the gastrointestinal tract, lowered LDL cholesterol by approximately 24%.The combination of simvastatin and ezetimibe also resulted in a significantly lower risk of cardiovascular events than that with statin monotherapy, with a 2.0-percentage point lower rate of the primary composite end point of cardiovascular death, major coronary events, or nonfatal stroke (hazard ratio, 0.936).

7.

Non-HDL cholesterol, which is derived from subtracting HDL cholesterol concentration from total cholesterol level, representing the sum of all atherogenic lipoproteins, has been identified as a secondary target of therapy in patients with elevated triglyceride levels. There is evidence to suggest that, in patients with diabetes, non-HDL cholesterol is a stronger predictor of mortality from coronary disease than LDL cholesterol. In a post hoc analysis of patients with diabetes from four prospective cohort studies—the Framingham Cohort Study, the Framingham Offspring Study, the Lipid Research Clinics Prevalence Follow-Up Study, and the usual-care group of the Multiple Risk Factor Intervention Trial—the relative risk of death for diabetic (compared with nondiabetic) patients was 7.2 for those with elevated non-HDL cholesterol ≥ 130 mg/dl) and low LDL (< 100 mg/ dl) and 5.7 for those with low non-HDL cholesterol (< 130 mg/dl) and elevated LDL (≥ 100 mg/dl).

Managing and monitoring nonHDL cholesterol may be particularly important for Asian Indians where, the prevalence of CHD is nearly two-fold higher in presence of combination of hypertriglyceridemia, low HDL-cholesterol level and higher prevalence of metabolic syndrome.

Thus one needs to individualize each patient based on clinical judgement and experience. Initiation of therapy should be done considering an individual’s clinical as well as laboratory parameters including lipid levels. The high risk patients should undergo moderate to high intensity statin therapy depending on clinical perspectives. LDL-C should be monitored for adequate control, assessing drug compliance and addition of other drugs needs to be considered once optimal LDL-C lowering is not achieved though there is no strong evidence supporting their use.

The use of fibrates and other group of drugs in addition to statins also may be appropriate if lipid fractions other than LDL-C are elevated, specialy in diabetics and those with atherogenic dyslipidemia. Setting a target will lead to better drug monitoring on the part of the physician and

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2.

6.

730

also better drug compliance on the part of the patient.

Time has come to set up our own set of guidelines that can be applied to our indigeneous population. As a foundation to that goal we need our own data and hence future large scale trials are necessary.

METABOLISM

REFERENCES

1. Kausik K. Ray, John J. P. Kastelein, S. Matthijs Boekholdt et al. The ACC/AHA 2013 guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: the good the bad and the uncertain :a comparison with ESC/EAS guidelines for the management of dyslipidaemias 2011. European Heart Journal 2014; 35:960968.

2. Muntner P, Colantonio LD, Cushman M, et al. Validation of the atherosclerotic cardiovascular disease Pooled Cohort risk equations. JAMA doi:10.1001/jama.2014.2630 3.

Kavousi M, Leening MJG, Nanchen D, et al. Comparison of application of the ACC/AHA guidelines, Adult Treatment Panel III guidelines, and European Society of Cardiology guidelines for cardiovascular disease prevention in a European cohort. JAMA. oi:10.1001/jama.2014.2632.

4. Enas EA, Garg A, Davidson MA, Nair VM, Huet BA, Yusuf S. Coronary heart disease and its risk factors in firstgeneration immigrant Asian Indians to the United States of America. Indian Heart J 1996; 48:343–353.

5. Gupta M, Doobay AV, Singh N, Anand SS, Raja F, Mawji F, Kho J, Karavetian A, Yi Q, Yusuf S. Risk factors, hospital management and outcomes after acute myocardial infarction in South Asian Canadians and matched control subjects. Can Med Assoc J 2002; 166:717–722.

6. Gupta M, Singh N, Warsi M, Reiter M, Ali K. Canadian South Asians have more severe angiographic coronary disease than European Canadians despite having fewer risk factors. Can J Cardiol 2001; 17 (suppl C): 226C. 7. King H, Aubert RE, Herman WH. Global burden of diabetes, 1995–2025: prevalence, numerical estimates, and projections. Diabetes Care 1998; 21:1414–1431.

8. Snehalatha C, Viswanathan V, Ramachandran A. Cutoff values for normal anthropometric variables in Asian Indian adults. Diabetes Care 2003; 26:1380–1384.

9. The IDF consensus worldwide definition of the metabolic syndrome. International Diabetes Federation 2005. Available at: http://www.idf.org/home. Accessed September 20, 2005.

10. Kulkarni HR, Nanda NC, Segrest JP. Increased prevalence of smaller and denser LDL particles in Asian Indians. Arterioscler Thromb Vasc Biol 1999; 19:2749–2755.

11. Gupta R, Prakash H, Kaul V. Cholesterol lipoproteins, triglycerides, rural-urban differences and prevalence of dyslipidaemia among males in Rajasthan. J Assoc Physicians India 1997;45:275-9.

12. Bhalodkar NC, Blum S, Rana T, Bhalodkar A, Kitchappa R, Kim KS, Enas E. Comparison of levels of large and small high-density lipoprotein cholesterol in Asian Indian men compared with Caucasian men in the Framingham Offspring Study. Am J Cardiol 2004; 94:1561–1563.

13. Anand SS, Yusuf S, Vuksan V, Devanesen S, Teo KK, Montague PA, Kelemen L, Yi C, Lonn E, Gerstein H, Hegele RA, McQueen M. Difference in risk factors, atherosclerosis, and cardiovascular disease between ethnic groups in Canada: the Study of Health Assessment and Risk in Ethnic groups (SHARE). Lancet 2000; 356:279–284.

14. Pontrelli L, Parris W, Adeli K, Cheung RC. Atorvastatin treatment beneficially alters the lipoprotein profile and increases low-density lipoprotein particle diameter in patients with combined dyslipidemia and impaired fasting glucose/type 2 diabetes. Metabolism 2002; 51:334-342.

15. Jonkers IJ, Mohrschladt MF, Westendorp RG, van der Laarse A, Smelt AH. Severe hypertriglyceridemia with insulin resistance is associated with systemic inflammation: reversal with bezafibrate therapy in a randomized controlled trial. Am J Med 2002; 112:275-80.

16. Liamis G, Kakafika A, Bairaktari E, et al. Combined treatment with fibrates and small doses of atorvastatin in patients with mixed hyperlipidemia. Curr Med Res Opin 2002; 18:125-8.

Pharmacotherapy of Obesity

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Sachin Kumar Jain, Rati Singh, Ramesh Aggarwal, Ritika Sud

INTRODUCTION

Obesity has emerged as a global public health crisis and obesity rates have sharply increased over past 30 years.

Global data suggests 500 million adults have obesity worldwide. India ranks third after United States and China in having highest number of obese people. US accounts for thirteen percent and India along with China accounts for 15% of the total obese population worldwide.

Obesity in Indian population is different from rest of the world as we have “Thin Fat” Indian phenotype, indicating that the proportion of body fat, abdominal obesity, subcutaneous fat, and intraabdominal fat is more in Indian overweight and obese phenotype.

A significant difference in prevalence of obesity is seen in urban and rural population in India. In Urban men aged 15-49 years prevalence is 26.5% and women is 25% as compared to rural population where prevalence is 5.6% and 7.4% respectively. The increasing prevalence of obesity in adolescent population has been documented in a study of adolescents (aged 14-18years) studying in public schools of Delhi in which 29% were overweight or obese.

DEFINITION

percentage of body fat even at a lower BMI as compared to matched Caucasians.

COMPLICATIONS

Obesity is not only associated with cardio metabolic diseases but also linked to malignancies, osteoarthritis, psychosocial ailments like depression and low selfesteem.

Various diseases predisposed by obesity is enumerated in Table 2.

With an increase in the morbidity and mortality associated with obesity comes its cost in terms of economic burden to patient’s family and country. So in order to tackle this complex problem, early recognition of obesity and associated comorbidities should be done by education and awareness and early institution of treatment.

EVALUATION AND MANAGEMENT

It includes thorough history including history of drug intake to rule out medication induced weight gain and detail physical examination.

Work up is depicted in Table 3

MANAGEMENT

I.

LIFE STYLE THERAPY

1.

Meal Plan

Although BMI is used as a measure of obesity, it has certain limitation in stratifying risk of an Indian patient.

It does not consider change in body composition, gender and central obesity all of which have a role in predicting comorbidities and mortality.

A healthy meal plan with reduced caloric intake is must for weight reduction and a daily deficit of at least 500-750 kilocalories is likely to help in weight loss.

WHO has lowered the obesity cut off for Asians/Indians still there is need to have separate cutoff for Indians to redefine obesity as Indians are known to have higher

Meal plans can include a Mediterranean diet, DASH, low carbohydrate, low fat diet and a high protein or a vegetarian diet, the stress being on reducing the total caloric intake.

2.

Physical Activity

Along with a healthy meal plan, physical activity

World Health Organization (WHO) defines overweight and obesity as “An abnormal or excessive fat accumulation that presents a risk to health.”

CLASSIFICATION (TABLE 1)

Table 1: Classification of obesity based on BMI Classification

For Europoid-WHO (1998) BMI (kg/m2)

Classification

For Adult Asians WHO (2008) BMI (kg/m2)

Underweight

<18.5

Underweight

<18.5

<18.5-24.9

Normal

<18.5-22.9

>25

Over weight

>23

Preobese

25-29.9

At risk

23-24.9

Obese I

30-34.9

Obese I

25-29.9

Obese II

35-35.9

Obese II

>30

Obese III

>40

Normal Over weight

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Table 2: Diseases Predisposed by Obesity

Table 3: Work Up for Obesity

Cardiovascular

History

Physical Examination

Investigation

Medical causes

Measure height and weight

Comprehensive metabolic profile

BMI

LFT

Endocrinal

METABOLISM

Gastrointestinal

Coronary artery disease, Corpulmonale, Varicose Veins, Congestive heart failure, Pulmonary embolism Metabolic syndrome, Type2 Diabetes, Dyslipidemia, Poly cystic ovarian syndrome Gastroesophageal reflux disease, Nonalcoholic fatty liver disease, Cholelithiasis, Hernias,

Drugs PCOS

Family history of Waist circumference obesity Thyroid Binge eating or bulimia

Musculoskeletal Hyperuricemia and gout, Osteoarthritis Respiratory

Dyspnea, Obstructive sleep apnea, Hypoventilation syndrome, Pickwickian syndrome, Asthma

Genitourinary

Urinary stress incontinence, Obesity related glomerulopathy, Male hypogonadism

Neurological

Stroke, Idiopathic intracranial hypertension, Meralgia paresthetica, Dementia

Psychological

Depression/ low self-esteem, Social stigma

Integument

Lymphedema, Striae distensae, Cellulitis, Intertrigo,carbuncle, Acanthosis nigricans Acrochordons, Hidredenitis supurativa, Stasis pigmentation

Cancers

Breast cancer, Uterine cancer, Cervix, Esophagus, Pancreas, Kidney, Prostate, Colon cancer

should be prescribed to obese individual as a part of life style therapy. Individual must be encouraged to reduce sedentary behavior. The goal is aerobic activity of ≥ 150 min/week performed in 3-5 daily sessions per week which may be achieved in progressive increments over a period .Addition of resistance training, 2-3 times per week helps in preserving muscle mass. Resistance exercises using major muscle groups in single set repetitions are evidenced to help in fat loss. Physical activity must be tailored to an individual taking into account their physical and health status.

3.

Behavioral Intervention

Behavioral therapy enhances adherence to a healthy meal plan and an exercise routine.

Behavioral therapy consists of:

1.

Self-monitoring of weight, food and caloric intake and physical activity

2.

Setting of goals for self which are reasonable but clear.

3.

Education regarding meal plan physical activity and obesity

4.

Stimulus control

Fasting blood glucose TSH

Oropharynx

Lipid profile

Acanthosis

PCOS workup if history suggestive

5.

Mobilization of social support

6.

Stress reduction

7.

Behavioral contracting

8.

Cognitive behavioral therapy

9.

Systematic problem solving

A multidisciplinary team consisting of (nurses, dieticians, educators, physical instructions and psychologist) for behavioral therapy enhances its effectiveness. Therapy should be intensified in case 2.5% weight is not achieved during the first month of treatment, as early weight loss is a predictor of successful long term weight loss. Behavioral intervention must take into account the patients cultural and socio-economic background and educational status.

II.

PHARMACO THERAPY

Drugs are indicated as an adjunct to life style and behavioral changes in individuals to achieve a sustainable reduction in body weight.

Pharmacotherapy may be instituted in patients with a BMI of ≥30kg/m2 or at ≥27/m2 when one or more co-morbid conditions exist that may benefit with weight loss.

Factors considered pharmacotherapy:

while

choosing

1. Willingness 2.

Current medication and possible drug to drug interaction

3. Diabetes/prediabetes 4.

Medical history of other co-morbid conditions in patient

Recent advances and approval of antiobesity drugs has opened the way to much more directed treatment approaches than ever before. Table 4 gives list of drugs, their mechanism side effects and contraindications.

Orlistat: Until recently Orlistat, a reversible pancreatic gastric lipase inhibitor was the only drug approved for use in chronic weight management.

In a 2-year, multicenter, randomized, double-

(37.5 mg/d)

Phentermine resin (ADIPEX)

32 mg / 360 mg 2 tablet QID (high dose)

3 mg injectable

Naltrexone/ Bupropion (CONTRAVE)

Liraglutide (VICTOZA)

15 mg P/92 mg P/T ER daily (high dose)

GLP1 agonist

Reuptake inhibitor of dopamine and norepinephrine (bupropion) and opioid antagonist (naltrexone)

FDA approved in 2014 for chronic weight management

FDA approved in 2014 for chronic weight management

FDA approved in 2012 for chronic weight management

GABA receptor modulation (T) plus norepinephrine releasing agent (P)

3.75 mgP/23 mgT ER QD (starting dose)

Phentermine (P)/ topiramate (T) (OSYMIA)

7.5 mg P/46 T ER daily (recommended dose)

FDA approved in 2012 for chronic weight management

5HT2c receptor agonist

10 mg BID

Lorcaserin (10 mg) (BELVIQ)

FDA approved in 1999 for chronic weight management

FDA approved in 1999 for chronic weight management

Pancreatic and gastric lipase inhibitor

Pancreatic and gastric lipase inhibitor

120 mg TID

Orlistat prescription (120mg) (XENICAL)

FDA Approved in 1960s for short term use(3mo)

Approved in 1960s for short term use(3mo)

Status

Orlistat, Over â&#x20AC;&#x201C;the- 60-120 mg TID counter (60 mg)

Norepinephrinereleasing action

(75 mg/d)

Norepinephrinereleasing action

Mechanism of action

Diethylpropion (TENUATE)

Lonamin (30-37.5 mg/d)

Dosage

Drug

Pregnancy and, breast feeding, Use with caution: SSRI, SNRI/ MAOI, triptans, buproprion, dextromethorphan

As stated above

Chronic malabsorption syndrome, pregnancy and, breast feeding, levothyroxine, warfarin, antiepileptic drugs

Same as phentermine

Anxiety, heart disease, uncontrolled hypertention, seizure, MAO inhibitors, pregnancy and breast feeding, hyperthyroidism, glaucoma, drug abuse, sympathomimetic amines

Contraindications

Nausea, vomiting, pancreatitis

Medullary carcinoma of thyroid, MEN2 history

Constipation, Headache, nausea Uncontrolled hypertention, vomiting, dizziness seizure, anorexia nervosa or bulimia, drug or alcohol withdrawl, MAOI

Insomnia, dry mouth, dizziness, Pregnancy and, breast parasthesia, constipation, feeding, hyperthyroidism, dysgeusia glaucoma, MAO inhibitor, sympathomimetic amines

Headache, nausea, dry mouth, dizziness, fatigue, constipation

AS stated above

Decrease absorption of fat soluble vitamins, steatorrhoea, oily spotting, fecal urgency and incontinence

Same as phentermine

Urticarial, impotence

Palpitation, tachycardia, hypertension, euphoria, psychosis

Constipation Insomnia, dry mouth, dizziness, constipation, dysgeusia

Headache ,nausea, dry mouth, fatigue,

Side effects

CHAPTER 157

Table 4: Drugs for Obesity

733

blind, placebo-controlled study by Rossner et al in patients with BMI 28 to 43 kg/m2 were randomized to placebo or Orlistat (60 or 120 mg) three times a day, combined with a hypo caloric diet during the first year and a weight maintenance diet in the second year of treatment to prevent weight regain.

Orlistat-treated patients lost significantly more weight (p<0.001) than placebo-treated patients after 1 year (6.6%, 8.6%, and 9.7% for the placebo, and Orlistat 60 mg and 120 mg groups, respectively.

During the second year, Orlistat therapy produced less weight regain than placebo (p = 0.005) for Orlistat 60 mg; p<0.001 for Orlistat 120 mg). It has also been documented to produce significant improvement in metabolic parameters.

METABOLISM

734

Lorcaserin- It is a highly selective agonist of 5HT2C receptor, the activation of which leads to increased satiety. Recommended for use in obese nondiabetic and diabetic individuals in a dose of 10mg BD. In a multicentric placebo controlled trial by Smith SR et al. in nondiabetic overweight and obese patients, on lifestyle modification therapy, addition of Lorcaserin in a dose of 10 mg twice daily was associated with ≥ 10% loss in body weight in significantly more patients vs placebo group after 52 weeks of therapy(p<0.001). Also in patients who achieved ≥5% weight loss during the first year on therapy, that loss was maintained more in patients on Lorcaserin during second year on therapy (67.9%) vs placebo(50.3%P<0.001). Locarserin was also documented to have a beneficial effect on insulin resistance, blood glucose and insulin levels significantly more so in the first year as compared to placebo.

In the BLOOM-DM trial in diabetic patients with (HbA1C between 7% and 10%) addition of Lorcaserin (10 mg once or twice daily for a year) in conjunction with the antidiabetic drugs(metformin and /or sulfonylurea) has been studied to causes ≥5% weight loss 37.5% and 44.7% respectively vs 16.1% in the placebo group in the first year. Improvement in HbA1C (1%) levels along with blood glucose was seen without any significant changes in blood pressure, triglyceride, LDL-C or HDL-C levels.

Lorcaserin interacts with MAO- inhibitors and SSRI, though it has a low rate of adverse effects.

Europe has not yet approved the use of Lorcaserin, labeling it as a drug with carcinogenic potential on long term use along with concerns regarding depression and valvulopathy.

Phentermine/Topiramate controlled release combination (PHEN/TPM CR) - phentermine acts on the hypothalamus to cause release of norepinephrine and dopamine. Topiramate primarily an antiepileptic drug (AED) causes weight loss by decreased caloric intake together with increased energy expenditure. Using an extended release combination of the two drugs allows for lower dosages of both components and lesser side effects.

In the 56 week EQUIP trial 66.7% patients with obesity (BMI ≥35kg/m2) receiving 15/92mg of PHEN/TPM CR lost ≥ 5%of body weight, as also 44.9% of those receiving 3.75/23mg of PHEN/TPM CR vs 17.3% of placebo patients.

The SEQUEL trial documented that after 108 weeks, the addition of PHEN/TPM CR to a standardized lifestyle modification led to substantial weight loss. The percentage changes in body weight from baseline were 1.8%, 9.3%, and 10.5% in subjects treated with placebo, PHEN/TPM CR 7.5/46, and PHEN/TPM CR 15/92, respectively (ITT-LOCF).

Importantly, both doses of PHEN/TPM CR were significantly more effective than placebo regardless of baseline BMI and were similarly effective at baseline BMI values extending from 30 to 40 kg/ m2. In those subjects with class III obesity (BMI ≥40 kg/m2), the 15/92 dose produced an even more pronounced degree of weight loss, exceeding that observed with 7.5/46.

Weight loss is documented to occur in a dose dependent fashion along with reduction in waist circumference, decrease in blood pressure and improved fasting glucose and Lipid profile.

Though the drug has not yet been approved for use in Europe due to its potential teratogenic effect.

Naltrexone SR/ Bupropion SR - Naltrexone is an opioid receptor antagonist primarily used to treat alcohol and opioid dependence. In addition it also reduces food craving. Bupropion is a reuptake inhibitor of norepinephrine and dopamine and is known to cause weight loss. This drug combination was shown to cause remarkable weight loss in patients of obesity with or without T2DM.

The COR-I trial documented a mean change in bodyweight of 1·3% in the placebo group, 6·1% in the naltrexone 32 mg plus bupropion 360 mg group (p<0·0001 vs placebo) and 5·0% in the naltrexone 16 mg plus bupropion 360 mg group (p<0·0001 vs placebo). 84 (16%) participants assigned to placebo had a decrease in bodyweight of 5% or more compared with 226 (48%) assigned to naltrexone 32 mg plus bupropion 360 mg (p<0·0001 vs placebo) and 186 (39%) assigned to naltrexone 16 mg plus bupropion 360 mg (p<0·0001 vs placebo). Significant improvement in weight and the cardio metabolic markers with a fall in HbA1c of 0.6% has also been documented in the COR-BMOD trial. The Gastro intestinal effects of nausea, vomiting, constipation may limit its tolerability and use. These may be mitigated by up titrating the dose weekly over a 4-week period.

This combination may cause increases in blood pressure and must be used with caution in hypertensives. It is not recommended for use in those with kidney and liver impairment.

Liraglutide: is GLP -1 receptor agonist and bears a strong homology to the native GLP-1. Liraglutide acts centrally on the GLP-1 receptor causing a

Table 5: Specific drugs can be selected for different meal related behavioral problems Increase appetite

Phentermine /Topiramate ER

Satiety problems

Lorcaserin

Craving problem

NaltrxoneSR/BuproprionER

Prediabetes/Diabetes

Liraglutide

Criteria for stopping pharmacotherapy (drug failure):

Lorcaserin - stop if <5% loss at 12 week

Phentermine/Topiramate CR - at 12 weeks, can increase the dose to 11.25mg/69mg for 14 days, then 15mg/96; stop if <5% loss at 12 week on maximum dose

NaltrxoneSR/Bupropion SR - stop if <5% loss at 12 week

Liraglutide 3 mg - stop if <4% loss at 16 week

III.

SURGICAL TREATMENT

Bariatric Surgery: It is indicated if BMI is ≥40kg/m2 and failure to lose weight with diet, exercise and drug therapy

BMI>35kg/m2 with comorbidities like diabetes mellitus ,dyslipidemia, impaired glucose tolerance with failed diet, exercise and drug therapy.

FUTURE THERAPY

Oxytocin is emerging as a treatment modality for metabolic disorders such as obesity and dysglycemia.

Few RCTs have evaluated the effect of intranasal oxytocin on weight loss.

Combination of GLP-1 RAs with SGLT 2 inhibitors is also a potential option under consideration for management of obesity.

735

Obesity is not only a lifestyle disorder but a “disease” as along with it comes inevitable predisposition to various cardio metabolic disorders. So in order to control the epidemic, we need to keep in mind the lower cut off of BMI as Indians. A multidisciplinary approach should be exercised involving NGOs, the Government, schools, family and society to which education and awareness is key.

REFERENCES

1. Allison DB, Gadde KM, Garvey WT et al.Controlledrelease phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring) 2012; 20:330-42.

2. Billes SK, Sinnayah P2, Cowley MA. Naltrexone/ bupropion for obesity: an investigational combination pharmacotherapy for weight loss.

3. Bhardwaj S, Misra A, Khurana L, et al Childhood obesity in Asian Indians: a burgeoning cause of insulin resistance, diabetes and sub-clinical inflammation. Asia Pac J CIin Nutr 2008; 17 Suppl 1:172-5 4. Davies MJ, Bergenstal R, Bode B et al. Efficacy of Liraglutide for Weight Loss Among Patients with Type 2 Diabetes: The SCALE Diabetes Randomized Clinical Trial 2015; 314:68799.

5. Elena Barengolts, OXYTOCIN –An emerging treatment for obesity and dysglycemia: Review of Randomized control trial and cohort studies. Endocrine Practice 2016; 22;885-894.

6. Finucane MM, Stevens GA, Cowan MJ, et al. National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9·1 million participants. Lancet 2011; 377:557-67.

7. Flegal KM1, Carroll MD, Kit BK, Ogden CL.Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999-2010. JAMA 2012; 307:491-7.

8. Misra A, Pandey RM, Devi JR,et al High prevalence of diabetes, obesity and dyslipidemia in urban slum population in northern India.

9. National Family Health Survey (NFHS-3), 2005–06: India 10. Ng M, Fleming T, Robinson M,et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014; 384:766815.

11. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, 20112012. JAMA 2014; 311:806-814.

12. O’Neil PM1, Smith SR, Weissman NJ, et al. Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM study. Obesity (Silver Spring) 2012; 20:1426-36.

13. Pi-Sunyer X, Astrup A, Fujioka K et al.A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management. N Eng J MED 2015; 373:11-22.

14. Rossner S1, Sjöström L, Noack R, et al.Weight loss, weight maintenance, and improved cardiovascular risk factors after 2 years treatment with Orlistat for obesity. European Orlistat Obesity Study Group. Obes Re Pharmacol Res 2014; 84:1-11.

15. Wadden TA1, Foreyt JP, Foster GD et al. Weight loss with naltrexone SR/bupropion SR combination therapy as an adjunct to behavior modification: the COR-BMOD trial.

Obesity (Silver Spring) 2011; 19:110-20.

CHAPTER 157

reduction in food intake, reduction in production of hepatic glucose and reduced glucose uptake by the muscle. The peripheral GLP-1 receptors increase Insulin secretion, reduce glucagon secretion and slow the gastric emptying time. (Table 5) Liraglutide earlier approved for use in T2DM has now been approved for use in obesity at a dose of 3mg/day. Liraglutide in a 2 year trial was compared with Orlistat and placebo and has been shown to cause significant weight loss as compared to both (5.8 kg more than placebo and 3.8 kg more than Orlistat) at 3mg/day by Astrup et al. In the SCALE Diabetes randomized controlled trial patients with T2DM and overweight, Liraglutide caused significant weight loss with 54.3% of patients on Liraglutide (3mg/day) losing >5% body weight vs 21.4% of patients on placebo. Liraglutide was also documented to reduce fasting blood glucose, HbA1c, systolic blood pressure and the waist circumference. The benefits of Liraglutide induced weight loss has been studied in both nondiabetic obese individuals and patients of T2DM.The drug may be started at a dose of 0.6mg SC once a day and up titrated by 0.6mg weekly going up to a maximum of 3mg/day.

CONCLUSIONS