In India, the major factors contributing obesity can be broadly listed as the distinct phenotype, the thrifty genotype, demographic transition and urbanization, nutritional transition, and several socio-economical/socio-cultural factors.

2.1. The Distinct Phenotype – Is it making Indians actually diverse?

Phenotype of obesity in several ethnic groups in developing countries appears to be different from that seen in white Caucasians in developed countries.³Several investigators have shown that body fat is higher in Asians, particularly south Asians, compared with white Caucasians for the similar level of BMI.³High percentage of body fat with low BMI value could be partly explained by body build (trunk to leg length ratio and slender body frame), muscularity, adaptation to chronic calorie deprivation, and ethnicity.³Importantly, obesity-related morbidities (diabetes, hypertension, dyslipidemia) occur more frequently at lower BMI levels in Asians than white Caucasians.⁵Data on Asian Indians, showed that about 66% of men and 88% of women, classified as nonobese based on international cutoff of BMI, had one or more cardiovascular risk factor(s).³Based on the different studiesdone on Asian Indians, The World Health Organization Asia Pacific guidelines validated BMI of 23 kg/m(2) for the designation of overweight; Waist Circumference of 87 cm for men and 82 cm for women as an appropriate cut points to identify cardiometabolic risk factors including prediabetes in urban Asian Indians.⁶South Asian population, with the difference in BMI and Waist Circumference; also exhibits a distinct feature of thick subcutaneous adipose tissue. Studies confirms that ethnic excess in insulin resistance in South Asians appears to be related more to excess truncal fat and dysfunctional adipose tissue than to excess visceral fat.⁷On the whole, South Asians particularly the Indians could be classified as ‘metabolically obese’⁸, i.e. they have several metabolic derangements but are nonobese by conventional BMI standards.

These body composition characteristics, individually or in combination, contribute to insulin resistance, dyslipidemia, hyperglycemia, and excess procoagulant factors which is seen commonly in South Asians.³

2.2. The Thrifty genotype – The inherited faulty genes

The concept was first articulated when gestational diabetes was described as being the result of a 'thrifty genotype rendered detrimental by progress'. More recently, this hypothesis has been extended to the concept of a 'thrifty phenotype' to describe the metabolic adaptations adopted as a survival strategy by a malnourished fetus; changes that may also be inappropriate to deal with a later life of affluence.⁹Both the thrifty genotype and the thrifty phenotype hypotheses predict that populations in developing world such as India would be at greater risk of obesity and its co-morbidities. To date thrifty genes remain little more than a nebulous concept propagated by the intuitive logic that man has been selected to survive episodic famine and seasonal hungry periods. Under such conditions those individuals who could lay down extra energy stores and use them most efficiently would have a survival advantage.⁹The phenotypic data estimating heritabilities and genetic correlations in Asian Indian families observed many significant genetic correlations between the traits, in particular between HOMA of insulin resistance (HOMA-IR) and BMI. This provide evidence that genetic factors contribute to a significant proportion of the total variance in insulin resistance and related metabolic disturbances in Asian Indian CHD families.¹⁰

2.3. Demographic transition - Growth generates health care challenges in booming India

The paradoxical co-occurrence of under- and overnutrition, and perhaps, more generally, the coexistence of diseases of poverty and affluence, is characteristic of rapidly developing economies.¹¹Emergence of obesity and the metabolic syndrome in developing countries is due to a number of factors. Demographic transition (shift to low fertility, low mortality, and higher life expectancy) and epidemiologic transition (from widely prevalent infectious diseases to a pattern of high prevalence of chronic lifestyle related Non communicable diseases) have occurred in developing countries as they become economically more resourceful (socioeconomic transition, shift of people from low socioeconomic strata to high socioeconomic strata), causing significant shifts in dietary and physical activity patterns (nutrition and lifestyle transitions, and stress). These changes cause significant effects on body composition and metabolism, often resulting in increase in BMI, excess generalized and abdominal adiposity, deposition of ectopic fat, and increase in dyslipidemia and diabetes.³ In India, a population-based multilevel study of 77,220 ever married women, aged 15-49 years, from 26 Indian states, derived from the 1998-99 Indian National Family Health Survey data concluded that for each standard deviation increase in income inequality, the odds ratio for being underweight increased by 19% (p = 0.02) and the odds ratio for being obese increased by 21% (p<0.0001).¹¹ Income inequality had a similar effect on the risk of being overweight as it did on the risk of obesity (p = 0.01), and state income inequality increased the risk of being pre-overweight by 9% (p = 0.01). This study suggests twin burden of undernutrition and overnutrition in India is more likely to occur in high-inequality states.¹¹Not only the Obesity, the lifestyle transition due to socio-economic growth in rural Indian population showed nearly a three-fold increase in age- and sex-adjusted prevalence of diabetes (from 2.20% to 6.36%).¹²Increased upper body adiposity and physical inactivity was significantly associated with this phenomenon.¹²The Indian Migration Study provided evidence that the rural-to-urban migration in India was associated with both an increased fat intake and reduced physical activity in both men and women, as compared with rural dwellers, and this likely contributed to the higher levels of obesity and diabetes observed in migrants.¹³

2.4. Nutritional Transition – The diverse diet pattern of India and the shifting paradigm

Diets across India have been experiencing a shift in the dietary patterns over the last few decades and many researchers believe that India may be in the midst of a “nutrition transition,” where changes in diet parallel an expanding industrial economy and a rapidly progressing epidemic of obesity and chronic, noncommunicable disease.¹⁴ With improvement in economy, people become affluent and consume diets high in saturated fats, cholesterol, and refined carbohydrates and low in polyunsaturated fatty acids and fiber, associated with markedly sedentary lifestyle and increased stress. A rapid shift in dietary pattern in these countries is clearly responsible for steep increase in obesity and the metabolic syndrome.³The India Health Study assessed the role of diet in India’s rapidly progressing chronic disease epidemic across North-South regions where across the regions, more than 80% of the participants met the criteria for abdominal adiposity. In Delhi, the “fruit and dairy” dietary pattern was positively associated with abdominal adiposity and hypertension; In Trivandrum, the “pulses and rice” pattern was inversely related to diabetes and the “snacks and sweets” pattern was positively associated with abdominal adiposity whereas in Mumbai, the “fruit and vegetable” pattern was inversely associated with hypertension and the “snack and meat” pattern appeared to be positively associated with abdominal adiposity.¹²The dietary patterns characterized by animal products, fried snacks, or sweets appeared to be positively associated with abdominal adiposity across all the regions.¹⁴The National Sample Survey Organisation (NSSO) conducts dietary intake surveys in rural and urban India, asking about household consumption over the past 30 days. The 2004-5 survey found total energy intake to be very similar in rural and urban areas (2047 kcal and 2020 kcal respectively), but fat intake was much higher in urban (48 g) compared with rural (36 g) areas. While the proportion of energy from cereals was higher in rural than urban people, the proportion of energy from most other food groups was higher in urban people, most notably milk products and oils and fats, but also fruit and vegetables.¹⁵A Cross-Sectional Study on Dietary Intake and Rural-Urban Migration in India found that migration from rural to urban areas was associated with higher energy intake and Rural to urban migration appears to be associated with both positive (higher fruit and vegetables intake) and negative (higher energy and fat intake) dietary changes.¹⁶

3. CHILDHOOD OBESITY IN INDIA – THE SILENT EXPLOSION:

Developing countries such as India is now facing the double burden of childhood underweight and obesity. Childhood obesity is a recent epidemic with a high magnitude in India. Recent meta-analysis including 92,862 subjects from nine studies estimated the prevalence of overweight to be 12.64% and that of obesity to be 3.39%.⁴Studies among school children in different parts of the country have demonstrated increasing prevalence of overweight and obesity, with great disparity between rural and urban parts of country. The prevalence of overweight was 37.5% in urban Delhi and 8% in rural Haryana. The prevalence of overweight and obesity is higher in upper socioeconomic class (17.2% overweight and 4.8% obese) as compared to lower socioeconomic class (4% and <1%, respectively).¹⁷ Different cross-sectional studies have shown that the children and adolescents across different age groups suffer from overweight and obesity. Studies conclude that at least 30% of obesity begins in childhood. Conversely 50 to 80 % obese children become obese adults.¹⁸ The cross-sectional study carried out by Bharati DR et al.¹⁸in all the 31 middle-schools (5th to 7th standard) and high-schools (8th to 10th standard) of Wardha city showed 3.1% (95% CI: 2.5-3.8%) and 1.2% (95% CI: 0.8-1.8%) prevalence respectively; together constitute 4.3 per cent (95% CI: 3.6-5.2%) for overweight/obesity. The underlying causes of overweight/obesity were urban residence, father and/or mother involved in service/business, English medium school and child playing outdoor games for less than 30 min.¹⁸Nutrition transition is also a core area of concern regarding the outbreak of Overweight and obesity in children. A review on available literature on nutritional status of Indian school children 6-18 years from middle and high socio economic status (MHSES) showed on one side, anemia prevalence (hemoglobin concentration <120 g/L) ranged from 19-88% across five different cities in India whereas Overweight and obesity were prevalent among 8.5-29.0% and 1.5-7.4% respectively among school children, as indicated by 11 studies.¹⁹ One of the largest study on secular trends in the prevalence of childhood obesity in the Indian subcontinent also showed an increasing trend in prevalence of overweight and obesity in urban Asian Indian adolescents. The data were derived from cross-sectional sampling of children, 3493 in year 2006 and 4908 in year 2009, aged 14–17 years studying in privately-funded and government-funded schools in New Delhi (North India)²⁰where prevalence of obesity increased significantly from 9.8% in 2006 to 11.7% in 2009 (p<0.01), whereas underweight decreased from 11.3% to 3.9% (p<0.001).Males and privately-funded school children had significantly higher increase in prevalence and risk of being overweight and obese over the three years linking the association with high socio-economic status.²⁰Not only restricted to the adolescent category, even the prevalence of Overweight and Obesity among Pre-school Children (2 to 5 years) is also a cause of concern. The study conducted to ascertain the prevalence of overweight and obesity in 425 pre-school children (2 to 5 years) using the new Child Growth Standards released by the World Health Organization showed the prevalence of overweight and obesity was 4.5% and 1.4%, respectively.²¹

3.1. Changing Food Habit and Home environment – The dark face behind Childhood Obesity

Over the past few decades, the food and home environments have changed tremendously. The change in diet, a decrease in physical activity and too much time spent in front of computer or television screens have been blamed for the growing number of overweight children, the world over. Increasing energy intakes with decrease in energy expenditure due to decreased physical activity or increased sedentary behaviors result in significant changes in bodyweight. There is a general misconception in parents in India and other developing countries that an obese child is a healthy child, and hence, feels that it is important to feed him/her in excess. Furthermore, mothers in India often have traditional belief that feeding oils, ghee (clarified butter), and butter to child would be beneficial to growth and impart strength. Another important factor is increasing pressure on children to perform in academics often forced by parents and teachers, which leads to reluctance of child to take part in sports or any other form of physical activity. Specifically, the majority of children in India are physically inactive when they are studying in classes when major examinations are held.Lack of playfields at school and open spaces around home, and decreased stress on games and physical training in schools has further led to decline in physical activity in children. Even the changing environment by making fast food outlets conveniently available has promoted consumption of energy dense foods high in fat and sugar. The traditional micronutrient rich foods are being replaced by energy dense processed micronutrient poor foods (snacks) like burgers, pizza, chowmein and cold drinks and fruit drinks in greatly increased portions. Lastly, but significantly, a steep increase in sedentary activities likes television viewing and computer usage has substantially contributed to a rise in obesity leaving hardly any time to get involved in leisure time physical activity.^22,23

4. MANAGEMENT OF OBESITY – THE NEED OF AN HOUR:

Many options are available for treating overweight and obese individuals. For each patient, the risks of each treatment option must be weighed against the benefit of the potential weight loss produced by that treatment. This risk/benefit assessment must take into account a patient’s BMI, waist circumference, and the presence of comorbidities and cardiovascular risk factors. Patients at a higher BMI or with existing obesity-related diseases are at more risk from their excess weight and, therefore, more aggressive treatments such as pharmacotherapy and surgery become appropriate options. Each treatment plan must be tailored to meet the BMI and risk/benefit assessment for each patient. The evidence-based NIH clinical guidelines for obesity treatment set the following general goals for weight loss and management: (1) to prevent further weight gain, (2) to reduce body weight, and (3) to maintain a lower body weight long term.²⁴Traditionally, the goal of obesity treatment was to achieve an ideal body weight, and for many people this meant losing extremely large amounts of weight. However, a reduction to ideal body weight is not necessary for health improvement and risk reduction. Clinical studies indicate that moderate weight reduction (i.e., 5–10% of the initial body weight) can correct or ameliorate many of the metabolic abnormalities associated with obesity and that small weight losses are associated with improvements in hypertension, dyslipidemia, and type 2 diabetes mellitus. Unfortunately, the treatment of adult obesity has been disappointing; less than 5% of adults who lost weight were able to maintain their weight at 5 yr and 62% regained all of the lost weight, thus the provider must work closely with the patient to help set realistic expectations and provide guidance in this area.²⁵

4.1. Non-Pharmacological Management of obesity

Dietary Modification - The universal component of dietary interventions for weight loss is a creation of an energy deficit.²⁴ Most recommendations encourage a slow rate of weight loss through an energy deficit (energy output minus energy intake) of 500–1000 kcal/day.²⁴This calorie deficit can be accomplished by suggesting substitutions or alternatives to the diet. Examples include choosing smaller portion size, eating more fruits and vegetables, consuming more whole-grain cereals, selecting leaner cuts of meat and skimmed dairy product, reducing fried foods and other added fats and oils, and drinking water instead of caloric beverages. It is important to monitor the rate of weight loss during the active weight loss phase. Initially, particularly at the greater energy deficits, diuresis may occur and weight will be dropped quickly. However, after this initial drop in weight, the rate of weight loss will slow and should not be greater than 1% body weight per week.²⁶ An energy deficit of 500–1000 kcal/day should produce about a 10% body weight reduction over 6 months.²⁴Diets containing low energy dense foods have been shown to control hunger and result in decreased caloric intake and weight loss. Lastly, it is important that the dietary counseling remains patient-centric and that the goals are practical, realistic, and achievable.

Physical Activity Modification – Physical activity has been used as a key component of obesity treatment. Although exercise alone is moderately effective for weight loss, the combination of dietary modification and exercise is the most effective behavioral approach for the treatment of obesity. Currently, the minimum public health recommendation for physical activity is 30 min of moderate intensity physical activity on most, preferably all, days of week.²⁷Focusing on simple ways to add physical activity into the normal daily routine through leisure activities, travel, and domestic work should be suggested.²⁷Examples include walking, using stairs, doing household work, and engaging in sport activities. Studies suggests that while physical activity alone may not have been that important for weight loss, but it is essential in prevention of weight regain.²⁷

Behavior Modification – The key behavioral modification components include self-monitoring techniques (e.g., recording of food intake, exercise activities, and/or weight change); stress management; stimulus control (e.g., using smaller plates, not eating in front of the television); social support especially from family and relatives to help patients develop more positive and realistic thoughts about themselves.²⁷

4.2. Pharmacological Management of Obesity

While diet, physical activity and behavior modification remain cornerstone of obesity management, yet has so far failed to halt the obesity pandemic. Given the enormity of the obesity problem adjunctive pharmacotherapy provides an attractive solution.²⁸Both the American Food and Drugs Administration (FDA) and the European agency for the Evaluation of Medicinal Products (EMEA) demand that any anti-obesity drug should produce significantly greater weight loss compared to placebo control over any trial. The FDA specifically demands that placebo-subtracted weight loss (i.e. drug induced weight loss minus placebo) is greater than 5%. Moreover, significantly more individuals in the drug treated group should have lost 5% or more of their initial body weight compared to placebo. The EMEA alternatively demands that the weight loss in the drug group is greater than 10% from baseline. Moreover, significantly more individuals in the drug treated group should have lost 10% or more of their initial body weight compared to placebo. The secondary outcome of anti-obesity drug trials is to ensure that this weight loss in sustained and that it produces a significant reduction in risk factors for a number of obesity related co-morbidities (e.g. fasting blood glucose, HbA1c, insulin, total plasma cholesterol, LDL-cholesterol, triglycerides, uric acid and blood pressure). The FDA also demands that drugs reduce total body fat mass and alter body fat distribution (specific risk factors for ill health). Finally, drug induced weight loss should have a positive impact on health related quality of life.²⁸

4.2.1. Orlistat – Place in therapy

Orlistat is a potent and reversible gastrointestinal lipase inhibitor preventing dietary fat absorption by 30% by inhibiting pancreatic and gastric lipase. Orlistat was approved in 1998 and is currently the only available drug for the long-term management of obesity. The prescribed dose is 120 mg capsule 3 times daily, and a half dose (60 mg) is available over-the-counter in some countries, including the U.S. The efficacy of orlistat for weight loss has been reported in several Randomized Clinical Trials for the long-term management of obesity (approximately 4 years).^29,30In meta-analyses of 12 and 15 trials, the mean difference in weight loss due to orlistat was -2.59 kg (95% CI, -3.46 to -1.74 kg) at 6 months and -2.9 kg (-3.2 to -2.5 kg) at 12 months³¹, which was more than the placebo. The beneficial effect on body weight is sufficient to improve several cardiometabolic parameters, including waist circumference, blood pressure, blood glucose levels, and lipid profiles.³⁰ In a meta-analysis which included 15 studies of approximately 10,995 participants who were treated with orlistat or placebo for at least 6 to 12 months, treatment with orlistat was associated with a significant decrease in total cholesterol after adjustment for weight loss,³¹ which indicates orlistat is a useful adjunctive tool for improving cardiovascular risk factor profiles in obese patients. Orlistat also reduced the incidence of type 2 diabetes from 9.0% to 6.2% (HR, 0.63; 95% CI, 0.46 to 0.86) in a longer 4-year trial.³²The most common side effects of orlistat are gastrointestinal and include diarrhea, fecal incontinence, oily spotting, flatulence, bloating, and dyspepsia. As a result of the adverse effects, orlistat may not be well tolerated. However, the side effects tend to occur early and can be reduced as patients learn how to avoid fat-rich diets. Recently, serious liver injury has been reported over the past 10 years. Between 1999 and 2008, the U.S. FDA received 32 reports of severe liver injury, including 6 cases of liver failure in patients using orlistat, which prompted the U.S. FDA to undertake a review of orlistat's treatment safety. The U.S. FDA advised healthcare professionals to continue prescription of orlistat in August 2009, because severe liver injury was rare. However, a review in May 2010 led to a label revision and the addition of a warning of severe liver injury to educate the public regarding the signs and symptoms of liver injury.³³

4.2.2. Management of Childhood and Adolescent Obesity

There are four modalities for current management of adolescent overweight and obesity: dietary management, increasing physical activity, pharmacological therapy and bariatric surgery.³⁴A recent guideline suggests considering pharmacotherapy in

(1) Obese children only after failure of a formal program of intensive lifestyle modification;

(2) Overweight children only if severe comorbidities persist despite intensive lifestyle modification, particularly in children with a strong family history for type 2 diabetes or premature cardiovascular disease. Pharmacotherapy should be provided only by clinicians who are experienced in the use of antiobesity agents and aware of the potential for adverse reactions.³⁵

Up to now, two drugs have been reported to reduce weight and/or body mass index (BMI) in adolescents: Orlistat, a pancreatic lipase inhibitor which reduces fat absorption, and metformin, an antihyperglycemic and insulin-sensitizing agent.³⁵

Orlistat - FDA in December 2003 approved orlistat use in adolescents aged 12 to 18 years old with a BMI (kg/m2) > 2 units above the reference value at the 95th percentile for age and gender. This conclusion was based on the results of a one year study evaluating 539 American adolescents submitted to a hypo-caloric diet plus exercise and behavioral therapy and that were randomized to orlistat versus placebo: a significant decrease in BMI was shown in the orlistat group (0.55 versus 0.31 kg/m2 for placebo; P<.01).³⁶ Moreover, body composition analysis showed that orlistat did not affect the normal increase in lean body mass physiologically observed in adolescents, and the weight difference between the placebo and orlistat groups was due to a difference in fat mass. The use of orlistat for 1 year in this adolescent population did not raise major safety issues although gastrointestinal adverse events, such as fatty or oily stools, oily spotting, increased defecation, cramps, and abdominal pain, were more common in the orlistat group.³⁵

Metformin - Metformin is an effective oral hypoglycemic agent used in the treatment of adults with type 2 diabetes and other conditions with insulin resistance.³⁵ Its hypoglycemic effect is largely caused by inhibition of hepatic gluconeogenesis, increased insulin-mediated glucose disposal, and inhibition of fatty acid oxidation. Reduction of intestinal glucose absorption has been hypothesized as another possible mechanism of action, although data have been inconsistent.³⁷ Metformin therapy for insulin resistance and obesity is safe and well tolerated and has a beneficial effect on weight, BMI, waist circumference, abdominal fat, fasting insulin, and fasting glucose although 6 months of therapy may not be sufficient to have an effect on visceral adipose tissue loss and insulin sensitivity.³⁸ The potential clinical application of metformin in the pediatric population was first described in the 1970s in a small published study demonstrating the beneficial effect on weight and insulin concentrations in 8–14-year-old obese children.³⁹ Subsequent pediatric randomized, controlled trial studies have shown improvement in BMI, fasting serum glucose, insulin, and lipid profile in patients on metformin therapy for exogenous obesity associated with insulin resistance.⁴⁰ Metformin treatment has been approved in children older than 10 years.

5. NEW THERAPIES IN OBESITY MANAGEMENT

Given the complexity of the neural pathways that regulate appetite and body weight, investigators are searching for therapies that target multiple pathways to enhance weight loss.⁴¹The development of obesity is highly influenced by genetics, with heritability estimates ranging between 20% and 80%. Most genes that contribute to this condition are still unknown. Identification of the pathways affected by these genes may elucidate novel targets for pharmacologic therapy. Development of receptor ligands (antagonists or agonists), or inhibitors of intracellular signaling mechanisms associated with these pathways, will be of great interest. Ever more sophisticated gene therapy techniques are being developed, in which inert virus vectors that encode particular genes (e.g., leptin) are able to restore deficiencies associated with depletion (or mutation) of that gene. A benefit of these techniques is the high degree of location specificity, as function can be restored in very specific areas of the central nervous system. These advanced genomics will yield valuable clues for novel pharmacologic targets.⁴¹

6. SUMMARY:

Obesity is a complex disease of multi-factorial origins. Globally, the magnitude of Obesity in increasing at a very high pace. Indian Obesity pattern is a complex pattern where many factors like distinct phenotype, the thrifty genotype, demographic transition and urbanization, nutritional transition, and several socio-economical/socio-cultural factors plays an important role. Not only about adult obesity, childhood obesity is also a silent explosion which is going to increase the prevalence at a whole. PCOS, one of the major complication in female gender is also associated with Obesity. Inspite of Lifestyle modification being the first line therapy, Pharmacological management plays an important role in the management of Obesity.

7. ACKNOWLEDGEMENT:

Author would like to thank Ms. Megha Bhatt for backing in writing a part of the article.

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Received on 23.03.2013

Modified on 10.04.2013

Accepted on 14.04.2013

Research J. Pharmacology and Pharmacodynamics. 5(4): July–August 2013, 220-226