Challenges and Opportunities in the Management of Obesity
Despite information on complex neural, hormonal, metabolic and inflammatory mechanisms in obesity, bariatric–metabolic surgery is the only current treatment for obesity that is effective in the long term. Lifestyle modification and current pharmacological approaches are generally associated with modest (average 5 kg) weight loss that is poorly sustained in a majority of patients. The paradox between the relatively low efficacy of treatments targeting the complex neurohormonal mechanisms in obesity and the greater efficacy of restrictive or malabsorptive surgery is illustrated by their effects on cardiovascular mortality. The Swedish Obese Subjects Trial is the largest prospective bariatric surgery study with long-term follow-up, and it showed a significant reduction in cardiovascular mortality; in contrast, the Look Ahead Trial, a randomised, controlled, National Institutes of Health (NIH)-sponsored trial in 5145 overweight/obese adults with type 2 diabetes designed to determine the long-term health benefits of weight loss achieved by lifestyle modification, showed no difference in cardiovascular mortality after 9 years of follow-up.
The two main non-surgical approaches for the treatment of obesity and related complications are intense lifestyle modification and medications. Guidelines, based on Category A evidence and published by the National Heart, Lung and Blood Institute in 1998, suggest "that a 10 percent reduction in body weight reduces disease risk factors. Weight should be lost at a rate of 1 to 2 pounds per week based on a calorie deficit of 500–1000 kcal/day". The guidelines also recommend increased physical activity and pharmacological approach to augment weight loss. This approach has been efficacious in multiple large-scale clinical trials: Diabetes Prevention Program showed that intense lifestyle modification prevented by 58% the incidence of diabetes when compared with placebo controls. Similarly, the Look Ahead Trial showed that intense lifestyle intervention resulted in 7% weight loss and improved diabetes control.
In recent years, somewhat efficacious pharmacological approaches (such as sibutramine and rimonabant) received initial regulatory approval but were subsequently withdrawn from the market because of adverse effects such as depression or hypertension resulting from their central actions on adrenergic, serotonergic or cannabinoid mechanisms. Until recently, the only approved medication was the pancreatic lipase inhibitor, orlistat, which is associated with relatively small changes in weight and GI adverse effects, such as bloating and diarrhoea, which reduce compliance with orlistat intake over the long term. New pharmacological approaches, recently approved by the FDA, decrease appetite and result in weight loss: Lorcaserin (Belviq) is a serotonin 2c (5-HT2C) receptor agonist that activates pro-opiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus, decreasing appetite and resulting in an average 5.8% weight loss when compared with 2.1% in the placebo group. A second, approved drug is the combination phentermine-topiramate extended release (ER) (Qsymia) that produces mean 8–10% weight loss in different trials when compared with 1.6% weight loss in the placebo group. This degree of weight loss is lower than that observed with bariatric surgery. In view of the potential for central nervous system (CNS)-mediated and cardiovascular adverse effects with these centrally-acting drugs, they require close postmarketing surveillance. Lorcaserin has high affinity and selectivity and is a full agonist for 5-HT2C receptors. By virtue of its high selectivity for 5-HT2C receptors relative to 5-HT2A (18-fold) and 5-HT2B (104-fold) receptors, lorcaserin avoids induction of hallucinations and cardiopulmonary toxicity, respectively. Nevertheless, the FDA approved phentermine-topiramate ER (Qsymia) with 10 postmarketing requirements.
Bariatric surgery remains the most effective treatment option for obese patients. Available procedures include laparoscopic and open Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy, adjustable gastric band, vertical banded gastroplasty, duodenal switch and biliopancreatic diversion. RYGB is currently the bariatric surgical procedure of choice. In a meta-analysis of 136 studies including 22 094 patients, RYGB resulted in an average excess body weight loss of 62%, with resolution of diabetes in 84%, of hypertension in 68%, and of obstructive sleep apnoea in 81%, and improved hyperlipidaemia in 97%. Unlike medications and lifestyle modifications, the effects of bariatric surgery seem to be sustained in the long term. Thus, the recently updated Swedish Obese Subjects Study demonstrated mean changes in body weight after bariatric surgery (specifically with 13% RYGB, 19% gastric banding and 68% vertical banded gastroplasty) −23% (at 2 years), −17% (at 10 years), −16% (at 15 years) and −18% (at 20 years).
Despite proven efficacy and the fact that mortality from bariatric surgery is comparable to that of cholecystectomy or appendectomy in bariatric centres with high surgical volumes, it is estimated that less than 1% of obese subjects who qualify for bariatric surgery will undergo such intervention. High costs and early and late complications of bariatric surgery are the main hurdles for widespread use. Early complications include anastomotic leaks, internal hernias, thromboembolic events, bowel obstruction, GI haemorrhage and wound complications. Late complications include gallstones formation, marginal ulceration, anastomotic stricture, incisional hernia, gastro-gastric fistula, dumping syndrome, micronutrient deficiencies and weight regain.
Given the current state of therapies for obesity, it is timely to question the 1998 guidelines that recommend slow weight loss with non-surgical approaches that produce modest and poorly sustained efficacy and potential centrally mediated side effects. The next sections review advances in our understanding of central and peripheral pathways controlling energy intake and expenditure in that order and discuss the potential to develop effective, minimally invasive treatments for obesity.
Current State of Obesity Treatment
Despite information on complex neural, hormonal, metabolic and inflammatory mechanisms in obesity, bariatric–metabolic surgery is the only current treatment for obesity that is effective in the long term. Lifestyle modification and current pharmacological approaches are generally associated with modest (average 5 kg) weight loss that is poorly sustained in a majority of patients. The paradox between the relatively low efficacy of treatments targeting the complex neurohormonal mechanisms in obesity and the greater efficacy of restrictive or malabsorptive surgery is illustrated by their effects on cardiovascular mortality. The Swedish Obese Subjects Trial is the largest prospective bariatric surgery study with long-term follow-up, and it showed a significant reduction in cardiovascular mortality; in contrast, the Look Ahead Trial, a randomised, controlled, National Institutes of Health (NIH)-sponsored trial in 5145 overweight/obese adults with type 2 diabetes designed to determine the long-term health benefits of weight loss achieved by lifestyle modification, showed no difference in cardiovascular mortality after 9 years of follow-up.
Non-surgical Interventions
The two main non-surgical approaches for the treatment of obesity and related complications are intense lifestyle modification and medications. Guidelines, based on Category A evidence and published by the National Heart, Lung and Blood Institute in 1998, suggest "that a 10 percent reduction in body weight reduces disease risk factors. Weight should be lost at a rate of 1 to 2 pounds per week based on a calorie deficit of 500–1000 kcal/day". The guidelines also recommend increased physical activity and pharmacological approach to augment weight loss. This approach has been efficacious in multiple large-scale clinical trials: Diabetes Prevention Program showed that intense lifestyle modification prevented by 58% the incidence of diabetes when compared with placebo controls. Similarly, the Look Ahead Trial showed that intense lifestyle intervention resulted in 7% weight loss and improved diabetes control.
In recent years, somewhat efficacious pharmacological approaches (such as sibutramine and rimonabant) received initial regulatory approval but were subsequently withdrawn from the market because of adverse effects such as depression or hypertension resulting from their central actions on adrenergic, serotonergic or cannabinoid mechanisms. Until recently, the only approved medication was the pancreatic lipase inhibitor, orlistat, which is associated with relatively small changes in weight and GI adverse effects, such as bloating and diarrhoea, which reduce compliance with orlistat intake over the long term. New pharmacological approaches, recently approved by the FDA, decrease appetite and result in weight loss: Lorcaserin (Belviq) is a serotonin 2c (5-HT2C) receptor agonist that activates pro-opiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus, decreasing appetite and resulting in an average 5.8% weight loss when compared with 2.1% in the placebo group. A second, approved drug is the combination phentermine-topiramate extended release (ER) (Qsymia) that produces mean 8–10% weight loss in different trials when compared with 1.6% weight loss in the placebo group. This degree of weight loss is lower than that observed with bariatric surgery. In view of the potential for central nervous system (CNS)-mediated and cardiovascular adverse effects with these centrally-acting drugs, they require close postmarketing surveillance. Lorcaserin has high affinity and selectivity and is a full agonist for 5-HT2C receptors. By virtue of its high selectivity for 5-HT2C receptors relative to 5-HT2A (18-fold) and 5-HT2B (104-fold) receptors, lorcaserin avoids induction of hallucinations and cardiopulmonary toxicity, respectively. Nevertheless, the FDA approved phentermine-topiramate ER (Qsymia) with 10 postmarketing requirements.
Bariatric (Metabolic) Surgery
Bariatric surgery remains the most effective treatment option for obese patients. Available procedures include laparoscopic and open Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy, adjustable gastric band, vertical banded gastroplasty, duodenal switch and biliopancreatic diversion. RYGB is currently the bariatric surgical procedure of choice. In a meta-analysis of 136 studies including 22 094 patients, RYGB resulted in an average excess body weight loss of 62%, with resolution of diabetes in 84%, of hypertension in 68%, and of obstructive sleep apnoea in 81%, and improved hyperlipidaemia in 97%. Unlike medications and lifestyle modifications, the effects of bariatric surgery seem to be sustained in the long term. Thus, the recently updated Swedish Obese Subjects Study demonstrated mean changes in body weight after bariatric surgery (specifically with 13% RYGB, 19% gastric banding and 68% vertical banded gastroplasty) −23% (at 2 years), −17% (at 10 years), −16% (at 15 years) and −18% (at 20 years).
Despite proven efficacy and the fact that mortality from bariatric surgery is comparable to that of cholecystectomy or appendectomy in bariatric centres with high surgical volumes, it is estimated that less than 1% of obese subjects who qualify for bariatric surgery will undergo such intervention. High costs and early and late complications of bariatric surgery are the main hurdles for widespread use. Early complications include anastomotic leaks, internal hernias, thromboembolic events, bowel obstruction, GI haemorrhage and wound complications. Late complications include gallstones formation, marginal ulceration, anastomotic stricture, incisional hernia, gastro-gastric fistula, dumping syndrome, micronutrient deficiencies and weight regain.
Given the current state of therapies for obesity, it is timely to question the 1998 guidelines that recommend slow weight loss with non-surgical approaches that produce modest and poorly sustained efficacy and potential centrally mediated side effects. The next sections review advances in our understanding of central and peripheral pathways controlling energy intake and expenditure in that order and discuss the potential to develop effective, minimally invasive treatments for obesity.
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