Another Agent for Obesity--Will This Time Be Different?

Over the past few decades, obesity has become a global epidemic that affects diverse societies across developed and developing countries. Obe­ sity rates correlate well with recent developments such as incessant enticements to sit and an un­ precedented availability, at low or no cost, of foods and beverages rich in poorly satiating calo­ ries. These rapid environmental changes interact with preexisting genetic tendencies, yet in a time­ scale so brief as to outstrip evolution. What is wrong with obesity? Extra weight once indicated prosperity and was considered to be attractive. But now we know that overnutri­ tion and underexertion beget a cluster of seem­ ingly unrelated problems labeled “the metabolic syndrome,” which includes, for example, visceral abdominal obesity, dysglycemia, dyslipoprotein­ emia, and hypertension. Similar amounts of ex­ cess weight among people of different races and ethnic groups have varying effects on risk fac­ tors, with certain groups hit particularly hard.1 Although obesity is associated with resistance to the plasma glucose­lowering actions of insulin,2 many other metabolic pathways still remain re­ sponsive to insulin (i.e., the actions of insulin become imbalanced). Compensatory hyperinsu­ linemia can drive insulin­responsive effects, such as extracellular signal­regulated kinase (ERK) activation and hepatic de novo lipogenesis, which may cause or worsen features of the metabolic syndrome.3 Moreover, exogenous insulin at high doses has recently attracted interest as a poten­ tial cardiovascular risk factor.4 Although numerous randomized trials of life­ style modification, medications, and bariatric surgery have shown that weight loss reduces morbidity,5 most patients cannot sustain suffi­ cient weight loss. Despite decades of drug devel­ opment, the benefits of medications to treat obesity remain limited because of side effects and inadequate efficacy, especially in the long term. Bariatric surgery results in the most weight loss and the highest rates of remission of type 2 diabetes,6 but the potential side effects are of concern. Furthermore, performing bariat­ ric surgery in approximately 400 million obese persons worldwide is not feasible. Enter another approach: glucagon­like pep­ tide­1 (GLP­1) mimetics stimulate insulin secre­ tion, lower postprandial glucagon levels, slow gastric emptying, and reduce appetite. Many trials have shown that treatment with GLP­1 mimetics also results in clinically significant weight loss.7 In this issue of the Journal, Pi­Sunyer et al.8 report on a large­scale, randomized, double­ blind trial of the GLP­1 mimetic liraglutide, ad­ ministered once daily at a high dose of 3.0 mg, versus placebo for weight management. In De­ cember 2014, after reviewing the results of phase 3 trials, including data from the trial by Pi­Sunyer et al., the Food and Drug Administra­ tion approved liraglutide as the first GLP­1 mi­ metic for weight loss in adults with a body­mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30 or higher (obese) or a BMI of 27.0 to 29.9 (mark­ edly overweight) and one or more weight­related coexisting illnesses. Participants in the trial by Pi­Sunyer et al. did not have diabetes and were either obese or mark­ edly overweight with weight­related complications of dyslipoproteinemia, hypertension, or both. More than 60% had prediabetes at enrollment. Lira­ glutide or placebo was administered in conjunc­ tion with lifestyle counseling over the course of 56 weeks to more than 3700 participants from six continents. At week 56, participants in the liraglutide