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A Long-Term Pharmaceutical Intervention for the Obese

We do not yet understand the long-term effects of semaglutide.

A new class of weight-loss drugs has become available with the potential of helping dieters lose significant amounts of weight while also normalizing their blood glucose levels. Semaglutide is an anti-diabetic medication that has been used for the treatment of Type 2 diabetes. Recently, it has taken on a new role: managing weight loss. The medication is available under the brand names Ozempic, Rybelsus, and Wegovy.

Semaglutide belongs to a class of medications known as glucagon-like peptide-1 (GLP-1) receptor agonists. These drugs function in the body to increase insulin secretion, thus lowering blood glucose levels, and to decrease the secretion of a hormone, glucagon, which normally increases the amount of sugar in the bloodstream. Finally, they may also delay the emptying of the stomach, prolonging the sense of fullness and satiety.

Until recently, the only form in which this medication was administered was by self-injection, but the FDA approved an oral form of the medication in September 2019. The medication is to be used, along with diet and exercise, to improve glycemic control, i.e., blood sugar levels in people with Type 2 diabetes. The availability of an oral form of semaglutide is, of course, an immense advantage to patients who would rather not have to administer the medication through injection.

Obese and overweight patients using semaglutide to manage their diabetes experienced weight loss as a positive side effect. Subsequently, studies were done to measure the efficacy of this medication in potentiating weight loss among those who do not have Type 2 diabetes. In one large, multi-center study, the weight loss associated with semaglutide was significant. In this trial, 803 overweight or obese adults were treated for twenty weeks with a weekly subcutaneous injection of semaglutide. They were, in addition, given lifestyle support to enhance the weight loss and told to follow a low-calorie diet and to exercise. None of the participants had diabetes.

The group lost an average of 10.6 percent of their starting weight during this 20-week period. Subsequently, half of the participants were continued on the drug, and the other half were given a placebo. They all continued to administer the drug or placebo by self-injection each week. None knew whether they were on the drug or placebo. As in the first part of the study, all the participants continued to receive lifestyle support, and were told to stay on a reduced-calorie food plan and exercise program. This second part of the study lasted 48 weeks.

The group that continued to receive the semaglutide lost another 8 percent of their body weight—much less per week than in the initial phase, but nevertheless, weight continued to be lost. However, during the 48-week period, the group on placebo gained back almost all their weight.

Regaining weight after a weight-loss medication is withdrawn is common, although the rapidity with which the dieters regained the weight was surprising since all the volunteers were aware of how to incorporate lifestyle changes, a low-calorie diet, and exercise into their lives. However, given the absence of the drug treatment, they were unable to adhere to dietary and behavioral practices that would have allowed them to continue to lose weight and/or maintain their previous weight loss.

Oral semaglutide is not without its side effects that include nausea, abdominal pain, and vomiting. It has to be taken on an empty stomach at least 30 minutes before anything else is put into the stomach—food, beverage, and other medications—and no more than 4 oz of plain water may be consumed in order to swallow the pill. The package instructions warn that not doing so may lessen the effect of the medication. And, since the medication may be taken for months or even years, the side effects may prove difficult for some patients.

The continued weight loss reported in JAMA could stimulate research interest in finding chronic weight-loss treatments for obesity. The traditional approach to using weight-loss interventions is to expect, or at least hope, that changes in behavior during the period of weight loss will, somehow, be permanent. That this is more of a hope than reality has been shown again and again among dieters who participate in national weight-loss support groups, follow liquid meal diets, do intermittent fasting, eat low-calorie prepackaged food, use psychological interventions, and undergo surgery to drastically reduce the size of the stomach. To be sure, some are successful in reaching their weight-loss goal and maintaining their weight loss. But the majority will regain at least some of the weight that has been lost. Many regain it all.

It is important to recognize that for some who are obese, their obesity, like diabetes, is a chronic disease. It is impervious to behavioral interventions and vulnerable to intermittent flare-ups that cause significant overeating and a decrease in physical activity. Such individuals may have tried many weight-loss support and intervention programs, either ending with no weight loss or by regaining any weight they lost later on. Eventually, the consequences of this lead to a variety of medical problems like diabetes, cardiovascular disease, and orthopedic issues, to name a few.

The efficacy of semaglutide in prolonging and maintaining weight loss, and the rapid regaining of the weight when the treatment is stopped, should cause us to rethink how we treat obesity. We must stop blaming the obese individual for failure to maintain weight loss, or keep off the weight that has been lost. For these individuals, diets, exercise, behavioral interventions, and even bariatric surgery may not be sufficient to sustain long-term weight loss and its maintenance.

Chronic treatment with semaglutide may be one possible solution, although we do not yet know what the long-term effects of treatment with this medication will be. But perhaps the results of treatment with this medication will produce other interventions that finally allow someone who is chronically obese to achieve a healthy weight.


“Oral Semaglutide,” Hughes S and Neumiller, J Clinical Diabetes 2020; 38:109-111.