As discussed in a past Biotics Research Forum, the review published in Clinical Obesity highlights several nutrient deficiencies associated with the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual GIP/GLP-1RA receptor agonists (referred to as antiobesity medications, AOMs). One in 8 adults in the U.S. is currently taking an AOM, and this number is expected to grow and remain high in the long term. A 2025 meta-analysis of AOMs, which included 18 randomized clinical trials, found that discontinuation is associated with significant rebounds not only in weight, but also in glycemic control, blood pressure, lipids, etc. Indeed, the weight rebound has been estimated at 60-163% of the prior weight lost, suggesting that many patients are likely to stay on them indefinitely. While there have been many documented benefits associated with these medications, it is worth highlighting potential concerns associated with their use to help mitigate complications. Targeted nutritional support, combined with behavioral change guidance for AOMs, should be the standard of care.
In a review published in Current Developments in Nutrition, the authors note that it is difficult to draw firm conclusions about the effects of AOMs on nutrient status based on current data. Yet there are a number of reasons to be concerned; for one, people attempting to lose weight often follow nutritionally inadequate diets, and obesity also increases the risk for nutrient deficiencies. For example, in a population of 200 people awaiting bariatric surgery for severe obesity, nutrient deficiencies, including vitamin D, folate, iron, calcium, vitamin B12, and albumin, were common, with inflammation increasing the likelihood of deficiency. An elevated C-reactive protein increased the likelihood of a B12 deficiency nearly 6-fold and a folate deficiency over 4-fold. Reduced caloric intake while attempting to lose weight is also associated with a higher likelihood of poor nutritional status. For example, in one small 8-week trial, women assigned to one of four different weight loss programs (Atkins, Ornish, etc.) with specific macronutrient targets found an inadequate intake of multiple micronutrients for most of these diets, including vitamin C, B vitamins, iron, etc. Specific deficits have been associated with low-carbohydrate diets as well, such as thiamine deficiency (as assessed by red-blood-cell thiamine diphosphate).
In a cross-sectional study of people taking AOMs for at least one month, a number of nutritional deficits were observed, including insufficient intake of fiber, calcium, iron, magnesium, potassium, etc., and even insufficient protein. This last may be of particular concern, given the loss of lean mass that accompanies AOM use, estimated to be 30-40% of the total weight lost. The inhibition of gastric emptying by GLP-1RAs is one of the mechanisms of action that contribute to adverse effects, such as vomiting, diarrhea, decreased thirst, constipation, and abdominal pain, which may also lead to inadequate micronutrient intake (though these typically occur early in treatment and lessen over time).
The incorporation of structured dietary and exercise interventions should be standard when implementing AOM therapy, as reviewed in JAMA Internal Medicine. This includes emphasizing protein to preserve lean mass, maintaining hydration (without typical thirst triggers), promoting a Mediterranean or plant-based diet with a focus on whole fruits and non-starchy vegetables, adding physical activity, especially resistance exercise to maintain lean mass, etc. One potential benefit of AOMs is a reduction in “food noise,” a continuous inner dialogue about food and food-related thoughts. Incorporating behavioral strategies that emphasize a Mediterranean diet, for example, may capitalize on reduced food cravings and promote cardiovascular benefits beyond those associated solely with weight loss, especially if diet quality is poor.
Resistance exercise may also be particularly important for people at risk for osteopenia/osteoporosis, as rapid weight loss has been associated with more rapid bone loss. A secondary analysis of a one-year randomized clinical trial was published in JAMA Network Open, emphasizing the importance of exercise. In this trial, after 8 weeks of a very low-calorie diet (800 calories/day), participants were randomized to one of four groups for the next 52 weeks: exercise, GLP-1 RA (liraglutide), a combination of the two, or placebo. Not only did the combination group lose the most weight over the study period, but bone mineral density was unchanged in the combo group compared with placebo, whereas the liraglutide-alone group showed significant decreases in hip and spine density.
In addition to assessing micro- and macronutrient status, behavioral interventions and lifestyle modifications may help promote greater weight loss and other benefits when combined with AOM use. Combining other weight-loss strategies with complementary mechanisms to AOMs, such as intermittent fasting, has also been proposed to either enhance effectiveness, reduce AOM dependence, or mitigate weight regain after discontinuation, though to date no clinical trials have been published. But multiple mechanisms of action associated with weight loss and cardiovascular health, including enhanced ketogenesis, fat oxidation, insulin sensitivity, and modulation of pathways such as the mechanistic target of rapamycin (mTOR), AMP‐activated protein kinase (AMPK), and autophagy, suggest significant potential. Much remains to be learned about these new medications, including optimal strategies to promote their effects and mitigate their harm.