Effect of GLP‐1 receptor agonist on nutrient intake: A narrative review

Abstract

Humans have a primitive defense mechanism called metabolic adaptation that slows voluntary weight loss. It works by downregulating hormones that reduce food intake and by lowering the metabolic rate. Second‐generation GLP‐1 receptor agonists, such as semaglutide or tirzepatide, promote weight loss by targeting this hormonal system to control appetite. Appetite can be divided into hunger, satiety, satiation, and reward eating. This review will examine how GLP‐1 receptor agonists and newer satiety hormone agonists influence appetite and its components. Research indicates that these new satiety hormone agonists significantly reduce meal size and may decrease overall water intake. Additionally, the choice of highly palatable foods is affected and may extend to alcohol consumption. Clinicians need to understand how these new drugs affect food intake to counsel patients effectively. Most patients will experience gastrointestinal side effects, which can often be managed with dietary adjustments. Other clinical issues stemming from the substantial decrease in food intake will also need to be monitored. Loss of lean tissue, including bone and muscle, has been reported. Clinicians can adjust dosing of these medications but will need to make nutritional adjustments to help mitigate these effects. Now that these powerful weight‐loss agents have been available for several years, vitamin deficiencies have been reported. Given the side effects of GLP‐1 receptor agonists and their intended appetite suppression, clinicians’ nutritional counseling and treatment become invaluable.

INTRODUCTION

In October 2025, 12.4% of Americans, or one in eight, reported using an injectable glucagon‐like peptide‐1 receptor agonist (GLP‐1 RA). This marks a doubling compared with a survey conducted in February 2024. ¹ This significant increase is driven by factors such as social media, advertising, celebrity endorsements, and, notably, efficacy. This increase is despite the fact that fewer than 50% of commercial health insurance plans cover weight‐loss medications; when they do, coverage is severely restricted. ²

Restricted insurance coverage has led to a sizable but unknown number of patients who get their GLP‐1 RAs from unregulated compounding pharmacies. This raises issues of safety, oversight, monitoring, and coordinated clinical care. ³

GLP‐1 RAs have been around since 2005, when exenatide was approved for type 2 diabetes. In 2014, liraglutide was the first GLP‐1 RA approved for weight loss. Its use resulted in a modest weight loss of 8% of body weight. ⁴ These older GLP‐1 RAs are considered first‐generation and required at least daily subcutaneous injection.

The significant increase in the use of GLP‐1 RAs began with the approval of the second‐generation GLP‐1 RAs, semaglutide and tirzepatide. These second‐generation GLP‐1 RAs are administered subcutaneously once weekly. The ability of a GLP‐1 RA to be administered weekly keeps satiety receptors continuously occupied, rather than for only several hours. In addition, semaglutide has a higher affinity for the glucagon‐like peptide‐1 (GLP‐1) receptor than native GLP‐1. This combination of higher affinity and continuous binding to the GLP‐1 receptor confers greater potency. ⁵

Although tirzepatide does not have a higher affinity for the GLP‐1 receptor, it combines a glucose‐dependent insulinotropic polypeptide receptor agonist (GIP RA) with a GLP‐1 RA. This combination of two satiety hormones increases potency. ⁶

These two second‐generation medications doubled and tripled the weight loss seen with first‐generation GLP‐1 RAs, resulting in 17%–21% weight loss. With an appropriate diet and exercise, many patients are achieving 25% weight loss. ⁷ , ⁸

To achieve this amount of weight loss, significant changes in both hunger and satiety are necessary. This review will focus on the effects of GLP‐1 RAs on energy intake, satiety, hunger, hedonic eating, fluid intake, and some unexpected appetite‐related effects.

METHODS

Data for this review were identified through a search of PubMed using the search terms ghrelin, glucagon‐like peptide‐1 receptor agonists (GLP‐1 RA), glucose‐dependent insulinotropic polypeptide (GIP) receptor agonist, and antagonist. Additional searches include amylin receptor agonist, glucagon receptor agonist, liraglutide, semaglutide, tirzepatide, hunger, satiation, satiety, appetite, cravings, and alcohol. The period covered included 1960–2026. Relevant articles were identified and selected for this review.

Physiology of appetite

The main mechanism of action of semaglutide and tirzepatide, is believed to be through regulation of appetite and caloric intake. ⁹ , ¹⁰ Appetite can be broken down into hunger, satiation, and satiety.

Hunger is a physical and biological drive for food and is increased by the hormone ghrelin. Satiation is the act of ending a meal and is triggered by satiety hormones such as GLP‐1, peptide YY, GIP, amylin, and many others. ¹¹

Satiety is a feeling of fullness and the duration until the next meal. ¹²

When humans are in a fasted state, the stomach begins to produce and release ghrelin into the bloodstream. Ghrelin then travels to the brain, increasing appetite. It activates many areas of the brain, including the hypothalamus (the master controller of weight), the brainstem, reward and motivation centers, memory, and learning centers. ¹³ Ghrelin is often called the “hunger hormone.”

When ghrelin is infused into rodents, they show improved memory and learning for food‐related tasks. When male rats are infused with large amounts of ghrelin directly into the third ventricle, they exhibit increased aggressive behavior. ¹⁴ Investigators believe this is a defensive mechanism to protect a limited food supply.

When humans have eaten a meal, the gastrointestinal tract releases numerous satiety hormones to regulate eating (see Table 1). Enteroendocrine cells (L‐cells), primarily concentrated in the distal small intestine, directly contact food, triggering the secretion of three satiety hormones: GLP‐1, GLP‐2, and PYY. These hormones enter the bloodstream and are distributed to various organs including the brain, pancreas, and gastrointestinal tract.

Table 1.

Hormones affecting appetite.

Hormone	Hunger	Satiety	Satiation
GLP‐1	↓	↑↑	↑↑
GIP agonists	?	↑	↑
GIP antagonists	?	↑	↑
Glucagon	↓	↑	↑
Amylin	↓	↑↑	↑↑
Ghrelin	↑↑↑	↓	↓

Abbreviations: GIP, glucose‐dependent insulinotropic polypeptide; GLP‐1, glucagon‐like peptide‐1.

↓ Indicates decrease.

↑ Indicates increase.

? indicates unknown at this time.

Please note there are many other hormones that affect appetite from the gastrointestinal tract.

References: ⁷ , ⁹ , ¹⁰ , ¹² , ¹³ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹

One of the main targets of GLP‐1 is the beta cells of the pancreas. ³⁰ If blood sugar is high, GLP‐1 stimulates insulin release. GLP‐1 also targets the pancreatic alpha cells to suppress glucagon release. ³¹ , ³² Another target organ with a large number of receptors for GLP‐1 is the brain. Similar to ghrelin, GLP‐1 travels to the hypothalamus, brainstem, reward, and motivation centers, signaling satiety and fullness. ³³ GLP‐1 receptors are also found in the gastrointestinal tract. GLP‐1 receptor binding in the intestine, slows the intestinal tract, leading to delayed gastric emptying. ¹⁶ , ³⁰ This signaling is believed to contribute to the many gastrointestinal side effects of GLP‐1 RAs. Additionally, GLP‐1 reduces ghrelin release from the stomach. ¹⁷ The reduction of ghrelin, is another key mechanism of action of GLP‐1 because it addresses both feelings of fullness and hunger.

Native GLP‐1 levels rise for about an hour after a meal and return to baseline by 2 h. ¹⁶ The half‐life of our native GLP‐1 is roughly 2–3 min, indicating that humans are designed to regulate appetite minute to minute. As long as there is food in the small intestine sensed by L‐cells, GLP‐1 is secreted and stays elevated in the circulation, and an individual will feel satiated. ¹⁶ , ³⁰

Effects of GLP‐1 RAs on gastric emptying

GLP‐1 RAs slow gastric emptying, which affects food intake and absorption. For individuals not using a GLP‐1 RA, the average stomach‐emptying time varies depending on whether the food is liquid or solid. Physiologists typically measure the time to empty half of the stomach contents (T _1/2) and the total time to fully empty the stomach. The T _1/2 for a liquid meal usually ranges from 60 to 90 min, whereas for a solid meal it can be 90 min to over 2 h. ²⁵ , ³⁴ Given this variation, including a control group is important when studying stomach‐emptying times.

In a meta‐analysis, Hiramoto and colleagues examined the time to empty half of the stomach in patients on a GLP‐1 RA (exenatide, liraglutide, lixisenatide, semaglutide). The authors found the T _1/2 for a solid meal to be 138 min, compared with 95 min for the control group. ³⁵ Notably, this analysis did not find a significant difference for liquid meals. In addition, most of the GLP‐1 RAs studied were first‐generation.

In a separate study of women with polycystic ovary syndrome taking a low‐dose 1 mg of semaglutide, more food remained in the stomach at all time points. There was 25% more food in the stomach at 2 h and 38% at 3 h. At 4 h, when the control group had completely emptied their stomachs, the subjects on a GLP‐1 RA still retained 30% of their original meal. As the dose of the GLP‐1 RA increased, the delay in gastric emptying time also increased. ²⁶

In some patients, this delay in gastric emptying can lead to mild to moderate gastrointestinal side effects such as nausea and vomiting. Depending on the dose, second‐generation GLP‐1 RAs have been associated with severe gastrointestinal side effects in 1.7%–4.1% of patients. ⁹ , ¹⁰ In the pivotal clinical trials, this moderate to severe side effect of nausea and vomiting can lead to 4.8%–6.8% of patients discontinuing their GLP‐1 RA.

Recent findings show that some patients on GLP‐1 RAs experience food aversion. The exact cause of this food aversion is not fully understood. Some cases may simply be due to severe slowing of gastrointestinal motility. Another possibility is a direct effect of the GLP‐1 RA on the brain. ³⁶ The evidence supporting the idea that GLP‐1 RAs cause food aversion through direct brain action is strong, so it is likely that both effects play a role. While food aversion might not cause immediate problems for someone with obesity, it could be a significant issue for a person of normal weight.

While no studies have examined discrete dietary strategies to address GLP‐1‐induced delayed gastric emptying, current recommendations include restricting meal size. Many healthcare providers also recommend avoiding high‐fat foods, as strong evidence shows that high‐fat meals further delay gastric emptying. ³⁷ Solid, high‐calorie foods also slow gastric emptying, which occurs at an average rate of 1–4 kcal/min. ³⁸ Educating patients to avoid or limit highly caloric‐dense foods is often beyond the skills of some physicians. Therefore, if lowering the dose of the GLP‐1 RA does not help with nausea and vomiting, having the patient see a dietitian can be beneficial. Although prokinetic agents such as erythromycin have been used in diabetics with slow gastric emptying, they have not been studied in patients on GLP‐1 RAs. ¹⁷ This author does not recommend using anti‐emetics or erythromycin in patients with GLP‐1 RA‐induced nausea. In this author's experience, decreasing the dose and making nutritional changes will improve the nausea to the patient's satisfaction.

Effect of GLP‐1 RAs on energy intake

Humans not severely diseased will defend against weight loss by lowering metabolic rate, increasing the hunger hormone ghrelin, and decreasing many satiety hormones, including GLP‐1. ³⁹ , ⁴⁰ In the case of obese patients taking these drugs for weight loss, GLP‐1 RAs and other satiety hormone agonists control this compensatory increase in hunger and decrease in satiety. ¹⁵

The science of measuring changes in caloric intake is highly standardized and produces accurate quantitative data. A common test for assessing caloric change is the “5‐h standardized breakfast test,” though it is somewhat of a misnomer because it measures changes in energy intake from a buffet lunch rather than from breakfast. ¹⁸

Participants in these feeding studies are randomized to receive either a placebo or the study drug. A baseline feeding study is completed before starting the study drug and again while on a therapeutic dose. Subjects arrive at the feeding laboratory around 7:00 a.m., undergo baseline laboratory testing, and complete appetite questionnaires. At 8:00 a.m., they consume a standardized breakfast that provides 30% of their daily resting metabolic needs, typically 500 to 600 calories, with 30% fat, 15% protein, and 55% carbohydrates. Subjects then fast until noon, when they have a buffet lunch. The subjects are instructed to eat until they are “pleasantly full.” The calories consumed at lunch are calculated, and the difference in caloric intake is compared with either the placebo group or the baseline caloric intake before starting the study medication. ¹²

A study by Blundell and colleagues examined the reduction in caloric intake with the first of the second‐generation GLP‐1 RAs. ¹⁸ The subjects were titrated to a low dose of 1 mg of semaglutide over 12 weeks. At the end of this period, they showed a decrease of 300 kcals in the ad libitum lunch after a standardized breakfast. Additionally, they experienced reductions in the evening meal and snacks. The total daily energy intake decreased by 24%. This resulted in a 5‐kg weight loss after 12 weeks.

Another well‐designed study tested a higher dose of semaglutide at 2.4 mg weekly for 20 weeks. ¹⁹ It again examined changes in caloric intake and used placebo controls. Semaglutide 2.4 mg decreased ad libitum lunch intake by 35% compared to the placebo. When the investigators compared the energy intake of the drug group before starting semaglutide and after 20 weeks of treatment, the reduction was 47.1%. In simple terms, the ad libitum lunch intake was nearly halved when compared with what patients ate before starting semaglutide 2.4 mg.

Using a different GLP‐1 RA, Martin and colleagues investigated the effects of tirzepatide 5 mg after 6 weeks of treatment. ²⁰ They observed a reduction of 524.6 calories in ad libitum lunch compared to placebo. When examining the change from baseline in the Tirzepatide group, calorie intake decreased by 56.6%.

The ability of second‐generation GLP‐1 RAs to reduce caloric intake is impressive. The upcoming GLP‐1 RAs may be even more potent. It is very likely that newer GLP‐1 RAs will reduce food intake by more than half in most patients. Currently, there are no studies showing that any single macronutrient is reduced more than the others. Therefore, it can be expected that protein, fats, and carbohydrates will all decrease by roughly equal amounts.

Effect of GLP‐1 RAs on fluid intake

Data from the National Health and Nutrition Examination Survey (NHANES), 2009–2012, on daily total water consumption shows that men drink an average of 3.46 liters (117 ounces) of water per day, and women drink 2.75 liters (93 ounces) per day. ⁴¹ Currently, the recommended daily total water intake is 3.7 liters for adult males and 2.7 liters for adult females. ⁴² Therefore, Americans not on a GLP‐1 RA generally meet the recommended daily total water intake, as relatively few Americans were on a GLP‐1 RA 15 years ago.

In the NHANES data above, 20% of total water intake came from food. If food intake is expected to decrease by approximately 50% with second‐generation GLP‐1 RAs, total water intake would decrease by only 10%. Unfortunately, GLP‐1 RAs have been shown to directly reduce fluid intake independent of food intake. ⁴³ In a study examining an older, less potent first‐generation GLP‐1 RA, total water intake was reduced by 300 cc over an 8‐h period. ⁴⁴ If the study had looked at 24‐h intake, it is very likely total water intake would have been reduced further. This author was unable to find any controlled trials examining the more potent second‐generation GLP‐1 RAs and their effects on total water intake, but it would be expected that total water intake would be significantly decreased.

Clinically, one of the more common side effects of GLP‐1 RAs is constipation. Depending on the specific GLP‐1 RA, 11%–24% of patients report experiencing constipation. Lifestyle strategies for managing constipation include increasing fiber intake, staying physically active, and maintaining proper hydration. ⁴⁵ It is important to remind patients on GLP‐1 RAs to stay well hydrated, as well as increase their fiber intake.

Effect on cravings and alcohol consumption

Food craving is defined as an intense desire to eat a particular type of food. In the US and Europe, chocolate is the food most craved by women. ⁴⁶ What distinguishes cravings from hunger is the focus on a particular food. Furthermore, cravings are not linked to hunger; people can crave a food even when they are not hungry. A common example is wanting dessert after a meal.

Physiologically, this behavior involves increased salivation and activation of reward‐related brain regions. Cravings can also be triggered by physiological factors (e.g., premenstrual ⁴⁷ ) or emotional factors (e.g., boredom or stress). ⁴⁸

For this review, cravings are considered part of food reward, addictive behaviors, and hedonistic eating—all of which involve eating for pleasure without regard to hunger.

Over time, as humans repeatedly encounter a highly appealing food, they begin to anticipate that food. When they become aware of a possible reward, dopamine levels rise in the reward centers, making the brain highly responsive to cues for that delicious food. ⁴⁹ This phenomenon also applies to natural rewards, drugs, and alcohol.

Ghrelin typically increases in the blood before meals and decreases after eating. It also rises in anticipation of highly palatable foods. Many researchers call ghrelin a hedonic hormone because it can influence the brain's reward centers and dopamine system. ⁵⁰ Conversely, GLP‐1 levels go up after a meal to promote feelings of fullness. Therefore, ghrelin and GLP‐1 act in opposite directions. When GLP‐1 levels are high, GLP‐1 will suppress ghrelin, reducing hunger and cravings for highly palatable foods. Human studies on GLP‐1 RA consistently show decreased caloric intake and less reward‐based eating behavior. ²¹ In short, GLP‐1 enhances control over reward‐driven eating and energy intake. Although the mechanism is complex, it appears to be related to GLP‐1's ability to lower ghrelin and directly dampen the brain's reward centers. ⁵¹

Alcohol is considered a fourth nonessential macronutrient, providing 7 kcal/g. Alcohol use disorder (AUD) affects 10.3% of American adults and 3% of adolescents. ²² In 2011, a poster abstract at the 71st American Diabetes Association annual meeting noted a decrease in alcohol consumption among 33 of 42 diabetic patients taking a first‐generation GLP‐1 RA, liraglutide. ²³ In 2013, researchers used a two‐bottle free‐choice drinking model to test rodents treated with either a GLP‐1 RA or a GLP‐1 receptor blocker. Rodents given the GLP‐1 RA reduced their alcohol intake, and more importantly, when the investigators blocked the GLP‐1 receptor, they showed an increase in alcohol consumption. ⁵²

The animal data is impressive, and observational studies also support a positive effect on AUD. In an observational study using data from the Swedish Universal National Health Service, 227,866 individuals with AUD were identified. Of these, 133,210 experienced an AUD hospitalization, and 4321 were on liraglutide or semaglutide for obesity or diabetes. The adjusted hazard ratio, or the risk of an AUD hospitalization, was 0.64, which was significantly better than the risk for patients on medication for AUD (disulfiram, acamprosate, naltrexone), who had a risk of 0.98. ⁵²

In randomized controlled studies, the effects on AUD have not been entirely clear. For instance, in a randomized controlled trial with 65 patients on exenatide and 65 patients on placebo, there appear to be mixed results. Exenatide did not significantly reduce the number of heavy drinking days compared with placebo among all participants. However, when the researchers conducted a subgroup analysis of patients with a body mass index (BMI) of 30 or higher, the number of heavy drinking days was significantly reduced in the exenatide group. ⁵³

In a randomized AUD study evaluating low‐dose semaglutide, 48 patients were randomized to receive either 0.5 mg of semaglutide (the usual dose is 1.7–2.4 mg) or placebo. The primary outcome was laboratory alcohol self‐administration, measured before and after treatment (0.5 mg/week). The average patient had a BMI of 32 and experienced nine heavy drinking days within 28 days. In the laboratory, patients on semaglutide showed a moderate to large reduction in grams of alcohol consumed, as confirmed by peak breath alcohol concentration. Patients were instructed to consume at their preferred pace to achieve their preferred effects over 120 min. Patients on placebo consumed approximately four drinks in the 120‐min period. Patients titrated to 0.5 mg of semaglutide consumed about two and a half drinks. They also reported fewer cravings and fewer drinks per drinking day. ⁵⁴ In short, the patients still drank but consumed less and found it easier (with fewer cravings) to do so.

The use of a GLP‐1 for AUD and substance abuse is currently under extensive research. ²⁴ Animal data look promising, but more human trials are needed.

Additional satiety hormone targets

While there has been significant attention on GLP‐1 and GLP‐1 RAs given their effectiveness as weight loss medications and incorporation into mainstream culture, additional saiety hormones do exist. These hormones include targets for newer weight loss agents.

Glucose‐dependent insulinotropic polypeptide (GIP)

The first dual saiety agent to be approved is tizepatide. Tizepatide combines a GLP‐1 RA and a GIP RA. Data on GIP's mechanism of action on appetite are complex. Studies show that using a GIP RA can promote weight loss, but blocking the GIP receptor can also lead to weight loss. ²⁷ , ²⁹ GIP's impact on appetite is currently debated. What is known is that GIP RAs can work synergistically with GLP‐1 RAs. ²⁸ , ⁵⁵ , ⁵⁶

Native GIP is made by intestinal K‐cells, which are located in the upper part of the small intestine and release GIP into the bloodstream in response to food. This response is similar to how GLP‐1 is secreted by L‐cells in the distal small bowel in response to food. Both GIP and GLP‐1 travel to pancreatic beta cells to stimulate insulin release in a glucose‐dependent manner. Both also go to the brain to increase satiety. Where they differ is in their effects on pancreatic glucagon secretion: GLP‐1 suppresses glucagon secretion, while GIP can increase glucagon secretion.

The concept of blocking the GIP receptor to achieve weight loss, however is supported by genetic data. ⁵⁷ Individuals born with a defective GIP receptor have consistently lower BMIs. There is now an anti‐obesity medication (AOM) in development that combines a monoclonal antibody designed to disable the GIP receptor with a GLP‐1 RA. Early‐phase studies have shown nearly 20% weight loss after 1 year. ²⁸

The idea that both stimulating and blocking the GIP receptor can lead to weight loss shows just how complex appetite regulation is. Gutgesell and colleagues showed that in mice GIP stimulation affects one part of the brain, while blocking the GIP receptor impacts another, both resulting in decreased food intake. ²⁹

Amylin

Amylin is a hormone produced by the same pancreatic beta cells that secrete insulin. When insulin is released in response to a meal, amylin is also released in a one‐to‐one ratio. Amylin improves glucose control and appears to work with insulin. An amylin analog, pramlintide, has been available since 2005 and approved for use in patients with diabetes on insulin. ⁵⁸

Although never officially approved as an AOM, pramlintide was studied for its effects on obesity. In an early efficacy study, patients lost about 1% of their body weight each month over a 4‐month trial. ⁵⁹ Early feeding studies by Smith and colleagues showed that 180 mcg of pramlintide before meals, reduced 24‐h caloric intake by 990 kcal. ⁶⁰ A notable sub‐study called the “fast food challenge” gave subjects a lunch of highly palatable foods, including pizza, ice cream, and soft drinks sweetened with high‐fructose corn syrup. The average caloric intake of the “fast food lunch” before starting pramlintide was 1550 calories. Despite the subjects rating the food as “tasty,” they consumed 385 to 528 fewer calories when on pramlintide.

Although patients with known binge eating disorder were excluded, binge eating was also assessed, and a binge eating score (BES) was recorded at the start and end of the study. There was a significant reduction in the BES, with 83% of pramlintide‐treated and 58% of placebo‐treated subjects categorized as having “mild‐to‐none” binge eating compared to 67% and 54% at baseline.

Unfortunately, back in 2005, pramlintide required subcutaneous injections three times a day with only modest weight loss. Thus, the idea of an amylin receptor agonist becoming an AOM was abandoned. Still, amylin remained an important hormone because of two important findings. First, early animal studies showed it produced weight loss while preserving lean mass. ⁶¹ Second, amylin combined with other satiety hormones produced impressive weight loss. ⁶²

In 2021, cagrilintide, a once‐weekly amylin receptor agonist, was first described in the literature. This amylin receptor agonist was combined with semaglutide, a GLP‐1 RA, and studied as an AOM. In a phase three trial, Garvey and colleagues showed that the combination produced 20.4% weight loss at 68 weeks. ⁶³ In December 2025, it was submitted to the FDA for approval.

The main effect of amylin receptor agonists appears to be promoting satiety and satiation—ending the meal and keeping the subject in a prolonged state of satiety. It is hard to be more specific because amylin interacts with many other satiety hormones. It is also possible that the metabolic effects of amylin are just as significant as its ability to induce satiation. ⁶⁴

Glucagon

Clinicians usually do not think of glucagon as a satiety hormone because it raises blood glucose during fasting. During fasting, glucagon acts on the liver to increase glycogen breakdown and glucose production. What has perplexed researchers is that glucagon increases energy expenditure while it counteracts hypoglycemia. Logically, one would think that hypoglycemia is a state of energy deficiency and the human body would want to conserve energy. It turns out that glucagon is part of a response to acute physiological stress and is part of the adaptive stress response. ⁶⁵

Interestingly, glucagon is released after eating. When administered to humans as a subcutaneous injection, it induces a feeling of fullness and reduces food intake. ⁶⁶ The impact of peripheral glucagon administration on reducing food intake is not completely clear and may be a secondary effect of glucagon's direct action on the liver. Glucagon may stimulate hepatic vagal nerve afferents, signaling the brain to stop eating. Therefore, glucagon operates via a gut‐to‐liver‐to‐brain pathway. ⁶⁷ , ⁶⁸

The measured effect of glucagon on appetite is well‐studied but complex. What is known is that glucagon will terminate a meal early (satiety) and promote satiation. An early 1961 study administering 1 mg of glucagon intramuscularly reduced food intake by 30% in healthy medical student volunteers. ⁶⁶

Currently, interest in glucagon as an AOM centers on its metabolic effects. Glucagon is released during fasting and boosts energy expenditure and fat oxidation. In addition, glucagon is released in response to cold exposure. Administration of glucagon is able to increase brown adipose tissue (BAT) mass and to stimulate BAT thermogenic capacity. Lastly, glucagon has a potent effect on lipids. This effect is mediated by inhibition of lipogenesis and stimulation of lipolysis. ⁶⁹

Using glucagon alone to treat obesity would lead to undesirable hyperglycemia. ⁶⁶ Therefore, a glucagon agonist would need to be combined with a glucose‐lowering medication. Recently, a combination of GLP‐1 RA and a glucagon agonist has been proven safe in type 2 diabetics, with significant improvements in blood sugar control and weight loss. ⁷⁰ A triple satiety hormone, composed of a glucagon agonist, GIP RA, and GLP‐1 RA, has also shown impressive weight loss and improved blood sugar levels. ⁷¹ Both treatments may be available by 2027.

The disease most likely to benefit from glucagon's metabolic effects on the liver is fatty liver disease. The liver is loaded with receptors for glucagon. When these receptors are stimulated hepatic‐oxidation of fatty acids and a reduction in de novo lipogenesis will commence. ⁷² , ⁷³ , ⁷⁴

Thus, glucagon is targeting the liver for fat oxidation. Several GLP‐1 RA/glucagon agonists are in development specifically for fatty liver disease and one is already approved in China for type 2 diabetes and obesity. ⁷⁵ , ⁷⁶

Summary and clinical considerations: Be careful what you wish for

It is not surprising that one in eight Americans is currently on a GLP‐1 RA for weight loss or comorbid diseases. With the second‐generation GLP‐1 RAs producing 20% weight loss, which rivals that of bariatric surgery, the number of bariatric surgical cases has decreased dramatically. ⁷⁷ As GLP‐1 RA induced weight loss approaches that achieved with bariatric surgery, clinicians will need to be alert for similar problems. Fat‐free mass or lean tissue loss is part of significant weight loss. In a review of 25 studies using dual‐energy X‐ray absorptiometry (DEXA) to measure fat and fat‐free mass during weight loss with GLP‐1 RAs, the average amount of fat‐free mass lost was 29%, and 71% was fat mass. ⁷⁸

Fat‐free mass is composed of many different tissues, including muscle, bone, liver, heart, and other tissues. The exact percentage of bone and muscle lost is not well known, but in terms of muscle, it appears there is a slight decrease in absolute muscle without negatively affecting strength. ⁷⁹

Bone loss is a well‐recognized negative side effect of bariatric surgery. Bone loss is even seen with the sleeve gastrectomy which is not considered a malabsorptive procedure. In the first year after surgery patients lost 5.9% bone mass in the femoral neck and 6.3% in the hip and over a 5‐year period will lose 9.7% in the femoral neck and 10.7% in the hip. ⁸⁰ This is clearly more than the average North American over 50, who loses 0.5%–1.0% of bone mass per year. ⁸¹

In a large 4.5‐year cardiovascular outcomes trial in older patients with known cardiovascular disease, a GLP‐1 RA (semaglutide) significantly reduced the risk of major adverse cardiac events by 20% compared with placebo. Among patients over age 75, there was a small increase in hip and pelvic fractures in the semaglutide group (2.4% vs. 0.6% in the placebo group). ¹⁰ In a 3‐year study comparing fracture rates in patients on semaglutide to those who had a sleeve gastrectomy, semaglutide was associated with 26% fewer fractures. Over the 3 years, the fracture rate was 2.98% for semaglutide versus 4.43% for sleeve gastrectomy. ⁸²

The exact mechanism is unknown, but from a dietary perspective, as with bariatric surgical patients, this author recommends that patients on GLP‐1 RAs be supplemented with calcium and vitamin D. As with bariatric surgery, Wernicke encephalopathy associated with GLP‐1RA use has also been reported. Between 2023 and 2024, 15 cases were reported to FDA Adverse Event Reporting System (FAERS), with most patients experiencing nausea, vomiting, and malnutrition. ⁸³

This is not surprising due to the nausea and vomiting commonly associated with GLP‐1 RAs and the weight loss approaching that of bariatric surgery. Again, this author recommends a multivitamin.

Due to the impressive decrease in energy intake, protein intake becomes a concern, and patients will require appropriate counseling. ⁸⁴ If second‐generation GLP‐1 RAs reduce food intake by 50%, it can be anticipated that many patients will lower protein intake by a similar amount. NHANES data from What We Eat in America show that the average protein intake is 69–104 g daily. If this is decreased by 50%, many patients will be below the 0.8 g per kilo RDA, the 1.2–1.6 g per kilo U.S. Federal dietary guidelines, and the 1.5 g per kilo for patients with obesity undergoing weight loss. ⁸⁵ Due to this impressive decrease in energy intake, protein will need to be prioritized.

The side‐effect profile of GLP‐1 RAs is primarily gastrointestinal, with nausea and vomiting common. Given the independent effect of GLP‐1 RAs in reducing total water intake, patients are at risk of dehydration. Patients should be reminded to monitor their fluid intake.

With daily caloric intake reduced by 50% in patients receiving some AOMs and Americans notorious for not meeting daily fiber recommendations, it is not surprising that constipation is a common complaint among patients on GLP‐1 RAs. ⁸⁶ To make matters worse, decreased total water intake is also influenced by GLP‐1 RAs. Fortunately, this can be addressed with proper counseling, either through fiber supplements, by encouraging patients to eat more fiber‐rich foods, and by increasing fluid intake.

The good news is that these potential adverse effects can respond to appropriate counseling. When reviewing second‐generation GLP‐1 RAs, all reports indicate that patients have improved “food control.” Patients often describe this as a decrease in “food noise” and find it easier to follow a healthy diet. This author has often heard patients say, “I can skip the ice cream, and I am fine with a piece of fruit.”

AUTHOR CONTRIBUTIONS

Ken Fujioka is the sole author and developed the concept and design of this article. He also drafted the manuscript. He critically revised it to ensure the accuracy and integrity of the work and read and approved the final manuscript.

CONFLICT OF INTEREST STATEMENT

Dr Fujioka is a consultant for Lilly, Novonordisk, Rhythm, Boehringer Ingelheim, and Vectiv Bio pharmaceutical companies.

Fujioka K. Effect of GLP‐1 receptor agonist on nutrient intake: a narrative review. Nutr Clin Pract. 2026;41:1307‐1317. 10.1002/ncp.70172