Anemia: A Lesser-Known Side Effect of GLP-1 Drugs?

 As use of GLP-1 receptor agonists (RAs) continues to rise exponentially, awareness of its most common side effects, such as nausea and vomiting, is growing. But the drugs come with some lesser-known potential risks, which may include micronutrient deficiencies, such as iron deficiency anemia (IDA).

“There may be a link between GLP-1 drugs and iron deficiency anemia, but the jury is still out, since not much research has been conducted in this area,” Stephen Hennigar, PhD, associate professor, Pennington Biomedical Research Center, Baton Rouge, Louisiana, told Medscape Medical News.

But even the possibility that GLP-1 RAs may contribute to iron or other nutritional deficiencies is concerning because the risk for anemia is already elevated in patients with obesity and/or type 2 diabetes (T2D), possibly due to increased inflammation and increased incidence of chronic kidney disease (CKD) in diabetes, Hennigar said.

“If you’re at risk for anemia or already have it, then initiating treatment with a GLP-1 could exacerbate what’s already there,” he said.

According to some estimates, anemia affects about 27% of patients with T2D, especially those who also have CKD. Contributing factors to anemia in this population include age, gender, level of glycemic control, diabetes duration, and the presence of chronic complications.

Individuals with obesity are also more prone to anemia, due to a variety of disturbances at the endothelial, hormonal, and inflammatory levels. Poor diet quality also could play a role.

“In the US, iron deficiency is the most common cause of anemia, but it’s not the only cause,” Hennigar said. “Individuals with type 2 diabetes taking metformin are at risk for long-term decreases in vitamin B₁₂ levels, which can cause anemia over time.”

Metformin is the first-choice drug for several conditions, including T2D and prediabetes, and is taken daily by approximately 150 million people. Adding another drug that could contribute to micronutrient deficiencies is “concerning,” Hennigar said.

What Does the Evidence Say?

Although strong evidence is lacking, some studies point to nutritional deficiencies in patients taking GLP-1 RAs.

Butsch et al. analyzed data from 461,382 patients with no prior history of nutritional deficiencies who were newly prescribed GLP-1 RAs between 2017 and 2021. Although 80.5% of patients had T2D, the population also included patients with type 1 diabetes, prediabetes, or no recorded diabetes diagnosis. Nutritional deficiencies were diagnosed in 12.7% of patients within 6 months of treatment initiation and in 22.4% within 12 months. IDA was diagnosed in 1.6% and 3.2% of patients, respectively.

When comparing 4505 patients with T2D taking metformin with an equal number of patients taking metformin plus a GLP-1 RA, the researchers found no statistically significant difference in anemia prevalence between the two groups, with IDA prevalence of about 3% for both. At 12 months, the overall incidence of nutrition deficiencies was higher in the GLP-1 group than in the metformin-only group (18.6% vs 16.5%; P < .01), driven by deficiencies in vitamin D and some B vitamins.

Another study analyzed data from 700 patients who received a prescription for GLP-1 RAs over a 1-year period. Following treatment initiation, the researchers observed a statistically significant decrease in hemoglobin levels, and 8.4% of patients developed anemia. Higher baseline hemoglobin levels were significantly associated with a lower likelihood of developing anemia (odds ratio, 0.31; P < .01).

Potential Mechanisms

One reason that people taking GLP-1 RAs may be vulnerable to anemia is because the drugs enhance satiety and reduce hunger, so patients eat less, Hennigar said. “If you’re consuming less food, you’re likely consuming less iron. And if you’re consuming less iron, then over time, this could lead to nutritional deficiencies resulting in anemia,” he explained.

GLP-1 RAs affect central appetite pathways and change how people eat, said Carolyn Newberry, MD, associate professor of clinical medicine and director of GI nutrition, Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York City.

“People may not be getting enough calories, particularly when they first start medication or when the dosage is raised,” Newberry, a spokesperson for the American Gastroenterological Association, told Medscape Medical News. “They may be eating more restrictive diets than they have in the past, so we wonder about micronutrient deficiencies, especially in iron and vitamin B₁₂.”

Indeed, individuals using GLP-1 drugs to treat obesity have been shown to experience significant reductions in appetite and a reduction in energy intake of 16%-39%. This can lead to insufficient intake of essential vitamins and minerals — especially when patients consume < 1200 kcal/d for females and < 1800 kcal/d for males.

A study of 69 patients who had been taking GLP-1 drugs for ≥ 1 month found that participants were consuming inadequate amounts of several key nutrients, including fiber and iron. Moreover, too large a portion of their caloric intake came from fat in general and saturated fat in particular. Participants did not meet the daily recommended MyPlate servings for fruit, vegetables, grains, or dairy.

Other potential pathways by which GLP-1 RAs might cause anemia involve their effects on motility and neurohormonal secretions, Newberry noted.

Delayed gastric emptying and gut microbiota modulation caused by the GLP-1 RAs might alter micronutrient metabolism and absorption, resulting in nutrient deficiencies.

“By slowing the movement of food from the stomach to the small intestine, where most nutrient absorption occurs, GLP-1 RAs could theoretically delay or reduce iron absorption,” Hennigar said. However, he added, “the mechanisms we’re discussing are still speculative.”

Findings of a prospective study support this hypothesized mechanism. Researchers studied 51 patients with poorly controlled T2D who initiated treatment with semaglutide, with dosages increasing every 2 weeks, followed by an additional 2 weeks of maintenance therapy. At baseline and at 10 weeks of treatment, participants underwent an oral iron absorption test in which they ingested a 350 mg ferrous fumarate capsule (115 mg elemental iron) after a 12-hour fast.

The median increase in serum iron levels, measured 2 hours after capsule ingestion, was lower after 10 weeks of semaglutide than at baseline. The median relative reduction in iron absorption was 13%. Nine patients (17.6%) experienced at least a 30% reduction in iron absorption with semaglutide therapy compared to baseline. Predictors of better iron absorption were lower body weight, BMI, and ferritin levels, as well as prior exposure to SGLT2 inhibitors, which promote erythropoiesis and may influence better iron utilization and absorption. 

Clinical Tips

There are currently no standard guidelines addressing anemia management in the context of GLP-1 RAs, Newberry said. However, there are some strategies that might be helpful in reducing risk for anemia and addressing the problem if it emerges.

The first step is to check the patient’s levels of hemoglobin, hematocrit, ferritin, and other hematologic indicators for anemia before initiating GLP-1 therapy, Hennigar said. Clinicians also should be vigilant about monitoring patients for potential anemia, especially those already at higher risk, such as women and people with T2D, overweight or obesity, preexisting anemia, or CKD.

For patients with diabetes at risk for anemia, Hennigar recommends considering the addition of an SGLT2 inhibitor to the medication regimen. He pointed to a recent study comparing SGLT2 inhibitors and GLP-1 RAs in 13,799 patients with T2D and CKD. The researchers found that those taking SGLT2 inhibitors had a lower incidence of composite anemia outcomes and a lower incidence of anemia events at a median of 2.5 years than those receiving treatment with GLP-1 RAs. They suggested that SGLT2 inhibitors may comprise an adjunct therapy to reduce anemia incidence in patients with T2D and CKD.

Nutritional management is key for patients taking GLP-1 RAs, Newberry said. In her clinic, patients receive a dietary assessment to make sure they’re meeting their nutritional needs before GLP-1 RA treatment is initiated. “And we monitor them for side effects, such as nausea or constipation, which might affect their food consumption or flag GI issues that are relevant to nutrient absorption. I check labs annually in patients who have been on long-term GLP-1 RA treatment, just to make sure nutritional deficiencies aren’t developing over time.”

A joint statement of four major medical societies offers priorities for nutrition and other lifestyle interventions relevant to treating obesity with GLP-1 RAs. These include completion of a baseline nutritional assessment and screening, management of GI side effects, navigation of dietary preferences and intake, and promotion of supportive lifestyle measures (eg, assessing and addressing physical activity, sleep habits, and food insecurity).

The statement recommends that clinicians “emphasize a diversity of nutrient-dense, minimally processed foods such as fruits, vegetables, whole grains, legumes, lean proteins, nuts, and seeds.” Dietary supplements can be considered for select patients at risk for or experiencing deficiencies in common nutrients, such as iron.

“I don’t think all patients taking GLP-1 drugs necessarily need to take dietary supplements,” Newberry said. “But if they have risk factors for anemia, if they have other conditions such as inflammatory bowel disease, or if they’re showing signs of anemia, we might consider being more aggressive with assessing their levels of these nutrients and recommending supplementation as appropriate.”

Patients taking GLP-1 drugs should be referred for nutrition therapy provided by a registered dietitian. “In our GI clinic, we have robust dietitian services,” Newberry said. “The dietitians are central in helping patients maintain adequate nutrition during their treatment with GLP-1 drugs.”

Hennigar disclosed having no relevant financial relationships. Newberry reported being a consultant for Eli Lilly and Co.

https://www.medscape.com/viewarticle/anemia-lesser-known-side-effect-glp-1-drugs-2025a1000ygo