GLP-1 analog therapy and hemoglobin levels: Insights from a retrospective study

ABSTRACT

Objectives:

To investigate the hematological impact of Glucagon-like peptide-1 (GLP-1) analogs, specifically changes in hemoglobin and ferritin levels. Glucagon-like peptide-1 analogs, pivotal in managing type 2 diabetes mellitus (T2DM) and obesity, exhibit diverse physiological effects. While their impact on glycemic control is well-established, understanding their influence on hematological parameters remains an active area of investigation.

Methods:

A cohort of 700 patients prescribed GLP-1 analogs between March 2021 and October 2022 was analyzed. Demographic data, baseline hemoglobin, ferritin levels, and subsequent measurements were collected. Statistical analyses included descriptive statistics, Wilcoxon signed-rank tests, Mann-Whitney U tests, subgroup analyses, and multivariable logistic regression.

Results:

Following GLP-1 analog initiation, a statistically significant decrease in hemoglobin levels was observed (median decrease: 0.2 g/dL), with 59 patients (8.4%) developing anemia. Ferritin levels showed no significant change. Subgroup analyses by gender and medication type revealed no significant differences in hemoglobin changes. Baseline hemoglobin demonstrated a significant inverse association with anemia development (OR=0.31, 95% CI: 0.21–0.44, p<0.01).

Conclusion:

This study contributes valuable insights into the complex interplay between GLP-1 analogs and hematological parameters. Clinicians should be aware of potential hematological effects, with baseline hemoglobin levels serving as a valuable predictor of anemia risk. Future prospective studies are warranted to deepen understanding and refine clinical strategies in the use of GLP-1 analogs.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by the intestinal epithelium in response to nutrient ingestion. Its physiological actions include enhancing insulin secretion, suppressing glucagon release, delaying gastric emptying, and inducing satiety.^1,2 In recent years, GLP-1 analogs have emerged as pivotal agents in the management of type 2 diabetes mellitus (T2DM) and obesity.³ Their therapeutic benefits extend beyond glycemic control, encompassing weight loss and cardiovascular risk reduction.^4,5 Among the various physiological effects of GLP-1 analogs, their influence on hematological parameters remains an area of active investigation.^6,7

Emerging evidence suggests that GLP 1 receptor agonists can influence iron metabolism and hematologic parameters. For example, in a Danish cohort of patients with type 2 diabetes and hereditary hemochromatosis, GLP-1 receptor agonists use was associated with significantly lower serum ferritin levels and a longer interval between phlebotomies.⁸ Preclinical models support this finding: in obese diabetic mice, liraglutide markedly attenuated hepatic iron overload by downregulating the transferrin receptor and upregulating ferroportin.⁹ These data imply that GLP 1 analogs may modestly reduce iron stores and circulating ferritin.

Separate studies have reported effects on hemoglobin as well. In a real-world cohort of dyslipidemic patients with T2D, initiation of dulaglutide led to a small but statistically significant decline in hemoglobin (and mean corpuscular volume) over 3 months.¹⁰ Notably, GLP 1 receptor agonists do not exhibit the hemoconcentrating (anti-anemic) effects seen with SGLT2 inhibitors. In fact, a Taiwanese registry study found that SGLT2 inhibitors – but not GLP-1 RAs – were associated with a lower incidence of anemia in T2D patients.¹¹ These findings suggest GLP-1 agonists are neutral or slightly suppressive for erythropoiesis.

Glucagon-like peptide-1 receptor agonists can also affect nutrient absorption and vitamin status. One study of obese patients with T2D reported that mean serum vitamin B12 fell significantly during 12 months of semaglutide therapy (from 567 to 494 pg/mL).¹² This decline in B12 (and similar drops in zinc and albumin) likely reflects reduced dietary intake and absorption as weight is lost. Although data on micronutrients are limited, the appetite-suppressing and gastric-emptying effects of GLP 1 drugs raise concern for potential deficiencies (iron, B12, etc.) during long-term therapy.

Glucagon-like peptide-1 analogs, such as semaglutide and liraglutide, exert their effects through the activation of GLP-1 receptors, primarily located in the pancreas.¹³ While the primary focus of GLP-1 analogs is on glucose homeostasis, their systemic effects extend to various organs and systems, including the hematopoietic system.^6,7 The intricate interplay between GLP-1 analogs and hematological parameters is an evolving field, and a comprehensive understanding of these interactions is essential for tailoring therapeutic approaches and anticipating potential side effects.⁸

Hematological alterations, particularly changes in hemoglobin levels, have been identified in patients receiving GLP-1 analog therapy.⁸ However, the precise mechanisms underlying these changes and their clinical implications remain incompletely elucidated. Existing literature offers varying perspectives, with some studies suggesting a potential association between GLP-1 analog use and alterations in iron metabolism, erythropoiesis, or nutritional status.^6,7 Nevertheless, a comprehensive examination of these effects, especially in diverse patient populations, is warranted to inform evidence-based clinical decision-making.

In this context, our study aims to bridge this knowledge gap by conducting a thorough investigation into the hematological impact of GLP-1 analogs in a sizable cohort of patients from King Abdulaziz University Hospital, Jeddah, Saudi Arabia. By exploring changes in hemoglobin and ferritin levels, we seek to contribute meaningful insights to the evolving understanding of GLP-1 analog therapy and its broader physiological effects.

Methods

This retrospective cohort study investigated changes in hemoglobin levels in patients following the initiation of GLP-1 analogs. The study design adhered to the principles outlined in the Declaration of Helsinki and was approved by the King Abdulaziz University Ethics Committee.

The study focused on a single-center cohort from King Abdulaziz University Hospital, comprising all patients prescribed GLP-1 analogs for glycemic control or weight loss between March 2021 and October 2022. Eligibility required complete medical records, including baseline hemoglobin and ferritin levels, and a minimum 90-day duration of GLP-1 analogs use. Exclusions applied to patients with pre-existing anemia or hematologic disorders, as well as those with incomplete medical records or missing laboratory data.

Initially, 908 patients were identified from the hospital information system, and after applying exclusion criteria, a final cohort of 700 patients from King Abdulaziz University Hospital was included in the study. During the study period, none of the patients initially prescribed liraglutide transitioned to semaglutide.

The hospital information system was utilized to compile a list of patients prescribed GLP-1 analogs. Subsequently, relevant laboratory tests, including hemoglobin (g/dL) and ferritin (ng/mL), were systematically gathered. The dataset encompassed demographic information, GLP-1 analogs initiation date, baseline hemoglobin, and ferritin levels, as well as subsequent measurements, along with other pertinent clinical parameters. Anemia was defined as a hemoglobin level of less than 11 g/dL. The median follow-up period was 9 months, with hemoglobin and ferritin measurements taken at different time points after the initiation of GLP-1 analog therapy.

Statistical analysis

Statistical analyses were performed using IBM SPSS Statistics for Windows version 27.0 (IBMCorp, Armonk, NY, USA). Descriptive statistics were applied to demographic variables. The distribution of hemoglobin and ferritin levels was examined using visual methods (such as, histograms and Q-Q plots) and statistical tests (such as Shapiro-Wilk test) to assess normality. As the data for both hemoglobin and ferritin were not normally distributed, non-parametric tests were utilized for comparisons. Within-group comparisons were conducted using Wilcoxon signed-rank tests. Between-group comparisons utilized Mann-Whitney U tests. Missing data were addressed through listwise deletion. Subgroup analyses were conducted to assess the generalizability of the findings. Multivariable logistic regression was employed to investigate factors associated with the development of anemia following the initiation of GLP-1 analogs. The independent variables included age, gender, type of GLP-1 analog (semaglutide versus [vs.] liraglutide), and baseline hemoglobin levels. All included variables were collectively adjusted for in the model to assess their association with anemia development. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated to assess the strength and direction of associations. The significance level was set at 0.05.

Results

The study included 700 patients, with a mean age of 51.0±14.5 years. Participants were distributed across various age groups, and the highest frequency was observed in the 46–60 (38%) age range, followed by the >60 (27.6%) age group. The gender distribution revealed a notable difference, with 253 male participants (36.1%) and 447 female participants (63.9%). In terms of medication, the majority were prescribed semaglutide (69.7%), while 30.3% were prescribed liraglutide. Diabetes mellitus was the primary indication for starting the medication in the majority of cases (84.9%). Of the 15.1% of patients who initiated the medication due to obesity, we further verified that these individuals were non-diabetic or prediabetic, as obesity management is a common indication for GLP-1 prescription in such patients (Table 1).

Table 1.

- Demographic and medical characteristics of study population (N=700).

Variables	n (%)
Age group (years)
18–30	67 (9.6)
31–45	174 (24.9)
46–60	266 (38.0)
>60	193 (27.6)
Gender
Male	253 (36.1)
Female	447 (63.9)
Medication
Semaglutide	488 (69.7)
Liraglutide	212 (30.3)
Primary indication
Diabetes mellitus	594 (84.9)
Obesity	106 (15.1)

The table summarizes the baseline characteristics of patients who initiated glucagon-like peptide-1 (GLP-1) analog therapy. Frequencies and percentages are reported for age groups, sex, prescribed GLP-1 analog (semaglutide or liraglutide), and the primary indication for treatment (diabetes mellitus or obesity).

Table 2.

- Subgroup analysis of hemoglobin levels before and after glucagon-like peptide-1 (GLP-1) analog initiation.

Variables subgroup	Baseline hemoglobin (g/dL)	Post-Treatment hemoglobin (g/dL)	Median change (g/dL)	P-value
Gender
Male	14.4 (IQR=1.7)	14.4 (IQR=1.9)	0.0	0.35
Female	12.6 (IQR=1.5)	12.6 (IQR=1.7)	0.0
Medication type
Semaglutide	13.3 (IQR=2.0)	13.2 (IQR=2.2)	-0.1	0.95
Liraglutide	12.9 (IQR=1.8)	12.8 (IQR=1.9)	-0.1

IQR: interqurtile range

Baseline measurements and changes in hemoglobin levels

Regarding baseline measurements, the median baseline hemoglobin level among participants was 13.2 g/dL (IQR=2.0), and the median baseline ferritin level was 36.6 ng/mL (IQR=78.3). After the initiation of the prescribed medication, the median hemoglobin level was 13.0 g/dL (IQR=2.2), with 8.4% of patients developing anemia. The median ferritin level was 36.2 ng/mL (IQR=62.0).

A Wilcoxon signed-rank test revealed a statistically significant decrease in hemoglobin levels after starting the medication (Z= −3.57, p<0.01). However, there was no statistically significant difference in ferritin levels before and after the medication (Z=−0.44, p=0.66).

Subgroup analysis

When examining hemoglobin levels based on gender, the median baseline hemoglobin levels were 14.4 g/dL (IQR=1.7) for both males and females. After starting the medication, the median hemoglobin level for both males and females was 12.6 g/dL, with no significant difference between male and female participants in the change in hemoglobin levels (U=54149, p=0.35).

Comparing the effects of different medications on hemoglobin levels, participants prescribed semaglutide had a median baseline hemoglobin level of 13.3 g/dL (IQR=2.0), while those prescribed liraglutide had a median baseline hemoglobin level of 12.9 g/dL (IQR=1.8). After treatment initiation, the median hemoglobin level for semaglutide users was 13.3 g/dL (IQR=2.0), and for liraglutide users, it was 12.9 g/dL (IQR=1.8). Statistical analysis using a Mann-Whitney U test revealed no significant difference between male and female participants in the change in hemoglobin levels (U=51584, p=0.95).

These subgroup analyses were conducted to explore potential variations in the hematological response across different patient groups and to assess the generalizability of our findings to a broader population. By evaluating the effect of sex and medication type on changes in hemoglobin levels, we aimed to determine whether these factors significantly influence the observed outcomes, thus contributing to a more comprehensive understanding of how GLP-1 analogs may affect diverse patient subgroups.

Factors influencing anemia development following GLP-1 analogs use

Table 3 shows the results of the multivariable logistic regression analysis examining factors associated with the development of anemia following the initiation of GLP-1 analogs. In this analysis, all the included variables—age, gender, choice of GLP-1 analog (semaglutide vs. liraglutide), and baseline hemoglobin levels—were adjusted for collectively. Notably, baseline hemoglobin demonstrated a significant inverse association with the development of anemia (OR=0.31, 95% CI: 0.21–0.44, p<0.01), indicating that higher baseline hemoglobin levels were associated with a lower likelihood of anemia occurrence. Age, female gender (compared to male), and the choice between semaglutide and liraglutide did not exhibit statistically significant associations with anemia development (p>0.05).

Table 3.

- Multivariable logistic regression analysis of factors associated with the development of anemia after the initiation of GLP-1 analogs.

Variables	OR	[95% CI]	P-value
Age (per year)	1.01	[1.00–1.03]	0.25
Female, gender (vs. Male)	1.30	[0.57–2.97]	0.54
Semaglutide (vs. Liraglutide)	1.20	[0.62–2.32]	0.58
Baseline Hemoglobin (per g/dL)	0.31	[0.21–0.44]	<0.01

The table shows adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for variables included simultaneously in the multivariable model.

The outcome variable was the development of anemia after starting glucagon-like peptide-1 (GLP-1) analog treatment. A 2-sided p-value of less than 0.05 was considered to indicate statistical significance. Vs: versus

Discussion

The current study sought to elucidate the impact of GLP-1 analogs on hematological parameters, with a focus on changes in hemoglobin levels and associated factors. Our findings reveal several noteworthy observations that warrant careful consideration and interpretation.

These observations align with our findings and recent literature on GLP-1 analogues and hematologic indices. For example, the Danish study noted above reported lower ferritin in GLP-1–treated patients,⁸ consistent with any reduction in iron stores we observed. Likewise, small decreases in hemoglobin have been reported in GLP-1 receptor agonists users,¹⁰ contrasting with the hemoglobin-raising effects of SGLT2 inhibitors.¹¹ The documented drop in vitamin B12 with semaglutide further suggests that GLP-1–induced changes in diet or absorption may contribute to mild anemia.¹² Taken together, these data support the idea that GLP 1 receptor agonists can subtly lower iron and hemoglobin levels. Clinicians should therefore consider monitoring ferritin, hemoglobin, and vitamin B12 in patients on GLP 1 therapy, especially those at risk for anemia or with prior bariatric surgery.

One of the primary findings of this study is the statistically significant decrease in hemoglobin levels following the initiation of GLP-1 analog therapy with the development of anemia in 8.4% of patients. Anemia is a multifactorial condition, and our findings suggest that GLP-1 analog use may contribute to its occurrence in a subset of patients. The clinical community must be attentive to this potential side effect, particularly in individuals with pre-existing risk factors for anemia.¹⁴ In contrast to some earlier investigations, our study did not observe a significant change in ferritin levels after GLP-1 analog initiation. For example, a previous study investigated the impact of GLP-1 receptor agonists on blood ferritin levels in individuals with both T2DM and hereditary hemochromatosis.⁸ The study, based on Danish registry data, explored the association between GLP-1 receptor agonist treatment and reduced ferritin levels, suggesting potential implications for the management of hemochromatosis in individuals with T2DM. The research also observed a correlation between GLP-1 receptor agonist use and a trend toward decreased phlebotomy frequency, providing insights into alternative therapeutic approaches for this condition. Hence, this discrepancy prompts further exploration into the potential variations in study populations, treatment durations, and dosage regimens across different studies that may contribute to divergent findings. Further exploration is warranted to understand the mechanisms through which GLP-1 analogs influence hemoglobin levels, including potential associations with factors such as iron metabolism, erythropoiesis, and nutritional status.

The subgroup analyses based on gender and medication type offer valuable insights into the heterogeneity of treatment effects. Contrary to expectations, there was no significant difference in the change in hemoglobin levels between males and females, indicating that sex may not be a significant modifier of the observed hematological response to GLP-1 analogs. Similarly, the lack of a significant difference in hemoglobin changes between patients prescribed semaglutide and liraglutide prompts consideration of the nuanced interactions between specific GLP-1 analogs and hematological parameters.

Perhaps the most intriguing aspect of our study lies in the identification of baseline hemoglobin levels as a significant predictor of anemia development. Higher baseline hemoglobin levels were associated with a lower likelihood of developing anemia following the initiation of GLP-1 analog therapy. This observation suggests a potential stratification approach in clinical decision-making, where patients with lower baseline hemoglobin levels may require closer monitoring and intervention to mitigate the risk of anemia.

While our study provides valuable insights, it is not without limitations. The retrospective design introduces inherent biases, and the generalizability of our findings may be influenced by the characteristics of our study population. Additionally, the specific mechanisms underlying the observed hematological changes remain elusive and warrant further investigation. The study did not specifically account for patients who were concurrently taking medications known to influence hemoglobin or ferritin levels, such as iron supplements, erythropoiesis-stimulating agents, or other medications affecting iron metabolism. This could be a potential confounding factor that might influence the observed hematological outcomes.

In conclusion, our study sheds light on the complex interplay between GLP-1 analogs and hematological parameters. The significant decrease in hemoglobin levels, the development of anemia in a subset of patients, and the nuanced responses across different subgroups underscore the need for continued research in this domain. Clinicians should be attuned to the potential hematological effects of GLP-1 analog therapy and consider baseline hemoglobin levels as a valuable predictor of anemia risk. Future prospective studies and mechanistic investigations are essential to deepen our understanding and refine clinical strategies in the use of GLP-1 analogs.