Anemia risk and mitigation strategies in type 2 diabetic patients: The role of novel antidiabetic agents

Abstract

Anemia is a common yet often overlooked complication in patients with type 2 diabetes mellitus (T2DM), particularly those with chronic kidney disease. It significantly impacts patients' quality of life, cardiovascular health, and treatment outcomes. Despite its high prevalence, current clinical guidelines lack specific recommendations for anemia prevention and management in T2DM, especially in the context of newer antidiabetic therapies. This review explores the potential of emerging antidiabetic medications, such as sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and combined GLP-1-RA/GIP to mitigate anemia risk. Early detection and management of anemia in T2DM patients are crucial for improving glycemic control, reducing cardiovascular morbidity, and enhancing overall treatment outcomes. This review underscores the need for further research to better understand the mechanisms by which these novel therapies influence anemia risk and to integrate these findings into clinical practice.

Key Words: Anemia; Type 2 diabetes mellitus; chronic kidney disease; Iron deficiency; Metformin; Sodium-glucose cotransporter-2 inhibitors; Glucagon-like peptide-1 receptor agonist; Glucagon-like peptide-1 receptor agonist/GIP dual agonists

Core Tip: This review focuses on the overlooked prevalence and effect of anemia in type 2 diabetes, particularly in the context of chronic kidney disease. It focuses on the complicated interplay between anemia, glucose management, and diabetes-related comorbidities, as well as the possibility of emerging antidiabetic medications (sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists) to reduce anemia risk. Furthermore, the study underlines the significance of early identification of anemia and the benefits of newer antidiabetic drugs in terms of cardiovascular and kidney outcomes.

INTRODUCTION

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder that often occurs alongside multiple comorbidities, including anemia. Anemia affects 27% of patients with T2DM[1], particularly those with chronic kidney disease (CKD)[2,3]. Several factors contribute to the prevalence of anemia in diabetic patients, such as age[4,5], gender[4,5], level of glycemic control[4,6-8], diabetes duration[5], the presence of chronic complications[8,9], and glomerular filtration rate (GFR)[10]. Additionally, treatment with metformin has been linked to an increased risk of vitamin B₁₂ deficiency, which may contribute to the development of anemia in patients with T2DM, although the exact mechanisms are not yet fully understood[11]. Emerging evidence indicates that newer diabetes treatments, such as sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) Ras, may influence the risk of anemia[12]. SGLT2 inhibitors have been shown to reduce the risk of anemia in individuals with T2DM, particularly those with comorbid conditions like CKD, by improving erythropoiesis, reducing inflammation, and enhancing iron utilization. In contrast, GLP-1 receptor agonists (GLP-1 RAs) may potentially increase the risk of anemia[12]. Anemia can negatively impact treatment outcomes, including glycemic control, cardiovascular health, and overall patient morbidity[13]. Currently, there are no specific clinical guidelines regarding the management of anemia in the context of newer antidiabetic therapies. This review aims to explore the interplay between anemia, glucose regulation, and diabetes-related comorbidities, focusing on the potential of novel antidiabetic agents to mitigate anemia risk in T2DM patients. By addressing this critical gap in the literature, we hope to provide valuable insights that can guide future research and clinical practice.

IMPACT OF ANEMIA ON GLUCOSE REGULATION

Anemia has a complex relationship with glucose regulation, as shown in both animal and human studies[14]. It significantly impairs quality of life by causing symptoms like fatigue, weakness, dizziness, and shortness of breath, which can disrupt daily routines, physical activity, and work performance. Hemoglobin A1c (HbA1c) is a measure of glycated hemoglobin over 3 months and is widely used to diagnose diabetes and evaluate the effectiveness of diabetes management[15]. However, interpreting HbA1c values can be challenging due to various influencing factors[16-18]. When assessing prediabetes, it is essential to consider erythrocyte indices, as anemia may require adjustments in HbA1c interpretation[19]. Moreover, factors such as red blood cell lifespan and blood transfusions can also affect these measurements[20].

ANEMIA RISK WITH CHRONIC DIABETIC COMPLICATIONS

Chronic complications of diabetes severely impact the quality of life and survival rates. Anemia plays a critical role in the progression of these complications. There is a clear association between low hemoglobin levels, even within the normal range, and an increased risk of kidney disease progression in T2DM patients not requiring insulin therapy[21]. Iron deficiency anemia disrupts glucose regulation and worsens glycemic control in both animal and human studies[14]. Anemia also exacerbates diabetic neuropathy and retinopathy by limiting the oxygen supply to affected tissues and increasing oxidative stress[22,23]. The prevalence of anemia is particularly high among patients with diabetic foot ulcers, with more than 75% of these patients experiencing moderate to severe anemia[24].

ANEMIA IN PATIENTS WITH CKD

Anemia is more prevalent in diabetic patients, even those with normal kidney function[25]. The prevalence of anemia increases with CKD progression, and CKD is a major cause of anemia in diabetic patients[2,26,27]. Diabetic patients with CKD are at a higher risk of anemia compared to those with CKD from other causes[28]. Anemia in CKD patients is associated with faster kidney disease progression, as well as increased cardiovascular complications and mortality[3].

CARDIOVASCULAR COMPLICATIONS AND ANEMIA IN DIABETIC PATIENTS

Anemia in diabetic patients also increases the risk for cardiovascular complications[29-31]. It highlights the need for early detection and comprehensive management of anemia in individuals with diabetes to prevent further complications and improve long-term health, knowing that cardiovascular disease is the leading cause of death in this population[32].

ANEMIA RISK WITH ANTIDIABETIC AGENTS (ALONE AND IN COMBINATIONS)

Managing T2DM requires antihyperglycemic therapy, a healthy diet, and regular physical activity. However, certain diabetes medications, particularly metformin, carry an increased risk of anemia[11,33]. For instance, studies such as the A diabetes outcome progression trial (ADOPT) and the United Kingdom Prospective Diabetes Study have shown that the risk of developing anemia is significantly higher in metformin users. This risk can manifest as early as 6 months after starting the medication compared to other treatment options[11].

Newer therapies, such as GLP-1 RAs and SGLT2 inhibitors, not only improve glycemic control but also offer additional health benefits. GLP-1RAs, in particular, have become widely adopted for managing T2DM due to their effectiveness in enhancing glycemic control, promoting weight loss, and reducing cardiovascular risks. The most studied GLP-1RAs are liraglutide, semaglutide, and dulaglutide. However, recent evidence suggests these agents may affect hemoglobin levels, potentially leading to mild anemia in clinical settings. Although the exact mechanisms are not fully understood, they may be related to the medications’ impact on gastrointestinal motility and stomach emptying, which can interfere with the absorption of vitamins, minerals, and other medications[12,34,35]. When iron supplementation is necessary, higher oral doses or intravenous iron therapy may be required due to decreased gastrointestinal absorption. On a positive note, the anti-inflammatory effects and kidney protection provided by GLP-1 RAs highlight their importance in the treatment of T2DM[36].

On the other hand, SGLT2 inhibitors may help reduce the risk of anemia, likely due to their positive effects on kidney function[12]. These medications also decrease cardiovascular risks and improve kidney outcomes in diabetic patients, which further lowers the risk of anemia. A recent study has shown that treatment with SGLT2 inhibitors in diabetic patients significantly lowers the neutrophil-to-lymphocyte ratio, a marker of systemic inflammation. This reduction in inflammation may contribute to alleviating the inflammatory burden in T2DM patients[37]. Additionally, research by Ferreira et al[37] indicates that anemia in heart failure patients with reduced ejection fraction (HFrEF) is associated with worse outcomes. Empagliflozin has been found to improve hematocrit levels and reduce the onset of new anemia, leading to better heart and kidney outcomes, regardless of the patient’s baseline anemia status[37]. Similarly, the dapagliflozin in patients with Heart Failure and Reduced Ejection Fraction trial discovered that while anemia in HFrEF patients correlates with poorer outcomes, dapagliflozin can effectively correct anemia and significantly improve heart failure outcomes, independent of initial anemia levels[38]. Furthermore, the dapagliflozin in patients with CKD trial revealed that dapagliflozin not only improves kidney and cardiovascular outcomes in patients with CKD but also helps to prevent and correct anemia, outperforming the placebo, regardless of whether the patient had anemia at the start[39].

The latest class of medications for the treatment of T2DM is the GLP/GIP dual agonists, with tirzepatide being a leading molecule that is already in wide use. However, the effects of this class of medication on anemia are not fully understood, and further studies are necessary[40]. The weight-loss potential of tirzepatide surpasses that of all previous medications used for obesity and diabetes treatment[40]. It is important to note that caloric restriction during weight loss may contribute to anemia due to the reduced intake of essential nutrients necessary for hematopoiesis. On the other hand, losing fat tissue can decrease inflammation and hepcidin levels, which may improve iron absorption from the intestine[41]. Table 1 compares various novel antidiabetic drugs and their effect on the risk of anemia.

Table 1 Effects of novel antidiabetic drugs on the risk of anemia.

Therapy	Mechanism	Effect on anemia risk	Clinical implications
SGLT2 inhibitors	Improves kidney function, reduces inflammation, enhances erythropoiesis	Reduces anemia risk, particularly in CKD patients	Improves cardiovascular and kidney outcomes; reduces anemia incidence
GLP-1 receptor agonists	Slows gastrointestinal motility, impairs nutrient absorption (iron, B12)	May increase anemia risk due to malabsorption; anti-inflammatory effects may offset risks	Effective in glycemic control and weight management; requires monitoring for anemia
GLP-1RA/GIP dual agonists	Promotes weight loss, reduces hepcidin levels, improves iron metabolism	Effects on anemia risk not fully understood; potential benefits from improved iron status	Significant potential in T2DM and obesity management; further studies needed

SGLT2: Sodium-glucose cotransporter-2; CKD: Chronic kidney disease; GLP-1: Glucagon-like peptide-1; T2DM: Type 2 diabetes mellitus; GLP-1RA: Glucagon-like peptide-1 receptor agonist.

CONCLUSION

Anemia is a common hematologic condition among individuals with T2DM that significantly impacts their quality of life and contributes to the progression of diabetes-related complications. Newer therapeutic agents, such as SGLT-2 inhibitors, have shown promise not only in managing diabetes but also in improving anemia through their positive effects on blood parameters. Additionally, GLP-1 receptor agonists, known for their benefits in glycemic control and weight management, may also help reduce inflammatory markers and improve cardiovascular outcomes. These effects could indirectly aid in the management of anemia in T2DM patients. Given the increased risk of iron deficiency anemia in this population, regular monitoring of red blood cell indices and iron levels is essential. Early detection and timely intervention for anemia are crucial for mitigating complications, enhancing patient outcomes, and improving overall clinical management. Further research is needed to assess the hematologic benefits of newer therapies like SGLT-2 inhibitors and GLP-1 receptor agonists, as well as to establish evidence-based guidelines for screening, monitoring, and managing anemia. This could ultimately improve clinical outcomes and quality of life for patients with T2DM.