Case report: Metformin-induced hemolytic anemia in a glucose-6-phosphate dehydrogenase–deficient patient

Abstract

This case report describes a male patient in his early 60s with a documented history of glucose-6-phosphate dehydrogenase deficiency, who developed significant hemolytic anemia following the initiation of metformin therapy for newly diagnosed type 2 diabetes mellitus.

Introduction

Metformin is a widely used first-line medication for managing type 2 diabetes mellitus (T2DM), recognized for its efficacy and generally favorable safety profile. ¹ Its mechanism of action involves reducing hepatic glucose production, enhancing glucose uptake, and improving peripheral insulin sensitivity. ² Although these effects contribute to its efficacy in managing T2DM, metformin may cause rare but serious adverse effects in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. ³ G6PD deficiency, also known as favism, is one of the most common human enzymopathies affecting red blood cells. It results from an inherited X-linked gene mutation and affects more than 400 million people worldwide.^4,5 G6PD is an oxidoreductase enzyme that catalyzes the conversion of glucose-6-phosphate into 6-phosphoglucono-lactone while reducing nicotinamide adenine dinucleotide phosphate to nicotinamide adenine dinucleotide hydrogen phosphate, which is essential for regenerating reduced glutathione. This key antioxidant protects red blood cells from oxidative stress (Figure 1).^6,7

Figure 1.

The mechanism of G6PD-normal (a) versus G6PD-deficient red blood cells (b). ⁷ In normal red blood cells (cell A), G6PD and 6-phosphogluconate dehydrogenase produce sufficient NADPH for glutathione regeneration, crucial for managing reactive oxygen species (ROS). Conversely, red blood cells with reduced G6PD activity have compromised NADPH production, leading to insufficient glutathione regeneration. This results in oxidative damage and hemolysis when exposed to ROS-generating compounds such as divicine and isouramil (cell B). Genetic evidence supports glutathione’s role in protection against fava bean glucoside-induced oxidative stress. ⁷ G6PD: glucose-6-phosphate dehydrogenase; NADPH; nicotinamide adenine dinucleotide hydrogen phosphate.

However, in individuals with G6PD deficiency, the ability of red blood cells to counteract oxidative stress is impaired, increasing their susceptibility to hemolytic anemia, which may be triggered by the metabolic effects of metformin. ⁵ The potential risk of inducing a life-threatening condition highlights the importance of obtaining a comprehensive patient history and screening for G6PD deficiency prior to initiating metformin therapy, particularly in populations with a higher prevalence of this genetic disorder. Healthcare providers should remain vigilant for signs of hemolysis in patients with G6PD deficiency receiving metformin and consider alternative diabetes management strategies when necessary.

This case report details the clinical course of a male patient in his early 60s with G6PD deficiency who developed significant hemolytic anemia immediately after initiating metformin therapy, emphasizing the importance of awareness and prompt management in such cases.

Case presentation

Patient information

The patient was admitted to Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia, in February 2025. He presented with significant weakness, fatigue, shortness of breath, and dark urine, with a documented history of G6PD deficiency. His medical history included essential hypertension and sickle cell trait, and he had recently been diagnosed with T2DM. Notably, he had started metformin therapy (500 mg every 12 h) 2 days prior to the onset of his symptoms.

Clinical findings

On examination, the patient was pale and jaundiced, with vital signs showing a temperature of 38.4°C, blood pressure of 130/85 mmHg, pulse of 95 beats per minute, and a respiratory rate of 22 breaths per minute. Laboratory investigations revealed a hemoglobin level of 6.6 g/dL, markedly lower than his baseline level of 13.8 g/dL. Additionally, the patient had an elevated reticulocyte count, lactate dehydrogenase, and bilirubin levels. A negative Coombs test excluded autoimmune hemolysis as a potential etiology. Noncontrast computed tomography of the abdomen and pelvis revealed no evidence of underlying abdominal or pelvic pathology. Other causes of hemolysis were systematically excluded: the direct antiglobulin test was negative, platelets and coagulation profile were normal with no schistocytes, and there was no history of prosthetic valves or sickle crisis. Viral panels were negative, liver enzymes were normal, and hemolysis coincided with the initiation of metformin in the context of known G6PD deficiency.

Therapeutic intervention

The diagnosis of metformin-induced hemolytic anemia secondary to G6PD deficiency was established, prompting the indefinite discontinuation of metformin to prevent further hemolysis. Early discontinuation of metformin and initiation of supportive care—including three units of packed red blood cells, hydration, and close monitoring of hemoglobin levels—resulted in hematologic recovery. His diabetes management was adjusted, and transitioning to alternative antidiabetic agents (empagliflozin and sitagliptin) achieved excellent glycemic control with HbA1c levels decreasing from 12.9% to 5.5%, demonstrating the feasibility of safe pharmacological substitution.

Follow-up and outcomes

After discontinuing metformin, the patient exhibited gradual improvement in hemoglobin levels and a reduction in hemolytic markers over the subsequent weeks. Regular follow-up appointments were scheduled to monitor recovery and manage diabetes using alternative pharmacotherapy. Metformin rechallenge was not attempted due to ethical considerations.

Discussion

G6PD deficiency affects an estimated 400 million people worldwide and demonstrates marked regional variability. ⁸ Reported prevalence ranges from 5% to 30% in the Middle East and sub-Saharan Africa, 2%–15% in the Mediterranean and Southeast Asia, and <5% in northern Europe and North America. ⁸

This case underscores the rare yet significant risk of metformin-induced hemolytic anemia in patients with G6PD deficiency. Although metformin is a first-line therapy for T2DM and is generally well-tolerated, it has the potential to induce oxidative stress, leading to hemolysis in susceptible individuals. The rapid onset of symptoms in this patient following the initiation of metformin therapy corresponds with the existing literature describing a temporal association between metformin use and hemolytic events in G6PD-deficient populations. ⁵

The mechanisms underlying metformin-induced hemolysis remain inadequately understood; however, they are believed to involve increased oxidative stress, which G6PD-deficient erythrocytes cannot sufficiently mitigate. As G6PD deficiency is the most common inherited red blood cell enzyme disorder, healthcare providers should exercise heightened caution when prescribing metformin to populations with a high prevalence of this deficiency, particularly in regions such as Africa, Mediterranean Europe, the Middle East, Southeast Asia, and Latin America. ⁹

Early recognition of hemolytic anemia, characterized by low hemoglobin and elevated lactate dehydrogenase and bilirubin levels, is crucial for timely intervention. In this case, the patient’s recovery after metformin discontinuation emphasizes the importance of prompt management. Moreover, educating patients about their condition and potential triggers, including specific medications and dietary restrictions, can enhance self-management and help prevent future episodes.

In evaluating this patient, it was essential to systematically exclude other potential causes of hemolytic anemia. The negative Coombs test effectively excluded autoimmune hemolytic anemia, whereas the absence of infections, confirmed through negative infectious screenings, helped eliminate infectious etiologies. Furthermore, the absence of diabetic ketoacidosis (DKA), negative screenings for recent antibiotic use, and the patient’s careful dietary habits significantly reduced the likelihood of hemolysis from various common triggers, such as DKA, antibiotic-induced hemolysis, and fava bean consumption in G6PD deficiency. Consequently, metformin was identified as the most plausible etiology of hemolytic anemia. ⁸ In Saudi Arabia and neighboring countries, the prevalence exceeds 10%, underscoring the clinical significance of this disorder in these regions.

This case report provides valuable insights into the management of patients with G6PD deficiency and highlights the urgent need for increased awareness among healthcare professionals regarding the potential adverse effects of metformin in this population. It advocates for routine screening and careful monitoring of at-risk individuals to reduce the likelihood of severe complications associated with this medication. Routine G6PD screening before initiating metformin warrants stronger consideration in these populations. Screening is cost-effective when the prevalence exceeds 3%–5% and feasible when incorporated into baseline laboratory evaluations. ¹⁰ Pre-emptive identification of patients at risk for complications enables clinicians to prescribe safer and more effective medications, such as sodium–glucose cotransporter-2 inhibitors, which provide significant benefits for cardiovascular health and kidney disease prevention compared with older drugs such as dipeptidyl peptidase-4 inhibitors. ¹¹

Contributions to medical knowledge

This case underscores the rare yet significant risk of metformin-induced hemolytic anemia in patients with G6PD deficiency, a condition that may not be widely recognized by healthcare providers. It highlights the urgent need for increased awareness of this rare adverse effect as a potential complication, particularly in at-risk populations. Furthermore, this case serves as an educational resource for medical professionals, illustrating the intersection between diabetes management and inherited genetic enzyme deficiencies. This emphasizes the importance of considering patient-specific factors, such as enzyme deficiencies, when prescribing medications, thereby offering substantial educational value to healthcare providers.

Additionally, this report highlights the importance of obtaining comprehensive medication histories, including prescribed medications, dietary habits, and over-the-counter drugs. Such a thorough approach can help identify the potential triggers of hemolysis. This case also provides insights into effective management strategies for patients with G6PD deficiency who require diabetes treatment. It supports the use of alternative medications, thereby reinforcing the significance of personalized medicine.

Patient’s perspective

“When my doctor first mentioned starting me on metformin, I didn’t know that my glucose-6-phosphate dehydrogenase (G6PD) status could affect my safety. After learning I had a deficiency, I felt relieved this was detected before beginning treatment. It gave me peace of mind knowing my care team considered this risk and adjusted my plan accordingly. Screening may seem like a small step, but for patients like me, it makes a big difference in feeling safe and cared for.”

This reflection demonstrates how preventive screening not only reduces clinical risk but also enhances patient reassurance and trust.

Changes in clinical practice

We recommend implementing routine screening for G6PD deficiency in patients diagnosed with T2DM, particularly in populations with high prevalence. This proactive approach can prevent adverse drug reactions and improve patient outcomes. Moreover, we advocate updating clinical guidelines for managing diabetes in patients with known enzyme deficiencies. These updates should include specific recommendations for alternative medications and monitoring strategies.

We propose developing educational programs and resources for healthcare providers, focusing on the risks associated with various medications in patients with enzymatic disorders. These initiatives could include case studies, workshops, and continuing medical education opportunities.

Additionally, we encourage establishing patient education initiatives to inform individuals with G6PD deficiency about the risks associated with certain medications and the importance of promptly reporting adverse symptoms.

Finally, we stress the need for interdisciplinary collaboration among endocrinologists, hematologists, and primary care providers to ensure the comprehensive management of patients with complex conditions, including diabetes and G6PD deficiency.

This case report highlights the critical need for the awareness of metformin’s potential to induce hemolytic anemia in patients with G6PD deficiency. Given the rarity of this adverse effect, healthcare providers must remain vigilant when prescribing metformin to patients with known enzymatic deficiencies. Early diagnosis and timely discontinuation of the offending medication are essential for effective management and recovery. This case reinforces the importance of patient education regarding G6PD deficiency and the need to monitor potential drug interactions to ensure safe diabetes management.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605251387872 - Supplemental material for Case report: Metformin-induced hemolytic anemia in a glucose-6-phosphate dehydrogenase–deficient patient

Supplemental material, sj-pdf-1-imr-10.1177_03000605251387872 for Case report: Metformin-induced hemolytic anemia in a glucose-6-phosphate dehydrogenase–deficient patient by Alaa M Salamat, Hani M Ammar, Ahmed I Alsagheir and Hayat S Mushcab in Journal of International Medical Research