Metformin-associated lactic acidosis in an elderly diabetic patient without classical risk factors: a case report

Abstract

Metformin is a cornerstone medication and first-line therapy for type 2 diabetes mellitus (T2DM), with a well-established safety profile and widespread use over many years. Its most common adverse effects are gastrointestinal in nature. However, the drug carries a rare but serious risk of lactic acidosis. Recognized risk factors for metformin-associated lactic acidosis (MALA) include renal or hepatic impairment, excessive alcohol consumption, poorly controlled diabetes, ketosis, prolonged fasting, and conditions predisposing to hypoxia. This paper presents a case of MALA in a 75-year-old patient with T2DM and schizophrenia who lacked any typical risk factors. This case underscores the importance of maintaining a high index of suspicion for this potentially fatal complication in all patients taking metformin. Early recognition and prompt intervention are critical to improving clinical outcomes.

Plain language summary

A case report: a serious complication in an elderly diabetes patient taking common medication, without known triggers

Metformin is the most common and trusted first-choice medicine for type 2 diabetes. It is generally safe, with stomach problems being its main side effect for most people. However, in very rare cases, it can cause a serious condition where too much lactic acid builds up in the blood, called metformin-associated lactic acidosis (MALA). Doctors know that certain things make this complication more likely, such as kidney or liver problems, heavy drinking, very high blood sugar, starvation, or serious illnesses that affect breathing. This article describes the case of a 75-year-old patient with type 2 diabetes and schizophrenia who developed MALA. What makes this case notable is that she did not have any of the common risk factors mentioned above. This story reminds us that even patients who seem low-risk can develop this dangerous complication. It is crucial for both doctors and patients to be aware of this possibility. Spotting the warning signs early and acting quickly are the most important steps to saving a patient’s life.

Introduction

Metformin is the first-line pharmacological treatment of choice and the most widely prescribed medication for type 2 diabetes mellitus (T2DM) worldwide.^1–3 It is highly regarded for its potent glucose-lowering efficacy, favorable safety profile, cost-effectiveness, and potential cardiovascular benefits. ⁴ The mechanisms through which metformin exerts its antihyperglycemic effects are complex and multifactorial, primarily involving the inhibition of hepatic gluconeogenesis, enhancement of peripheral insulin sensitivity, and delayed intestinal glucose absorption. ⁵ In addition, various cellular and molecular pathways through which metformin exerts its effects continue to be investigated.^6,7 The drug is generally well-tolerated; most adverse effects are mild and transient, typically occurring during the initial treatment phase. Gastrointestinal disturbances, such as nausea, vomiting, diarrhea, abdominal discomfort, loss of appetite, and a metallic taste, are the most frequently reported side effects. ⁸

It is important to note, however, that metformin use is associated with a rare but serious adverse event: metformin-associated lactic acidosis (MALA). Recognized risk factors for MALA include renal impairment, conditions predisposing to tissue hypoxia (e.g., severe heart failure, significant infection, acute myocardial infarction, and chronic respiratory failure), excessive alcohol consumption, and liver disease. Common symptoms of MALA include nausea, vomiting, fatigue, drowsiness, decreased body temperature, as well as severe acute manifestations such as vision loss.^9,10 Timely and appropriate symptomatic treatment is crucial for the recovery from MALA. This article presents a case of MALA in a patient with chronic schizophrenia and T2DM, who did not exhibit obvious predisposing factors or typical symptoms of MALA and benefited from timely lactate level monitoring. This case highlights the importance of vigilance for MALA in elderly patients with underlying conditions such as cardiovascular and cerebrovascular diseases when treated with metformin.

Case presentation

As shown in the Supplemental File 1, the reporting of this study conforms to the CARE statement. ¹¹ A 75-year-old female patient has been receiving long-term inpatient care in the Geriatric Psychiatry Unit of the Mental Health Center at Affiliated Xiaoshan Hospital, Hangzhou Normal University. Her medical history includes chronic schizophrenia, essential hypertension, myocardial injury, and cerebral ischemic foci. Around the age of 40, following an interpersonal conflict, the patient began experiencing progressively worsening sleep disturbances, developed persecutory delusions that others intended to harm her, and started reporting auditory hallucinations of voices talking to her, along with exhibiting verbal aggression toward unseen entities. She was initially diagnosed with schizophrenia in the outpatient clinic of our hospital and was subsequently maintained on antipsychotic medications with periodic follow-ups, though her symptoms fluctuated over the years. In 2020, her condition deteriorated significantly: she refused food and medication, consumed only minimal water, remained in bed for most of the day, withdrew from social interactions, and engaged in prominent self-talk. Since the patient was hospitalized in our hospital in 2020, her symptoms have been basically stable, with occasional sleep disorders accompanied by intermittent strange behaviors. Her current regimen includes olanzapine and quetiapine.

The patient’s current diagnoses include chronic schizophrenia, primary hypertension, T2DM, myocardial injury, cerebral ischemic focus, constipation, cough variant asthma, and a left femoral neck fracture. The medication regimen consists of metformin tablets at 1 g twice daily, olanzapine tablets at 12.5 mg once daily, quetiapine tablets at 0.6 g once daily, valsartan capsules at 80 mg once daily, atorvastatin calcium tablets at 20 mg once daily, trimetazidine tablets at 20 mg three times daily, omeprazole enteric-coated capsules at 20 mg once daily, celecoxib capsules at 0.2 g twice daily, montelukast sodium tablets at 10 mg once daily, lactulose oral solution at 15 mL once daily, and lorazepam tablets at 1.5 mg once daily. Laboratory findings on August 10, 2025, revealed the following: Liver function tests showed a reduced globulin level of 23.9 g/L. Lipid profile indicated mild dyslipidemia, with total cholesterol at 2.70 mmol/L, LDL cholesterol at 1.31 mmol/L, and apolipoprotein B at 0.42 g/L; all other parameters were within normal limits. On August 12, elevated whole-blood lactate was detected at 4.4 mmol/L, accompanied by oxygen saturation fluctuating around 92%. Coagulation studies and D-dimer testing showed a prolonged partial thromboplastin time of 44.4 s and a reduced standardized prothrombin time ratio of 0.84. Arterial blood gas analysis under actual body temperature conditions revealed acidosis (pH 7.329), mildly reduced partial pressure of oxygen (82.1 mmHg), hyponatremia (135.0 mmol/L), hyperchloremia (122.0 mmol/L), elevated standardized ionized calcium (1.13 mmol/L), and a reduced anion gap (−10.2 mmol/L). Follow-up testing on August 13 showed persistent metabolic disturbances: whole-blood lactate increased to 5.2 mmol/L, pH decreased to 7.312, extracellular base excess was –3.3 mmol/L, actual base excess was –3.7 mmol/L, standard bicarbonate was 21.3 mmol/L, sodium remained low at 135.0 mmol/L, chloride was 116.0 mmol/L, ionized calcium was 1.1 mmol/L, fasting blood glucose was 6.4 mmol/L, and postprandial glucose levels were 8.0, 8.9, and 6.8 mmol/L after meals, and the anion gap was −3.1 mmol/L. By August 14, the whole-blood lactate had further increased to 7.2 mmol/L, pH had further dropped to 7.299, and the anion gap was −3.2 mmol/L.

During the clinical course, the patient’s liver function was normal, with all relevant biochemical markers within the reference range. Renal function was also preserved, as indicated by an estimated glomerular filtration rate (eGFR) of 92.6 mL/(min·1.73 m²) on August 10 and 82.2 mL/(min·1.73 m²) on August 14, and 91.5 mL/(min·1.73 m²) on August 26; the eGFR in this study was calculated using the modified Modification of Diet in Renal Disease (MDRD) formula. ¹² And the serum creatinine levels on August 10, August 14, and August 26 were 65.4, 72, and 66 μmol/L, respectively. Considering the patient’s metformin therapy, the presence of a blood lactate concentration exceeding 5 mmol/L, and a pH below 7.35—alongside the exclusion of other potential causes of lactic acidosis—the association between metformin and the lactic acidosis in this case was assessed as “probable” according to the World Health Organization - Uppsala Monitoring Centre (WHO-UMC) causality assessment criteria. Several key differential diagnoses were systematically ruled out. First was diabetic ketoacidosis, characterized by the classic triad of marked hyperglycemia (typically >13.9 mmol/L), significant ketonemia/ketonuria, and an elevated anion gap; it was excluded due to the patient’s relatively well-controlled blood glucose and negative urine ketones. The second possibility, type A lactic acidosis, which is driven by clear tissue hypoxia or hypoperfusion (e.g., shock, severe anemia, heart failure, or carbon monoxide poisoning), was dismissed given the absence of such clinical conditions. Finally, hepatic failure, wherein lactate accumulation results from impaired hepatic clearance, was excluded as there were no clinical signs or laboratory evidence of underlying liver disease or significant hepatic dysfunction.

The medical treatment and management measures were as follows: after elevated blood lactate levels were detected on August 12 and August 13, the patient was managed with a daily intravenous infusion of 500 mL of 0.9% sodium chloride injection for volume expansion, along with supplemental oxygen administered via nasal cannula. Starting from August 14, metformin tablets were discontinued, and the patient was treated once daily with a glucose-insulin-potassium (GIK) solution consisting of 500 mL of 5% glucose injection, 4 units of insulin injection, and 10 mL of potassium chloride injection, administered intravenously until August 20. Following the discontinuation of metformin and the corresponding treatment, the patient’s whole-blood lactate level declined rapidly: it decreased to 2.1 mmol/L by August 15 and further dropped to 1.6 mmol/L by August 19. As of December 15th, the patient’s blood lactate levels have remained normal, liver and kidney function are stable, and there has been no recurrence of MALA.

Discussion

MALA is a rare but serious adverse drug reaction. Its early manifestations typically include fatigue, nausea, vomiting, abdominal pain, deep and rapid breathing (Kussmaul respirations), drowsiness, and even coma, which can be life-threatening in severe cases. There have also been reports of MALA leading to acute vision loss, with improvement following prompt and active treatment.^9,10 In the present case, the patient did not exhibit the obvious typical symptoms mentioned above, presenting only with a decline in oxygen saturation. We believe this may be related to the timely monitoring of lactate levels and the subsequent immediate intervention the patient received. On the other hand, as the patient has chronic schizophrenia, their impaired ability to articulate symptoms may have contributed to the lack of reported classic complaints. This case underscores the importance of routine lactate level monitoring in patients treated with metformin.

From a pathophysiological perspective, metformin primarily acts by inhibiting mitochondrial electron transport chain complex I, which reduces Adenosine Triphosphate (ATP) synthesis and increases the cytoplasmic Adenosine Diphosphate (ADP)/ATP ratio, thereby activating the glycolytic pathway. This process promotes the generation of pyruvate, which—under hypoxic conditions—is extensively converted to lactate.^13,14 Concurrently, metformin suppresses hepatic gluconeogenesis, a major pathway for lactate clearance. Under normal physiological conditions, these two effects remain balanced; however, in vulnerable individuals, this equilibrium can be readily disrupted. The present patient likely had underlying microcirculatory dysfunction and compromised tissue oxygen delivery. Although these conditions did not meet the diagnostic criteria for conventional “hypoxic diseases,” they were sufficient to disrupt lactate metabolism, particularly under the influence of metformin. Therefore, this case offers several important insights for clinical practice. First, it demonstrates that MALA can occur even in the absence of classic contraindications, particularly in elderly patients with complex comorbidities—especially those with subclinical cardiovascular insufficiency. Such patients may exist in a “subclinical” at-risk state that conventional screening indicators may fail to detect. Second, it highlights the necessity of implementing individualized treatment strategies in older adults with polypharmacy, taking into account potential risk factors such as age-related physiological decline, underlying chronic conditions, and drug interactions. Third, it serves as a critical reminder that clinicians should focus not only on glycemic control but also on the patient’s overall condition, including fluid-electrolyte balance, oxygenation status, and tissue perfusion.

In this case study involving an elderly patient with type 2 diabetes and comorbid chronic schizophrenia, the occurrence of MALA in the absence of significant hepatic or renal dysfunction suggests a susceptibility rooted in a multi-layered state of metabolic vulnerability that extends beyond classical mechanisms of organ impairment. Primarily, the patient’s underlying schizophrenia and advanced age inherently predispose individuals to insulin resistance, chronic low-grade inflammation, and subtle mitochondrial dysfunction, collectively establishing a foundational metabolic disturbance.^15–17 Secondly, the long-term use of atypical antipsychotic medications such as olanzapine or quetiapine, which act as antagonists at 5-Hydroxytryptamine (5-HT) receptors, significantly exacerbates weight gain, insulin resistance, and skeletal muscle fat infiltration. ¹⁸ This not only further compromises systemic insulin sensitivity but may also reduce lactic acid metabolic capacity in muscle tissue, while their sedative effects could potentially induce relative tissue hypoperfusion or concealed hypoxia during acute illness. Within this context, although metformin does not directly cause toxicity, its core pharmacological action of inhibiting hepatic gluconeogenesis through mild suppression of the mitochondrial respiratory chain may serve as a critical second hit to a pre-existing state of subclinical metabolic stress. When confronted with acute triggers such as infection or dehydration, the body’s surging demand for energy metabolism exposes these synergistic multi-system defects—including increased lactate production in muscle, potentially insufficient hepatic metabolic reserve, and possible microcirculatory compromise—which together lower the threshold for maintaining lactate homeostasis, thereby enabling the onset of severe lactic acidosis even in the absence of overt abnormalities in routine hepatic or renal function tests. Consequently, for patients with schizophrenia treated with olanzapine or quetiapine, their profound systemic metabolic dysregulation constitutes a high-risk background condition that necessitates heightened vigilance when prescribing metformin or managing acute intercurrent illnesses, even in the presence of normal routine liver and kidney function tests.

Based on the present case study and existing evidence, we strongly recommend that a systematic and proactive risk management strategy must be established for elderly patients with cardiovascular disease who are prescribed metformin. The core of this strategy lies in recognizing that such patients occupy a unique and high-risk continuum shaped by the convergence of age-related decline in renal function, the underlying predisposition to tissue hypoperfusion from cardiovascular disease, and the influence of multiple concomitant medications. Regular monitoring of the eGFR, rather than relying solely on serum creatinine, serves as the cornerstone for assessing the basis of metformin excretion and achieving dose individualization. While routine blood lactate monitoring is not advised for stable patients, it should be considered a critical diagnostic tool during any episode of acute clinical deterioration. Crucially, risk management must extend beyond static laboratory tests and be dynamically integrated throughout the patient’s entire clinical course. Any acute physiological stressor, such as infection, dehydration, acute heart failure, or myocardial infarction, can abruptly disrupt the fragile metabolic equilibrium by potentially causing a rapid decline in renal function through hypotension, diuretic use, or renal hypoperfusion, leading to metformin accumulation, while simultaneously increasing systemic lactate production due to enhanced anaerobic metabolism in tissues from reduced cardiac output or hypoxia. The convergence of these two pathways during periods of stress significantly elevates the risk of lactic acidosis. Therefore, clinical vigilance should focus on early, nonspecific warning signs. Patients and caregivers must be clearly informed that new or unexplained progressive fatigue, drowsiness, loss of appetite, nausea, abdominal discomfort, or mild confusion may not simply be signs of “aging” or minor issues, but could be early manifestations of life-threatening metabolic acidosis. Therefore, comprehensive care for elderly patients with T2DM is particularly important. ¹⁹ Personalized risk assessment grounded in this understanding necessitates that clinicians proactively perform a tripartite evaluation during every prescription review and acute care visit, encompassing the current renal function status, the presence of any acute precipitating factors, and the existence of the aforementioned warning symptoms. This proactive, symptom-driven monitoring and assessment model aims to effect a paradigm shift from treating crises after the fact to preventing risks beforehand, which is of fundamental importance for ensuring medication safety in this vulnerable population.

The findings and conclusions of this study are subject to several important limitations. First, as a single case report, the results lack statistical generalizability, and the observed associations may be influenced by unmeasured confounding factors specific to this patient, such as particular genetic background, insufficiently documented dietary or lifestyle habits, or the concurrent use of other over-the-counter medications. Second, the inherently retrospective and observational nature of the study design precludes the establishment of a direct causal relationship between schizophrenia, specific antipsychotic medications like olanzapine or quetiapine, and MALA, allowing only for the proposal of a pathophysiologically plausible associative hypothesis. Third, although we focused on discussing the potential mechanisms of metabolic and drug interactions, it was not possible to quantify the specific contribution of each individual risk factor, such as the degree of insulin resistance or the presence of subclinical mitochondrial dysfunction. Furthermore, the diagnosis in this case relied primarily on clinical presentation and laboratory findings, lacking histological or more advanced metabolomic evidence that could have precisely delineated the patient’s pre-morbid metabolic state.

Conclusion

This case enriches our understanding of MALA—a rare yet life-threatening complication—by delineating its clinical course in a patient without traditional risk factors. It underscores the critical importance of personalized medication management and ongoing risk assessment in patients with complex comorbidities. Furthermore, it highlights the necessity for clinicians to maintain a high index of suspicion for MALA in all patients prescribed metformin, urging timely recognition and intervention upon early signs to improve patient outcomes.

Supplemental Material

sj-docx-1-taw-10.1177_20420986261428996 – Supplemental material for Metformin-associated lactic acidosis in an elderly diabetic patient without classical risk factors: a case report

Supplemental material, sj-docx-1-taw-10.1177_20420986261428996 for Metformin-associated lactic acidosis in an elderly diabetic patient without classical risk factors: a case report by Yali Zheng, Jia Sun, Peng Zhang and Quanfeng Zhu in Therapeutic Advances in Drug Safety