Concurrent metformin-associated lactic acidosis and euglycemic diabetic ketoacidosis from tirzepatide starvation ketosis

Abstract

Summary

We describe a case of concurrent metformin-associated lactic acidosis (MALA) and euglycemic diabetic ketoacidosis (EDKA) in a 64-year-old woman with type 2 diabetes mellitus (T2DM) treated with metformin and tirzepatide who presented with shock, encephalopathy, and severe high anion gap metabolic acidosis after two weeks of markedly reduced oral intake following tirzepatide dose escalation. While incretin-based therapies, including dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonists (GIP/GLP-1 RAs) such as tirzepatide, are highly effective for glycemic control and weight management, gastrointestinal (GI) adverse effects may lead to prolonged caloric restriction and starvation physiology. In this patient, starvation ketosis progressed to EDKA, while concurrent dehydration and acute kidney injury (AKI) impaired metformin clearance, resulting in MALA with markedly elevated lactate. The patient required endotracheal intubation, vasopressor support, and continuous renal replacement therapy (CRRT), with rapid clinical and metabolic improvement following discontinuation of metformin and tirzepatide. This case highlights the potential for severe overlapping metabolic complications involving starvation-related ketoacidosis, dehydration, AKI, and impaired metformin clearance when incretin-based therapies are continued during prolonged poor oral intake.

Learning points

• Prolonged GI intolerance from incretin-based therapies (GIP/GLP-1 receptor agonists) can precipitate severe metabolic decompensation, particularly when associated with reduced oral intake and dehydration.

• Starvation ketosis in patients with diabetes may progress to EDKA during periods of prolonged caloric restriction or gastrointestinal intolerance.

• Severe ketonemia (β-hydroxybutyrate > 6 mmol/L) with only modest hyperglycemia should prompt evaluation for EDKA rather than isolated starvation ketosis.

• AKI and volume depletion significantly increase the risk of MALA due to impaired drug clearance.

• Early recognition of reduced oral intake or acute illness should prompt reassessment and temporary discontinuation of metformin and incretin-based therapies to prevent life-threatening metabolic complications.

• Patients receiving tirzepatide or other incretin-based therapies should receive counseling regarding sick-day management and temporary discontinuation of metformin during periods of vomiting, dehydration, or markedly reduced oral intake.

Background

GIP/GLP-1 RAs have become integral to the management of T2DM and obesity. Tirzepatide is currently FDA-approved as Mounjaro for improving glycemic control in T2DM and as Zepbound for chronic weight management in patients with obesity or overweight with weight-related comorbidities, as well as obstructive sleep apnea in adults with obesity. Their therapeutic benefits are mediated largely through GLP-1 receptor agonist (GLP-1 RA) effects, including delayed gastric emptying, appetite suppression, and early satiety, which frequently result in nausea and reduced oral intake (1, 2). While these effects are often transient, persistent GI intolerance may lead to dehydration and metabolic stress. Severe caloric restriction may induce starvation ketosis through reduced insulin signaling and increased counterregulatory hormone activity. In patients with diabetes, starvation-driven ketogenesis may exceed physiologic adaptive ketosis and progress to ketoacidosis despite only modest hyperglycemia (3).

MALA is a rare but life-threatening complication, typically occurring in the setting of renal impairment, hypoperfusion, or dehydration (4, 5). Starvation ketosis and EDKA have also been described in association with GLP-1 receptor agonists, particularly when caloric intake is markedly reduced (6, 7, 8). To our knowledge, reports describing the simultaneous occurrence of MALA and GIP/GLP-1 RA-associated starvation ketosis progressing to EDKA remain extremely limited.

Case presentation

A 64-year-old female with a history of insulin-dependent T2DM diagnosed in 2015, hypertension, hypothyroidism, chronic pain, and schizoaffective disorder presented to the emergency department with shortness of breath, altered mental status, and hypotension. At presentation, her weight was 77.1 kg (170 lbs), height was 1.63 m, and body mass index was 29.0 kg/m². Her schizoaffective disorder was managed outpatient with Aristada long-acting injectable therapy. There were no documented recent psychiatric medication changes or clear psychiatric decompensation preceding presentation. Prior to admission, her outpatient diabetes regimen included metformin 1,000 mg twice daily, tirzepatide 10 mg weekly, insulin degludec 30 units nightly, and insulin aspart 10 units with meals. She was not taking a sodium–glucose cotransporter-2 (SGLT2) inhibitor and had no prior history of SGLT2 inhibitor use. The family reported a two-week history of reduced oral intake associated with persistent nausea and early satiety following tirzepatide dose escalation. Tirzepatide was increased from 7.5 mg weekly to 10 mg weekly approximately two weeks prior to presentation. During tirzepatide therapy, her weight decreased from 96.2 kg in November 2024 to 73.5 kg by November 2025, representing a 22.7-kg (50-lb) reduction and supporting a significant weight loss in the setting of reduced oral intake and caloric restriction.

On presentation, she was hypothermic, tachypneic, acutely ill, and encephalopathic with dry mucous membranes and diffuse lower extremity mottling, concerning for shock. Neurologic examination demonstrated stupor with inconsistent command following. The remainder of the physical examination was unremarkable. Given worsening mental status and severe metabolic derangements, she was intubated for airway protection and admitted to the intensive care unit (ICU).

Investigation

Initial laboratory evaluation (Table 1) showed an arterial blood gas, which demonstrated profound metabolic acidosis with pH < 6.82, HCO₃⁻ 5.3 mmol/L, and base excess −20. The anion gap was >38 mmol/L at presentation and improved to 12 mmol/L approximately 24 h after the initiation of CRRT and supportive management. Serum CO₂ on arrival was <6 mmol/L and improved to 18 mmol/L approximately 24 h later. Whole blood lactate was markedly elevated at 23 mmol/L. Serum chemistry revealed sodium 129 mmol/L, potassium 6.2 mmol/L, chloride 90 mmol/L, blood urea nitrogen 81 mg/dL, and creatinine 7.07 mg/dL. Her baseline creatinine was approximately 1.0 mg/dL, supporting AKI rather than chronic renal dysfunction as the precipitating factor for reduced metformin clearance. Serum glucose ranged from 113 to 229 mg/dL. β-hydroxybutyrate was significantly elevated at 6.67 mmol/L, and urinalysis demonstrated large ketonuria, supporting a ketoacidotic process. Urinalysis was not concerning for urinary tract infection, with no significant leukocyturia, nitrites, or bacteriuria.

Table 1.

Relevant laboratory values on admission and approximately 24 h after admission.

Laboratory tests	On admission	24 h post-admission	Reference
Arterial blood gas
pH	<6.82	7.36	7.35–7.45
Arterial HCO3− (mmol/L)	5.3	18.3	21–28
PaCO2 (mmHg)	31.5	32.1	32–48
PaO2 (mmHg)	35.9	122.0	83–108
Serum chemistry
Sodium (mmol/L)	129	135	136–145
Potassium (mmol/L)	6.2	4.7	3.6–5.1
Chloride (mmol/L)	90	98	98–107
CO2 (mmol/L)	<6	18	22–32
Anion gap	>38	12	8–18
Glucose (mg/dL)	209	163	70–99
BUN (mg/dL)	81	38	8–20
Creatinine (mg/dL)	7.07	2.69	0.60–1.30
Whole blood lactate (mmol/L)	23	3.3	0.5–2.0
Complete blood count
White blood cell count (K/mcL)	17.2	10.2	4.6–10.2
Red blood cell count (M/mcL)	3.29	2.51	3.74–5.34
Hemoglobin (g/dL)	10.6	8.0	12–16
Hematocrit (%)	34.20	22.40	34.3–47.9
Platelets (K/mcL)	429	178	142–424
Other laboratory findings
β-hydroxybutyrate (mmol/L)	6.67	N/A	<=0.30

The measured serum osmolality was 329 mOsm/kg with a calculated osmolal gap of 30.0 mOsm/kg. Ethanol and volatile alcohol screening, including methanol, ethylene glycol, acetone, and isopropanol, was negative. Blood cultures obtained on admission were initially negative. A single blood culture drawn three days after admission grew gram-positive organisms, which was felt to represent contamination, as the patient was clinically improving and had been weaned off vasopressor support at the time of culture positivity. No clear infectious source was identified on computed tomography (CT) of the head, chest, abdomen, or pelvis. Thyroid-stimulating hormone was within normal range at 0.44 mIU/L. Serum cortisol was >120 μg/dL, arguing against adrenal insufficiency as the primary etiology of shock or encephalopathy. Lipase levels were within normal limits, and CT imaging demonstrated no radiographic evidence of pancreatitis.

The differential diagnosis for severe high anion gap metabolic acidosis included toxic alcohol ingestion, septic shock with lactic acidosis, classic diabetic ketoacidosis, starvation ketosis, and MALA. Toxic ingestion was considered given the elevated osmolal gap but was excluded by negative volatile alcohol testing. The combination of severe hyperlactatemia, AKI, and ongoing metformin exposure was most consistent with MALA, while significant ketonemia with only modest hyperglycemia supported concurrent EDKA in the setting of starvation physiology. The degree of ketonemia was disproportionate to the level of hyperglycemia and exceeded what is typically observed in isolated starvation ketosis, supporting pathologic ketoacidosis rather than physiologic starvation alone. Serum insulin, C-peptide, and latent autoimmune diabetes in adults (LADA) levels were not obtained; however, the presence of marked ketonemia with modest hyperglycemia and the absence of a prior history of diabetic ketoacidosis further support an acute ketoacidotic process rather than baseline insulin deficiency or isolated starvation ketosis.

Serum insulin, C-peptide, and pancreatic autoantibody testing were not obtained during hospitalization, and latent autoimmune diabetes in adults (LADA) could not be definitively excluded. However, the patient had a long-standing history of T2DM without prior documented diabetic ketoacidosis and developed ketoacidotic physiology in the setting of profound caloric restriction following tirzepatide dose escalation.

Treatment

The patient required endotracheal intubation, vasopressor support, and empiric broad-spectrum antimicrobial therapy. She received sodium bicarbonate 150 mEq in 5% dextrose (D5W) administered at 100 mL/hour for severe metabolic acidosis. Supportive care included aggressive volume resuscitation, glucose-containing intravenous fluids, and close monitoring of electrolyte levels and serum glucose. CRRT was initiated for refractory metabolic acidosis, hyperkalemia, and AKI and was required for two days. Metformin and tirzepatide were discontinued. Given severe ketonemia and ongoing ketoacidotic physiology despite only modest hyperglycemia, insulin therapy was initiated using a reduced-dose subcutaneous regimen with regular insulin 10 units, as insulin degludec was not available on the hospital formulary. She was subsequently transitioned to insulin glargine with insulin lispro sliding-scale coverage. Subcutaneous insulin was selected to suppress ketogenesis while minimizing hypoglycemia risk and allowing dose titration based on frequent glucose and electrolyte monitoring. Intravenous insulin infusion was deferred due to concern for rapid hypoglycemia in the setting of euglycemia, concurrent dextrose administration, and improving metabolic parameters following initiation of CRRT and bicarbonate therapy. Given concern for dehydration-associated MALA, metformin was permanently discontinued.

Outcome and follow-up

Following initiation of CRRT and cessation of metformin and tirzepatide, lactate levels rapidly declined, the anion gap closed, and acid–base status normalized. Renal function improved, allowing discontinuation of CRRT. The patient was successfully extubated and weaned off vasopressors. She was discharged with endocrinology follow-up and advised to avoid future use of metformin and GIP/GLP-1 RAs.

Discussion

GIP/GLP-1 RAs have gained increasing popularity due to their favorable effect profile of regulating blood glucose and oral intake. These widely used agents are commonly prescribed to diabetic patients, with well-known potential for mild GI side effects, but can also lead to serious side effects, such as pancreatitis, retinopathy, increased risk of medullary thyroid carcinoma in animal studies, and kidney injury (9). EDKA has been increasingly reported in association with tirzepatide and other GLP-1 receptor agonists, particularly in the setting of severe caloric restriction or prolonged gastrointestinal intolerance. However, starvation ketosis progressing to EDKA in conjunction with MALA presents a novel critical care case.

Tirzepatide is a dual incretin receptor agonist targeting both the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors. It enhances glucose-dependent insulin secretion, suppresses glucagon secretion, delays gastric emptying, and reduces appetite. These combined effects can result in significant caloric restriction, particularly during dose escalation, which may predispose susceptible patients to starvation physiology and ketogenesis (10). Metformin primarily lowers glucose through suppression of hepatic gluconeogenesis and inhibition of mitochondrial respiratory chain complex I, with additional effects on mitochondrial glycerophosphate dehydrogenase (10). These mechanisms reduce hepatic glucose production but, in the setting of renal dysfunction or hypoperfusion, may contribute to lactate accumulation and MALA.

The incidence of MALA is typically between 1 and 9 cases per 100,000 (4). MALA is most commonly observed in two clinical settings, metformin overdose, either intentional or accidental, and therapeutic use in the setting of acute illness or renal dysfunction. It typically occurs via the suppression of complex 1 in the mitochondrial respiratory chain and increasing serum lactate secondary to interference with the metabolism of pyruvate via inhibition of pyruvate carboxylase (10). The increase in lactic acid and hydrogen ions from the inhibition of complex 1 may lead to a life-threatening acidotic state.

Several objective findings strengthen the proposed synergistic metabolic model. The patient experienced rapid weight loss over a short interval, supporting severe caloric restriction and starvation physiology. AKI developed from a baseline creatinine of approximately 1.0 to 7.07 mg/dL on presentation, markedly reducing metformin clearance. Rapid correction of bicarbonate and anion gap abnormalities within 24 h of CRRT initiation and medication cessation further supports MALA with concurrent ketoacidosis rather than isolated shock-related hyperlactatemia or toxin exposure.

We propose an overlapping metabolic interaction rather than a strictly sequential cascade. GIP/GLP-1 RA-related GI intolerance likely produced severe caloric restriction and starvation physiology promoting ketogenesis, while concurrent dehydration and AKI reduced metformin clearance and increased the risk of MALA. These overlapping metabolic stressors likely amplified one another, resulting in profound acidemia and shock. The markedly elevated lactate level, severe AKI, continued metformin exposure, and rapid lactate clearance following CRRT strongly support a diagnosis of MALA rather than isolated shock-related hyperlactatemia (4, 5). Additionally, metformin is readily dialyzable, and CRRT likely facilitated accelerated drug clearance and rapid correction of acidemia and hyperlactatemia.

This case underscores how prolonged GIP/GLP-1 RA-related GI intolerance can precipitate severe metabolic complications. Two weeks of markedly reduced oral intake likely produced starvation physiology and ketogenesis, contributing to EDKA, while concurrent dehydration and AKI reduced metformin clearance and increased the risk of MALA. The combination resulted in profound metabolic acidosis with an elevated osmolal gap. In this case, negative toxicology screening and rapid biochemical correction following CRRT supported the conclusion that endogenous acid accumulation, rather than exogenous toxin exposure, was the cause. Clinically, prolonged nausea, early satiety, or markedly reduced oral intake should prompt reassessment of concurrent metformin and GLP-1-based therapies until nutritional status and renal function are assured. This case also highlights the importance of counseling patients regarding sick-day protocols and temporary discontinuation of metformin during periods of dehydration, vomiting, or inability to tolerate adequate oral intake. Early recognition may prevent progression to severe multisystem metabolic decompensation.

A major limitation of this case is that serum insulin, C-peptide, and pancreatic autoantibody testing were not obtained during hospitalization. Therefore, latent autoimmune diabetes in adults could not be definitively excluded. As a result, this case cannot establish a direct causal relationship between tirzepatide and EDKA. Rather, it highlights a clinically important association between GIP/GLP-1 receptor agonist therapy, prolonged gastrointestinal intolerance, severe caloric restriction, and possible EDKA in a patient with diabetes. Although the patient had a long-standing diagnosis of type 2 diabetes without prior documented diabetic ketoacidosis, unrecognized insulin deficiency remains a potential contributing factor. The findings should therefore be interpreted as supportive of an overlapping metabolic process involving starvation physiology, ketogenesis, dehydration, AKI, and impaired metformin clearance, rather than definitive proof of tirzepatide-induced EDKA.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Informed patient consent for publication

Written informed consent for publication of their clinical details was obtained from the patient.

Author contribution statement

FE conceived and supervised the study. All authors were involved in data collection and drafted and critically revised the manuscript. All authors read and approved the final version of the manuscript. FE is the article guarantor.

Data availability

Original data generated and analyzed during this study are included in this published article.