The First Report of Tirzepatide-Induced Diabetic Ketoacidosis in Latent Autoimmune Diabetes in Adults

1. Introduction and Clinical Significance

Latent autoimmune diabetes in adults (LADA) is an autoimmune form of diabetes characterized by diabetes-associated autoantibodies, most commonly glutamic acid decarboxylase antibodies (GADA/GAD65), in adults who do not require insulin at diagnosis. It accounts for approximately 2–12% of adult-onset diabetes cases and is often misdiagnosed as T2DM because of its initial insulin-independent presentation and phenotypic overlap, including overweight or obesity in many patients. Progressive autoimmune beta-cell destruction leads to declining C-peptide levels and eventual insulin dependence, placing LADA patients at inherent risk for diabetic ketoacidosis (DKA) [1,2].

Tirzepatide is a first-in-class dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist approved for glycemic control in T2DM and for chronic weight management in adults with obesity [3]. Its prescribing information states that it is not indicated for use in patients with T1DM but does not specifically address LADA. Notably, a post hoc analysis of the SURPASS 2–5 trials found that tirzepatide improved HbA1c and body weight in GADA-positive individuals, with efficacy comparable to that in GADA-negative participants, potentially supporting off-label use in this population [4].

However, the risk of DKA with incretin-based therapies in autoimmune diabetes remains poorly characterized. Although the international expert consensus on LADA management warns of DKA risk with sodium-glucose cotransporter 2 (SGLT2) inhibitors and recommends autoantibody testing before initiating them, analogous warnings for incretin-based therapies are absent [5,6]. Only one case of GLP-1 receptor agonist–induced DKA in LADA has been reported: a patient who developed DKA after initiation of dulaglutide during concurrent insulin discontinuation [7]. Pharmacovigilance analyses of the FDA Adverse Event Reporting System (FAERS) have identified emerging signals for tirzepatide-associated ketoacidosis, with starvation ketoacidosis generating the strongest signal [8,9,10].

No cases of tirzepatide-induced DKA in LADA have been published. To our knowledge, we present the first such case, which is particularly noteworthy because DKA occurred despite continued adherence to a basal-bolus insulin regimen. This report aims to alert clinicians to this risk and to highlight the importance of screening for autoimmune diabetes markers before initiating incretin-based therapies.

Clinical Significance: This case report describes the first published case of tirzepatide-induced DKA in a patient with LADA. A 57-year-old woman with confirmed LADA (GAD65 titer >25,000 U/mL, C-peptide <0.1 ng/mL) developed severe DKA two weeks after initiating tirzepatide for weight management, despite full adherence to her basal-bolus insulin regimen. This case demonstrates that the risk of DKA with tirzepatide in LADA is not limited to insulin withdrawal and may reflect the inherent vulnerability of patients with advanced autoimmune beta-cell destruction to metabolic decompensation when exposed to agents that alter appetite, caloric intake, and incretin-mediated insulin-glucagon dynamics. As the use of tirzepatide expands globally for both glycemic control and weight management, and as post hoc analyses of clinical trial data may encourage its off-label use in GADA-positive individuals, clinicians must exercise heightened vigilance for undiagnosed autoimmune diabetes in patients labeled as T2DM. Screening for GAD antibodies and C-peptide levels, patient education on ketoacidosis symptoms, and close monitoring during tirzepatide initiation are essential to mitigate this potentially life-threatening risk.

2. Case Presentation

2.1. Patient Demographics and Medical History

A 57-year-old woman with a body mass index (BMI) of 32 kg/m² presented to the emergency department with intractable vomiting. Her past medical history was significant for hypertension and diabetes mellitus, initially diagnosed as type 2 diabetes mellitus (T2DM) in 2002. In 2018, further evaluation revealed a markedly elevated glutamic acid decarboxylase 65 antibody (GAD65) titer of >25,000 U/mL and a C-peptide level of <0.1 ng/mL, consistent with near-complete beta-cell failure, leading to reclassification of her diabetes as latent autoimmune diabetes in adults (LADA). Her most recent hemoglobin A1c (HbA1c) prior to admission was 8.6%. There was no personal or family history of other autoimmune conditions. The patient had no history of diabetic ketoacidosis.

2.2. Symptoms and Signs

Two weeks before presentation, her primary care physician at an outside facility had started tirzepatide for weight management; the exact prescribed dose was not available for review. Her home medications included insulin glargine 27 units at bedtime and insulin lispro 7 units three times daily with meals. The patient reported full adherence to her insulin regimen in the days preceding presentation. After starting tirzepatide, she developed progressive nausea and intractable vomiting, with significantly reduced oral intake.

On arrival, the patient's vital signs were as follows: temperature 98.4°F (36.9°C), heart rate 102 beats per minute, blood pressure 128/78 mmHg, respiratory rate 22 breaths per minute, and oxygen saturation 99% on room air. She was afebrile, and there were no clinical signs of infection. Physical examination was notable for dehydration, including dry mucous membranes. Mild tachycardia and tachypnea were consistent with compensatory responses to metabolic acidosis and volume depletion. The remainder of the examination was unremarkable.

Laboratory investigations revealed the following: blood glucose: 608 mg/dL; arterial pH: 7.13; serum bicarbonate: 6 mEq/L; anion gap: 24 mEq/L; beta-hydroxybutyrate: 7.5 mmol/L; serum ketones: positive; sodium: 136 mEq/L; potassium: 3.8 mEq/L; blood urea nitrogen (BUN): 52 mg/dL; creatinine: 0.7 mg/dL; lactate: 1.2 mmol/L; urinalysis: glucose >1,000 mg/dL; ketones >80 mg/dL.

A diagnosis of severe diabetic ketoacidosis (DKA) was established based on hyperglycemia, arterial pH <7.24, serum bicarbonate <10 mEq/L, an elevated anion gap, and markedly elevated beta-hydroxybutyrate. An infectious workup, including blood cultures, urinalysis, and chest radiography, was unremarkable. Troponin was negative. No other precipitating factors for DKA, including medication non-adherence, infection, acute coronary syndrome, or concurrent use of sodium-glucose cotransporter 2 (SGLT2) inhibitors, were identified.

2.3. Treatment and Intervention

The patient was admitted to the intensive care unit (ICU) and managed with aggressive intravenous fluid resuscitation with 0.9% normal saline and a continuous insulin infusion, per the institutional DKA protocol. Potassium levels were monitored serially and repleted as needed. Tirzepatide was permanently discontinued. The patient's metabolic derangements, including acidosis, hyperglycemia, and ketonemia, resolved during her 2-day ICU stay.

2.4. Outcomes and Follow-Up

After stabilization, the patient was transitioned back to subcutaneous insulin therapy and discharged on hospital day 3 on an adjusted regimen of insulin glargine 24 units nightly and insulin lispro 9 units with each meal. Outpatient endocrinology follow-up was arranged.

At her most recent follow-up visit, approximately one month after discharge, the patient had no recurrence of DKA or ketosis. Her HbA1c had improved to 7.5%, and she remained on her adjusted basal-bolus insulin regimen without tirzepatide. No further episodes of nausea or vomiting were reported after discontinuing tirzepatide.

2.5. Ethical Considerations

Informed consent was obtained from the patient. Patient confidentiality was maintained throughout, and all identifying information has been removed.

2.6. Data Availability

All clinical data for this case are included in the manuscript. No additional datasets, computer code, or specialized protocols were generated or used. Access to the original medical records is restricted in accordance with patient privacy regulations under the Health Insurance Portability and Accountability Act (HIPAA).

2.7. Use of Generative Artificial Intelligence

GenAI was used for grammar/spelling/formatting.

3. Discussion

To our knowledge, this case is the first published report of tirzepatide-induced DKA in a patient with LADA. The temporal relationship between tirzepatide initiation and the development of DKA, occurring within two weeks of starting the medication, together with the absence of alternative precipitants (infection, insulin non-adherence, acute coronary syndrome, or concurrent SGLT2 inhibitor use) and the resolution of symptoms after drug discontinuation, supports a causal association.

Several mechanisms may explain how tirzepatide precipitated DKA in this patient: First, tirzepatide's insulinotropic effect is glucose-dependent, stimulating insulin secretion only when glucose levels are elevated [11,12]. In LADA, where progressive autoimmune beta-cell destruction has reduced functional beta-cell mass, this glucose-dependent mechanism may be insufficient to suppress lipolysis and ketogenesis, even with exogenous basal-bolus insulin. Second, tirzepatide causes significant appetite suppression, with up to 14% of patients reporting decreased appetite as an adverse event. Cases of euglycemic diabetic ketoacidosis (EDKA) have recently increased with the heightened use of SGLT-2 inhibitors and consequent appetite loss [13]. FAERS data show that starvation ketoacidosis has the strongest disproportionality signal among all tirzepatide-associated ketoacidosis subtypes [9]. In this patient, intractable vomiting, a known gastrointestinal side effect of tirzepatide, likely contributed to reduced caloric intake and dehydration, creating conditions favorable for ketogenesis. Third, tirzepatide's dual receptor agonism introduces complex glucagon dynamics. While GLP-1 receptor agonism suppresses glucagon secretion, GIP receptor agonism may paradoxically stimulate glucagon under certain conditions [14]. In the setting of declining beta-cell function, any relative glucagon excess promotes hepatic ketone body production. Fourth, although this patient's insulin was not discontinued, adding tirzepatide to her regimen may have altered the balance between insulin availability and metabolic demand. The gastrointestinal side effects of tirzepatide, particularly vomiting, may have impaired nutrient absorption and contributed to a state of relative insulin deficiency.

To contextualize this case, a comparison with previously published cases of incretin-associated ketoacidosis is presented in Table 1.

The most directly comparable case is reported by Zhang et al., in which a 50-year-old woman with LADA, initially misdiagnosed as T2DM, developed severe DKA one day after her first dulaglutide injection [7]. Several key differences distinguish the two cases. In the Zhang et al. case, insulin was discontinued when dulaglutide was initiated, a clear precipitant for DKA in a patient with autoimmune beta-cell destruction. In contrast, our patient continued her full basal-bolus insulin regimen throughout, demonstrating that the risk of DKA with incretin-based therapies in LADA is not limited to scenarios of insulin withdrawal. Furthermore, the onset of DKA in our case was more insidious (two weeks vs. one day), suggesting that the mechanism may have involved a gradual accumulation of metabolic stress from tirzepatide-induced vomiting and reduced caloric intake rather than an acute insulin deficit.

Campana et al. reported a case of tirzepatide-associated euglycemic DKA (EDKA) in a patient on tirzepatide monotherapy without concurrent SGLT2 inhibitor use, presenting with a glucose level of only 167 mg/dL but severe anion-gap metabolic acidosis [15]. Unlike our patient, this patient had T2DM rather than LADA, and the presentation was euglycemic. Our patient presented with marked hyperglycemia (glucose 608 mg/dL), reflecting the near-complete beta-cell failure characteristic of advanced LADA (C-peptide <0.1 ng/mL). This distinguishes the pathophysiology from euglycemic presentations, where residual insulin secretion partially suppresses hepatic glucose output.

Sawamura et al. described EDKA in a patient receiving both tirzepatide and an SGLT2 inhibitor during a sick day, with successful reintroduction of both agents after recovery [14]. The SGLT2 inhibitor's role as a co-precipitant in that case makes it difficult to attribute ketoacidosis solely to tirzepatide. In our case, the patient was not taking an SGLT2 inhibitor, strengthening the causal link to tirzepatide alone.

Alduraibi et al. reported EDKA in a 45-year-old man with T2DM three days after initiating dulaglutide, in the context of concurrent SGLT2 inhibitor use and extreme carbohydrate restriction [16]. Again, the presence of an SGLT2 inhibitor and dietary restriction complicates attributing the effect to the GLP-1 receptor agonist alone.

As shown in Table 1, the present case is unique in three important respects. First, it is the only case of tirzepatide-induced DKA in a patient with confirmed LADA—the Zhang et al. case involved dulaglutide rather than tirzepatide, and the remaining cases involved patients with T2DM. Second, it is the only case in which insulin was explicitly continued at the time of DKA onset. Third, it is the only case presenting with frank hyperglycemic DKA rather than euglycemic DKA, reflecting the near-complete beta-cell failure characteristic of advanced LADA. Across these cases, a consistent pattern emerges: incretin-based therapies may precipitate ketoacidosis through gastrointestinal side effects that reduce caloric intake, particularly in patients with limited beta-cell reserve or those concurrently using other ketosis-promoting agents.

Tirzepatide prescribing information states that it is not indicated for use in patients with type 1 diabetes mellitus but does not specifically address LADA [3]. This is a critical gap, as LADA patients share the autoimmune pathophysiology of T1DM and are at inherently higher risk for DKA. An international expert consensus on LADA management warns of the risk of DKA with SGLT2 inhibitors and recommends autoantibody testing before initiating these agents, but analogous warnings for incretin-based therapies are absent from current guidelines [5].

Based on this case and the existing literature, several clinical considerations merit emphasis. Screening for autoimmune diabetes markers (GAD antibodies and C-peptide) should be considered before initiating tirzepatide or other incretin-based therapies in patients with features suggestive of LADA, including late-onset diabetes with a relatively low BMI, early insulin requirement, personal or family history of autoimmune disease, or poor response to oral hypoglycemic agents.

If tirzepatide is prescribed to a patient with known or suspected LADA, close monitoring for ketosis should be implemented, particularly during the dose-titration phase, when gastrointestinal side effects are most common. Patients should be educated about DKA symptoms and instructed to check ketone levels if they experience persistent nausea, vomiting, or reduced oral intake.

Insulin doses should not be reduced empirically when initiating tirzepatide in patients with LADA. The occurrence of DKA in our patient despite continued basal-bolus insulin therapy suggests that even maintained insulin doses may be insufficient to prevent ketoacidosis when tirzepatide-induced gastrointestinal effects significantly reduce caloric intake and disrupt metabolic homeostasis.

The results and their implications should be discussed in the broadest context possible. Future research directions may also be highlighted.

4. Conclusions

This case highlights the risk of DKA when tirzepatide is prescribed to patients with LADA, a population characterized by progressive autoimmune beta-cell destruction and limited insulin reserve. As the use of tirzepatide expands for glycemic control and weight management, clinicians must remain vigilant for autoimmune diabetes in patients labeled T2DM. Screening for GAD antibodies and C-peptide, patient education on ketoacidosis symptoms, and close monitoring during tirzepatide initiation are essential to mitigate this risk.