Euglycemic diabetic ketoacidosis related to SGLT2 inhibitor use in a patient with cobalamin C deficiency and diabetes

Abstract

A 24-year-old female with cobalamin C deficiency (CblC), autoimmune thyroiditis, and recently diagnosed diabetes mellitus presented with weight loss, emesis, and abdominal pain. She had been placed on sodium-glucose cotransporter inhibitor (SGLT2i) therapy due to metformin intolerance, with the addition of a dipeptidyl peptidase-4 inhibitor. Biochemical analyses demonstrated severe acidosis, initially attributed to CblC-associated metabolic decompensation. Subsequent evaluation led to the diagnosis of SGLT2i-induced euglycemic diabetic ketoacidosis in a patient with insulin-dependent diabetes. This case highlights the importance of assessing for insulin deficiency when evaluating acidosis and the management challenges of common diseases in adults with inherited metabolic disorders.

Background

Cobalamin C (CblCD) is the most common inherited disorder of cobalamin metabolism, leading to impaired methionine production and branched-chain amino acids catabolism (Figure 1A) (1). A progressive multisystemic disorder, it leads to intellectual disability (ID), seizures, retinopathy, macrocytic anemia, cardiomyopathy, pulmonary lesions, and renal disease. CblCD is primarily diagnosed through newborn screening, but later-onset variants present in childhood with lethargy, feeding difficulties, or atypical hemolytic uremia, or in adulthood with gait abnormalities, disorientation, incontinence, and macrocytic anemia. Treatment involves high dose parenteral hydroxocobalamin and betaine (a methyl donor) to reduce homocysteine levels, and methionine supplementation (1). Previously implemented protein-restricted diets are no longer recommended because associated amino acid deficiencies may worsen neurocognitive outcomes (2). Medication adherence minimizes sequelae without preventing ID, retinopathy, or renal disease. Acute metabolic decompensation with anion gap metabolic acidosis (AGMA) occurs rarely (3). As this cohort ages, new challenges arise in managing common adult-onset comorbidities.

Figure 1.

A. The effects of CblC deficiency are illustrated here. CblC deficiency leads to impaired formation of both metabolically active forms of cobalamin, methylcobalamin and adenosylcobalamin, which leads to accumulation of methylmalonic acid and homocysteine. B. SGLT2 inhibitors block proximal renal tubule glucose reabsorption at the sodium-glucose cotransporter to promote normoglycemia, but also have other effects, as illustrated in black. Hypovolemia from glucosuria stimulates release of glucagon, along with other counterregulatory hormones, which promotes insulin resistance and lipolysis and worsens ketosis. C. Methylmalonylic acid likely competes with ketones for urinary excretion.

Objective

To highlight the importance of a broad differential diagnosis and choosing treatment carefully when diabetes mellitus (DM) and a rare metabolic disorder co-exist. To provide an example of new care challenges for adults with inherited metabolic disorders (IMDs).

Case Report

A 24-year-old female of South Asian descent with congenital CblCD (OMIM 609831), autoimmune thyroiditis, and DM presented to the emergency department with three weeks of intermittent non-bloody, non-bilious emesis, and abdominal pain, acutely worsened one day prior. Her CblCD diagnosed in infancy manifested with microcephaly, progressive pigmentary retinopathy, mild ID, and well-controlled seizures, and had been treated with dietary protein restriction. She had been diagnosed with type 2 DM five months prior due to random hyperglycemia (14.2 mmol/L [256 mg/dL]) and elevated HbA1c of 47.5 mmol/mol (6.5%). She did not tolerate initial management with metformin and was switched to ertugliflozin, a sodium-glucose cotransporter inhibitor (SGLT2i), four months prior. Alogliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor, was added one month later for persistent hyperglycemia. She consistently took her medications, which also included levothyroxine, levocarnitine, hydroxocobalamin, methionine, betaine, carbamazepine, calcium carbonate, sodium citrate-citric acid, a multivitamin, and cholecalciferol. Review of systems was notable for anorexia, fatigue, and unintentional 16.5-kilogram weight loss over the preceding five months. There was no recent infection. Family history was negative for DM. Physical examination demonstrated heart rate 98 beats per minute, blood pressure 115/67, respirations of 20 per minute, temperature 36.9°C, body mass index (BMI) 18.1 kg/m² (reduced from 25.1 kg/m² five months prior) and signs of dehydration. Biochemical studies demonstrated an AGMA with mild hyperglycemia, elevated beta-hydroxybutyrate (β-OHB) and normal lactate concentrations, and stably elevated homocysteine and methylmalonic acid (MMA) levels consistent with her CblCD (Table 1).

Table 1.

Lab results

Test	Result	Reference Range
pH, venous	7.187	7.320 - 7.420
CO2, venous	16.0 mmHg	35.0-45.0 mmHg
Base excess, venous	−20 mmol/L	-
Glucose	7.66 mmol/L (138 mg/dL)	3.33 – 6.38 mmol/L (60 - 115 mg/dL)
WBC	7.6 K/uL	4.4 - 9.7 K/uL
Sodium	138 mmol/L	137 - 145 mmol/L
Potassium	3.8 mmol/L	3.6 - 5.0 mmol/L
Chloride	109 mmol/L	98 - 107 mmol/L
Carbon Dioxide	5 mmol/L	22 - 30 mmol/L
Lipase	140 U/L	23 - 300 U/L
HbA1c	66.1 mmol/mol (8.2%)	18.0-41.0 mmol/mol (3.8 - 5.9 %)
Methylmalonic Acid	4,500 nmol/L	0-370 nmol/L
Homocysteine	125.4 umol/L	10.5 - 16.7 umol/L
β-OHB	11.0 mmol/L	0.0 - 0.3 mmol/L
Urine Ketone	Moderate, 7.8 (80)	negative mmol/L (mg/dL)
Urine Specific Gravity	1.015	1.003 - 1.035
Insulin	<2.0 uIU/mL	-
C-peptide	0.6 ng/mL	-
Insulin Ab	18 uU/mL	<5.0 uU/mL
GAD 65 Ab	>120 uU/mL	<5.0 uU/mL
ICA512 Ab	21 U/mL	<7.5 U/mL
Znt8 Ab	157 U/mL	<15 U/mL

Initially, her AGMA was attributed to CblC-associated metabolic decompensation. When elevated serum levels of β-OHB were noted, suspicion arose for SGLT2i-induced euglycemic DKA given the mild hyperglycemia. She responded well to intravenous insulin infusion and transitioned to basal-bolus insulin. Ertugliflozin and alogliptin were discontinued. Subsequent evaluation demonstrated undetectable insulin and low C-peptide concentrations with elevated diabetes-associated pancreatic antibodies titers, consistent with autoimmune DM (Table 1). Eighteen months after DM presentation, she had regained weight (BMI 20.9 kg/m²) and had no further episodes of DKA. HbA1c was 64 mmol/mol (8.0%).

Discussion

Multidisciplinary review identified three main DKA risk factors. First, unrecognized insulin deficient DM predisposed this patient to DKA. Her age at presentation and South Asian ancestry may have led clinicians to diagnose type 2 DM, rather than autoimmune insulin deficiency. Yet, presentation with a BMI of only 25.1 kg/m², absent type 2 DM family history, weight loss, and a pre-existing autoimmune condition should have triggered evaluation for type 1 DM.

Second, CblCD exacerbated DKA severity. MMA likely competes with β-OHB for urinary excretion due to similar size and structure (Figure 1B) (4, 5). Reduced β-OHB excretion augments the risk of developing DKA. Our patient’s β-OHB concentration was significantly elevated with only moderately increased urinary ketones, despite fairly concentrated urine (Table 1). With mitochondrial dysfunction, urinary acetoacetate measurements can underestimate ketosis due to accumulation of reduced nicotinamide adenine dinucleotide (NADH) relative to oxidized nicotinamide adenine dinucleotide (NAD⁺) and therefore increased β-OHB compared to acetoacetate (6). Additionally, CblCD-related ID may have impaired communication of symptoms and fluid intake in response to dehydration. Finally, the patient’s protein-restricted, high-carbohydrate, diet potentially exacerbated DKA severity.

Third, SGLT2i use can lower blood glucose levels to near normal while promoting ketosis, decreasing suspicion for DKA. Blood ketone concentration increases via multiple mechanisms still under investigation (Figure 1C). Impaired urinary ketone excretion and possible stimulation of glucagon secretion promote ketone production (7). The hypovolemia resultant from glycosuria also increases levels of glucagon and other counterregulatory hormones that promote lipolysis and insulin resistance, worsening ketosis (8). By decreasing blood glucose levels and removing the stimulus for insulin secretion and/or administration, an SGLT2i can produce a “mismatch” between insulin concentration and effect—namely insufficient lipolysis and ketogenesis suppression (7). A state of relative insulin deficiency and resistance and hyperketonemia results (7, 8). The persistent catabolic state from insulin deficiency may provoke metabolic decompensation in an individual with CblCD, compounding the SGLT2i effects of increased production and decreased ketone clearance.

The etiology of an AGMA can be elusive in individuals with IMD, particularly those with multiple risk factors. There are at least 10 published cases of pediatric patients with impaired MMA metabolism who were mistakenly initially diagnosed with primary DKA in countries without universal newborn screening for these disorders (9-10). Six of nine patients died in one series (10). Defects in methylmalonyl-CoA mutase (an enzyme for which adenosylcobalamin is a required cofactor) have been associated with concurrent methylmalonic acidemia and neonatal diabetes secondary to pancreatic beta-cell agenesis (11). To our knowledge, ours is the first report of co-existent autoimmune diabetes and CblC deficiency. Together these reports highlight the importance of accurate ascertainment of the etiology of AGMA.

The case also highlights that choosing DM therapies for individuals with IMDs warrants special consideration (Table 2). For instance, metformin carries risk of lactic acidosis (for which our patient was monitored) and cobalamin deficiency. Consequently, the appropriateness of metformin DM treatment is unclear for individuals with concomitant inherited disorders of cobalamin metabolism or other IMDs with renal manifestations or mitochondrial dysfunction. On the other hand, SGLT2i use has been associated with reductions in cardiovascular death, heart failure hospitalizations, and progression of renal disease, even in those without DM (12), which may be of benefit in IMD-related cardiomyopathy and renal disease, as seen in CblCD (1). However, these benefits should be balanced with the increased ketosis risk with an SGLT2i.

Table 2.

Class-specific benefits, risks and relative contraindications of common medications to consider for treatment of diabetes in individuals with IMDs

Medication Class	Benefits	Risks and Relative Contraindications	Potential Effects on Metabolism
Insulin	Commonly used and familiar to most medical providers Well-tolerated without off target effects based on extensive long-term safety data Necessary in insulin-deficient diabetes	Hypoglycemia Excess weight gain in T2D Dose adjustments are needed in CKD	Promotes anabolism Frequent treatment for acute metabolic decompensations
Biguanides (Metformin)	Extensive long-term safety data available, including in early-stage CKD	Gastrointestinal distress with nausea, vomiting, and diarrhea may increase risk of metabolic decompensation—can be mitigated by starting with the lowest metformin dose followed by slow incremental dose adjustments Cobalamin (B12) deficiency (due to Metformin-associated impaired ileal cobalamin absorption) Review safety in CKD stages 3b-5	Risk of lactic acidosis in patients with mitochondrial disease, renal dysfunction
DPP4 inhibitor (e.g. alogliptin, linagliptin)	Decreased intestinal lipoprotein absorption and hepatic steatosis in animal models though unclear benefit to liver transaminases in humans Linagliptin can be used in CKD Possible improved mitochondrial function (brain, hippocampus in animal models)	Gastrointestinal distress with nausea, vomiting, and diarrhea Risk of pancreatitis	Gastrointestinal side effects may precipitate metabolic decompensation Risk of exacerbating gastroparesis in individuals with primary or secondary mitochondrial dysfunction
GLP-1 agonists (e.g., liraglutide, semaglutide)	Potentially cardioprotective Possible positive impact on central nervous system function Possible improved mitochondrial function (pancreatic beta cells, cardiomyocytes, and retinal ganglion cells in animal models) Weight loss for individuals with obesity	Possible risk of pancreatitis Risk of cholelithiasis Typically discontinued in stages 4-5 CKD	Case reports noted benefit for individuals with mitochondrial diabetes (i.e., Wolfram syndrome) May compound underlying pancreatitis risk in organic acidemias GI side effects may precipitate metabolic decompensation Weight loss (possible benefit or risk depending on patient) Risk of tachycardia could be a concern depending on underlying condition
SLGT2 inhibitors (e.g., ertugliflozin, dapaglifozin, empaglifozin)	Benefit in heart failure Benefit in chronic kidney disease	Euglycemic ketosis/DKA Urinary tract infections Typically discontinued in stages 3b-5 CKD	Increase β-oxidation of long chain fatty acids Decrease PDH activity through PDH kinase upregulation Improves neutropenia in GSD1b

IMD = inherited metabolic disorder, T2D = type 2 diabetes, CKD = chronic kidney disease, PDH = pyruvate dehydrogenase, GSD = glycogen storage disease

For a comprehensive review of these and other agents used in the management of diabetes mellitus see PMID 34964831 (2022 American Diabetes Association pharmacologic treatment guidelines).

This case is a reminder to assess for insulin deficiency in adults presenting with DM and introduces a growing patient cohort–adults with IMDs, individually rare but collectively common with an incidence of 1:1500 (13). Over 90% of individuals diagnosed with IMDs reach age 20 years due to expanded newborn screening and detection and intensive medical management (14). Adults with IMDs face challenges transitioning to adult healthcare, including lack of knowledgeable clinicians and the loss of a medical home (15). Inexperienced clinicians may be quick to attribute symptoms to a patient’s underlying IMDs leading to diagnostic delays. Close collaboration between adult clinicians and biochemical geneticists will be necessary to tailor management and prevent adverse outcomes.