Diagnosis and Treatment > Investigation > C-peptide (blood)
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Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
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Summary
Hyperglycemic hyperosmolar state (HHS) and diabetic ketoacidosis (DKA) are the most severe acute complications of diabetes mellitus (DM). HHS is characterized by severe hyperglycemia and hyperosmolality without significant ketosis and acidosis. A 14-year-old Japanese boy presented at the emergency room with lethargy, polyuria and polydipsia. He belonged to a baseball club team and habitually drank sugar-rich beverages daily. Three weeks earlier, he suffered from lassitude and developed polyuria and polydipsia 1 week later. He had been drinking more sugar-rich isotonic sports drinks (approximately 1000–1500 mL/day) than usual (approximately 500 mL/day). He presented with HHS (hyperglycemia (1010 mg/dL, HbA1c 12.3%) and mild hyperosmolality (313 mOsm/kg)) without acidosis (pH 7.360), severe ketosis (589 μmol/L) and ketonuria. He presented HHS in type 1 diabetes mellitus (T1DM) with elevated glutamate decarboxylase antibody and islet antigen 2 antibody. Consuming beverages with high sugar concentrations caused hyperglycemia and further exacerbates thirst, resulting in further beverage consumption. Although he recovered from HHS following intensive transfusion and insulin treatment, he was significantly sensitive to insulin therapy. Even the appropriate amount of insulin may result in dramatically decreasing blood sugar levels in patients with T1DM. We should therefore suspect T1DM in patients with HHS but not those with obesity. Moreover, age, clinical history and body type are helpful for identifying T1DM and HHS. Specifically, drinking an excess of beverages rich in sugars represents a risk of HHS in juvenile/adolescent T1DM patients.
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Hyperglycemic hyperosmolar state (HHS) is characterized by severe hyperglycemia and hyperosmolality without significant ketosis and acidosis.
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The discrimination between HHS of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) in initial presentation is difficult.
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Pediatrician should suspect T1DM in patients with HHS but not obesity.
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Age, clinical history and body type are helpful for identifying T1DM and HHS.
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Children with T1DM are very sensitive to insulin treatment, and even appropriate amount of insulin may result in dramatically decreasing blood sugar levels.
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Summary
Coexistence of autoimmune diabetes and maturity-onset diabetes of the young (MODY) is rare. We report the first case of coexisting latent autoimmune diabetes of adulthood (LADA) and glucokinase (GCK) MODY. A 32-year-old woman was treated with insulin for gestational diabetes at age 32 years; post-partum, her fasting blood glucose was 6.0 mmol/L and 2-h glucose was 11.8 mmol/L following an oral glucose tolerance test, and she was maintained on diet alone. Five years later, a diagnosis of LADA was made when she presented with fasting blood glucose of 20.3 mmol/L and HbA1C 125 mmol/mol (13.6%). GCK-MODY was identified 14 years later when genetic testing was prompted by identification of a mutation in her cousin. Despite multiple daily insulin injections her glycaemic control remained above target and her clinical course has been complicated by multiple episodes of hypoglycaemia with unawareness. Although rare, coexistence of latent autoimmune diabetes of adulthood and monogenic diabetes should be considered if there is a strong clinical suspicion, for example, family history. Hypoglycaemic unawareness developed secondary to frequent episodes of hypoglycaemia using standard glycaemic targets for LADA. This case highlights the importance of setting fasting glucose targets within the expected range for GCK-MODY in subjects with coexisting LADA.
Learning points:
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We report the first case of coexisting latent autoimmune diabetes of adulthood (LADA) and GCK-MODY.
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It has been suggested that mutations in GCK may lead to altered counter-regulation and recognition of hypoglycaemia at higher blood glucose levels than patients without such mutation. However, in our case, hypoglycaemic unawareness developed secondary to frequent episodes of hypoglycaemia using standard glycaemic targets for LADA.
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This case highlights the importance of setting fasting glucose targets within the expected range for GCK-MODY in subjects with coexisting LADA to avoid hypoglycaemia.
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Summary
Insulin autoimmune syndrome (IAS), a rare cause of autoimmune hyperinsulinaemic hypoglycaemia, is relatively well known in Japan. The incidence in Caucasians is less than one-fifth of that reported in Japanese people, but it is becoming increasingly recognised worldwide in non-Asians as well. Drugs containing sulphydryl groups are known to be associated with the disease in genetically predisposed individuals. Moreover, several recent reports showed a direct association between the onset of IAS and the consumption of dietary supplements containing alpha-lipoic acid (LA). Insulinoma remains the most prevalent cause of hypersulinaemic hypoglycaemia in Caucasians. Consequently, primary investigation in these patients is generally focused on localisation of the pancreatic tumour, often with invasive procedures followed by surgery. We described a case of an Italian woman presenting to us with severe recurrent hypoglycaemia associated with high insulin and C-peptide levels and no evidence of pancreatic lesions at imaging diagnostic procedures. She had taken LA until 2 weeks before hospitalisation. After an evaluation of her drug history, an autoimmune form of hypoglycaemia was suspected and the titre of insulin autoantibodies was found to be markedly elevated. This allowed us to diagnose LA-related IAS, thus preventing any unnecessary surgery and avoiding invasive diagnostic interventions.
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IAS is a rare cause of hyperinsulinaemic hypoglycaemia that typically affects Asian population, but it has been increasingly recognised in Caucasian patients.
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It should be considered among the differential diagnosis of hyperinsulinaemic hypoglycaemia to avoid unnecessary diagnostic investigations and surgery.
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It should be suspected in the presence of very high serum insulin levels (100–10 000 μU/mL) associated with high C-peptide levels.
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There is a strong association with administration of drugs containing sulphydryl groups included LA, a dietary supplement commonly used in Western countries to treat peripheral neuropathy.
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Summary
Insulin autoimmune syndrome (IAS), or Hirata disease, is a rare hypoglycaemic disorder caused by the presence of high titer of insulin autoantibodies (IAA) in patients without previous exposure to exogenous insulin. Even though its pathogenesis is not fully understood, striking evidences link IAS to previous exposure to sulphydryl-containing medications, like alpha-lipoic acid, a widely used nutritional supplement. Although challenging, a careful differential diagnosis from other causes of hyperinsulinaemic hypoglycaemia (such as insulinoma) is mandatory, since these conditions require different therapeutic approaches. In the present study, we report a 35-year-old woman originally from Sri Lanka who was referred to our University Hospital on suspicion of occult insulinoma. Her medical history was positive for endometriosis, treated with estroprogestins and alpha-lipoic acid. The latter supplement was begun 2 weeks before the first hypoglycaemic episode. Our tests confirmed the presence of hypoglycaemia associated with high insulin and C-peptide concentrations. When insulin concentrations were compared using different assays, the results were significantly different. Moreover, insulin values significantly decreased after precipitation with polyethylene glycol. An assay for IAA proved positive (530 U/mL). A genetic analysis revealed the presence of HLA-DRB1*04,15, an immunogenetic determinant associated with IAS. On the basis of clinical data we avoided a first-line approach with immunosuppressive treatments, and the patient was advised to modify her diet, with the introduction of frequent low-caloric meals. During follow-up evaluations, glucose levels (registered trough a flash glucose monitoring system) resulted progressively more stable. IAA titer progressively decreased, being undetectable by the fifteenth month, thus indicating the remission of the IAS.
Learning points:
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Insulin autoimmune syndrome (IAS) is a rare cause of hyperinsulinaemic hypoglycaemia, whose prevalence is higher in East Asian populations due to the higher prevalence of specific immunogenetic determinants. Nevertheless, an increasing number of IAS cases is being reported worldwide, due to the wide diffusion of medications such as alpha-lipoic acid.
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Differential diagnosis of IAS from other causes of hyperinsulinemic hypoglycaemia is challenging. Even though many tests can be suggestive of IAS, the gold standard remains the detection of IAAs, despite that dedicated commercial kits are not widely available.
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The therapeutic approach to IAS is problematic. As a matter of fact IAS is often a self-remitting disease, but sometimes needs aggressive immunosuppression. The benefits and risks of any therapeutic choice should be carefully weighted and tailored on the single patient.
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Summary
There has been an increasing awareness of post gastric bypass hypoglycemia (PGBH). Histopathologic findings from such patients who underwent partial/total pancreatomy, however, can vary widely from minimal changes to classic nesidioblastosis, making the pathologic diagnosis challenging. PGBH typically presents as postprandial hypoglycemia, as opposed to insulinoma, which presents as fasting hypoglycemia. Herein, we describe an unusual case of a patient with PGBH who initially presented with postprandial hypoglycemia three years after surgery, but later developed fasting hyperinsulinemic hypoglycemia as the disease progressed. Our hypothesis for this phenomenon is that this disease is progressive, and later in its course, the insulin release becomes dissociated from food stimulation and is increased at baseline. Future studies are needed to investigate the prevalence as well as etiology of this progression from postprandial to fasting hypoglycemia.
Learning points:
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There has been an increasing awareness of post gastric bypass hypoglycemia (PGBH).
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Histopathologically, PGBH can vary from minimal changes to nesidioblastosis.
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Although uncommon, patients with PGBH after Roux-en-Y gastric bypass may present with both postprandial and fasting hyperinsulinemic hypoglycemia as disease progresses.
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Our hypothesis for this phenomenon is that the insulin release becomes dissociated from food stimulation and is increased at baseline with disease progression.
Eastern Health Clinical School, Monash University, Victoria, Australia
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Medical Imaging, Eastern Health, Box Hill, Victoria, Australia
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Department of Medicine and Radiology, University of Melbourne, Victoria, Australia
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Eastern Health Clinical School, Monash University, Victoria, Australia
Department of Medicine, Eastern Health, Box Hill, Victoria, Australia
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Summary
Mitochondrial diseases are rare, heterogeneous conditions affecting organs dependent on high aerobic metabolism. Presenting symptoms and signs vary depending on the mutation and mutant protein load. Diabetes mellitus is the most common endocrinopathy, and recognition of these patients is important due to its impact on management and screening of family members. In particular, glycemic management differs in these patients: the use of metformin is avoided because of the risk of lactic acidosis. We describe a patient who presented with gradual weight loss and an acute presentation of hyperglycemia complicated by the superior mesenteric artery syndrome. His maternal history of diabetes and deafness and a personal history of hearing impairment led to the diagnosis of a mitochondrial disorder.
Learning points:
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The constellation of diabetes, multi-organ involvement and maternal inheritance should prompt consideration of a mitochondrial disorder.
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Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS) and maternally inherited diabetes and deafness (MIDD) are the most common mitochondrial diabetes disorders caused by a mutation in m.3243A>G in 80% of cases.
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Metformin should be avoided due to the risk of lactic acidosis.
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There is more rapid progression to insulin therapy and higher prevalence of diabetic complications compared to type 2 diabetes.
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Diagnosis of a mitochondrial disorder leads to family screening, education and surveillance for future complications.
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Superior mesenteric artery syndrome, an uncommon but important cause of intestinal pseudo-obstruction in cases of significant weight loss, has been reported in MELAS patients.
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Summary
A frail 79-year-old lady with dementia presented with a 2-year history of frequent falls. Recurrent hypoglycaemic episodes were diagnosed and treated with continuous glucose infusion in multiple hospital admissions. Hypoadrenalism and hypothyroidism were ruled out. Whilst hypoglycaemic (blood glucose 1.6 mmol/L), both plasma C-peptide and proinsulin concentrations, were inappropriately elevated at 4210 pmol/L (174–960) and >200 pmol/L (0–7) respectively with plasma insulin suppressed at 12 pmol/L (0–180). Whilst reported cases of proinsulinoma are typically pancreatic in origin, radiological investigations of the pancreas in this patient did not identify abnormalities. Unexpectedly contrast CT identified a heterogeneously enhancing mass (6.6 cm) at the lower pole of the left kidney consistent with renal cell carcinoma. Non-islet cell tumour-induced hypoglycaemia has been associated with renal malignancy; however, a serum IGF2:IGF1 ratio measured at <10 effectively excludes this diagnosis. Concomitantly on the CT, extensive peripherally enhancing heterogeneous mass lesions in the liver were identified, the largest measuring 12 cm. A palliative approach was taken due to multiple comorbidities. On post-mortem, the kidney lesion was confirmed as clear cell renal carcinoma, whilst the liver lesions were identified as proinsulin-secreting neuroendocrine tumours. In conclusion, the diagnosis of proinsulinoma can be missed if plasma proinsulin concentration is not measured at the time of hypoglycaemia. In this case, the plasma insulin:C-peptide ratio was too high to be accounted for by the faster relative clearance of insulin and was due to proinsulin cross-reactivity in the C-peptide assay. In addition, the concomitant malignancy proved to be a challenging red herring.
Learning points:
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Even in non-diabetics, hypoglycaemia needs to be excluded in a setting of frequent falls. Insulin- or proinsulin-secreting tumours are potentially curable causes.
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Whilst investigating spontaneous hypoglycaemia, if plasma insulin concentration is appropriate for the hypoglycaemia, it is prudent to check proinsulin concentrations during the hypoglycaemic episode.
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Proinsulin cross-reacts variably with C-peptide and insulin assays; the effect is method dependent. In this case, the discrepancy between the insulin and C-peptide concentrations was too great to be accounted for by the faster relative clearance of insulin, raising the suspicion of assay interference. The C-peptide assay in question (Diasorin liaison) has been shown to be 100% cross reactive with proinsulin based on spiking studies with a proinsulin reference preparation.
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Whilst reported cases of proinsulinoma and 99% of insulinomas are of pancreatic origin, conventional imaging studies (CT, MRI or ultrasound) fail to detect neuroendocrine tumours <1 cm in 50% of cases.
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The concomitant renal mass identified radiologically proved to be a red herring.
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In view of the rarity of proinsulinoma, no conclusive association with renal cell carcinoma can be established.
Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
German Center for Diabetes Research (DZD), München-Neuherberg, Germany
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Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
German Center for Diabetes Research (DZD), München-Neuherberg, Germany
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Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
German Center for Diabetes Research (DZD), München-Neuherberg, Germany
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Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
German Center for Diabetes Research (DZD), München-Neuherberg, Germany
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Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
German Center for Diabetes Research (DZD), München-Neuherberg, Germany
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Summary
Diabetic ketoacidosis is a life-threatening complication of diabetes mellitus. It usually occurs in patients with type 1 diabetes where it is typically associated with only moderately increased blood glucose. Here, we report the case of a 52-year-old female patient who was admitted to the emergency unit with severely altered mental status but stable vital signs. Laboratory results on admission revealed very high blood glucose (1687 mg/dL/93.6 mmol/L) and severe acidosis (pH <7) with proof of ketone bodies in serum and urine. Past history revealed a paranoid schizophrenia diagnosed 10 years ago and for which the patient was treated with risperidone for many years. Acute treatment with intravenous fluids, intravenous insulin infusion and sodium bicarbonate improved the symptoms. Further laboratory investigations confirmed diagnosis of autoimmune type 1 diabetes. After normalization of blood glucose levels, the patient could soon be discharged with a subcutaneous insulin therapy.
Learning points:
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Diabetic ketoacidosis as first manifestation of type 1 diabetes can occur with markedly elevated blood glucose concentrations in elder patients.
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Atypical antipsychotics are associated with hyperglycemia and an increased risk of new-onset diabetes.
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First report of risperidone-associated diabetic ketoacidosis in new-onset type 1 diabetes.
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Patients treated with atypical antipsychotics require special care and regular laboratory examinations to detect hyperglycemia and diabetic ketoacidosis.
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In cases when the diagnosis is in doubt, blood gas analysis as well as determination of C-peptide and islet autoantibodies can help to establish the definite diabetes type.
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Summary
We report a case of a 63-year-old man who developed diabetic ketoacidosis (DKA) associated with canagliflozin, a sodium glucose co-transporter 2 (SGLT-2) inhibitor. He presented acutely unwell with a silent myocardial infarction, diverticulitis and DKA with a minimally raised blood glucose level. Standard therapy for DKA was initiated. Despite this, ketonaemia persisted for a total of 12 days after discontinuation of canagliflozin. Glucosuria lasting for several days despite discontinuation of the medications is a recognised phenomenon. However, this is the longest duration of ketonaemia to be reported. The cause of prolonged SGLT-2 inhibition remains uncertain. Deviation from the normal DKA treatment protocol and use of personalised regimens may be required in order to prevent relapse into ketoacidosis while avoiding hypoglycaemia in those that develop this condition.
Learning points:
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Diabetic ketoacidosis (DKA) may develop in the presence of lower-than-expected blood glucose levels in patients treated with a sodium glucose co-transporter 2 (SGLT-2) inhibitor.
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Certain individuals prescribed with SGLT-2 inhibitors may be more at risk of DKA, for example, those with a low beta cell function reserve, excessive alcohol consumption and a low carbohydrate diet.
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In order to reduce the risk of SGLT-2 inhibitor-associated DKA, all patients must be carefully selected before prescription of the medication and appropriately educated.
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Increased serum ketone levels and glucosuria have been reported to persist for several days despite discontinuation of their SGLT-2 inhibitor.
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Physicians should consider individualised treatment regimens for subjects with prolonged DKA in the presence of SGLT-2 inhibition.
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Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia
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Summary
We report a case of a 67-year-old man with type 2 diabetes presented with diabetic ketoacidosis, two weeks after his first dose of nivolumab therapy for non–small-cell lung carcinoma. He was started on empagliflozin two days prior in the setting of hyperglycaemia after the initiation of nivolumab therapy. Laboratory evaluation revealed an undetectable C-peptide and a positive anti-glutamic acid decarboxylase (GAD) antibody. He was treated with intravenous fluids and insulin infusion and was subsequently transitioned to subcutaneous insulin and discharged home. He subsequently has developed likely autoimmune thyroiditis and autoimmune encephalitis.
Learning points:
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Glycemic surveillance in patients receiving immune checkpoint inhibitors is recommended.
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Early glycemic surveillance after commencement of anti-programmed cell death-1 (PD-1) inhibitors may be indicated in selected populations, including patients with underlying type 2 diabetes mellitus and positive anti-glutamic acid decarboxylase (GAD) antibody.
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Sodium-glucose co transporter-2 (SGLT2) inhibitors should be used with caution in patients on immunotherapy.
