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Letter to the Editor

DIABETIC KETOACIDOSIS IN PATIENTS WITH TYPE 2 DIABETES


RECENTLY COMMENCED ON SGLT-2 INHIBITORS:
AN ONGOING CONCERN

Mohamed Ahmed, PGD (Diab), MBBS; Malachi J. McKenna, MD; Rachel K. Crowley, MD

ABSTRACT
Abbreviations:
Objective: Sodium-glucose cotransporter 2 (SGLT-2) DKA = diabetic ketoacidosis; SGLT-2 = sodium-
inhibitors are increasingly used as an adjunctive treatment glucose cotransporter 2; T2D = type 2 diabetes
for type 2 diabetes. We report the occurrence of diabetic
ketoacidosis (DKA) in 3 patients with type 2 diabetes
recently commenced on SGLT-2 inhibitors. INTRODUCTION
Methods: Clinical presentation, laboratory data, and
treatment outcomes of all 3 cases are described. Sodium-glucose cotransporter 2 (SGLT-2) inhibi-
Results: All 3 patients had documented history of tors are a new class of oral hypoglycemics that are now
longstanding type 2 diabetes. The presentation in all widely used for the treatment of type 2 diabetes (T2D).
patients was that of hyperglycaemia, acidosis, and ketosis They improve glycemic control by inhibiting renal glucose
occurring within 4 weeks of commencing SGLT-2 inhibi- re-absorption. They are oral agents, and other potential
tors. The risk factors for developing DKA were infection, benefits of the class include weight loss, lower risk of
myocardial infarction, and alcohol excess. DKA resolved hypoglycemia, and blood pressure reduction (1,2). In May
within 24 hours of initiating intravenous fluids and insulin 2015, based on the identification of 20 reported cases of
in all cases. diabetic ketoacidosis (DKA) in patients treated with SGLT-
Conclusion: This case series illustrates the impor- 2 inhibitors, the U.S. Food and Drug Administration issued
tance of careful patient selection, education, and monitor- a drug safety communication warning of this potential
ing when starting this group of antidiabetic medications. complication of SGLT-2 inhibitors (3).
(Endocr Pract. 2017;23:506-508)
CASE SERIES

The first patient was a 76-year-old man. Three weeks


after canagliflozin was added, he presented with nausea and
vomiting; however, there was mild evidence of dehydra-
tion (elevated creatinine, see Table 1). His blood glucose
was 11.7 mmol/L with capillary ketones 3.4 mmol/L (refer-
ence range, <0.6 mmol/L). His troponin was elevated at
Submitted for publication June 13, 2016
Accepted for publication January 5, 2017 5.9 ng/mL (normal, <0.005 ng/mL), and he was treated for
From the Department of Endocrinology, St. Vincent’s University Hospital acute coronary syndrome and DKA.
and University College Dublin, Dublin, Ireland.
The second patient was a 75-year-old man with T2D
Address correspondence to Dr. Mohamed Ahmed, St. Vincent’s University
Hospital, Elm Park, Dublin 4, Ireland. for 33 years and poor glycemic control who was not a
E-mail: mohamedomer07@gmail.com candidate for insulin due to cognitive impairment and poor
Published as a Rapid Electronic Article in Press at http://www.endocrine
social circumstances. Four weeks after dapagliflozin was
practice.org. DOI: 10.4158/EP161447.LT
To purchase reprints of this article, please visit: www.aace.com/reprints. commenced, he presented with anorexia, nausea, and confu-
Copyright © 2017 AACE. sion. He was dehydrated, with dry mucous membranes and

506 ENDOCRINE PRACTICE Vol 23 No. 4 April 2017 Copyright © 2017 AACE
Copyright © 2017 AACE Letter to the Editor, Endocr Pract. 2017;23(No. 4) 507

tachycardia, and his blood glucose was 19.8 mmo/L with 1 summarizes the clinical characteristics of all 3 patients
serum ketones of 5.8 mmol/L. with DKA.
The third patient was commenced on canagliflozin 1
week before admission. He had approximately 12 units DISCUSSION
of alcohol the night before presentation and was admitted
with abdominal pain and vomiting. He was clinically dehy- The exact mechanism of SGLT-2 inhibitor-related
drated with hypotension, and his blood glucose was 18.4 DKA is not yet fully known. In subjects with type 2 diabe-
mmol/L with capillary ketones of 4.1 mmol/L. He required tes mellitus, SGLT-2 inhibitor use results in a significant
intensive care monitoring and inotropic support. glucose excretion of 50 to 100 g/day (4), with a reduction
Ketoacidosis resolved within 24 hours after initiating in glucose-mediated beta-cell stimulation and a consequent
fluids and insulin in all cases. None of these patients had fall in plasma insulin level. Plasma glucagon level increas-
a previous history of DKA, which developed relatively es due to diminished insulin inhibition and the suppression
rapidly after introduction of an SGLT-2 inhibitor; nor did of SGLT-2 receptors located on the pancreatic alpha-cells
DKA recur after withdrawal of SGLT-2 inhibitor. Table (5,6). Furthermore, animal studies reveal that glucagon

Table 1
Clinical Characteristics of Cases with DKA
Case patient 1 2 3
Age (years) 76 75 60
Sex Male Male Male
Duration of DM (years) 15 33 12
Sitagliptin/Metformin Metformin 1,000 mg
Metformin 1,000 mg
Oral hypoglycaemic Agents (50/1,000 mg) Gliclazide MR 120 mg
Linagliptin 5 mg
Gliclazide MR 120 mg Linagliptin 5 mg
Insulin No No No
BMI (kg/m2) 24.7 22.2 32.1
Prior A1C (mmol/L [%]) 79 (9.4) 110 (12.2%) 63 (7.9%)
Previous DKA No No No
SGLT-2 inhibitor/dose Canagliflozin/100 mg Dapagliflozin/10 mg Canagliflozin/100 mg
Duration of SGLT-2 (weeks) 3 4 1
Plasma glucose (mg/dL [mmol/L]) 210.8 (11.7) 356.7 (19.8) 331.5 (18.4)
Serum ketones
3.4 5.8 4.1
(β-hydroxybutyrate) (mmol/L)
pH 7.26 7.29 6.88
Bicarbonate (mEq/L) 17.0 16 8
pCO2 (kPa) 2.28 4.34 3.32
Chloride (mmol/L) 105 111 106
Sodium (mmol/L) 130 139 136
Potassium (mmol/L) 3.2 4.4 4.5
BUN 6.9 22.1 11.3
Creatinine 116 185 169
Anion gap (mEq/L) 11.2 16.4 26.5
Potential contributors Myocardial infarction Urinary tract infection Excess alcohol
Clinical area managed Coronary care unit Medical ward ICU
Abbreviations: A1C = hemoglobin A1C; BMI = body mass index; BUN = blood urea nitrogen; DKA = diabetic ketoacidosis; DM =
diabetes mellitus; ICU = intensive care unit; SGLT-2 = sodium-glucose cotransporter 2.
508 Letter to the Editor, Endocr Pract. 2017;23(No. 4) Copyright © 2017 AACE

inhibits glucose-stimulated insulin secretion via hepatic CONCLUSION


kisspeptin 1 production (7). The net result of these changes
is increased glucagon concentration and a reduction in insu- In conclusion, for the right patient, the SGLT-2 inhibi-
lin to glucagon ratio, which leads to enhanced fat oxidation, tor class may be a very useful tool, and we have found
lipolysis, and ketogenesis (8). Another proposed mechanism this to be the case in our own practice. However, this case
is the increased levels of renal tubular fluid sodium concen- series illustrates the importance of careful patient selection
tration due to the inhibition of SGLT-2–mediated sodium when choosing SGLT-2 inhibitors. Patient selection and
re-absorption, which leads to an increased re-absorption of safety issues should be highlighted both in guidelines and
the negatively charged ketone bodies through an electrome- in product information provided with this drug class.
chanical gradient carrier-mediated mechanism, resulting in
increased levels of circulating ketone bodies and increasing DISCLOSURE
the risk of developing DKA (9).
External factors reported to increase the risk of DKA The authors have no multiplicity of interest to disclose.
associated with SGLT-2 inhibitors include reduction in
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