Paradoxical Diabetic Ketoacidosis in a Type 2 Diabetes patient
on Dapagliflozin: A Brief Case Report
1Venkata Vinod Kumar Matli, MD;2Nidhi Bansal, MD
From the 1Departments 1Internal
Medicine and 2Endocrinology, SUNY Upstate Medical
University, Syracuse, NY 13210.
Address correspondence to Venkata Vinod Kumar Matli, MD SUNY Upstate
Medical University, Dept. of Medicine; 750 E. Adams Street, Syracuse,
NY-13210 US. E-mail:
drvinmatli@yahoo.com
Author disclosure/Conflict of interest Statement: The authors have
nothing to disclose.
Article Guarantor: Venkata Vinod Kumar Matli MD
Conflicts of Interest: All the Authors have no conflict of interest and
none declared.
Funding: Nothing to declare.
Informed Consent: I confirm that the informed patient consent was
obtained for case publication.
Abstract:
A 48-year -old male patient with Type 2 diabetes mellitus(T2D) on
insulin replacement therapy, glipizide and Dapagliflozin presented with
generalized weakness with weight loss of 40 pounds in 6 months ever
since he was started on dapagliflozin. He was hemodynamically stable on
arrival with a finger stick glucose of 121 gm%. Physical exam was also
unremarkable except for dry mucus membranes. His lab results on arrival
are shown in Table 1. His serum osmolar gap was within the normal range.
He was treated insulin dripper DKA protocol and gap was closed, the
patient was clinically and biochemically back to baseline, and he was
discharged home.
Delayed diagnosis of normoglycemic diabetic ketoacidosis (DKA) in adults
with diabetes treated with multiple anti-diabetic drugs (e.g., sodium
glucose cotransporter-2 [SGLT-2] inhibitors) can potentially
increase morbidity and mortality. Patient education in terms of symptoms
and signs, physician awareness of early recognition of ketoacidosis in
the setting of paradoxically normal or near normal blood glucose levels
in these patients is the primary focus of this case study. This is
paradoxical DKA because theoretically patient is not meeting one of the
criterion for DKA which include triad of hyperglycemia, Ketoacidosis
with widened anion gap, Ketonemia.
This is a short case report of presumed SGLT2 inhibitor euglycemic
diabetic ketoacidosis. The main teaching point is recognition and early
diagnosis of this issue when multiple diabetic medications are present
with the absence of hyperglycemia.
Case Presentation:
The patient was a 48-year-old male with type 2 diabetes (T2D) requiring
insulin glargine daily with preprandial aspart insulin, metformin with
glipizide (500 mg + 5 mg) daily, and dapagliflozin (10 mg once daily).
His medical history was significant for hypothyroidism, hyperlipidemia,
and vitamin D deficiency. He presented to the emergency room with
complaints of generalized weakness for a few days, nausea, loss of
appetite, lightheadedness, polydipsia, and polynocturia. He had also
lost 40 pounds in the 6 months since he was started on dapagliflozin. He
denied abdominal pain, chest pain, cough, shortness of breath, diarrhea,
and urinary tract infection symptoms.
He was hemodynamically stable on
arrival with a finger stick glucose of 121 gm%. Physical exam was also
unremarkable except for dry mucus membranes. His lab results on arrival
are shown in Table 1. His serum osmolar gap was within the normal range.
Cardiac, pancreatic enzyme, electrocardiogram, and imaging studies were
unremarkable. He was managed initially with an insulin drip and
intravenous fluids in the emergency room, which was continued upon
admission to the critical care unit. After ~15 hours,
the anion gap was closed, the patient was clinically and biochemically
back to baseline, and he was discharged home. He was counseled about
medication compliance and regular follow-up with his primary care
physician.
Discussion:
Dapagliflozin is an SGLT-2 inhibitor, a novel class of
anti-hyperglycemic drugs approved by the U.S. Food & Drug
Administration (FDA) in 2013. SGLT-2 is expressed in the proximal
convoluted tubule of the nephron and mediates reabsorption of
approximately 90% of filtered glucose. Gliflozins inhibit these
transporters, thus promoting urinary glucose excretion. Officially, the
FDA approved them only for T2D because of their beneficial effects on
postprandial hyperglycemia, weight loss (to some extent), lack of
hypoglycemic effects, and decreasing daily insulin requirements. They
also lower blood pressure, which may be beneficial in hypertensive
patients.
The incidence of normoglycemic diabetic ketoacidosis (DKA) in patients
managed on SGLT-2 inhibitors has been rising [5], and triggers
include insulin compliance issues, starvation, strenuous exercise,
influenza, carbohydrate restriction, heavy alcohol abuse, and
appendicitis. The FDA issued black box warning on this life-threatening
complication. Peters et al [1] reported 13 episodes of normoglycemic
DKA, including 9 on SGLT-2 inhibitors for off-label use in patients with
type 1 diabetes. Hine et al [3] described two patients who developed
normoglycemic DKA while being managed on dapagliflozin, which is similar
to the present case.
The exact mechanism by which SGLT-2 inhibitors cause paradoxical DKA is
not clear; however, it is possible that they induce ketone body acidosis
[3] as shown in Figure 1. The increased glucagon/insulin ratio
activates lipases, leading to adipose tissue lysis and the release of
free fatty acids. These ultimately undergo beta oxidation in the liver,
contributing to ketone body production. Phlorizin is a natural glucoside
that has been used as a physiological and pharmacological tool for
research purposes [4,5]. It nonselectively inhibits both SGLT-1 and
SGLT-2. It blocks glucose absorption in the intestine and prevents
glycosuria by inhibiting glucose and sodium reabsorption in the kidney.
As a result, sodium concentration in the tubule increases, creating an
electrochemical gradient that drives acetoacetate reabsorption. If
dapagliflozin exerts a similar effect, it could also contribute to
ketone body acidosis while maintaining normal or near normal glucose
levels by glycosuria. Interestingly, SGLT-2 inhibitors can reportedly
increase serum glucagon levels by acting directly on the pancreatic
alpha cells to increase pre-proglucagon gene expression [5]. We
routinely rely on the assessment of urine ketone body levels rather
serum levels for diagnosing ketone body acidosis. As SGLT-2 inhibitors
decrease urine ketone body levels, it is prudent to also measure serum
levels and avoid potential delays in diagnosing DKA [3].
The learning objective in this case study is early diagnosis and
management of DKA in SGLT-2-treated patients with signs or symptoms of
academia, ketonemia, or ketonuria. Educating treating physicians and
patients who use SGLT-2 inhibitors about early DKA recognition and
management is of paramount importance to reduce both morbidity and
mortality. Suspicious signs and symptoms of acidosis include nausea,
vomiting, abdominal discomfort or pain, weakness, myalgias, history of
polynocturia, signs of dehydration, and ketonuria even in the setting of
normoglycemia.
Table 1: Laboratory Results
CBC BMP
WBC: 9500 cells/L Sodium: 129 mmol/L
Hb: 18.8 g/dL Potassium: 4.4 mmol/L
Hct: 56% Chloride: 97 mmol/L
Platelets:230 cells//L Bicarbonate 12 mmol/L
Blood urea nitrogen: 18 mg/dL
Creatinine: 1.1 mg/dL
Glucose: 130 mg/dL
Anion gap: 20 mmol/dL
Beta hydroxybutyrate: 3 mmol/L
ABG: pH, 7.1; pO2, 127; pCO2, 18; FiO2, 21%
Abbreviations: ABG, arterial blood gas; BMP, basic metabolic panel; CBC,
complete blood count; FiO2, fraction of inhaled gas that is O2; Hb,
hemoglobin; Hct, hematocrit; pCO2, partial pressure of carbon dioxide;
pO2, partial pressure of oxygen; WBC, white blood cells.
Figure:1 Putative mechanism showing how SGLT-2 inhibitors can cause
normoglycemic DKA (SGLT-2:Sodium Glucose co transporter-2, FFA: Free
Fatty Acids, DKA: Diabetic Ketoacidosis)
References:
1. Peters AL, Buschur EO, Buse JB, et al. Euglycemic diabetic
ketoacidosis: a potential complication of treatment with sodium-glucose
cotransporter 2 inhibition. Diabetes Care 2015. doi:10.2337/dc15-0843.
2. Hine J, Paterson H, Abrol E, et al. SGLT inhibition and euglycaemic
diabetic ketoacidosis. Lancet Diabetes Endocrinol 2015; 3: 503–504.
3. Simeon I. Taylor, Jenny E. Blau, Kristina I. Rother; SGLT2 Inhibitors
May Predispose to Ketoacidosis, The Journal of Clinical Endocrinology &
Metabolism, Volume 100, Issue 8, 1 August 2015, Pages 2849–2852,
https://doi.org/10.1210/jc.2015-1884
4. Ehrenkranz, J. R. L., Lewis, N. G., Ronald Kahn, C. and Roth, J.
(2005), Phlorizin: a review. Diabetes Metab. Res. Rev., 21: 31–38.
doi:10.1002/dmrr.532
5. Bonner C, Kerr-Conte J, Gmyr V, et al. Inhibition of the glucose
transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers
glucagon secretion. Nat Med. 2015;21:512–517.