Send Orders for Reprints to
[email protected] Reviews on Recent Clinical Trials, 2018, 13, 1-5
1
CASE REPORT
Diabetic Ketoacidosis in Patients with Type 2 Diabetes on Sodium-Glucose Cotransporter-2 Inhibitors - A Case Series Purva V. Sharma1,*,#, Yash B. Jobanputra1,#, Karen Lewin2, Stuart Bagatell1 and Daniel M. Lichtstein1 1 2
Department of Internal Medicine, University of Miami Palm Beach Regional Consortium, Atlantis, Fl, USA; JFK Medical Center, Atlantis, Fl, USA Abstract: Background: Diabetic ketoacidosis (DKA) is a serious complication of diabetes seen commonly in autoimmune Type 1 diabetes mellitus (DM), however patients with Type 2 diabetes are also at risk. Diabetic ketoacidosis may be precipitated by the catabolic stress of acute illness such as trauma, surgery, or infections. Recent studies have suggested that sodium-glucose cotransporter-2 (SGLT-2) inhibitors precipitate DKA in Type 2 diabetes. We present a case series of four patients on SGLT-2 inhibitors who presented with DKA.
AR TIC LE H ISTORY Received: December 25, 2017 Revised: February 28, 2018 Accepted: February 28, 2018 DOI: 10.2174/1574887113666180314101436
Methods: Medical records were reviewed and patients who were admitted with diabetic ketoacidosis in the last one year at our institute were identified. The charts of such patients were reviewed and we were able to identify 4 patients who were admitted with DKA and were on SGLT-2 inhibitors at the time of admission for the management of their diabetes. Results: The age group of the four patients was between 45-65 years. Interestingly, all four patients were female. The admission blood glucose levels of these patients ranged from 203 to 400(mg/dl). The pH at the time of admission was in the acidotic range with anion gap ranging from 19 to 24. Two of these four patients had symptoms of a localized infection at the time of admission, which was confirmed by laboratory and radiological evaluation. Three of these patients required management in the intensive care unit. Conclusion: Ketoacidosis is a rare but serious side effect of SGLT2 inhibitors. It is being increasingly reported as these drugs are now commonly being prescribed in the primary care setting. Awareness that DKA can occur in the setting of relative euglycemia is critical to recognize this life-threatening complication of diabetes. More research is needed to better understand the underlying pathophysiology and precipitating factors leading to ketoacidosis in SGLT-2 inhibitor treated patients.
Keywords: Canagliflozin, diabetes mellitus, diabetic ketoacidosis, empagliflozin, SGLT-2 inhibitors. 1. INTRODUCTION
2. CASE REPORTS
Diabetic ketoacidosis (DKA) is a serious complication of diabetes mellitus. DKA is most commonly seen in autoimmune Type 1 diabetes mellitus. However, patients with Type 2 diabetes are also at risk of developing DKA. Diabetic ketoacidosis may be precipitated by the catabolic stress of acute illness such as trauma, surgery, or infections [1].
2.1. Case 1
Recent studies have shown that the class of oral hypoglycemic agents SGLT-2 inhibitors may precipitate DKA in patients with Type 2 Diabetes [2]. We present a case series of four patients on SGLT-2 inhibitors for Type 2 DM who presented with DKA. *Address correspondence to this author at the Department of Internal Medicine, University of Miami Palm Beach Regional Consortium, 5301 S. Congress Avenue, Atlantis, Fl-33462, USA; Tel: +1 561 965 7300; E-mail:
[email protected] # Both authors contributed equally to the study. 1574-8871/18 $58.00+.00
A 56-year-old woman with poorly controlled diabetes diagnosed 5 years ago, presented to the ED with symptoms of pain and swelling of the skin of her left flank. On physical exam, the skin of her left flank had subdermal induration measuring 5x3 in. Studies revealed leukocytosis of 16500, blood glucose of 377, anion gap of 19 and moderate serum ketones. Arterial blood gas revealed a pH of 7.39 with HCO3 of 16. A CT scan of the abdomen and pelvis showed diffuse subcutaneous fat stranding and dermal thickening in the left posterior flank region suggesting cellulitis. She was diagnosed with diabetic ketoacidosis at the time of admission and cellulitis. Patient’s UA was also consistent with a UTI and her urine cultures grew Klebsiella. She was treated with IV antibiotics for the UTI and cellulitis. Her blood glucose was also controlled with insulin drip, which was later changed to subcutaneous insulin. © 2018 Bentham Science Publishers
2
Reviews on Recent Clinical Trials, 2018, Vol. 13, No. 2
Sharma et al.
Her home regimen included long-acting Levemir insulin and metformin. The patient admitted to not being compliant with her insulin. She also mentioned that her physician had given her samples of invokana (canagliflozin) about 2-3 weeks prior to presenting.
was admitted to the ICU for management of DKA and was started on insulin drip. She was also diagnosed with acute viral enteritis. Patient’s blood culture was positive for Klebsiella pneumoniae likely from enteritis and was started on IV antibiotics.
At the time of discharge, the patient was advised to stop canagliflozin due to the potential risk of DKA and to discuss this further with her primary physician.
Please see Table 1 for baseline characteristics on all 4 patients.
2.2. Case 2 The 57-year-old woman, recently diagnosed with diabetes, had been started on metformin. She presented to the ED with symptoms of nausea and abdominal pain for 2 days along with altered mentation. On physical examination, the patient appeared confused and was oriented only to person, the rest of the physical examination was unremarkable. Laboratory evaluation showed leukocytosis of 15.9 x 103/ul blood glucose of 235, anion gap of 24 and large ketones in her serum. She was acidemic with a pH of 7.18 and HCO3 9. The patient was started on an insulin drip and admitted to the ICU for management of her DKA. The patient’s son informed us that the patient had not seen a physician for more than 20 years and had very recently been diagnosed with diabetes. She was started on metformin and pioglitazone at the time of diagnosis. She was also given samples of invokana to take along with the prescribed medications. 2.3. Case 3 The 46-year-old morbidly obese woman presented to the ED with symptoms of nausea and diarrhea for two days. The patient was diagnosed with diabetes only five days earlier and was started on metformin, pioglitazone and invokana. The patient was afebrile, tachycardic at 125 beats/min and blood pressure was 150/85mmHg. Her physical examination was unremarkable. Laboratory examination revealed a leukocytosis of 26 x 103/ul, glucose of 203, HCO3 of 8 and anion gap of 23. The pH was 7.07 and she had large serum ketones. The patient was admitted to the ICU with a diagnosis of diabetic ketoacidosis. She began on an insulin drip. She was discharged home on metformin and pioglitazone and was also started on long-acting levemir insulin. 2.4. Case 4 A 63-year-old woman presented to the ED with complaints of generalized weakness, abdominal pain and diarrhea for four days prior to presentation. The patient also complained of nausea and had a few episodes of vomiting in the last two days. She reported being poorly compliant with her diabetes medications which were metformin and dulaglutide. On physical examination, she was afebrile with blood pressure 142/80mmHg, HR 82/minute. There was mild epigastric tenderness on palpation of her abdomen. Her lab tests showed leukocytosis of 14.7 x 103/ul, glucose of 400 with a HCO3 of 9 and an anion gap of 22. Arterial blood gas showed a pH of 7.24 with pCO2 of 20. Her CT scan at the time of admission showed mild enteritis involving the duodenum with fluid-filled lumen and mild dilatation. Patient
3. DISCUSSION Diabetic ketoacidosis is one of the most serious acute complications of diabetes. DKA is defined as a metabolic state characterized by hyperglycemia, increased anion gap metabolic acidosis, ketogenesis and increased total body ketones [1]. The National Diabetes Surveillance Program of the Centers for Disease Control (CDC) estimated that there were 140,000 hospital discharges for DKA in 2009 in the United States, compared to 80,000 in 1988 [2]. DKA usually presents in the setting of hyperglycemia with a relative or absolute insulin deficiency. Sufficient insulin is not present for oxidation of free fatty acids and to suppress lipolysis. This results in ketone body production resulting in metabolic acidosis. There is also an increase in counter-regulatory hormones such as glucagon. DKA occurs more frequently in type 1 diabetes, although 10% to 30% of cases occur in patients with type 2 diabetes [3]. DKA is more common among patients younger than 65 years. A precipitating event is usually identified when a patient presents with DKA, infection being one of the most common. Other major precipitating events are noncompliance with insulin treatment and new-onset Type 1 diabetes. Sodium glucose cotransporter 2 (SGLT-2) inhibitors have been found recently to precipitate DKA in some patients [4]. This newer class of anti-hyperglycemic drugs was first marketed in 2013 [5]. They have been approved for use in patients with type 2 diabetes, and clinical trials are ongoing in individuals with type 1 diabetes. Their use may have increased after the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) reported a remarkable reduction in cardiovascular and all-cause mortality with empagliflozin [6]. SGLT2 inhibitors are increasingly being prescribed as an adjunctive medication in the treatment of type 2 DM in combination with metformin, pioglitazone and insulin. SGLT-2 inhibitors work by increasing the urinary excretion of glucose. (Please see supplementary material). One of the most common adverse effects associated with SGLT-2 inhibitors is vulvovaginal candidiasis [7]. Other less common adverse events are orthostatic hypotension, acute kidney injury and bone fracture. The other adverse event that has increasingly been associated with SGLT-2 inhibitors is diabetic ketoacidosis. In May 2015 the Food and Drug Administration (FDA) warned that treatment with SGLT2 inhibitors may increase the risk of ketoacidosis [8]. According to the FDA, between March 2013 and June 2015, 73 cases of ketoacidosis requiring hospitalization were reported in patients taking SGLT2 inhibitors.
Diabetic Ketoacidosis in Patients with Type 2 Diabetes
Table 1.
Reviews on Recent Clinical Trials, 2018, Vol. 13, No. 2
3
Patient characteristics.
Patient Characteristics
Case 1 June 2017
Case 2 September 2017
Case 3 January 2016
Case 4 June 2017
Age
56
57
46
63
Sex
Female
Female
Female
Female
T1/T2 DM
Type 2
Type 2
Type 2
Type 2
Duration of DM
5 years
2 weeks
5 days
20 years
BMI (kg/m )
41.8
25
45.5
30.9
Last HbA1C
12.1
12
10.6
12.4
SGLT2 inhibitor (dose)
Canagliflozin (300mg daily)
Co-morbidities
HTN, HLD
2
Lisinopril Other medications
Simvastatin Levemir 50 units QHS Metformin
Canagliflozin
Canagliflozin
Empagliflozin
(300mg daily)
(300 mg daily)
(10mg daily)
HTN
HLD
HTN, HLD
Amlodipine Atorvastatin Lisinopril
Pioglitazone
Metoprolol
Metformin
Metformin
Atorvastatin
Dulaglutide Metformin
Pioglitazone
Family history of DM
Mother with DM2
No
No
Unknown
Time to DKA post SGLT-2 inhibitor initiation
2-3 weeks
2 weeks
5 days
Unknown
Potential contributors
UTI/Cellulitis
None
None
URI/viral gastroenteritis
Insulin dose reduction prior to DKA
No
N/A
N/A
N/A
Presenting plasma glucose(mg/dl)
377
235
203
400
pH
7.39
7.18
7.07
7.24
pCO2 (mmHg)
31.6
16.2
20.4
20
HCO3 (mmol/L)
16
9
8
9
Anion gap (mmol/L)
19
24
23
22
Mental status
Oriented
Altered
Oriented
Oriented
Ketones
Moderate
Large
Large
Large
Initial inpatient care
Step down unit
ICU
ICU
ICU
APACHE II Score on admission
N/A
10
8
7
The literature supporting this evidence has largely been reported in patients with Type 1 diabetes mellitus. An 8 week open label clinical trial studying the adjunctive effects of the SGLT-2 inhibitor empagliflozin to insulin on glycemic control reported that the drug could contribute towards ketosis as 2 out of 42 patients had to be withdrawn from the study due to ketosis [9]. Although the patients did have other precipitating factors to develop ketosis (such as insulin pump failure and acute gastroenteritis) the trial suggested that the risk of ketosis in the setting of use of empagliflozin needed further evaluation. Recently case reports are also being pub-
lished about the incidence of ketoacidosis in patients with Type 2 diabetes. A case report was published in Endocrine Society of a T2D patient presenting to the emergency department with euglycemic ketoacidosis 2 days after the initiation of canagliflozin in combination with metformin and glipizide [10]. This case presentation is very similar to case #2 described in this series where the patient was given samples of canagloflozin in combination with metformin and pioglitazone and presented to the emergency department with euglycemic ketoacidosis with an anion gap of 24mEq/L within two weeks of starting the medication.
4
Reviews on Recent Clinical Trials, 2018, Vol. 13, No. 2
Sharma et al.
Fig. (1). Pathogenesis of ketoacidosis due to SGLT-2 inhibition.
The mechanism by which SGLT-2 inhibitors can cause diabetic ketoacidosis has been researched extensively in both Type 1 and Type 2 diabetics. (Fig. 1) (Please see supplementary material for details). A combination of increased production as well as decreased renal clearance of ketones could lead to the development of ketoacidosis. Diabetic ketoacidosis reported with the use of SGLT-2 inhibitors is frequently euglycemic. (plasma blood glucose
