DKA and SGLT-2 inhibitors
One of the greatest aspects of medicine that I enjoy is a continual process of learning. We must continue to grow in our profession, seeking knowledge and experience as much as possible. One such incident occurred recently while on shift… and talk about being a little late to the party! In 2015, the US food and drug administration issued a drug safety communication that warned of an increased risk of DKA with uncharacteristically mild to moderate to glucose elevations (euglycemic DKA). This warning was based on diabetic medications involving SGLT-2 inhibitors. In fact this was based on 20 clinical cases requiring hospitalization captured between March 2013 and June 2014 in the FDA adverse event reporting system database. SGLT-2 inhibitors first came into market in 2013. What are SGLT-2 inhibitor medications?
“In people without diabetes about 180 grams is filtered daily by the renal glomeruli and then reabsorbed by the proximal convoluted tubule. This is achieved by passive transporters, facilitated glucose transporters and active co-transporters, namely sodium glucose co-transporters. There are six identified SGLT’s, of which two, SGLT-1 and SGLT-2, are considered most important. These are sodium-glucose co-transporter inhibitor medications. The first SGLT-2i discovered was Phlorizin, a naturally occurring compound derived from apple tree bark. Because of its nonselective nature it has caused severe gastrointestinal symptoms. Due to this and its poor viability, work on its development could not continue. Drugs which specially inhibit SGLT-2, thereby avoiding gastrointestinal effects related to SGLT-1 inhibition, have now been developed. Some of these are as follows: Canagliflozin, Dapagliflozin, Empagliflozin, Ipragliflozin, Luseogliflozin, Tofogliflozin.” (3)
“Mechanism of action- sodium-glucose cotransporter-2 inhibitors work by inhibiting SGLT-2 in the PCT to prevent reabsorption of glucose and excretion in urine. As glucose is excreted, its plasma levels fall, leading to an improvement in all glycemic parameters. The mechanism of action is dependent on blood glucose levels, and unlike the actions of other diabetic medications it is independent of the action of insulin. Thus, there is minimal potential of hypoglycemia and no risk of overstimulation or fatigue of the [pancreatic] beta cells. Because their mode of action depends on normal renal glomerular-tubular function, SGLT-2 efficacy is reduced in persons with renal impairment.” (3)
“DKA is an overt serious clinical condition that may be missed only if presenting with mild to moderate hyperglycemia, as it may be the case with use of SGLT2 inhibitors, which could delay diagnosis and treatment and even accelerate the progressive metabolic deterioration.” (1)
DKA Case Study
The patient was brought in by EMS with a chief complaint of “weakness.” The patient stated that he was a diabetic and had not been feeling well over the last few days with decreased PO intake and that he felt “dehydrated.” His wife stated he had not been “acting himself” and that she had tried to get him something to eat but he wasn’t eating. The patient stated no other complaints. On exam was a 40 year-old male, moderately overweight, slightly tachycardic, hypertensive, with dry mucus membranes. I immediately started the patient on fluids, and ordered the following: FSBS, UA, labs and drew a VBG. Results were as follows:
- FSBS: 200
- VBG: pH – 7.25, HCO3 – 16
- Labs: K – 3.5, CO2 – 14, Anion gap – 20, Glucose – 195
- Serum ketones: +
- UA: glucose +, ketones +
As the information reveals above, the patients case presentation is screaming DKA but without the elevated blood sugar. The clinical triad of diabetic ketoacidosis (DKA) encompasses increased anion gap metabolic acidosis, hyperglycemia, and increased ketone bodies. Elevated glucose (usually greater than 250) is considered the classic diagnosis of DKA.
“In euDKA, insulin deficiency and insulin resistance are milder (and insulin resistance may actually be improved); therefore, glucose overproduction and underutilization are quantitatively less than in DKA. More importantly, renal glucose clearance (i.e., the ratio of glycosuria to prevailing glycemia) is twice as large with euDKA than with DKA.” (1)
“The pathogenesis of DKA is well established. Briefly, absolute insulin deficiency leads to reduced glucose utilization and enhanced lipolysis; increased delivery of free fatty acids (FFAs) to the liver coupled with raised glucagon levels promotes FFA oxidation and production of ketone bodies. In both T1D and T2D, DKA presents with marked hyperglycemia (>250 mg/dL, typically 350–800 mg/dL), profuse glycosuria (2–4 mg ⋅ min−1 ⋅ kg−1), and hyperketonemia (plasma β-hydroxybutyrate 4.2–11.0 mmol/L). The hyperglycemia of DKA is associated with extreme insulin resistance, manifesting itself as markedly (>70%) reduced tissue glucose disposal and increased endogenous glucose production (EGP).”(1)
“However, there is a subset of patients in whom the serum glucose levels are within the normal limits, and this condition is termed euglycemic DKA (EDKA). This phenomenon was first described by Munro et al. where 37 out of 211 DKA patients had normal glucose levels (<300 mg/dL) along with a plasma bicarbonate level of <10 mmol/L at presentation. Later, normoglycemia was redefined as <250 mg/dL. Thus, EDKA is defined as a triad comprising high anion gap metabolic acidosis with positive serum and urine ketones when serum glycemic levels are <250 mg/dL.” (2)
In conclusion, with euglycemic diabetic ketoacidosis, “physicians and patients need to be made aware that such risk may be increased in long-standing type 2 diabetic patients with marked β-cell insufficiency or in latent autoimmune diabetes in adults with rapid evolution toward type 1 diabetes and during prolonged starvation, after surgery, or during intercurrent illness.” (1) “Diagnosis of EDKA is difficult as it is primarily a diagnosis of exclusion. Other forms of ketoacidosis like starvation ketoacidosis have to be ruled out. Also, other causes of increased anion gap metabolic acidosis like lactic acidosis, increased toxic serum alcohols (methanol, ethylene glycol, etc.), drug toxicity, paraldehyde ingestion and renal failure have to be excluded. Once diagnosed, management of EDKA is simple and is almost similar to the management of DKA. The mainstay of treatment involves rapid correction of dehydration using intravenous fluids. The second most important step in the management is the use of insulin drip along with a dextrose containing solution until the anion gap, and bicarbonate levels normalize. Periodic checking of urine for ketones and arterial blood gas analysis to estimate anion gap are warranted until the values normalize.” (2) Although the patient looked like DKA, and a majority of his labs were leaning toward DKA, I had trouble diagnosing the patient with DKA until I did some research and found a majority of the information within this article. Though limited in documented cases, euglycemic diabetic ketoacidosis is real and potentially deadly.
- Euglycemic Diabetic Ketoacidosis: A Predictable, Detectable, and Preventable Safety Concern With SGLT2 Inhibitors – Diabetes Care 2015 Sep; 38(9): 1638-1642
- Euglycemic diabetic ketoacidosis: a diagnostic and therapeutic dilemma – Endocrinol Diabetes Metab Case Rep. 2017; 2017: 17-0081
- Sodium Glucose Co-Transporter-2 (SGLT2) Inhibitors: A Review of Their Basic and Clinical Pharmacology – Diabetes Ther. 2014 Dec; 5(2): 355–366