From the Guidelines
Empagliflozin (Jardiance) can cause euglycemic diabetic ketoacidosis (EDKA) through several interconnected mechanisms, including a state of relative insulin deficiency, increased lipolysis and fatty acid oxidation, and enhanced glucagon secretion, as reported in recent studies 1. The pathophysiology of Jardiance-induced EDKA is complex and involves multiple factors. As a sodium-glucose cotransporter-2 (SGLT2) inhibitor, empagliflozin blocks glucose reabsorption in the kidneys, leading to increased urinary glucose excretion and reduced blood glucose levels. This creates a state of relative insulin deficiency, as patients may reduce their insulin doses due to improved glycemic control. The reduced insulin levels trigger increased lipolysis and fatty acid oxidation, resulting in ketone body production. Some key points to consider in the pathophysiology of EDKA include:
- Increased glucagon secretion, which further promotes hepatic ketogenesis
- Enhanced renal reabsorption of ketones, contributing to ketone accumulation
- Risk factors, such as insulin dose reduction, low carbohydrate intake, surgery, acute illness, alcohol consumption, and dehydration
- The potential for EDKA to develop rapidly, typically within days to weeks of starting empagliflozin, and the need for prompt treatment with insulin, fluids, and carbohydrates despite normal glucose levels, as highlighted in recent guidelines 1. The underlying mechanism of EDKA is similar to that of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS), which involves a reduction in the net effective action of circulating insulin coupled with a concomitant elevation of counterregulatory hormones, such as glucagon, catecholamines, cortisol, and growth hormone, as described in earlier studies 1. However, the specific mechanisms and risk factors associated with EDKA are distinct and require careful consideration in clinical practice.
From the FDA Drug Label
JARDIANCE causes intravascular volume contraction [see Warnings and Precautions (5. 1)] and can cause renal impairment [see Adverse Reactions (6. 1)]. Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors, including JARDIANCE. Patients treated with JARDIANCE who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels, as ketoacidosis associated with JARDIANCE may be present even if blood glucose levels are less than 250 mg/dL
The pathophysiology of Jardiance (Empagliflozin) induced euglycemic diabetic ketoacidosis (EDKA) is not fully explained in the provided drug labels, but it is associated with:
- Intravascular volume contraction
- Renal impairment
- Increased ketones in the blood or urine
- Severe metabolic acidosis It is recommended to monitor for ketoacidosis and temporarily discontinue JARDIANCE in clinical situations known to predispose to ketoacidosis 2.
From the Research
Pathophysiology of Jardiance Induced Euglycemic Diabetic Ketoacidosis
The pathophysiology of Jardiance (Empagliflozin) induced euglycemic diabetic ketoacidosis (EDKA) involves several key mechanisms:
- Enhanced lipolysis and ketone body reabsorption due to the inhibition of sodium-glucose cotransporter 2 (SGLT2) [ 3 ]
- Stimulation of pancreatic alpha cells and inhibition of beta cells, causing an imbalance in glucagon/insulin levels and contributing to lipolysis and ketogenesis [ 3 ]
- Increased urinary glucose excretion, leading to poor glucose availability and ketone body production [ 4 ]
- Insulin deficiency or resistance with glucagon release, resulting in increased ketone body production [ 4 ]
Risk Factors and Triggers
Several risk factors and triggers have been identified for Jardiance induced EDKA, including:
- Perioperative fasting [ 3 ]
- Pancreatic etiology [ 3 ]
- Low carbohydrate or ketogenic diet [ 3 ]
- Obesity [ 3 ]
- Malignancy [ 3 ]
- Acute illness [ 5 ]
- Decreased carbohydrate intake [ 5 ]
- Decrease in dose or discontinuation of insulin [ 5 ]
Clinical Presentation
Patients with Jardiance induced EDKA may present with:
- Nausea [ 4 ]
- Vomiting [ 4 ]
- Malaise [ 4 ]
- Fatigue [ 4 ]
- Dyspnea [ 5 ]
- Epigastric pain [ 6 ]
- Loss of appetite [ 6 ]
Diagnosis and Management
Diagnosis of Jardiance induced EDKA involves laboratory assessment, including venous blood gas for serum pH, bicarbonate, and ketones [ 4 ]. Management includes: