Why does Jardiance (Empagliflozin), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, increase the risk of diabetic ketoacidosis (DKA) in a patient with type 2 diabetes?

Why Jardiance Increases DKA Risk

Jardiance (empagliflozin) increases diabetic ketoacidosis risk through three primary mechanisms: it increases glucagon secretion which drives lipolysis and ketone production, decreases renal clearance of ketones, and causes volume depletion that exacerbates metabolic derangement. 1, 2, 3

Pathophysiological Mechanisms

SGLT2 inhibitors fundamentally alter metabolic homeostasis by blocking glucose reabsorption in the kidney, forcing urinary glucose excretion. This creates a state of relative carbohydrate deprivation at the cellular level despite adequate circulating glucose. 3

The key mechanisms are:

• Altered insulin-to-glucagon ratio: By lowering blood glucose through urinary excretion rather than insulin action, SGLT2 inhibitors shift the hormonal balance toward glucagon dominance, which directly stimulates lipolysis and hepatic ketone production (β-hydroxybutyrate and acetoacetate). 1, 3

• Decreased renal ketone clearance: The same SGLT2 transporters that reabsorb glucose also facilitate ketone excretion. When blocked, ketones accumulate in the bloodstream even as glucose is being eliminated. 1, 2

• Volume depletion: The osmotic diuresis from glycosuria causes intravascular volume contraction, which triggers counter-regulatory hormone release (cortisol, catecholamines) that further promotes lipolysis and ketogenesis. 2, 4

The Euglycemic DKA Phenomenon

The most dangerous aspect is that DKA can occur with blood glucose levels below 250 mg/dL—often even below 200 mg/dL—creating a diagnostic trap. 3, 4 The FDA label explicitly warns that ketoacidosis may be present even with glucose levels less than 250 mg/dL. 4

This occurs because SGLT2 inhibitors are simultaneously:

• Removing glucose from the bloodstream (keeping glucose "normal")
• Promoting ketone production through the mechanisms above
• Creating a state of cellular starvation despite adequate blood glucose 3, 5

High-Risk Clinical Scenarios

The FDA label and American Diabetes Association identify specific precipitants that dramatically increase DKA risk: 4, 3

• Insulin dose reduction >20% when initiating SGLT2 inhibitors 2
• Acute illness (infections, COVID-19, any febrile illness) 3, 4, 6
• Reduced caloric intake: fasting for surgery, illness-related poor oral intake, or intentional fasting 3, 4
• Very low-carbohydrate or ketogenic diets: these directly add exogenous ketone production on top of SGLT2 inhibitor-induced ketogenesis 3, 7
• Surgery or procedures requiring fasting (should discontinue SGLT2 inhibitors at least 3 days prior) 3
• Excessive alcohol consumption 3, 4
• Pancreatic insulin deficiency: type 1 diabetes, history of pancreatitis, pancreatic surgery 4, 6

Quantifying the Risk

While the absolute risk remains relatively low in type 2 diabetes, it is clinically significant:

• Incidence in type 2 diabetes: 0.6–4.9 events per 1,000 patient-years 3
• Relative risk increase: 2.46-fold in randomized trials, 1.74-fold in observational studies 3
• Perioperative risk: Higher at 1.02 vs 0.69 per 1,000 patients, with emergency surgery carrying 1.1% risk versus 0.17% for elective procedures 3
• Type 1 diabetes: Eight-fold increase in DKA compared to placebo when SGLT2 inhibitors used off-label 1

Critical Clinical Pitfall

The most common error is dismissing DKA because glucose is "not high enough." 4, 5 In two of three cases in one series, diagnosis was delayed specifically because providers did not suspect DKA with normal or mildly elevated glucose. 6

The FDA label mandates: "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." 4

Classic presentation includes nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath—but without the expected severe hyperglycemia, polyuria, and polydipsia. 4, 5

Prevention Strategy

Before prescribing Jardiance, assess these specific risk factors: 4

• History of pancreatic insulin deficiency (type 1 diabetes, pancreatitis, pancreatic surgery)
• Current or planned caloric restriction or ketogenic diet
• Alcohol use patterns
• Upcoming surgical procedures

Patient education must include: 3

• Symptoms of DKA (nausea, vomiting, abdominal pain, malaise, shortness of breath)
• Instructions to check ketones during illness or with these symptoms
• Maintain basal insulin even when not eating
• Temporarily stop SGLT2 inhibitor during acute illness or before surgery

When initiating in patients on insulin, reduce insulin dose by only 20% maximum—larger reductions dramatically increase DKA risk. 2