Understanding Drug-Induced Ketoacidosis
Ketoacidosis is a serious metabolic state where the body produces high levels of blood acids called ketones. It typically occurs when the body can't produce enough insulin, leading to a breakdown of fat for energy. While often associated with uncontrolled type 1 diabetes, certain medications are a significant precipitating factor for developing both diabetic ketoacidosis (DKA) and a more insidious form called euglycemic diabetic ketoacidosis (euglycemic DKA or euDKA). Euglycemic DKA is particularly challenging because it occurs with normal or only slightly elevated blood glucose levels (often below 200 mg/dL), which can delay diagnosis and treatment.
Primary Medications Implicated in Ketoacidosis
While various drugs can influence glucose and ketone metabolism, one class stands out for its association with ketoacidosis, particularly euDKA.
SGLT2 Inhibitors
Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a class of oral medications used to treat type 2 diabetes, heart failure, and chronic kidney disease. The FDA has warned that these drugs may lead to ketoacidosis.
- Examples: Canagliflozin (Invokana), Dapagliflozin (Farxiga), Empagliflozin (Jardiance), and Ertugliflozin (Steglatro).
- Mechanism: SGLT2 inhibitors increase glucose excretion in urine, leading to lower blood glucose and a relative insulin deficiency. This triggers an increase in glucagon, which promotes ketone production in the liver. The glucose in urine can mask the high blood sugar typical of DKA, resulting in a euglycemic presentation. Studies suggest SGLT2 inhibitors can increase DKA risk compared to other diabetes medications.
- Risk Factors: Risk increases during physiological stress, such as surgery, infection, trauma, dehydration, excessive alcohol, or very low-carbohydrate diets. Onset can occur as early as two weeks after starting the medication.
Other Notable Medications
Other medications can also increase ketoacidosis risk, typically by causing high blood sugar and insulin resistance.
- Corticosteroids: Drugs like prednisone are known to raise blood sugar by increasing insulin resistance and glucose production, especially at higher doses.
- Thiazide Diuretics: Medications like hydrochlorothiazide can impair glucose tolerance, potentially by affecting the pancreas and causing low potassium levels, which reduces insulin secretion.
- Atypical Antipsychotics: Certain antipsychotics, including olanzapine, have been linked to DKA, possibly due to weight gain and insulin resistance.
- GLP-1/GIP Receptor Agonists: Case reports indicate ketoacidosis, specifically starvation ketoacidosis, in non-diabetic patients using tirzepatide for weight loss. This may be due to poor food intake and existing insulin resistance.
Comparison of Medication Classes Causing Ketoacidosis
| Medication Class | Primary Mechanism | Common Examples | Type of Ketoacidosis | Key Risk Factors |
|---|---|---|---|---|
| SGLT2 Inhibitors | Increased urinary glucose excretion, leading to lower insulin and higher glucagon levels | Canagliflozin, Dapagliflozin, Empagliflozin | Primarily Euglycemic DKA (euDKA) | Surgery, illness, dehydration, low-carb diet |
| Corticosteroids | Increased insulin resistance and hepatic glucose production | Prednisone, Hydrocortisone | Hyperglycemic DKA | High doses, long-term use |
| Thiazide Diuretics | Decreased insulin secretion (possibly due to hypokalemia) | Hydrochlorothiazide, Chlorthalidone | Hyperglycemic DKA | High doses |
| Atypical Antipsychotics | Insulin resistance, potentially linked to weight gain | Olanzapine, Clozapine | Hyperglycemic DKA | Specific agent used, underlying metabolic health |
Symptoms and Recognition
Recognizing drug-induced ketoacidosis is critical. Symptoms often include nausea, vomiting, abdominal pain, fatigue, and shortness of breath. Euglycemic DKA's normal blood sugar makes a high index of suspicion necessary for patients on implicated medications. Patients on SGLT2 inhibitors with these symptoms should be evaluated for ketoacidosis regardless of blood glucose.
Conclusion
While SGLT2 inhibitors are the most prominent medications causing ketoacidosis, particularly euDKA, other drugs like corticosteroids, certain diuretics, and antipsychotics also increase risk, mainly by causing high blood sugar. Awareness of these risks, their mechanisms, and patient education on symptoms are vital for prevention and management. Patients experiencing symptoms while taking these medications should seek immediate medical attention.
Disclaimer: This article is for informational purposes only and does not constitute medical advice. Always consult with a qualified healthcare professional before making any decisions about your health or medications.
For more in-depth information from an authoritative source, you can review the FDA's safety communication on SGLT2 inhibitors: FDA Drug Safety Communication
