C-Peptide Testing Is Not Routinely Recommended Before SGLT2 Inhibitor Initiation
Current guidelines do not recommend routine C-peptide measurement before initiating SGLT2 inhibitors to prevent euglycemic ketoacidosis. Instead, major cardiology and endocrinology societies emphasize clinical risk assessment, patient education, and maintaining adequate insulin therapy in insulin-requiring patients 1, 2.
Why C-Peptide Testing Is Not Standard Practice
The available evidence does not support C-peptide as a screening tool for euglycemic ketoacidosis risk before SGLT2 inhibitor initiation. Guidelines from the American College of Cardiology, American Diabetes Association, and KDIGO consensus reports make no mention of C-peptide testing as part of pre-initiation assessment 1.
The focus is on identifying clinical risk factors rather than laboratory markers of endogenous insulin production 1, 2, 3.
What Actually Matters: Clinical Risk Assessment
High-Risk Populations to Identify
Patients with Type 2 diabetes requiring insulin are at particular risk for euglycemic ketoacidosis 1. The key clinical factors to assess include:
- History of diabetic ketoacidosis - this is a contraindication or requires extreme caution 1
- Insulin-requiring diabetes - these patients need special precautions 1, 2
- Recent insulin dose reductions or discontinuation 2, 4
- Chronic pancreatitis or conditions affecting insulin secretion 4
- Planned surgery or procedures requiring prolonged fasting 3, 5
The Critical Intervention: Maintain Insulin Therapy
To mitigate euglycemic ketoacidosis risk, it is essential to maintain at least low-dose insulin in insulin-requiring individuals when starting SGLT2 inhibitors 1, 2. This is far more important than measuring C-peptide levels.
The 2022 ADA/KDIGO consensus specifically states that maintaining at least low-dose insulin is a key risk mitigation strategy 1. This recommendation is based on the understanding that relative insulinopenia combined with SGLT2 inhibitor effects creates the perfect storm for ketoacidosis 5, 6.
Evidence-Based Prevention Strategies
Patient Education (Most Critical)
Educate patients regarding symptoms of diabetic ketoacidosis (nausea, vomiting, abdominal pain, weakness) and that diabetic ketoacidosis can occur even if blood glucose readings are in the 150-250 mg/dL range 1. Patients must understand to seek urgent medical attention if these symptoms develop 1, 2.
Sick Day Protocols
Institute a sick day protocol that includes instructions to pause SGLT2 inhibitors during periods of acute illness, reduced oral intake, vomiting, or dehydration 1, 2, 3. The pharmacologic effects may persist beyond several half-lives of elimination, so holding the medication 3 days before major surgery is recommended 3, 5.
Ketone Monitoring Supplies
Provide blood or urine ketone monitoring supplies and educate patients to check ketones when feeling unwell 1, 2, 3. Blood β-hydroxybutyrate measurement is more accurate than urine ketones 2.
Insulin Dose Management
If HbA1c is well-controlled at baseline or there is a history of frequent hypoglycemic events, consider reducing total daily insulin dose by approximately 20% when starting SGLT2 inhibitor therapy, but never discontinue insulin entirely 1. This prevents hypoglycemia while maintaining sufficient insulin to suppress ketogenesis 1, 2.
Common Pitfalls to Avoid
The most dangerous error is dismissing the diagnosis of ketoacidosis because glucose is normal 2. SGLT2 inhibitors cause glycosuria that prevents glucose accumulation while ketoacidosis progresses unchecked 2, 5.
Never allow patients to discontinue insulin during illness 2. Case reports consistently show that reduced oral intake combined with continued SGLT2 inhibitor use and inadequate insulin leads to euglycemic ketoacidosis 4, 5, 7, 6.
High clinical suspicion is necessary in patients on SGLT2 inhibitors presenting with nausea, vomiting, abdominal pain, dyspnea, or generalized weakness, even when glucose appears reassuring 2. The absence of hyperglycemia, polyuria, and polydipsia leads to delayed diagnosis 4.
When to Reconsider SGLT2 Inhibitor Use
For patients with ketonuria at baseline, address the underlying cause of ketosis before considering an SGLT2 inhibitor 3. Alternative glucose-lowering agents that don't increase ketone production should be used in patients at very high risk for ketoacidosis 3.
History of diabetic ketoacidosis is listed as a consideration for alternative agents in ACC guidelines 1.
The Bottom Line on C-Peptide
While C-peptide theoretically reflects endogenous insulin secretion capacity, no guideline recommends its routine measurement before SGLT2 inhibitor initiation 1. One case report noted that a patient's C-peptide level was consistent with blood glucose on admission, indicating adequate insulin secretion, yet she still developed euglycemic ketoacidosis due to inadequate food intake 7. This demonstrates that clinical risk factors (reduced oral intake, acute illness, surgical stress) are more predictive than C-peptide levels 4, 5, 7, 6.
The evidence-based approach prioritizes clinical assessment, patient education, sick day protocols, ketone monitoring supplies, and maintaining adequate insulin therapy over laboratory screening with C-peptide 1, 2, 3.