Can Empagliflozin and Novomix Be Given Together?
Yes, empagliflozin and Novomix (premixed insulin) can be given at the same time, but there is a definite increased risk of hypoglycemia that requires proactive insulin dose reduction of approximately 20% when initiating empagliflozin. 1
Understanding the Hypoglycemia Risk
The combination of empagliflozin with insulin creates hypoglycemia risk through an additive glucose-lowering effect, though empagliflozin itself carries minimal inherent hypoglycemia risk due to its insulin-independent mechanism. 1, 2
Key mechanistic points:
- Empagliflozin causes urinary glucose loss of 50-100g per 24 hours, equivalent to 200-400 kcal/day energy expenditure 3
- This glucose-lowering effect is independent of insulin but additive when combined with insulin 4, 5
- The FDA drug label explicitly states that coadministration with insulin increases hypoglycemia risk 2
Required Insulin Dose Adjustment Strategy
When initiating empagliflozin in patients already on premixed insulin (Novomix):
- Reduce the total daily insulin dose by approximately 20% at the time of empagliflozin initiation 1
- This reduction applies particularly if HbA1c is well-controlled at baseline or if there is a history of frequent hypoglycemic events 1
- For patients on premixed insulin regimens specifically, maintain consistent meal timing and do not skip meals to further reduce hypoglycemia risk 1
Monitoring requirements:
- Patients must carry a source of quick-acting carbohydrates at all times 1
- More frequent blood glucose monitoring is necessary during the first few weeks of combination therapy 1
- Reassess and adjust insulin doses based on glucose patterns within 2-4 weeks 1
Timing and Administration Considerations
For premixed insulin (Novomix) specifically:
- Insulin doses must be taken at consistent times every day 1
- Meals need to be consumed at similar times every day 1
- Empagliflozin can be taken once daily at any time, independent of meals 1
- There is no contraindication to taking both medications at the same time of day
Additional Safety Considerations Beyond Hypoglycemia
Volume depletion risk:
- Empagliflozin may cause intravascular volume contraction, particularly in elderly patients or those on diuretics 1
- Consider reducing diuretic doses if applicable when starting empagliflozin 1
Diabetic ketoacidosis (DKA) risk:
- While rare, euglycemic DKA can occur with SGLT2 inhibitors 6
- Risk is higher during periods of reduced caloric intake, illness, or surgery 6
- Discontinue empagliflozin 3-4 days before scheduled surgery 6
Renal function monitoring:
- Empagliflozin efficacy decreases with eGFR <45 mL/min/1.73 m² 1
- Use is not recommended for glycemic control when eGFR <45 mL/min/1.73 m² 1
- Contraindicated when eGFR <30 mL/min/1.73 m² or on dialysis 1
Common Pitfalls to Avoid
Do not:
- Start empagliflozin without reducing insulin dose in well-controlled patients 1
- Skip the 20% insulin dose reduction if HbA1c is already near target 1
- Ignore the need for consistent meal timing when on premixed insulin 1
- Continue empagliflozin during acute illness without close monitoring for DKA 6
Do:
- Educate patients about hypoglycemia recognition and treatment before starting combination therapy 1
- Provide specific instructions about maintaining carbohydrate intake at meals 1
- Coordinate care with the patient's diabetes team when making insulin adjustments 1
- Monitor for genital mycotic infections, which occur more frequently with empagliflozin 1
Clinical Trial Evidence
In the EASE trials evaluating empagliflozin as adjunct to insulin therapy, severe hypoglycemia was rare and frequency was similar between empagliflozin and placebo groups when appropriate insulin dose adjustments were made. 7 The EMPA-REG OUTCOME trial demonstrated that empagliflozin added to standard care (which included insulin in many patients) reduced cardiovascular mortality by 38% without increasing severe hypoglycemia rates when used appropriately. 4, 8