Management of Hyperglycemia on Jardiance and Januvia
Add a GLP-1 receptor agonist (semaglutide or liraglutide) to the current regimen of empagliflozin and sitagliptin to achieve glycemic control. 1
Rationale for Treatment Intensification
The combination of empagliflozin (SGLT-2 inhibitor) and sitagliptin (DPP-4 inhibitor) is an appropriate dual therapy with complementary mechanisms of action, but when hyperglycemia persists despite this combination, treatment intensification is necessary rather than discontinuation 2.
The American Diabetes Association recommends adding a GLP-1 receptor agonist as the preferred third agent when SGLT2 inhibitors and DPP-4 inhibitors fail to achieve glycemic targets, providing robust HbA1c reduction of 1.0-1.5%, weight loss, and cardiovascular benefits 1.
Continue both empagliflozin and sitagliptin as they provide cardiorenal protection independent of their glucose-lowering effects, with empagliflozin reducing cardiovascular death by 38% and sitagliptin demonstrating cardiovascular safety with neutral effects 2, 1.
Specific GLP-1 Receptor Agonist Selection
For patients with established cardiovascular disease, prioritize semaglutide or liraglutide due to their demonstrated cardiovascular outcome benefits 1.
Semaglutide Dosing:
- Start with 0.25 mg subcutaneously once weekly for 4 weeks 1
- Increase to 0.5 mg weekly, with option to escalate to 1.0 mg weekly if needed for glycemic control 1
Liraglutide Dosing (Alternative):
- Start at 0.6 mg daily subcutaneously 1
- Increase to 1.2 mg after one week, with option to increase to 1.8 mg if needed 1
Pre-Treatment Assessment
Before initiating GLP-1 therapy, complete the following evaluations:
Assess renal function to ensure empagliflozin continuation is appropriate (eGFR should be ≥20 mL/min/1.73 m² for empagliflozin use, though not recommended when eGFR is persistently <45 mL/min/1.73 m²) 1, 3
Screen for contraindications to GLP-1 receptor agonists, including personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 1
Evaluate for volume depletion risk factors before continuing empagliflozin, including concomitant diuretics, ACE inhibitors, ARBs, or NSAIDs 3
Monitoring Strategy
Reassess HbA1c in 3 months after GLP-1 receptor agonist initiation 1
If target HbA1c <7% is not achieved, consider further dose escalation of the GLP-1 receptor agonist before adding a fourth agent 1
Monitor for GLP-1 side effects, particularly gastrointestinal symptoms (nausea, vomiting, diarrhea) which typically improve over time 1
Continue monitoring for empagliflozin-related adverse effects, including genital mycotic infections, urinary tract infections, and volume depletion 3
Critical Safety Considerations
Avoid sulfonylureas and insulin as third-line agents due to their association with hypoglycemia risk and weight gain, which would be counterproductive 1.
Temporarily discontinue empagliflozin in settings of reduced oral intake (acute illness, fasting) or fluid losses (gastrointestinal illness, excessive heat exposure) to prevent acute kidney injury 3
Discontinue empagliflozin at least 3 days before planned surgery to prevent postoperative euglycemic ketoacidosis 2
The risk of hypoglycemia with this triple combination remains low since none of these agents are insulin secretagogues, though sitagliptin may cause mild hypoglycemia when combined with other agents 3
Expected Outcomes
HbA1c reduction of 1.0-1.5% from baseline with GLP-1 receptor agonist addition 1
Weight loss of 2-4 kg over 6 months due to GLP-1 receptor agonist effects 1
Continued cardiovascular and renal protection from empagliflozin independent of glucose-lowering effects 2, 1
Common Pitfalls to Avoid
Do not discontinue effective medications prematurely—the combination of empagliflozin and sitagliptin is evidence-based and should be continued while adding a third agent 2, 1.
Do not add insulin or sulfonylureas as the next step unless GLP-1 receptor agonists are contraindicated or not tolerated, as these older agents increase hypoglycemia risk and cause weight gain 1.
Do not ignore volume status—empagliflozin causes osmotic diuresis, and patients on diuretics or with reduced oral intake are at higher risk for volume depletion and acute kidney injury 3.