Alternative Diabetic Agents to Jardiance (Empagliflozin)
For patients with type 2 diabetes requiring an alternative to Jardiance, the best options depend on cardiovascular and renal status: GLP-1 receptor agonists (liraglutide, semaglutide, or dulaglutide) are the preferred first alternative for patients with established cardiovascular disease or high cardiovascular risk, while other SGLT2 inhibitors (dapagliflozin or canagliflozin) provide similar cardiovascular and renal benefits if the issue is cost or availability rather than drug class intolerance. 1
Primary Alternatives Based on Patient Profile
For Patients with Established Cardiovascular Disease or High CV Risk
GLP-1 receptor agonists with proven cardiovascular benefit are the recommended alternative, specifically liraglutide, semaglutide, or dulaglutide, as these agents have demonstrated significant reductions in cardiovascular events in outcomes trials similar to empagliflozin 1
These agents reduce the risk of major adverse cardiovascular events (MACE) and provide cardiovascular death benefits independent of A1C reduction, making them appropriate substitutes when SGLT2 inhibitors cannot be used 1
GLP-1 RAs offer additional benefits including low hypoglycemia risk, weight loss, and potential slowing of CKD progression 1
For Patients with Chronic Kidney Disease
Semaglutide (a GLP-1 RA) is now recommended as a first-line agent for patients with CKD, based on recent dedicated kidney outcomes trials showing beneficial effects on cardiovascular disease, mortality, and kidney outcomes 1
Alternative SGLT2 inhibitors (dapagliflozin or canagliflozin) provide similar renal protection benefits, with dedicated kidney outcomes trials demonstrating slowing of CKD progression 1
For patients with eGFR 20-45 mL/min/1.73 m², SGLT2 inhibitors can still be initiated but have reduced glucose-lowering efficacy at this level of kidney function 1
Metformin remains appropriate if eGFR is ≥45 mL/min/1.73 m², though it should be dose-reduced when eGFR falls below 45 and discontinued when eGFR is <30 mL/min/1.73 m² 1
For Patients with Heart Failure
Other SGLT2 inhibitors (dapagliflozin or canagliflozin) are the most direct alternatives, as they share empagliflozin's Class I recommendation for reducing cardiovascular death and heart failure hospitalization in patients with heart failure and reduced ejection fraction (LVEF ≤40%) 2
For heart failure with preserved ejection fraction (LVEF >40%), empagliflozin and dapagliflozin both carry recommendations to decrease heart failure hospitalizations 2
Secondary Alternatives When SGLT2 Inhibitors and GLP-1 RAs Are Not Options
DPP-4 Inhibitors
DPP-4 inhibitors (sitagliptin, linagliptin, saxagliptin, alogliptin) can be used as add-on therapy to metformin, providing moderate A1C reductions of approximately 0.7-1.0% 1
These agents have low hypoglycemia risk and are weight-neutral, though they lack the cardiovascular and renal benefits of SGLT2 inhibitors and GLP-1 RAs 1
Monthly costs range from $234-$568 for maximum approved doses, making them moderately expensive options 1
Thiazolidinediones (Pioglitazone)
Pioglitazone can be added to metformin or sulfonylureas, with clinical trials showing A1C reductions of 0.8-1.67% when combined with other agents 3
This option is considerably less expensive (monthly cost $283-$349 for maximum dose) compared to SGLT2 inhibitors ($354-$627) 1
Important caveat: Pioglitazone causes weight gain and is associated with fluid retention, making it inappropriate for patients with heart failure 3
Sulfonylureas
Glimepiride or other second-generation sulfonylureas provide effective glucose lowering when added to metformin, with A1C reductions of 0.9-1.67% 1, 4
These are the most cost-effective options, with monthly costs of only $4-$11 for maximum approved doses 1
Critical limitation: Sulfonylureas carry a 24% risk of confirmed hypoglycemia compared to only 2% with empagliflozin, and cause weight gain rather than weight loss 5
Hypoglycemia risk is particularly concerning in patients with CKD, where sulfonylureas require close monitoring and dose adjustment as eGFR declines 1
Insulin Therapy
Basal insulin (NPH, glargine, detemir, or degludec) can be added to metformin when other oral agents are insufficient 1
Starting doses are typically 0.1-0.2 units/kg/day, with individualized titration based on self-monitoring of blood glucose 1
Longer-acting basal analogs (U-300 glargine or degludec) may convey lower hypoglycemia risk compared to U-100 glargine when used with oral agents 1
Clinical Decision Algorithm
Step 1: Determine if the patient has established cardiovascular disease, heart failure, or CKD:
- If YES → Choose GLP-1 RA (semaglutide, liraglutide, dulaglutide) or alternative SGLT2 inhibitor (dapagliflozin, canagliflozin) 1
- If NO → Proceed to Step 2
Step 2: Consider cost and tolerability:
- If cost is a major barrier → Sulfonylurea (glimepiride) or pioglitazone, but counsel about hypoglycemia risk and weight gain respectively 1, 4
- If weight loss is desired → GLP-1 RA preferred over all other options 1
- If hypoglycemia risk is a concern → Avoid sulfonylureas; choose DPP-4 inhibitor or GLP-1 RA 1, 5
Step 3: For patients with declining renal function (eGFR <45 mL/min/1.73 m²):
- Prioritize GLP-1 RAs (particularly semaglutide) as they maintain glucose-lowering efficacy regardless of kidney function 1
- SGLT2 inhibitors have reduced glucose-lowering efficacy but maintain cardiovascular and renal benefits 1
- Reduce or discontinue metformin as outlined above 1
Important Safety Considerations
When switching from empagliflozin to a sulfonylurea, there is a 12-fold increase in hypoglycemia risk (from 2% to 24%), requiring patient education and glucose monitoring 5
GLP-1 RAs increase gastrointestinal side effects and are contraindicated in patients with family history of medullary thyroid cancer 1
Pioglitazone should not be used in patients with heart failure due to fluid retention risk 3
Cost considerations are substantial, with monthly costs ranging from $4 for sulfonylureas to $627 for SGLT2 inhibitors at maximum approved doses 1