What is the next step for a patient not tolerating Jardiance (empagliflozin) or metformin?

Next Steps for Patients Not Tolerating Jardiance or Metformin

For patients who cannot tolerate Jardiance (empagliflozin) or metformin, a GLP-1 receptor agonist is the recommended next step due to its proven cardiovascular benefits, weight reduction effects, and low hypoglycemia risk.

Understanding Medication Intolerance

Intolerance to diabetes medications can manifest in different ways:

• Metformin intolerance: Primarily gastrointestinal side effects including diarrhea, nausea, flatulence, indigestion, vomiting, and abdominal discomfort 1
• Jardiance (SGLT2 inhibitor) intolerance: Commonly genital mycotic infections, urinary tract infections, volume depletion, or euglycemic ketoacidosis 2

Decision Algorithm for Next Steps

First-Line Alternative: GLP-1 Receptor Agonists

GLP-1 receptor agonists are the preferred next option because:

• Demonstrated cardiovascular risk reduction in clinical trials 2, 3
• Substantial weight loss benefits 3
• Low hypoglycemia risk compared to other alternatives 3
• Can be used with reduced kidney function (most formulations) 2

Practical tips when initiating GLP-1 RAs:

• Start at the lowest dose and titrate slowly to minimize gastrointestinal side effects 3
• Consider once-weekly formulations for better adherence
• Monitor for potential side effects including nausea, vomiting, and diarrhea

Second-Line Alternative: DPP-4 Inhibitors

If GLP-1 RAs are not suitable or tolerated:

• Well-tolerated in renal impairment with appropriate dose adjustments 2, 3
• Weight neutral (unlike sulfonylureas which cause weight gain) 3
• Low hypoglycemia risk 3
• Oral administration (advantage over injectable GLP-1 RAs)

Dose adjustments needed for most DPP-4 inhibitors with reduced kidney function, except linagliptin which requires no adjustment 2

Third-Line Alternative: Consider Other Classes Based on Patient Factors

If neither GLP-1 RAs nor DPP-4 inhibitors are suitable:

• Thiazolidinediones (e.g., pioglitazone): Consider for patients without heart failure risk or osteoporosis 3
• Sulfonylureas: Effective but carry hypoglycemia and weight gain risks 3
• Insulin therapy: Consider when A1C ≥10% or blood glucose ≥300 mg/dL with symptoms 2

Special Considerations

For Patients with Cardiovascular Disease

• GLP-1 RAs with proven cardiovascular benefit should be prioritized 2, 3
• If GLP-1 RAs cannot be used, consider alternative agents with neutral cardiovascular effects

For Patients with Reduced Kidney Function

• Most GLP-1 RAs (dulaglutide, liraglutide, semaglutide) can be used without dose adjustment in moderate renal impairment 2
• Avoid exenatide and lixisenatide with eGFR <30 mL/min/1.73 m² 2

For Patients with Gastrointestinal Sensitivity

• If metformin intolerance was due to GI effects, start GLP-1 RAs at the lowest possible dose and titrate very slowly
• Consider DPP-4 inhibitors which have fewer GI side effects than GLP-1 RAs

Common Pitfalls to Avoid

1. Therapeutic inertia: Don't delay treatment intensification if glycemic targets aren't met within 3-6 months 2, 3
2. Overlooking cardiovascular benefits: Prioritize agents with proven cardiovascular benefits in high-risk patients 2, 3
3. Ignoring patient preferences: Consider factors such as injection aversion, cost concerns, and side effect tolerance 3
4. Failing to address the root cause of intolerance: For metformin, extended-release formulations may be better tolerated before abandoning completely 1

Monitoring After Medication Change

• Reassess glycemic control after 3 months of therapy 2, 3
• Monitor for medication-specific adverse effects
• Adjust therapy if glycemic targets are not achieved or side effects occur