Adding an SGLT-2 Inhibitor to a Patient on Glipizide

Rationale for Combination Therapy

• The Kidney International guidelines suggest that SGLT-2 inhibitors provide cardiovascular and renal benefits independent of their glucose-lowering effects, making them valuable add-on therapy for patients with type 2 diabetes 1
• The American College of Cardiology recommends adding an SGLT-2 inhibitor to existing therapy for patients who are not meeting glycemic targets or who can safely attain a lower target 1
• SGLT-2 inhibitors have a complementary mechanism of action to sulfonylureas like glipizide, working by increasing urinary glucose excretion rather than stimulating insulin secretion, as reported in Diabetes Care 2

Hypoglycemia Risk Management

• When adding an SGLT-2 inhibitor to a patient on a sulfonylurea like glipizide, consider reducing the sulfonylurea dose to minimize hypoglycemia risk, according to the Journal of the American College of Cardiology 1, 3
• The KDIGO guidelines recommend that for patients in whom additional glucose-lowering may increase risk for hypoglycemia, it may be necessary to stop or reduce the dose of an antihyperglycemic drug other than metformin to facilitate addition of an SGLT2i 1
• Consider reducing the dose of glipizide by 50% when adding an SGLT-2 inhibitor, especially if the patient's current glycemic control is good, as suggested by the Journal of the American College of Cardiology 3

Implementation Algorithm

• Confirm eGFR ≥30 mL/min/1.73m² before initiating SGLT-2 inhibitor, as recommended by the Kidney International and the Journal of the American College of Cardiology 1, 4
• If eGFR <30 mL/min/1.73m², do not start an SGLT-2 inhibitor, according to the Journal of the American College of Cardiology 4
• If patient is meeting glycemic targets on glipizide, reduce glipizide dose by 50% when adding SGLT-2 inhibitor, as recommended by the Kidney International and the Journal of the American College of Cardiology 1, 3

Important Precautions

• Monitor for volume depletion, especially if patient is also on diuretics, as recommended by the Kidney International 1
• Be aware of the risk of euglycemic diabetic ketoacidosis with SGLT-2 inhibitors, as reported in Diabetes Care 2
• Expect a small, reversible decrease in eGFR after starting an SGLT-2 inhibitor, which is generally not a reason to discontinue therapy, according to the Kidney International 1

Benefits Beyond Glycemic Control

• SGLT-2 inhibitors provide additional benefits including modest weight loss, blood pressure reduction, and reduced risk of heart failure hospitalization, as reported in Diabetes Care 2

SGLT2 Inhibitors for Cardiovascular Risk Reduction in Type 2 Diabetes

Benefits of SGLT2 Inhibitors

• The American College of Cardiology recommends SGLT2 inhibitors for patients with type 2 diabetes who have established atherosclerotic cardiovascular disease (ASCVD) or are at high risk for ASCVD to reduce cardiovascular events 5, 6
• SGLT2 inhibitors provide cardiovascular benefits independent of their glucose-lowering effects, including reduced risk of heart failure hospitalization and cardiovascular death 7, 8

Selection of Specific SGLT2 Inhibitor

• The American College of Cardiology suggests that canagliflozin, dapagliflozin, or empagliflozin would all be appropriate choices based on their proven cardiovascular benefits 5, 7

Important Considerations

• Dose adjustments of other antihyperglycemic agents may be necessary to minimize hypoglycemia risk 9
• Monitoring for signs of volume depletion is necessary, especially in patients already on beta-blockers like carvedilol 10, 9
• Patients on SGLT2 inhibitors should be monitored for genital mycotic infections, which are more common with these medications 11, 9
• There is a risk of euglycemic diabetic ketoacidosis, which requires patient education on symptoms 10, 9
• SGLT2 inhibitors should not be initiated if eGFR is <30 mL/min/1.73m² 11

Implementation Strategy

• The American College of Cardiology recommends confirming the patient's eGFR is ≥30 mL/min/1.73m² before initiating SGLT2 inhibitors 5
• Consider reducing doses of other antihyperglycemic medications if the patient is at risk for hypoglycemia 9
• Schedule follow-up within 4 weeks to assess tolerability and efficacy 9

Conclusion

• The American College of Cardiology and European Heart Journal guidelines support the use of SGLT2 inhibitors for patients with type 2 diabetes who have or are at high risk for cardiovascular disease 5, 8, 12

Adding SGLT2 Inhibitors to Sitagliptin and Metformin for Cardiovascular and Renal Protection

Introduction to SGLT2 Inhibitors

• The American College of Cardiology recommends adding an SGLT2 inhibitor to a patient's current regimen of sitagliptin and metformin, prioritizing empagliflozin, canagliflozin, or dapagliflozin based on cardiovascular and renal comorbidities 13, 14

Recommended SGLT2 Inhibitors and Dosing

• Empagliflozin has proven cardiovascular and renal benefits and can be safely added to sitagliptin and metformin, with a starting dose of 10 mg orally once daily and a maximum dose of 25 mg orally once daily 13, 15, 16
• Canagliflozin is an appropriate choice with a starting dose of 100 mg orally once daily and a maximum dose of 300 mg once daily, and has an FDA-approved indication to reduce the risk of CV death in adults with T2D and CV disease 13, 15, 16
• Dapagliflozin is a suitable option with proven ASCVD, heart failure, or diabetic kidney disease benefit, and no dose titration is required 14

Clinical Decision Algorithm

• The American College of Cardiology suggests verifying patient eligibility by confirming eGFR ≥30 mL/min/1.73 m², excluding pregnancy or breastfeeding, and verifying patient is ≥18 years old 14, 16
• Selecting a specific SGLT2 inhibitor based on comorbidities, such as established ASCVD, heart failure, or CKD, is crucial, with any of the three agents being appropriate for ASCVD 14, 16

Monitoring and Safety Considerations

• The Kidney International guidelines recommend monitoring for adverse effects, including genital mycotic infections, volume depletion, urinary tract infections, and euglycemic diabetic ketoacidosis 13, 16
• Anticipating a small, reversible decrease in eGFR within the first 6 weeks of SGLT2 inhibitor therapy is essential, and this hemodynamic change is not an indication to discontinue therapy 16

Cardiovascular and Renal Benefits

• SGLT2 inhibitors provide mortality and morbidity benefits independent of their glucose-lowering effects, including significant reduction in cardiovascular mortality, heart failure hospitalization, and slowing of chronic kidney disease progression 13, 14, 16, 17
• These benefits persist even at lower eGFR levels, making SGLT2 inhibitors valuable additions for cardiovascular and renal protection regardless of current glycemic control 13, 16

SGLT2 Inhibitor Treatment Monitoring and Management

Initial Monitoring and Medication Adjustments

• The American College of Cardiology recommends instructing patients to monitor glucose more closely at home for the first 4 weeks of SGLT2 inhibitor therapy, especially if they are taking insulin, sulfonylureas, or glinides 18
• If a patient has well-controlled blood sugar levels at baseline or a history of frequent low blood sugar events, the American College of Cardiology suggests reducing sulfonylurea dose or discontinuing it entirely when starting the SGLT2 inhibitor 18
• Consider reducing total daily insulin dose by approximately 20% when initiating SGLT2 inhibitor therapy to minimize low blood sugar risk, as recommended by the American College of Cardiology 18

Safety Monitoring and Patient Education

• The American College of Cardiology recommends monitoring for volume depletion, particularly if the patient is also taking diuretics, and considering reducing diuretic dose if dehydration symptoms are present 18
• Educate patients that diabetic ketoacidosis can occur even with blood glucose readings in a relatively normal range (euglycemic DKA), and instruct them to seek urgent medical attention if they experience nausea, vomiting, abdominal pain, or weakness, as advised by the American College of Cardiology 18
• The American College of Cardiology suggests educating patients regarding symptoms of dehydration and to hold medication if experiencing low oral intake, particularly during intercurrent illness or situations that may lead to volume depletion 18

Renal Function Monitoring

• Monitor estimated glomerular filtration rate (eGFR) periodically, recognizing that SGLT2 inhibitors can be continued as long as eGFR remains ≥30 mL/min/1.73 m² for empagliflozin and dapagliflozin, according to the American College of Cardiology 19
• For canagliflozin specifically, the FDA label allows use down to eGFR of 30 mL/min/1.73 m² in patients with diabetic kidney disease, as noted by the American College of Cardiology 18, 19

Long-Term Benefits and Monitoring

• The American Diabetes Association and other organizations acknowledge that the cardiovascular and renal benefits of SGLT2 inhibitors occur independently of blood sugar level reduction, so continuation should not be based solely on glycemic response 20