In a 40-60-year-old patient with chronic kidney disease, hypertension, type 2 diabetes, currently on metformin, an angiotensin-converting enzyme inhibitor, and a statin, and with an atherosclerotic cardiovascular disease risk of 18%, what is the next recommended therapy?

Recommended Next Therapy: Dapagliflozin (SGLT2 Inhibitor)

For this 40-60-year-old patient with CKD, hypertension, type 2 diabetes, and an ASCVD risk of 18%, the next recommended therapy is dapagliflozin (or another SGLT2 inhibitor), as this drug class provides critical cardiorenal protection independent of glucose-lowering effects and is strongly recommended by current guidelines for patients with diabetes and CKD. 1

Why SGLT2 Inhibitors Are the Priority

SGLT2 inhibitors are the cornerstone of therapy for patients with type 2 diabetes and CKD, regardless of baseline HbA1c or glycemic control. 1 The evidence supporting this recommendation is compelling:

• KDIGO 2020 guidelines provide a 1A recommendation (the highest level of evidence) for SGLT2 inhibitors in patients with type 2 diabetes, CKD, and eGFR ≥30 mL/min/1.73 m². 1

• The 2024 BMJ guideline panel issued a strong recommendation for SGLT2 inhibitors in adults at high or very high risk of CKD progression and complications, which applies to all adults with CKD irrespective of diabetes status. 1

• SGLT2 inhibitors reduce all-cause mortality, cardiovascular mortality, hospitalization for heart failure, kidney failure, non-fatal myocardial infarction, and non-fatal stroke in patients with CKD. 1

• The Mayo Clinic 2022 guideline explicitly states that SGLT2 inhibitors and/or GLP-1 RAs are recommended regardless of HbA1c, with choice prioritizing agents with documented kidney or cardiovascular benefits. 1

Why Not the Other Options?

B. Sulfonylurea - Avoid

• Sulfonylureas are not recommended as add-on therapy in CKD when safer alternatives like SGLT2 inhibitors are available. 2
• They markedly increase hypoglycemia risk in CKD due to accumulation of active metabolites and impaired renal gluconeogenesis. 2
• They provide no cardiovascular or renal protection and are associated with higher mortality compared to metformin. 3

C. Fibrate - Not Indicated

• Fibrates are not part of the recommended treatment algorithm for patients with diabetes and CKD in current guidelines. 1
• While this patient has an 18% ASCVD risk, lipid management should focus on statin therapy (already prescribed) with potential addition of ezetimibe if LDL-C targets are not met. 1
• The KDIGO guideline recommends statin or statin/ezetimibe combination for patients ≥50 years with CKD, not fibrates. 1

D. Ezetimibe - Secondary Priority

• Ezetimibe is appropriate for lipid management but is a secondary consideration after SGLT2 inhibitors. 1
• The KDIGO guideline recommends statin/ezetimibe combination for adults ≥50 years with CKD, but this addresses lipid control, not the comprehensive cardiorenal protection needed. 1
• SGLT2 inhibitors provide broader benefit by reducing cardiovascular events, slowing CKD progression, and reducing mortality—benefits that ezetimibe cannot match. 1

Implementation Strategy

Initiation

• Start dapagliflozin 10 mg daily (or empagliflozin 10 mg or canagliflozin 100 mg as alternatives, all with documented cardiovascular and kidney benefits). 1, 4
• Verify eGFR ≥30 mL/min/1.73 m² before initiating; SGLT2 inhibitors can be started immediately if this threshold is met. 4

Metformin Adjustment

• Continue metformin but adjust dose based on eGFR: for eGFR 45-59 mL/min/1.73 m², reduce to half of maximum dose; for eGFR 30-44 mL/min/1.73 m², reduce to maximum 1000 mg daily and monitor every 3-6 months; discontinue if eGFR <30 mL/min/1.73 m². 3, 4

Monitoring After SGLT2 Inhibitor Initiation

• Within 2-4 weeks: assess for volume depletion symptoms, expect a modest reversible eGFR decline (10-15%), educate on genital mycotic infection symptoms and diabetic ketoacidosis warning signs. 4
• Long-term: monitor eGFR every 3-6 months if eGFR <60 mL/min/1.73 m²; continue SGLT2 inhibitor even if eGFR declines, as long-term eGFR preservation occurs with continuation. 4

If SGLT2 Inhibitor Is Contraindicated or Not Tolerated

Add a GLP-1 receptor agonist (liraglutide, dulaglutide, or semaglutide) as the next best alternative, which provides cardiovascular protection, reduced albuminuria, preserved eGFR, weight loss, and low hypoglycemia risk. 1, 4

Common Pitfalls to Avoid

• Do not withhold SGLT2 inhibitors based solely on HbA1c levels; their primary value in CKD is cardiorenal protection, not glucose lowering. 1
• Do not discontinue SGLT2 inhibitors if eGFR declines modestly (up to 15%) in the first few weeks; this is expected and reversible, with long-term benefit maintained. 4
• Do not add sulfonylureas in patients with CKD who have access to SGLT2 inhibitors or GLP-1 RAs; the hypoglycemia risk outweighs any glycemic benefit. 3, 2
• Do not overlook the need for high-intensity statin therapy in all patients with diabetes and CKD to reduce cardiovascular risk, regardless of baseline lipid levels. 2