Optimal Adjunct Therapy with SGLT2 Inhibitors in Type 2 Diabetes and CKD
For patients with type 2 diabetes and CKD already on an SGLT2 inhibitor, add a GLP-1 receptor agonist (liraglutide or semaglutide) if additional glycemic control is needed, and ensure maximal-dose ACE inhibitor or ARB therapy if hypertension or albuminuria is present. 1
Foundation: RAS Blockade as Primary Adjunct
ACE inhibitors or ARBs should be initiated and titrated to the maximum approved tolerated dose in all patients with diabetes, CKD, hypertension, and albuminuria. 1 This represents the cornerstone adjunctive therapy alongside SGLT2 inhibitors, with Class I, Level A evidence supporting this combination. 1
Specific RAS Blockade Protocol:
- Initiate ACE inhibitor or ARB in patients with albuminuria (ACR ≥30 mg/g) and hypertension 1
- Titrate to maximum approved dose that is tolerated 1
- Monitor serum creatinine and potassium within 2-4 weeks of initiation or dose increase 1
- Continue therapy unless creatinine rises >30% within 4 weeks 1
- Manage hyperkalemia with potassium-lowering strategies (dietary modification, diuretics, sodium bicarbonate, GI cation exchangers) rather than immediately stopping RAS blockade 1
Important caveat: For patients with albuminuria but normal blood pressure, ACE inhibitor or ARB therapy may still be considered, though the evidence is less robust than for those with concurrent hypertension. 1
GLP-1 Receptor Agonists as Second-Line Adjunct
A GLP-1 receptor agonist with proven cardiovascular benefit (specifically liraglutide or semaglutide) should be added for patients who do not meet individualized glycemic targets with metformin and SGLT2 inhibitor, or who cannot use these medications. 1 This recommendation carries Class IIa, Level B evidence. 1
GLP-1 RA Selection and Use:
- Liraglutide and semaglutide have demonstrated reductions in renal endpoints in cardiovascular outcome trials 1
- These agents are appropriate for patients with eGFR >30 mL/min/1.73 m² 1
- GLP-1 RAs provide additional glycemic control beyond SGLT2 inhibitors while offering cardiovascular and modest renal protection 1
Metformin as Foundational Therapy
Metformin should be continued as foundational therapy in patients with eGFR ≥30 mL/min/1.73 m². 1 This represents standard first-line therapy that complements SGLT2 inhibitor action.
Metformin Dosing by Renal Function:
- Full dose (up to 2000 mg daily) for eGFR ≥45 mL/min/1.73 m² 1
- Reduce to 1000 mg daily for eGFR 30-44 mL/min/1.73 m² 1
- Also reduce to 1000 mg daily for eGFR 45-59 mL/min/1.73 m² in patients at high risk of lactic acidosis 1
- Discontinue if eGFR falls below 30 mL/min/1.73 m² 1
Emerging Adjunct: Nonsteroidal Mineralocorticoid Receptor Antagonists
For patients with persistent albuminuria (ACR ≥30 mg/g) despite SGLT2 inhibitor and RAS blockade, consider adding a nonsteroidal MRA with proven kidney and cardiovascular benefit. 1, 2
ns-MRA Eligibility Criteria:
- eGFR ≥25 mL/min/1.73 m² 1
- Normal serum potassium concentration 1
- Albuminuria ACR ≥30 mg/g 1
- Already on SGLT2 inhibitor and RAS inhibitor therapy 2
This represents the most recent guideline addition (2022 ADA/KDIGO consensus) for triple therapy in high-risk patients. 1
Lipid Management
All patients with type 2 diabetes and CKD require statin therapy regardless of other medications. 1
- Moderate-intensity statin for primary prevention of ASCVD 1
- High-intensity statin for patients with known ASCVD or multiple ASCVD risk factors 1
Blood Pressure Targets
Target systolic blood pressure to 130 mmHg and <130 mmHg if tolerated, but not <120 mmHg. 1 This should be achieved through the combination of RAS blockade, SGLT2 inhibitor effects, and additional antihypertensive agents as needed.
Monitoring Strategy for Combined Therapy
Renal Function Monitoring:
- Baseline eGFR and urine ACR before initiating any therapy 3
- Monitor eGFR every 3-6 months if <60 mL/min/1.73 m² 3
- Monitor eGFR annually if ≥60 mL/min/1.73 m² 3
- Monitor urine ACR annually, or more frequently if elevated 3
Safety Monitoring:
- Assess volume status before initiating SGLT2 inhibitors, particularly in elderly patients or those on loop diuretics 1, 3
- Monitor for genital mycotic infections with SGLT2 inhibitors 3
- Educate patients about volume depletion symptoms (lightheadedness, orthostasis, weakness) 3
- Reduce diuretic doses when initiating SGLT2 inhibitors 3
Critical Pitfalls to Avoid
Do not discontinue SGLT2 inhibitors due to initial eGFR decline. An expected reversible decrease of 3-5 mL/min/1.73 m² is hemodynamically mediated and not a reason to stop therapy. 2 Once initiated, SGLT2 inhibitors can be continued even if eGFR falls below 20 mL/min/1.73 m² unless not tolerated or kidney replacement therapy is initiated. 2
Do not withhold RAS blockade due to mild hyperkalemia or modest creatinine elevation (<30% increase). These can typically be managed with supportive measures rather than stopping nephroprotective therapy. 1
Temporarily withhold SGLT2 inhibitors during prolonged fasting, surgery, or critical illness to reduce ketoacidosis risk. 3, 4