A 63-year-old woman with advanced chronic kidney disease (estimated glomerular filtration rate ≈16 mL/min/1.73 m²) is taking pioglitazone (Actos) 15 mg daily and dapagliflozin (Farxiga) 10 mg daily; what is the recommended management of her antidiabetic therapy?

Discontinue Pioglitazone and Continue Dapagliflozin for Cardiorenal Protection

At an eGFR of 16 mL/min/1.73 m², dapagliflozin 10 mg daily should be continued for cardiovascular and renal protection, while pioglitazone (Actos) should be discontinued due to fluid retention risk and lack of evidence supporting its use in advanced CKD. 1, 2, 3

Dapagliflozin Management at eGFR 16 mL/min/1.73 m²

Continue Current Therapy

• Continue dapagliflozin 10 mg once daily even though eGFR has fallen below 25 mL/min/1.73 m². The FDA label explicitly states: "If the eGFR falls below 25 mL/min/1.73 m² while receiving treatment with DAPAGLIFLOZIN TABLETS, patients may continue DAPAGLIFLOZIN TABLETS 10 mg orally once daily to reduce the risk of eGFR decline, ESKD, CV death and hHF." 3

• The 2022 ADA/KDIGO consensus confirms that dapagliflozin should not be discontinued when eGFR falls below 25 mL/min/1.73 m² if already on treatment, as cardiovascular and renal protective benefits persist until dialysis is required. 1, 2

• At this eGFR level, dapagliflozin provides no glycemic benefit (mechanism of action requires functional tubular glucose reabsorption), but the drug's hemodynamic and anti-inflammatory effects continue to slow CKD progression and reduce cardiovascular mortality. 1, 2

Evidence Supporting Continuation

• The DAPA-CKD trial enrolled patients with eGFR as low as 25 mL/min/1.73 m² and demonstrated a 39% reduction in the composite of sustained eGFR decline, end-stage kidney disease, or cardiovascular/renal death (HR 0.61,95% CI 0.51–0.72). 2, 4

• Dapagliflozin reduced the kidney-specific composite outcome by 44% (HR 0.56,95% CI 0.45–0.68) and cardiovascular death or heart failure hospitalization by 29% (HR 0.71,95% CI 0.55–0.92). 2, 4

• Subgroup analyses showed consistent benefit across the entire eGFR range studied, with no safety signal at lower eGFR levels. 2, 5

Pioglitazone (Actos) Discontinuation

Rationale for Stopping

• Thiazolidinediones cause fluid retention and increase heart failure risk, which is particularly dangerous in advanced CKD (eGFR 16 mL/min/1.73 m²) where volume management is already compromised. 1

• The 2022 ADA/KDIGO consensus states that thiazolidinediones "retain antihyperglycemic effects" in advanced CKD but notes that "fluid retention and HF are concerns with low eGFR and require careful monitoring." 1

• There is no evidence that pioglitazone provides cardiovascular or renal protection in advanced CKD, unlike SGLT2 inhibitors and GLP-1 receptor agonists. 1

• At eGFR 16 mL/min/1.73 m², this patient is at imminent risk of requiring dialysis or kidney transplantation, and fluid retention from pioglitazone could precipitate pulmonary edema or accelerate the need for renal replacement therapy. 1

Alternative Glycemic Management Strategy

Preferred Agents for eGFR <30 mL/min/1.73 m²

• GLP-1 receptor agonists (liraglutide, semaglutide, or dulaglutide) are the preferred glucose-lowering agents at this eGFR level because they:

  • Have been studied with eGFR as low as 15 mL/min/1.73 m² and retain glucose-lowering potency. 1
  • Reduce ASCVD events and albuminuria in large RCTs. 1
  • Do not cause hypoglycemia when used alone. 1
  • Provide cardiovascular protection with at least as much benefit in patients with eGFR <60 mL/min/1.73 m² compared to higher eGFR. 1

• Insulin therapy remains effective regardless of kidney function and can be dose-adjusted based on clinical response, though doses typically need reduction due to decreased insulin clearance. 1

• DPP-4 inhibitors (with appropriate dose adjustment) provide a safe and effective option for patients not treated with GLP-1 receptor agonists, though they lack the cardiovascular and renal benefits of GLP-1 agonists. 1

Agents to Avoid

• Metformin is contraindicated at eGFR <30 mL/min/1.73 m² due to lactic acidosis risk. 1

• Sulfonylureas should be avoided or used with extreme caution due to high hypoglycemia risk from reduced renal clearance of active metabolites. 1

Critical Safety Monitoring

Dapagliflozin-Specific Precautions

• Temporarily withhold dapagliflozin during acute illness with reduced oral intake, fever, vomiting, or diarrhea to prevent volume depletion and euglycemic diabetic ketoacidosis. 2, 3

• Stop dapagliflozin at least 3 days before major surgery or procedures requiring prolonged fasting. 2, 3

• Monitor for genital mycotic infections (occur in ~6% of patients on SGLT2 inhibitors vs. 1% on placebo) and educate about daily hygiene measures. 2

• Counsel about euglycemic diabetic ketoacidosis risk, which can occur even with normal blood glucose levels; patients should seek immediate care for malaise, nausea, vomiting, or abdominal pain. 2

Volume Status Assessment

• Assess volume status carefully at each visit, as the patient is at high risk for both volume overload (due to advanced CKD) and volume depletion (from dapagliflozin's osmotic diuresis). 2, 3

• Consider reducing concurrent diuretic doses if the patient is on loop or thiazide diuretics to prevent excessive volume depletion. 2

Renal Function Monitoring

• Check eGFR and creatinine at least every 3–6 months or more frequently if clinically indicated. 1, 2

• An initial eGFR dip of 2–5 mL/min/1.73 m² within the first 2–4 weeks is expected and reversible; this should not prompt discontinuation. 2, 5

• Paradoxically, patients who experience an acute eGFR reduction >10% at 2 weeks had better long-term renal outcomes with slower eGFR decline (-1.58 vs. -2.44 mL/min/1.73 m²/year) compared to those without an initial dip. 5

Integration with Other CKD Therapies

Continue Renin-Angiotensin System Blockade

• Do not discontinue ACE inhibitors or ARBs when continuing dapagliflozin; more than 99% of DAPA-CKD participants were on RAS blockade, and the combination provided additive renal protection. 2

• Hyperkalemia associated with ACE inhibitors or ARBs can often be managed with measures to reduce serum potassium (dietary modification, diuretics, sodium bicarbonate, or GI cation exchangers) rather than stopping the RAS blocker. 1

Consider Mineralocorticoid Receptor Antagonists

• When combined with dapagliflozin, mineralocorticoid receptor antagonists (e.g., finerenone) provide additive renal benefits and dapagliflozin may lessen hyperkalemia risk. 2

Common Pitfalls to Avoid

• Do not stop dapagliflozin solely because eGFR has fallen below 25 mL/min/1.73 m²; cardiovascular and renal protective benefits persist even when glycemic efficacy is lost. 1, 2, 3

• Do not discontinue dapagliflozin because of the expected initial eGFR dip in the first 2–4 weeks; this hemodynamic change is reversible and does not indicate tubular injury. 2, 5

• Do not reduce the dapagliflozin dose below 10 mg for cardiovascular or renal indications, even at very low eGFR; all outcome trials used the fixed 10 mg dose. 2, 3

• Do not continue pioglitazone in advanced CKD due to fluid retention risk and lack of evidence for cardiovascular or renal protection. 1