For a diabetic patient with proteinuria who is intolerant to Angiotensin-Converting Enzyme Inhibitors (ACEIs), can gliclazide and empagliflozin be used?

Can Gliclazide and Empagliflozin Be Used Together?

Yes, gliclazide and empagliflozin can be used together in diabetic patients with proteinuria who are intolerant to ACE inhibitors, but empagliflozin should be prioritized as the foundational therapy for cardiovascular and renal protection, with gliclazide added only if additional glucose lowering is needed beyond what empagliflozin provides. 1

Prioritizing Empagliflozin for Cardiorenal Protection

The 2022 KDIGO guidelines provide a Class 1A recommendation to treat patients with type 2 diabetes, CKD, and eGFR ≥20 mL/min per 1.73 m² with an SGLT2 inhibitor like empagliflozin, independent of baseline HbA1c or need for additional glucose lowering. 1 This recommendation is based on empagliflozin's proven ability to reduce cardiovascular death, heart failure hospitalization, and kidney disease progression—benefits that gliclazide does not provide. 2

• Empagliflozin reduces the risk of cardiovascular death or heart failure hospitalization by 26-29% and slows kidney disease progression by 39-44% in patients with diabetic kidney disease. 3, 4
• These cardiovascular and renal protective effects persist even at lower eGFR levels (down to 20 mL/min/1.73 m²), where glucose-lowering efficacy is reduced. 1, 3
• In patients with nephrotic-range proteinuria (UACR ≥2200 mg/g), empagliflozin was estimated to double the median hypothetical time to projected end-stage kidney disease. 4

Clinical Decision Algorithm

Step 1: Assess Renal Function and Proteinuria Status

• Check eGFR and urine albumin-to-creatinine ratio (UACR) before initiating therapy. 1
• If eGFR ≥20 mL/min/1.73 m² and UACR ≥200 mg/g, empagliflozin is strongly indicated for cardiorenal protection. 1, 3

Step 2: Initiate Empagliflozin as Foundation

• Start empagliflozin 10 mg once daily (or dapagliflozin 10 mg once daily) as the foundational therapy. 1, 3
• This fixed dose requires no titration and is used for all indications (cardiovascular, renal, and glycemic control). 3
• An initial eGFR dip of 3-5 mL/min/1.73 m² typically occurs within 1-4 weeks and is transient, reversible, and not a reason to discontinue therapy. 1, 3

Step 3: Assess Need for Additional Glucose Lowering

• After 3 months on empagliflozin, reassess HbA1c. 1
• If HbA1c remains above target (typically 7.0-8.0% for patients with advanced CKD and multiple comorbidities), consider adding gliclazide. 5
• Gliclazide can be started at 40-80 mg once daily with breakfast, titrated based on glucose monitoring to maximum 320 mg daily. 6

Step 4: Monitor for Hypoglycemia Risk

• When combining empagliflozin with gliclazide, the risk of hypoglycemia increases due to gliclazide's insulin-secretagogue mechanism. 6
• Educate patients on hypoglycemia symptoms and advise glucose monitoring, particularly during the first 2-4 weeks of combination therapy. 3
• Consider reducing gliclazide dose by 50% when initiating empagliflozin if patient is already on gliclazide, then re-titrate based on glucose response. 3

Alternative to ACE Inhibitors for Proteinuria Management

Since the patient is intolerant to ACE inhibitors, consider these alternatives:

• Angiotensin receptor blockers (ARBs): Losartan 50-100 mg daily or irbesartan 150-300 mg daily are first-line alternatives for reducing proteinuria and hard renal outcomes in diabetic CKD. 7
• Finerenone: The nonsteroidal mineralocorticoid receptor antagonist finerenone is recommended to reduce CKD progression and cardiovascular events, with lower rates of hyperkalemia compared to steroidal MRAs. 1
• SGLT2 inhibitors alone: Empagliflozin itself provides significant antiproteinuric effects independent of glucose lowering, though the effect may be modest in non-diabetic proteinuric kidney disease. 4, 8

Critical Safety Precautions

Volume Status Assessment

• Assess volume status before starting empagliflozin, particularly in patients on diuretics or with tenuous volume status. 1, 3
• Consider reducing concurrent diuretic doses to prevent excessive volume depletion. 1, 3

Sick Day Management

• Temporarily discontinue empagliflozin during acute illness with reduced oral intake, fever, vomiting, or diarrhea to prevent euglycemic diabetic ketoacidosis and volume depletion. 3
• Maintain at least low-dose insulin in insulin-requiring patients even when empagliflozin is held. 3
• Withhold empagliflozin at least 3 days before major surgery or procedures requiring prolonged fasting. 1, 3

Monitoring Parameters

• Check eGFR and potassium within 1-2 weeks after initiation, then every 3-6 months if eGFR 30-59 mL/min/1.73 m². 1, 3
• Monitor for genital mycotic infections (occur in ~6% of patients on SGLT2 inhibitors vs 1% on placebo) and urinary tract infections. 1, 3
• Educate patients about symptoms of euglycemic diabetic ketoacidosis (malaise, nausea, vomiting, abdominal pain) even with normal blood glucose levels. 3

Common Pitfalls to Avoid

• Do not discontinue empagliflozin solely because eGFR falls below 45 mL/min/1.73 m², as cardiovascular and renal protective benefits persist even when glycemic efficacy is lost. 1, 3
• Do not combine ACE inhibitors with ARBs (dual RAS blockade), as this increases adverse events including hyperkalemia and acute kidney injury without additional cardiovascular benefit. 1
• Do not use aliskiren (direct renin inhibitor) with ACE inhibitors or ARBs in diabetic patients, as this is contraindicated due to increased risk of kidney impairment, hypotension, and hyperkalemia. 1
• Do not reduce gliclazide dose excessively when adding empagliflozin, as this may compromise glycemic control; instead, monitor glucose closely and adjust based on response. 3

When to Consider Replacing Gliclazide with Empagliflozin Alone

If the patient is already on gliclazide and you are considering adding empagliflozin, strongly consider replacing gliclazide entirely with empagliflozin rather than combining them. 3 This approach:

• Eliminates hypoglycemia risk from gliclazide while maintaining or improving glycemic control. 3, 6
• Provides superior cardiovascular and renal protection that gliclazide cannot offer. 3, 2
• Reduces pill burden and improves medication adherence. 3
• Promotes weight loss (1.5-2 kg) rather than weight gain associated with sulfonylureas. 8, 6

If additional glucose lowering is needed after empagliflozin monotherapy, consider adding a GLP-1 receptor agonist (such as semaglutide 0.5 mg weekly) rather than gliclazide, as GLP-1 RAs provide additional cardiovascular benefits and can be used safely at eGFR >30 mL/min/1.73 m². 5