Can a patient with uncontrolled diabetes mellitus (DM) and normal blood pressure be started on lisinopril or Farxiga (dapagliflozin)?

Treatment Recommendation for Uncontrolled Diabetes with Normal Blood Pressure

Start Farxiga (dapagliflozin) immediately for cardiovascular and renal protection, and consider adding lisinopril if albuminuria is present, regardless of blood pressure status. 1, 2, 3

Primary Recommendation: Farxiga (Dapagliflozin)

For a patient with uncontrolled diabetes and normal blood pressure, dapagliflozin is the superior choice because it provides:

• Cardiovascular risk reduction including reduced hospitalization for heart failure and cardiovascular death, independent of blood pressure lowering 2, 3
• Renal protection with slowed progression of diabetic kidney disease 4
• Improved glycemic control without increasing hypoglycemia risk when used as monotherapy 3
• Mortality benefit in patients with type 2 diabetes and cardiovascular risk factors 2

Dosing for Dapagliflozin

• Fixed dose of 10 mg orally once daily for cardiovascular and renal indications 3
• Can be combined with metformin if eGFR ≥30 mL/min/1.73 m² 5

Monitoring Requirements

• Assess for genital mycotic infections (occurs in ~6% of patients) 5
• Monitor for euglycemic diabetic ketoacidosis, particularly during acute illness 5, 3
• Temporarily discontinue at least 3 days before major surgery or prolonged fasting 3
• Check volume status, especially if on other medications affecting fluid balance 5

Secondary Recommendation: Lisinopril

Lisinopril should be added if the patient has albuminuria (UACR ≥30 mg/g), even with normal blood pressure. 1

Evidence Supporting ACE Inhibitors in Normotensive Diabetics

The strongest evidence comes from the EUCLID trial, which demonstrated that:

• Lisinopril slows progression of renal disease in normotensive patients with insulin-dependent diabetes and microalbuminuria 6
• In patients with microalbuminuria at baseline, lisinopril reduced albumin excretion rate by 49.7% over 24 months 6
• No increased risk of hypoglycemic events compared to placebo 6
• Greatest benefit seen in those with microalbuminuria (AER ≥20 μg/min) 6

When to Use Lisinopril in Normotensive Diabetics

Check urine albumin-to-creatinine ratio (UACR) first:

• If UACR ≥300 mg/g (macroalbuminuria): ACE inhibitor or ARB is strongly recommended as first-line treatment 1
• If UACR 30-299 mg/g (microalbuminuria): ACE inhibitor or ARB should be considered 1
• If UACR <30 mg/g (normoalbuminuria): Lisinopril provides minimal benefit (only 12.7% reduction in AER, not statistically significant) 6

Dosing for Lisinopril

• Start with 2.5-5 mg daily, titrate up to 10-40 mg daily as tolerated 7, 8
• Lower doses needed if significant renal impairment present 8

Monitoring with Lisinopril

• Serum creatinine/eGFR and potassium at least annually, more frequently if eGFR <60 mL/min/1.73 m² 1
• Acceptable for creatinine to rise up to 30% after initiation (reflects hemodynamic changes, not kidney damage) 1
• Discontinue if creatinine rises >30% or hyperkalemia develops 1

Combination Therapy: The Optimal Approach

If albuminuria is present, use both dapagliflozin AND lisinopril together for synergistic renoprotection. 4

Recent evidence shows:

• Combination therapy is superior to either agent alone in hypertensive diabetic rats with nephropathy 4
• Empagliflozin (same class as dapagliflozin) plus lisinopril reduced proteinuria, glomerular injury, and renal fibrosis more effectively than monotherapy 4
• The combination controls blood glucose while providing additive renal protection 4

What NOT to Do

Do not withhold ACE inhibitors solely because blood pressure is normal if albuminuria is present—the renoprotective effects are independent of blood pressure lowering. 1, 6

Avoid the misconception that antihypertensive medications are only for hypertension. In diabetes with albuminuria, ACE inhibitors provide organ protection beyond blood pressure control. 1

Clinical Algorithm

1. Measure UACR immediately 1
2. Start dapagliflozin 10 mg daily for all patients with uncontrolled diabetes 2, 3
3. If UACR ≥30 mg/g: Add lisinopril starting at 2.5-5 mg daily 1, 6
4. If UACR <30 mg/g: Continue dapagliflozin alone; recheck UACR annually 1
5. Monitor creatinine and potassium within 2-4 weeks of starting lisinopril 1
6. Titrate lisinopril to maximum tolerated dose if albuminuria persists 1

Additional Cardiovascular Benefits

Beyond renal protection, this approach provides:

• Reduced mortality in diabetic patients post-MI (37 lives saved per 1000 treated with lisinopril) 9
• 32-35% reduction in heart failure hospitalization with SGLT2 inhibitors 2
• Slowed progression of diabetic retinopathy with ACE inhibitors 7