What are the recommended first-line treatments using Renin-Angiotensin System (RAS) inhibitors for patients with hypertension, heart failure, or diabetic nephropathy?

First-Line Treatments with RAS Inhibitors for Hypertension, Heart Failure, and Diabetic Nephropathy

ACE inhibitors and ARBs are the recommended first-line RAS inhibitors for patients with hypertension, heart failure, or diabetic nephropathy due to their proven benefits in reducing cardiovascular events and slowing kidney disease progression. 1

Hypertension Management with RAS Inhibitors

First-Line Recommendations

• ACE inhibitors or ARBs are preferred first-line agents for hypertension in patients with diabetes, especially those with albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g) 1
• For patients with established coronary artery disease and hypertension, ACE inhibitors or ARBs are strongly recommended as first-line therapy 1
• In patients with hypertension but without albuminuria, ACE inhibitors/ARBs have not shown superior cardioprotection compared to thiazide-like diuretics or dihydropyridine calcium channel blockers 1

Target Blood Pressure Goals

• Target blood pressure should be <130/80 mmHg in patients with diabetes 1
• For patients with blood pressure ≥150/90 mmHg, initial treatment with two antihypertensive medications is recommended to achieve adequate control 1
• Most patients will require multiple drugs (typically 3-4) to reach target blood pressure goals 1

Heart Failure Management

• ACE inhibitors are indicated to reduce signs and symptoms of systolic heart failure 2
• ARBs have been shown to reduce major cardiovascular outcomes in patients with congestive heart failure, including diabetic subgroups 1, 3
• Valsartan is specifically indicated to reduce the risk of hospitalization for heart failure in adult patients with NYHA class II-IV heart failure 3
• For patients with heart failure with reduced ejection fraction, angiotensin receptor/neprilysin inhibitors (ARNIs) are first choice, with ACE inhibitors being the second choice 4

Diabetic Nephropathy Management

• ACE inhibitors or ARBs are strongly recommended for patients with diabetes and urine albumin-to-creatinine ratio ≥300 mg/g creatinine 1
• In type 1 diabetes with nephropathy and serum creatinine <2.5 mg/dl, ACE inhibitors like captopril have shown to reduce kidney disease progression by 48% and the composite endpoint of death, dialysis, and transplantation by 50% 1
• For type 2 diabetes with nephropathy, ARBs have demonstrated superiority over calcium channel blockers in reducing heart failure and slowing progressive loss of kidney function 1
• RAS inhibitors should be used even in patients with advanced renal insufficiency (GFR 10-30 ml/min/1.73m²), as they safely slow GFR decline and progression to end-stage renal disease 5

Comparative Efficacy of RAS Inhibitors

• ACE inhibitors may be superior to dihydropyridine calcium channel blockers in reducing cardiovascular events in diabetic patients 1
• When compared to calcium channel blockers, RAS inhibitors decrease heart failure (ARR 1.2%) but increase stroke risk (ARI 0.7%) 6
• Compared to thiazide diuretics, RAS inhibitors increase the risk of heart failure (ARI 1.0%) and stroke (ARI 0.6%) 6
• When compared to beta-blockers, RAS inhibitors decrease total cardiovascular events (ARR 1.7%) and stroke (ARR 1.7%) 6

Important Considerations and Monitoring

• Monitor serum creatinine and potassium within 7-14 days after initiation of therapy and at least annually, especially in patients with reduced kidney function 1
• A rise in creatinine may occur after starting RAS inhibitors due to reduced intraglomerular pressure; consider dose reduction or discontinuation only if creatinine increases by >30% or hyperkalemia develops 1
• Avoid combining ACE inhibitors with ARBs due to increased risk of adverse events (hyperkalemia, syncope, acute kidney injury) without added cardiovascular benefit 1
• ACE inhibitors and ARBs are contraindicated during pregnancy due to risk of fetal damage 1

Special Populations

• For kidney transplant recipients with diabetes, metformin can be used according to eGFR guidelines, but more data is needed before recommending SGLT2 inhibitors 1
• In patients with type 2 diabetes and persistent albuminuria despite standard care, consider adding finerenone (a non-steroidal mineralocorticoid receptor antagonist) to the treatment regimen 1
• For patients who cannot tolerate ACE inhibitors (commonly due to cough), ARBs are the recommended alternative 4

Practical Implementation

• Most patients will require 3 or more antihypertensive agents to achieve blood pressure targets, particularly those with diabetic kidney disease 1
• When selecting antihypertensive agents, consider cost, side effects, convenience, and effects on diabetes management 1
• Carvedilol may be a better beta-blocker choice than metoprolol when combined with RAS inhibitors in patients with type 2 diabetes and hypertension, as it better stabilizes glycemic control and reduces microalbuminuria 1

RAS inhibitors remain cornerstone therapies for hypertension, heart failure, and diabetic nephropathy due to their proven benefits in reducing cardiovascular events and slowing kidney disease progression beyond blood pressure control alone.