Which Angiotensin-Converting Enzyme inhibitors (ACE inhibitors) or Angiotensin Receptor Blockers (ARBs) demonstrate renal protective effects in patients with Type 2 Diabetes Mellitus?

From the Guidelines

For type 2 diabetes patients requiring kidney protection, both ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are the preferred first-line agents due to their proven benefits for prevention of CKD progression, as recommended by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO) 1. The use of ACEIs or ARBs has been standard of care in patients with type 1 and type 2 diabetes and chronic kidney disease (CKD) for decades.

• Key benefits of ACEIs and ARBs include:
  • Reduction of intraglomerular pressure
  • Decrease in proteinuria
  • Slowing of the progression of diabetic kidney disease
  • Prevention of CKD progression
• The ADA and KDIGO recommend an ACEI or ARB for treatment of hypertension among people with type 1 or type 2 diabetes who have hypertension and albumin-to-creatinine ratio (ACR) ≥30 mg/g 1.
• It is essential to monitor kidney function and potassium levels regularly, especially during the first few weeks of treatment, and to use these medications cautiously in patients with advanced kidney disease (eGFR <30 ml/min) due to increased risk of hyperkalemia.
• If a dry cough develops with an ACEI, switching to an ARB is recommended as they provide similar kidney protection without this side effect.
• The combination of ACEIs and ARBs is not recommended due to the increased risk of adverse events, particularly hyperkalemia and acute kidney injury (AKI) 1.

From the FDA Drug Label

1. 4 Dual Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy The Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial enrolled 1448 patients with type 2 diabetes, elevated urinary-albumin-to-creatinine ratio, and decreased estimated glomerular filtration rate (GFR 30 to 89.9 mL/min), randomized them to lisinopril or placebo on a background of losartan therapy and followed them for a median of 2. 2 years.

The losartan shows kidney protection for type 2 diabetes, as it was used in the VA NEPHRON-D trial as a background therapy for patients with type 2 diabetes and decreased estimated glomerular filtration rate. However, the trial found that adding lisinopril to losartan did not provide additional benefit for kidney protection, but instead increased the risk of hyperkalemia and acute kidney injury 2.

• Losartan may provide kidney protection for type 2 diabetes patients.
• Lisinopril and losartan combination does not provide additional kidney protection benefit and increases the risk of hyperkalemia and acute kidney injury.
• Aliskiren should not be coadministered with losartan in patients with diabetes.

From the Research

ACE Inhibitors and ARBs for Kidney Protection in Type 2 Diabetes

• ACE inhibitors and ARBs can slow the progression of diabetic nephropathy, as evidenced by studies such as 3 and 4.
• Combination therapy of ACE inhibitors and ARBs may be beneficial in reducing cardiovascular outcomes in high-risk patients, as shown in the ACCOMPLISH trial 3.
• The use of ACE inhibitors or ARBs can reduce the risk of progressing to end-stage renal disease, as found in a study published in 2020 5.
• ACE inhibitors and ARBs may also slow the progression of nephropathy, but they do not appear to decrease all-cause or cardiovascular mortality in people with Type 2 diabetes and proteinuria 5.

Specific ACE Inhibitors and ARBs

• Losartan and lisinopril are examples of ACE inhibitors and ARBs that have been studied for their effects on kidney disease in patients with diabetes, as seen in the VA NEPHRON-D trial 4.
• The combination of an ACE inhibitor and a calcium channel blocker may provide a significant additive effect on blood pressure reduction and synergistically reduce proteinuria and the rate of decline in glomerular filtration rate, as evidenced by the GUARD trial 3.

Underuse of ACE Inhibitors and ARBs

• Despite their benefits, ACE inhibitors and ARBs are often underutilized in elderly patients with diabetes, as found in studies published in 2005 6 and 2010 7.
• The underuse of these medications may be due to concerns about potential complications, such as hyperkalemia, but the benefits of ACE inhibitors and ARBs in reducing the risk of kidney disease and cardiovascular outcomes may outweigh these risks 7.