Interpretation Of 2022 Edition ADA Guidelines For Diagnosis And Treatment Of Diabetic Nephropathy Recommended Update Points

The American Diabetes Association (ADA) Diabetes Medical Diagnosis and Treatment Standards, which is updated annually, is one of the most influential guidelines for the diagnosis and treatment of diabetes. Compared with the 2021 version of the guidelines, the 2022 version of the guidelines has a separate chapter on "chronic kidney disease (CKD) and risk management" for type 2 diabetes mellitus (T2DM) and has made important updates. Now we will explain the updated points.

1. Choice of hypoglycemic drugs

The new guideline recommends the initial application of sodium-glucose cotransporter 2 inhibitors (SGLT2i) or glucagon-like peptide-1 receptor agonist (GLP-1RA) for hypoglycemic therapy in patients with T2DM and CKD, and according to the With or without metformin as required. For the first time, the initial hypoglycemic status of SGLT2i or GLP-1RA in T2DM patients with CKD is higher than that of metformin, especially SGLT2i.

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For many years, metformin has been the recommended drug for the initial treatment of T2DM blood sugar management. In recent years, with the continuous enrichment of evidence-based evidence, it has been shown that SGLT2i or GLP-1RA treatment can reduce proteinuria, delay the progression of renal function, and reduce The role of cardiovascular events has a significant advantage compared with traditional hypoglycemic drugs.

Therefore, for patients with T2DM and CKD [especially urinary albumin/creatinine ratio (UACR) ≥ 300 mg/g or/and estimated glomerular filtration rate (eGFR) ≤ 60 ml/min/1.73m2], the new version of the guidelines, regardless of blood glucose If the situation is controlled, SGLT2i should be given, which can delay the progression of CKD and reduce the risk of heart failure. SGLT2i may be more effective in patients at high risk of CKD progression. Furthermore, randomized clinical trials have not found an increased risk of acute kidney injury with SGLT2i use.

If the cardiovascular risk is the main factor in patients with T2DM and CKD, it is recommended to use GLP-1RA, which can reduce the risk of cardiovascular events and hypoglycemia, and reduce proteinuria, which may slow down the progression of CKD. Some GLP-1RAs require dose adjustment when eGFR decreases (except liraglutide, dulaglutide, and semaglutide).

2. To relax the eGFR range of SGLT2i for patients with T2DM and CKD

For patients with T2DM combined with CKD or diabetic kidney disease (DKD), the new guideline recommends the use of SGLT2i when UACR≥300 mg/g and eGFR≥25 ml/min/1.73 m2, to delay the progression of CKD and reduce cardiovascular events; while the old guideline eGFR application The range is >30 ml/min/1.73m2.

This update is based on new clinical research DAPA-CKD study results. The previous CREDENCE study included T2DM patients with 30≤eGFR≤90 ml/min/1.73m2 and UACR≥300 mg/g, showing that SGLT2i can reduce proteinuria, delay CKD progression, and reduce cardiovascular events; while DAPA-CKD The research subjects were T2DM patients with 25≤eGFR≤75 ml/min/1.73m2 and UACR≥300 mg/g, and the effect of delaying the progression of CKD and reducing cardiovascular events were also obtained. Given this, ADA has further relaxed the range of eGFR in SGLT2i treatment of diabetic patients with CKD or DKD.

SGLT2i is a class of hypoglycemic drugs that increase glucose excretion from the kidneys. As eGFR decreases, the hypoglycemic efficacy of such drugs decreases. For hypoglycemic treatment, it is generally recommended in the drug instructions of various SGLT2i that the SGLT2i application population is T2DM patients with eGFR ≥ 45 ml/min/1.73m2.

However, in the study of T2DM combined with CKD or DKD, it was found that diabetic patients with eGFR<45 ml/min/1.73m2 were treated with SGLT2i, which can reduce proteinuria, delay CKD progression, reduce cardiovascular events and eGFR≥45 ml/min/1.73 The m2 population is the same, indicating that its effects of reducing proteinuria and delaying the progress of renal function are independent of the hypoglycemic effect.

3. Recommended non-steroidal mineralocorticoid receptor antagonist finerenone for patients with T2DM and CKD

Finerenone is a new type of non-steroidal mineralocorticoid receptor antagonist (MRA). The FIDELIO-DKD study showed that, compared with the placebo, finerenone significantly reduced the level of proteinuria in patients with T2DM and CKD, reduced the renal composite endpoint (HR 0.82, 95%CI: 0.73~0.93, P=0.001) and cardiovascular composite endpoint. Endpoint (HR 0.86, 95%CI: 0.75~0.99, P=0.03).

Therefore, for T2DM patients with CKD, if there is an increased risk of cardiovascular events or CKD progression or SGLT2i cannot be used, the ADA recommends the use of finerenone to delay the progression of CKD and reduce cardiovascular events.

4. Optimizing blood pressure control and reducing blood pressure variability can help reduce the risk of CKD or slow down the progression of kidney disease

The 2022 guideline emphasizes that achieving stable blood pressure control and reducing blood pressure variability can reduce the risk of DKD and slow down the progression of diabetes complicated with CKD. Continue to recommend the use of ACEI or ARB, and at the same time, it is recommended to monitor blood potassium levels to reduce the risk of hyperkalemia. It should be noted that ACEI and ARB should be used at the maximum tolerated dose, and low doses cannot provide renal clinical benefit. The maximum tolerated dose of ACEI and ARB can effectively reduce mortality and slow down the progress of CKD. The application of ACEI and ARB does not have to be excessively limited by the increase in serum creatinine. When the increase in serum creatinine is within 30% and there is no associated hyperkalemia, RAS blocking therapy should be continued.

The eGFR of diabetic patients enrolled in existing ACEI or ARB clinical studies are all ≥ 30 ml/min/1.73m2; however, recent studies have shown that patients with eGFR ≤ 30 ml/min/1.73m2 continued to use ACEI/ARB compared with those who stopped using The mortality rate was lower, suggesting that patients with eGFR≤30 ml/min/1.73m2 could benefit from continued use of ACEI and ARB.

5. To delay the progression of CKD, it is recommended that T2DM patients with UACR ≥ 300 mg/g reduce UACR ≥ 30%

For a long time, the clinical endpoint to evaluate whether a certain treatment strategy has renal benefit is end-stage renal failure, and the doubling of serum creatinine level and the reduction of eGFR by more than 40% are considered effective surrogate endpoints for clinical endpoints. Many studies in recent years have shown that in CKD patients with UACR ≥ 300 mg/g if the proteinuria is reduced by more than 30%, it can effectively delay the progression of CKD and reduce end-stage renal failure.

After discussion by a scientific working group jointly supported by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), a decrease in urinary albumin >30% from baseline was recognized as a valid surrogate for renal benefit. Therefore, the new version of ADA guidelines recommends delaying the progression of CKD and reducing UACR ≥ 30%.

In summary, the 2022 version of the ADA guidelines put more emphasis on clinical practicability and operability, and clinical measures are determined according to CKD staging, which is convenient for clinical implementation. In particular, it is recommended that SGLT2i, finerenone, and RAS blockade at the maximum tolerated dose may achieve greater clinical benefits in CKD.

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