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Tullis-Tulane Alumni Chair in Diabetes
Professor of Medicine
Chief, Section of Endocrinology
Tulane University School of Medicine
New Orleans, Louisiana
Vivian A. Fonseca, MD, FRCP, has disclosed that he has received consulting fees from Abbott, Asahi, AstraZeneca, Bayer, Intarcia, Novo Nordisk, Sanofi, and Takeda; has received funds for research support paid to his institution from Fractyl and Jaguar Gene Therapy; and has ownership interest in Amgen, Bravo, and Mellitus.
Chronic kidney disease (CKD) in patients with diabetes, or diabetic kidney disease (DKD), is a serious and frequent complication of both type 1 and type 2 diabetes mellitus (T2DM). End‑stage renal disease (ESRD) is common, and there is a high risk of cardiovascular disease (CVD). Proper management requires routine screening and evidence-based therapeutics with demonstrated efficacy in slowing CKD progression and limiting cardiovascular events.
CKD Screening and Treatment—When Is It Too Late?
Guidelines strongly recommend that all patients with diabetes are screened for diabetic kidney disease, as early intervention can slow progression. Screening should be done in patients with T2DM at diagnosis and annually thereafter, whereas one could wait up to 5 years to screen an individual with type 1 diabetes.
As CKD worsens, management becomes more challenging. It is never too late to improve glycemic control, but the therapeutic strategy will depend on relative contraindications to available drugs and the need to avoid hypoglycemia, which is common in CKD. With proper treatment, we can also help prevent cardiovascular events, including chronic heart failure, while slowing the progression of CKD. Finally, we want to improve quality of life and keep a handle on cost and complexity of care, which is a challenge for patients and healthcare systems.
RAAS Blockade in T2DM
Several trials assessing blockade of the renin-angiotensin-aldosterone system (RAAS) in patients with T2DM have demonstrated therapeutic benefit, including a reduction in proteinuria, less progression of CKD, and fewer CVD events. However, the absolute risk reduction is modest, and many patients progress to develop ESRD and cardiovascular death. The residual risk remains substantial and additional intervention is needed.
The SGLT2 inhibitors have added a new dimension to the management of CKD in patients with and without diabetes. Initial CVD outcome trials were not designed to demonstrate a CKD benefit, but a reduction in composite renal outcomes was noted, albeit in less high-risk patients. Subsequent renal outcome trials in higher-risk people with diabetic CKD, such as DAPA‑CKD and CREDENCE, demonstrated a clear slowing of disease progression and other benefits such as reduction in CVD events independent of glucose control. These findings led to an approved indication for SGLT2 inhibitors in patients with CKD (including canagliflozin and dapagliflozin, with and without diabetes) that have been incorporated into several guidelines.
The mechanisms underlying the cardiorenal benefits of SGLT2 inhibitors are unclear. While they clearly reduce glucose, blood pressure, and weight, other effects may play a role—including a reduction in juxtaglomerular feedback in the kidney, reduced oxidative stress, increased ketone utilization as an efficient fuel, reduced uric acid, and increased erythropoietin.
Novel Approaches to Reducing CKD Progression
To better manage CKD, several important pathophysiologic processes in the kidney should be addressed, including renal inflammation and fibrosis. Spironolactone has been used to address increased mineralocorticoid activity through aldosterone, though side effects including hyperkalemia have been problematic.
The recent approval of finerenone for patients with diabetic kidney disease offers promise. Results from the phase III FIDELIO and FIGARO trials demonstrated that finerenone reduces CKD progression and CVD events in high-risk patients. This new approval offers a therapeutic pathway for further reducing residual risk after more established therapy.
Furthermore, the GLP-1 receptor agonist semaglutide is currently under investigation in patients with diabetic kidney disease.
Clinical Practice Guidelines
The American Diabetes Association (ADA) has rapidly incorporated clinical trial results into its guidelines, though it still recommends metformin as first‑line therapy for persons with T2DM with a glomerular filtration rate (GFR) ≥30 mL/min/1.73. For those on metformin who develop heart failure or CKD, adding an SGLT2 inhibitor is appropriate and preferable to a GLP-1 receptor agonist. Likewise, adding a GLP‑1 receptor agonist has proven benefit in those with atherosclerotic disease. For the latter, one could also consider an SGLT2 inhibitor. Further, if a patient has chronic kidney disease and good glycemic control, adding an SGLT2 inhibitor for CKD benefit is appropriate.
The ADA has also updated recommendations about blood pressure. In general, a patient with diabetes should have a systolic blood pressure <140 mmHg. In my view, we should aim for even lower blood pressure in patients with CKD, if they can tolerate it. Most patients with DKD should receive RAAS blockade along with SGLT2 inhibitors (unless they cannot tolerate them); these therapies should be continued when the GFR drops below 30 mL/min/1.73. The guidelines are less clear on what to add after these drugs as the disease progresses (perhaps mineralocorticoid receptor antagonists?).
Advanced CKD in T2D: Summary
In summary, advanced CKD is a high‑risk clinical entity with high morbidity and mortality. SGLT2 inhibitors and the nonsteroidal mineralocorticoid receptor antagonist finerenone can reduce CKD progression and cardiovascular risks, but novel approaches to reducing CKD progression are still needed.
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