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TOPLINE:

Among adults with type 2 diabetes (T2D) and nephrotic-range proteinuria, an extremely high-risk phenotype, initiating SGLT2 inhibitors instead of DPP-4 inhibitors was associated with lower long-term risks for major adverse kidney events (MAKEs), end-stage kidney disease requiring dialysis, and death from any cause.

METHODOLOGY:

• Although SGLT2 inhibitors have demonstrated clear cardiorenal benefits in major randomized trials, it remains uncertain whether those benefits apply across the full spectrum of diabetic kidney disease — especially in patients with nephrotic-range proteinuria who were underrepresented in trials.
• Researchers conducted a retrospective cohort study using a new-user, active-comparator target trial emulation design to compare the effect of initiating SGLT2 inhibitors vs DPP-4 inhibitors in adults with T2D and nephrotic-range proteinuria.
• After propensity score matching, 2102 participants (mean age, approximately 61 years; 53%-55% men) were included (1051 per group); eligibility required age 18 years or above, at least two outpatient diagnoses of T2D, and at least one record of urine protein-to-creatinine ratio > 3500 mg/g or urine albumin-to-creatinine ratio > 1967 mg/g.
• The primary outcome was MAKEs, encompassing end-stage kidney disease, kidney transplant, and death; secondary outcomes included overall mortality, major adverse cardiovascular events (MACEs), end-stage renal disease, acute myocardial infarction, heart failure, stroke, sepsis, and hospitalization.
• Follow-up began 1 day after the initiation of SGLT2 inhibitors or DPP-4 inhibitors; the mean follow-up duration was 860 days for the SGLT2 inhibitor group and 999 days for the DPP-4 inhibitor group.

TAKEAWAY:

• The initiation of SGLT2 inhibitors was associated with a 25% lower risk for MAKEs than the initiation of DPP-4 inhibitors (30.0% vs 41.2%; hazard ratio [HR], 0.75; P < .001).
• Participants in the SGLT2 inhibitor group also showed a lower risk for end-stage kidney disease (HR, 0.73; P < .001) and all-cause mortality (HR, 0.71; P = .007) than those in the DPP-4 inhibitor group; no clear differences were observed between SGLT2 inhibitor and DPP-4 inhibitor users for MACEs (P = .102).
• Safety outcomes including genital infection (HR, 0.85; 95% CI, 0.68-1.05), urinary tract infection (HR, 0.86; 95% CI, 0.68-1.07), diabetic ketoacidosis (HR, 1.40; 95% CI, 0.74-2.66), and hypoglycemia (HR, 0.86; 95% CI, 0.59-1.25) showed no statistically significant differences between the groups.

IN PRACTICE:

“These real-world findings support the kidney-protective potential of [SGLT2 inhibitors] in this very high-risk population,” the authors wrote.

SOURCE:

The study was led by Jia-Jin Chen, Linkou Chang Gung Memorial Hospital in Taoyuan, Taiwan. It was published online in Diabetes, Obesity and Metabolism.

LIMITATIONS:

Nephrotic-range proteinuria was defined using single-spot urine protein-to-creatinine ratio or urine albumin-to-creatinine ratio values rather than standardized repeat measurements or 24-hour urine collections. Disease classification and outcome definitions relied on diagnostic and procedural codes without ascertainment of prescription indications, and mortality was recorded only as all-cause death without distinguishing renal or cardiovascular causes. Residual confounding may have persisted from unmeasured factors such as diabetes duration, adherence, lifestyle, frailty, and chronicity of nephrotic-range proteinuria.

DISCLOSURES:

The authors declared having no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.