SGLT2 inhibitors showed significantly improved mortality benefits compared with DPP-4 inhibitors in patients with diabetic kidney disease (DKD) in a large target trial emulation study that adds real-world data to inconsistent survival outcomes of previous clinical trials.

“These findings reinforce and extend prior evidence from randomized controlled trials (RCTs) demonstrating cardiovascular and kidney protection by showing that SGLT2 inhibitors may confer a meaningful survival benefit in a broader, older population underrepresented in clinical trials,” reported the authors in research published in Diabetes, Obesity and Metabolism.

DKD is associated with an increased risk for cardiovascular disease and mortality compared with either chronic kidney disease (CKD) or diabetes alone, with a notably higher risk, particularly of mortality, among older adults.

While previous large RCTs have demonstrated benefits of SGLT2 inhibitors on various kidney outcomes in DKD, their effects on all-cause mortality have been less consistent. For instance, the DAPA-CKD trial, which enrolled patients with significant albuminuria, suggested possible survival benefits in patients with CKD, both with and without diabetes. In contrast, the EMPA-KIDNEY and SCORED studies, which both included patients with less severe or no albuminuria, did not show significant reductions in mortality.

“[M]any older adults with DKD in routine clinical practice have more heterogeneous clinical profiles, including lower levels of albuminuria or higher age than typical RCT participants,” the study authors noted. “Understanding whether, and in which subgroups, SGLT2 inhibitors confer survival benefits in this broader population is therefore crucial for informing real-world clinical decision-making.”

A Real-World Population

To investigate the effects in a real-world population, senior author Hidehiro Kaneko, MD, of the Department of Cardiovascular Medicine, the University of Tokyo, Tokyo, Japan, and colleagues utilized the target trial emulation approach.

Under the protocol, a hypothetical RCT was emulated using observational real-world data on 5371 adults aged 65 years or older with DKD who were enrolled in a nationwide claims and health checkup database in Japan.

The participants, who had a median age of 71 years and were 35.5% female, initiated either an SGLT2 inhibitor (n = 1464) or a DPP-4 inhibitor (n = 3907) between January 2016 and August 2023 and had data available on health checkups and mortality.

Among them, 83.4% had hypertension and 83.2% had dyslipidemia. Renin-angiotensin system inhibitors were prescribed to 53.8% of participants, and statins were prescribed to 50.0% of participants.

Those receiving SGLT2 inhibitors were less likely to be female (30.8% vs 37.3%), had more recent enrollment vs those on DPP-4 inhibitors, and had a slightly higher BMI vs the DPP-4 inhibitor group (25.9 vs 24.6).

However, after adjusting for multivariate factors in overlap propensity score weighting, the groups were well balanced at baseline.

With a median follow-up of 2.23 years, there were 437 deaths in the group overall.

SGLT2 inhibitor use was found to be associated with a significantly lower rate of all-cause mortality than DPP-4 inhibitor use (hazard ratio [HR], 0.51), with consistent results in a per-protocol analysis (HR, 0.50), “underscoring the robustness of this finding,” the authors wrote.

The survival benefit was strongest in those younger than 80 years, with the effect weakening in strength with advancing age, and among individuals with a BMI of at least 22 (normal range) or higher, regardless of comorbidities (Charlson Comorbidity Index).

“The age-related variation may reflect competing risks of noncardiovascular death, age-related frailty, or differential drug tolerability in the oldest old,” the study authors noted.

However, the findings importantly address the concerns of treatment of DKD in older adults, including issues of frailty, polypharmacy, and limited life expectancy, they stated.

“Our results provide reassuring evidence that even in this vulnerable population, SGLT2 inhibitors may offer a meaningful reduction in mortality.”

SGLT2 Inhibitor Benefits Span Albuminuria Levels

In a separate recent study, João Pedro Ferreira, MD, PhD, and colleagues evaluated the effects of SGLT2 inhibitors across albuminuria levels in a pooled analysis of RCTs across the spectrum of 26,750 patients with different cardiovascular, kidney, and metabolic risks.

They found that, compared with placebo, SGLT2 inhibitor treatment was consistently associated with a reduced risk for kidney and cardiovascular events across the full spectrum of albuminuria, without evidence of benefit attenuation, even among patients with albuminuria levels considered normal (< 30 mg/g), and independent of estimated glomerular filtration rate.

While studies in their analysis compared SGLT2 inhibitors with a placebo, the new findings showing the mortality benefit compared with DPP-4 inhibitors were not surprising, Ferreira, professor with the Unit of Cardiovascular Research and Development – Unic@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal, told Medscape Medical News.

“SGLT2 inhibitors have beneficial effects far beyond glucose control, and they are superior to DPP-4 inhibitors in terms of cardiovascular and kidney benefits,” he said. “Incretin-based therapies (like DPPR inhibitors) are very different from SGLT2 inhibitors, and their beneficial effects seem to be independent and complementary,” he added. “Thus, these agents can be combined in selected high-risk patients.”

Further commenting on the study, Susanne B. Nicholas, MD, PhD, professor of medicine, hypertension specialist and interim academic chief of nephrology at the David Geffen School of Medicine at the University of California, Los Angeles, agreed that the study offered important insights.

“The study addresses an important gap in having a better understanding of SGLT2 inhibitors on survival benefit in DKD for older adults (median age, 71 years), which is a subgroup that has not been routinely included in large cardiovascular outcome, randomized, placebo-controlled trials,” she told Medscape Medical News.

“The significance of the study is that the prevalence of DKD is over 45% in older individuals over 65 years, yet this age group has not been routinely included in large cardiovascular outcome trials.”

Of note, the study’s target emulation design “supersedes a conventional observational study design that makes causal assumptions more explicit and more reliable,” she explained. “However, the design does not fully replace or reflect a randomized controlled trial.”

Kaneko reported receiving research funding and scholarship funds from Medtronic Japan Co., Ltd.; Boston Scientific Japan; BIOTRONIK Japan, Inc.; and SIMPLEX QUANTUM, Inc. The other study authors’ disclosures are detailed in the published study. Ferreira reported receiving research support from Boehringer Ingelheim, AstraZeneca, Novartis, Bayer, BIAL, Amgen, and Salamandra. Nicholas reported having consulting and/or other relationships with Boehringer Ingelheim/Eli Lilly and Company, Bayer, and Wearable Artificial Kidney.