SGLT2i Benefit Mortality, Cognition in Older CKD Patients

DENVER — Treatment with SGLT2 inhibitors was associated with notable survival and cognitive benefits in older patients with chronic kidney disease (CKD), findings from two new studies showed.These medications were linked to “a reduced risk of mortality as well as improved cardiovascular and renal outcomes,” said Bernhard M.W. Schmidt, MD, of the Department of Nephrology and Hypertension at Hannover Medical School in Hannover, Germany, who presented one of these studies at Kidney Week 2026: American Society of Nephrology Annual Meeting.“Even the oldest CKD patients benefited from SGLT2 inhibitor treatment,” Schmidt told meeting attendees.Though observational, the two studies shed light on older age groups, who, according to the CDC, are known to have the highest rates of CKD but, paradoxically, are among the most underrepresented in clinical trials.Retrospective Study Using the TriNetX DatabaseIn Schmidt’s retrospective study, the authors utilized data from the TriNetX database, identifying 23,765 patients aged 80 years or older with CKD who were treated with SGLT2 inhibitors between January 2021 and January 2025.For a propensity score analysis, an equal number of nonusers were identified, and the two groups were matched based on factors including comorbidities, laboratory parameters, and frailty-associated factors.The study excluded patients with type 1 diabetes, end-stage renal disease (ESRD), stage 5 CKD, dependence on dialysis, or an estimated glomerular filtration rate ≤ 20 mL/min/1.73 m2 and kidney transplant recipients.With regard to the primary outcome, over a 2-year follow-up, those treated with SGLT2 inhibitors showed a significant reduction in mortality — based on International Classification of Diseases codes — of about 27% compared with the nonusers (adjusted hazard ratio [aHR], 0.734; P < .0001).The mortality benefit remained significant across the subgroups of age, sex, BMI, type 2 diabetes (T2D), heart failure, and CKD stage.With regard to the secondary outcomes, SGLT2 inhibitor treatment was associated with a reduction of about 22% in major adverse kidney events (aHR, 0.779; P < .0001). However, there were no significant differences between the groups in terms of major adverse cardiac events (MACEs; aHR, 1.007; P = .84).In terms of specific renal and cardiac events, the SGLT2 inhibitor group had lower rates of incident dialysis (aHR, 0.513), ESRD (aHR, 0.569), and cardiac arrest (aHR, 0.763), with slightly higher rates of acute kidney injury (aHR, 1.107).Of note, the acute myocardial infarction (MI) rate was higher after treatment with SGLT2 inhibitors (aHR, 1.426), as were the rates of acute heart failure (aHR, 1.517) and cerebral bleeding (aHR, 1.165).For adverse events, the rate of candidiasis was higher with SGLT2 inhibitor treatment, (aHR, 2.358), as was the rate of ketoacidosis (aHR, 1.388).Schmidt noted that with some prior studies showing only small or no effects on MACEs, the MACE results in the current study were not surprising.“MI and stroke are atherosclerotic diseases, which might not be so well prevented by SGLT2i,” he told Medscape Medical News.In terms of the higher MI and heart failure rates observed after treatment with SGLT2 inhibitors, Schmidt speculated that the effect could reflect “the competing risk mortality, [ie], non-SGLT2i users die before they have an MI or heart failure event.”In addition, residual confounding could play a role, with SGLT2 inhibitor users being prescribed the drugs possibly because they are at a higher risk for MACEs, he noted.A third suggestion — that the higher risks are indeed true effects — “I believe is the least plausible explanation,” Schmidt added.Overall, Schmidt said he believes the benefits of SGLT2 inhibitors “definitely” outweigh those risks.“There is no reason to withhold SGLT2 inhibitors based on age,” he concluded.Cognitive Decline?CKD is also associated with an increased risk for cognitive impairment, which is of higher concern in the aging population. The authors of the second study evaluated the cognitive effects of SGLT2 inhibitors, noting previous research linking the drug class to a lower dementiarisk in older patients.Their study, a national target-trial emulation, also utilized data from the TriNetX database, including 43,005 adults aged 65 years or older with T2D, of whom 25,025 had baseline CKD.Of these patients, 28,713 had initiated SGLT2 inhibitors between 2020 and 2022 and 14,292 had initiated DPP-4 inhibitors, representing the comparator group.The participants had no prior cognitive impairment or ESRD.With a follow-up of up to 3 years, after adjusting for competing death, those treated with SGLT2 inhibitors showed a 16% reduction (subdistribution hazard ratio [sHR], 0.84) in the rate of the combined outcome of dementia or mild cognitive impairment (MCI), and a 22% reduction in the rate of dementia alone (sHR, 0.78) but no reduction in the rate of MCI alone (sHR, 1.02).In a subanalysis focusing on patients with CKD, the rate of cognitive impairment was 24% lower among those treated with SGLT2 inhibitors (n = 17,090) than among those treated with DPP-4 inhibitors (n = 7935; sHR, 0.76; P = .003), and the rate of dementia alone was 27% lower among those treated with SGLT2 inhibitors (sHR, 0.73; P value not available).As in the full cohort, the reductions in the rates of MCI were not significant between the groups with CKD (sHR, 0.93).Of note, in an exploratory analysis of the CKD treatment groups, the rates of Alzheimer’s disease and vascular dementia were 34% and 36% lower, respectively, with SGLT2 inhibitor treatment (sHR, 0.66 and 0.64, respectively).The effects observed “were consistent with earlier observational evidence, [and] the stronger combined outcome association in CKD was particularly interesting clinically,” first author Farrukh M. Koraishy, MD, PhD, a professor of nephrology/medicine at the Division of Nephrology and Hypertension at Stony Brook University in Stony Brook, New York, told Medscape Medical News.He speculated that “kidney and cardiovascular protection could plausibly reduce vascular injury, affecting cognition.”However, he noted that “our study did not establish a mechanism, and these diagnosis code-based subtype findings require confirmation.”Furthermore, “prevention and treatment are different questions, and neither drug class has established dementia prevention efficacy.”Commenting on Schmidt’s study, Koraishy added that the results on mortality outcomes are also “encouraging for an underrepresented population.”“The reported adverse outcomes also reinforce the need for individualized treatment and monitoring,” he said, underscoring that “observational survival associations should be interpreted cautiously.”Older Age Dominant in CKDCommenting on the two studies, Jia Hwei Ng, MD, an associate professor of medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York, who co-moderated the session, agreed that “older patients have been understudied,” consequently leaving many important clinical questions unanswered.“As our population is aging, it is important to conduct studies on this population,” she told Medscape Medical News.“Most of the time, we treat them the same as the younger population, but there are nuances. Sometimes we do not know what the best thing to do [is] in certain situations.”Of note, Ng said that at the general CKD clinic that she runs, “the age range of my patients is between ages 60-103. Those aged in their forties and fifties are my outliers.”Concerns in PrescribingIn addition to the key concern of polypharmacy, specific reservations clinicians may have regarding prescribing SGLT2 inhibitors in older patients include their potential effects on increasing urination, which can be problematic for older women, who may have bladder incontinence, and for older men due to enlarged prostates, which can cause nocturia, Ng said.Furthermore, she noted that she is also concerned about using SGLT2 inhibitors for patients with frailty.“Frail patients don’t eat well, [and] they may be bed bound,” Ng said. “SGLT2 inhibitors may cause them to lose even more weight. If they are bedbound or have to wear pull-ups, I am worried about urinary tract or perineal infection.”She agreed that as retrospective studies, the two studies have the limitations of possible confounding, as mentioned by Koraishy.Regarding the cognitive impairment findings, Ng noted that the evidence of a biological mechanism underlying the effects of SGLT2 inhibitors on cognitive impairment is, so far, “inadequate,” but she added: “I think this study brings an interesting early — very early — signal on the association of SGLT2 inhibitors’ effect on cognitive impairment.”“With new drugs coming out, we need to extend the studies to older population,” she underscored. “Clinicians want more guidance in terms of treatment in specific populations.”Schmidt reported having received lecturer fees, honoraria, and travel support from ADVITOS, Amgen, AstraZeneca, Bayer Vital, Berlin-Chemie Menarini, Boehringer Ingelheim, CytoSorbents, Daiichi Sankyo, Miltenyi Biotec, Novartis, TriNetX, and CSL Vifor. Koraishy and Ng had no disclosures to report.