In the prevention of kidney disease in patients with type 2 diabetes (T2D) and mildly reduced kidney function, SGLT2 inhibitors (SGLT2i) showed a stronger benefit than GLP-1 receptor agonists (RA) and other diabetes drugs, however, an SGLT2i/GLP-1 combination showed greater efficacy than either therapy alone, results of a new study showed.
Importantly, the utilization of a clinical risk score could further improve the treatment efficacy by assigning patients to the most appropriate therapy, the study authors noted.
“Our take-home message is that SGLT2 inhibitors give better kidney protection than GLP-1 receptor agonists, regardless of the individual, and clinical risk scores could help identify high-risk individuals who might benefit from SGLT2/GLP-1 combination treatment,” first author Thijs Jansz, MD, University of Exeter, Exeter, England, told Medscape Medical News.
The study was presented at the European Association for the Study of Diabetes (EASD) 2025 Annual Meeting.
With SGLT2i and GLP-1s each supported by evidence showing benefits in the prevention of kidney disease in people with T2D, Jansz and colleagues sought to further understand the comparative efficacy of the drugs and which patient subgroups might benefit the most from which treatment.
They evaluated health data from UK primary care records on large cohorts of patients with T2D who were treated between 2013 and 2023.
While inclusion criteria included those with an estimated glomerular filtration rate (eGFR) above 20 mL/min/1.73 m2, the vast majority had an eGFR above 60 mL/min/1.73 m2, suggesting mildly reduced kidney function.
Patients were stratified based on treatment with one of four therapeutic regimens: GLP-1 RA only (n = 40,265), SGLT2i only (n = 119,473), GLP-1 RA plus SGLT2i combination treatment (n = 20,402), or DPP-4 inhibitors or sulfonylureas (DPP-4i/SU; n = 151,071).
The groups had an average age of approximately 59 years, and about 57% were men; however, those treated with a GLP-1 RA were more likely to be women and have a higher BMI, with an average BMI of 37 compared with 35 in the GLP-1/SGLT2i combination group, 33 in the SGLT2i group, and 32 in the DPP-4i/SU group.
Over a 3-year follow-up, after a multivariate adjustment, the rate of kidney disease progression, defined as a 50% or more decline in eGFR or end-stage kidney disease, was lower with SGLT2i compared with GLP-1s (hazard ratio [HR], 0.81), with the effect consistent across ethnic and gender subgroups, as well as based on BMI, age, A1c, eGFR, urine albumin-creatinine ratio, and by baseline risk.
“The bottom line is SGLT2i give better kidney protection than GLP-1s, regardless of the individual,” Jansz said.
Combination Treatment
In a further comparison using DPP-4i/SU as the reference, the GLP-1 RA/SGLT2i combination therapy had the greatest effect in slowing kidney disease progression, with a 56% reduction in progression (HR, 0.54), followed by SGLT2i alone (HR, 0.61) and GLP-1s alone (HR, 0.75).
The difference between the combination of SGLT2i/GLP-1 and SGLT2i alone was significant, with an HR of 0.84 (P = .05).
“We should interpret that difference cautiously due to the low number of events, however, it does suggest a potentially additive effect of the combination treatment,” Jansz noted.
He added that the HRs for the SGLT2 and GLP-1 RA groups are consistent with estimates reported in a recent meta-analysis of 16 randomized trials.
Risk Score Prediction
After stratifying patients using the internationally validated Chronic Kidney Disease Prognosis Consortium (CKD-PC) risk score, the estimated 3-year absolute reduction in the risk for kidney disease with treatment with the GLP-1/SGLT2i combination would be 1.1% compared with SGLT2i-only treatment, and 4.7% compared to DPP-4i/SU, the authors noted.
Patients in the top 10% using the CKD-PC risk score would have a 3-year number needed to treat (NNT) of 169 with the SGLT2i/GLP-1 combination, whereas for those with a risk in the lowest 10%, the 3-year NNT would be 2005 with the combination therapy.
“Even if the additional relative risk reduction [of combination therapy] is not large, a patient with a significant residual risk after having tried SGLT2 treatment alone could still expect a clinically relevant absolute risk reduction,” Jansz said. “This is why we suggest using a risk score to identify individuals with high residual risk.”
Jansz noted that, while SGLT2 use was associated with an increased risk for diabetic ketoacidosis and fungal genital infections compared with DPP-4/SU use, “the combination treatment was not associated with a higher risk compared with SGLT2 only.”
Pillar Risk-Based Treatment Approach?
While treatment of CKD has traditionally involved a stepwise, sequential approach, the alternative pillar risk-based approach, calls for controlling glucose and blood pressure with a more simultaneous or rapid sequential initiation of multiple therapies, including renin-angiotensin system inhibitors, SGLT2i, a nonsteroidal mineralocorticoid receptor antagonist (finerenone), and GLP-1s.
Regarding how the new findings fit in, Jansz said the pillar approach can be beneficial — for the right patients.
“I think our findings support a pillar approach for people with CKD who are at high risk of progression,” he said. “These people would benefit from getting established on full treatment without delays.”
“On the other hand, for people with early-stage or no CKD and with low risk, the decision is probably more nuanced, and a stepwise approach may still be appropriate.”
Added Benefit ‘Reassuring,’ Risk Score Hard
Commenting on the study, Alice Y.Y. Cheng, MD, Trillium Health Partners, Toronto, Ontario, Canada, noted that “in the absence of head-to-head randomized controlled trials, we turn to observational data like these to provide some information on comparative effects of different treatments.”
“This study supports the kidney protective effects of SGLT2is and GLP-1 RAs, and it is reassuring to see that they are indeed additive. These results are in keeping with other observational data on this topic,” Cheng, who was first author on the pillar risk-based approach review, told Medscape Medical News.
She added that the risk score described in the study is not currently widely used.
“In general, risk scores are difficult to implement into busy clinical practices unless done automatically by electronic medical records,” she explained. “However, in the spirit of medication and cost stewardship, being able to identify the people who will benefit the most is welcome.”
A caveat is that, as costs of treatments come down, “even an incremental reduction in risk is worthwhile for a given individual,” Cheng said. “I would not want the mandatory use of a risk score to stand in the way of someone receiving organ-protective therapy.”
Ultimately, “the decision to combine these therapies will need to be guided by access considerations, and the greatest benefit is among those with the highest risk,” she concluded.
Jansz had no disclosures to report. Cheng’s disclosures included having advisory board, consulting and/or speaking relationships with Abbott, Amgen, Aspen, AstraZeneca, Bausch, Bayer, Biomea Fusion, Boehringer Ingelheim, Dexcom, Eisai, Eli Lilly, GlaxoSmithKline, HLS Therapeutics, Insulet, Medtronic, Novo Nordisk, Pfizer, Sandoz, Sanofi, and Vertex.
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