Do SGLT2 Inhibitors Benefit Everyone With T2D and CKD?

MADRID — Nearly half of people with type 2 diabetes (T2D) currently recommended to receive sodium-glucose cotransporter 2 (SGLT2) inhibitors for kidney protection would not actually benefit from them, new research suggests. 
Current guidelines recommend SGLT2 inhibitors for kidney protection for a broad range of people with T2D, but many weren’t represented in key kidney outcome trials. Data from cardiovascular outcomes trials including such patients suggested a relative risk reduction. However, this new research suggests that only people with a reduced estimated glomerular filtration rate (eGFR), severely increased albuminuria, or preserved eGFR and low-level albuminuria but high-risk scores receive absolute benefit, “which is relevant in the context of prescription costs, given the large population affected,” lead author Thijs Jansz, MD, PhD, academic clinical lecturer at the University of Exeter and specialty registrar in renal medicine at North Bristol NHS Trust, United Kingdom, told Medscape Medical News. 
The data suggest limited benefit for others, who account for 46% of those recommended SGLT2 inhibitors for kidney protection.
“For glucose-lowering, SGLT2 inhibitors would be my first choice for a patient with T2D and preserved eGFR who requires additional antihyperglycemic treatment, given the additional benefits. However, for patients with T2D and preserved eGFR who are stable and do not require further glycemic management, I would engage in a shared decision-making process to determine the best course of action, considering the patient’s individual risk and preferences,” Jansz said. 
This approach contrasts with the 2022 joint consensus statement from the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO), which recommend SGLT2 inhibitors for all patients with T2D who have an eGFR ≥ 20 mL/min/1.73 m2 and chronic kidney disease (CKD), defined as an eGFR < 60 mL/min/1.73 m2 or albuminuria > 30 mg/g (3 mg/mmol). 
The recommendation was based on findings from key kidney outcome trials including CREDENCE, DAPA-CKD, and EMPA-KIDNEY that showed significant kidney protection benefit in patients with severely increased albuminuria (> 300 mg/g [30 mg/mmol]) or significantly reduced eGFR (20-45 mL/min/1.73 m2). 
These trials didn’t include patients with preserved eGFR (≥ 60 mL/min/1.73 m2) and low-level albuminuria (30-300 mg/g [3-30 mg/mmol]). A meta-analysis of cardiovascular outcome trials that did include such patients suggested a relative risk reduction with SGLT2 inhibitors, but this study is the first to evaluate the absolute risk reduction, Jansz noted. 
“Our data suggest that clinicians should actively offer SGLT2 inhibitors treatment to certain high-risk groups…and consider treatment for others with preserved eGFR on a case-by-case basis, rather than as a blanket approach,” he advised. 
Asked to comment, Janaka Karalliedde, MD, MBBS, PhD, clinical reader in diabetes and cardiovascular disease at King’s College London, United Kingdom, offered a different perspective. “When we’re approaching the treatment of someone with type 2 diabetes, we’re not just thinking of kidney disease outcomes. We’re thinking of cardiovascular risk. And when we’re choosing therapies like [glucagon-like peptide 1] agonists or SGLT2 inhibitors, we are thinking of cardiorenal disease, not just nephrocentric outcomes. That’s what we should be aiming for, rather than just looking at one endpoint like kidney disease, but treating the competing risk of cardiovascular disease, which is so prominent in people with diabetes.” 
Should Guidelines Adopt a More ‘Stratified Approach?’ 
The study included 134,420 adults with T2D, eGFR ≥ 20 mL/min/1.73 m2, and no cardiovascular disease or heart failure who started an SGLT2 inhibitor (34%) or a dipeptidyl peptidase 4 (DPP-4) inhibitor/sulfonylurea (66%) in UK primary care, with data recorded in the Clinical Practice Research Datalink during 2013-2020. 
Jansz and colleagues first validated the hazard ratio for kidney disease progression, defined as ≥ 50% eGFR decline, end-stage kidney disease, or kidney-related death, from the SGLT2 inhibitor trial meta-analysis. They then integrated that with the established prediction model CKD Prognosis Consortium risk score for 3-year risk for kidney disease progression to estimate SGLT2 inhibitor benefit in terms of absolute risk reduction (ARR). 
After multivariable adjustment, the hazard ratio for kidney disease progression with an SGLT2 inhibitor vs a DPP4 inhibitor/sulfonylurea was 0.60, consistent with that seen in the SGLT2 inhibitor trial meta-analysis and across eGFR and albuminuria subgroups. 
The predicted SGLT2 inhibitor benefit was substantial (ARR ≥ 0.85%) in two groups: (1) people with either an eGFR < 60 mL/min/1.73 m2 (3-year number needed to treat [NNT], 52) or albuminuria ≥ 30 mg/mmol (NNT, 82), and (2) those with eGFR ≥ 60 mL/min/1.73 m2, albuminuria 3-30 mg/mmol, and risk score ≥ 80th percentile (NNT, 118). 
For all others with eGFR ≥ 60 mL/min/1.73 m2, the ARR was ≤ 0.38%. This group accounts for 46% of those ADA and KDIGO recommend to receive SGLT2 inhibitors, Jansz said. 
In fact, the 3-year NNT for those with an eGFR ≥ 60 mL/min/1.73 m2, albuminuria 3-30 mg/mmol, and predicted benefit 0-80th percentile — for whom ADA/KDIGO recommends SGLT2 inhibitor treatment — was 264. This is nearly as high as the NNT of 287 for those with an eGFR ≥ 60 mL/min/1.73 m2 and albuminuria < 3 mg/mmol, for whom treatment is not recommended, he pointed out. 
“Our approach integrates validated relative risk estimates from clinical trials with established risk prediction models, offering a higher level of evidence than observational data alone. This enables targeted use of SGLT2 inhibitors in patients likely to benefit from kidney protection. Currently, SGLT2 inhibitor kidney protection benefits are limited for nearly half of people with T2D eligible for treatment under existing guidelines. Therefore, I believe the guidelines should adopt a more stratified approach, where some patients are ‘offered’ treatment and others are advised that it could be ‘considered,’ depending on a combination of predicted absolute benefit and individual preferences. This approach could reduce treatment burden and allow for more efficient use of healthcare resources,” Jansz told Medscape.
Karalliedde countered, “Over a short term, we obviously need to look at risk, but we also need to look at lifelong risk…What can we do to prevent people getting kidney disease and cardiovascular disease? The evidence is limited, but maybe we should be thinking about early adoption.”
He also noted that the comparator drugs in this study, DPP-4 inhibitors/sulfonylureas, don’t have the additional benefits that the SGLT2 inhibitors do, and sulfonylureas carry an added risk for hypoglycemia. “We probably need to factor in the comparator group, lifelong risk, and thinking more holistically of cardiometabolic and kidney risk.”
The research was funded by the Medical Research Council, and supported by EFSD/Novo Nordisk. Jansz has no further disclosures. Karalliedde has research grants from AstraZeneca and Sanofi paid to his institution. He also receives speaker fees and is on advisory boards for Boehringer Ingelheim, Lilly, AstraZeneca, Daiichi Sankyo, and Menarini. 
Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR’s Shots blog, and Diatribe. She is on X (formerly Twitter) @MiriamETucker.
 
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