SGLT2 inhibitors versus GLP-1 receptor agonists for renal patients: does it matter?

In the last ten years, the advent of sodium–glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) has been shown in several landmark trials to have had striking benefits on diabetic, cardiovascular and renal outcomes. This has led to the rapid adoption of these agents in many treatment guidelines. In renal medicine especially, SGLT2is represent a paradigm shift in the preventative approach to chronic kidney disease (CKD).¹

In contrast to SGLT2is, which have been widely lauded for their pleiotropic renoprotective effects, GLP-1 RAs are not similarly utilised in clinical practice to prevent the progression of CKD.^2,3 Although the majority of trials so far have focused on diabetic and cardiac patient populations, with the incidence of major adverse cardiovascular events as the primary outcome, almost all have included renal data as one of their secondary outcomes.

In this meta-analysis, Brockmeyer et al sought to define the absolute treatment benefits of SGTL2is and GLP-1 RAs on renal outcomes.⁴ They analysed twelve cardiovascular outcome trials that included composite renal outcomes and Kaplan–Meier plots. Although the definition of composite renal endpoint varied, all included pre-specified increase in serum creatinine/decrease in eGFR and incident end-stage kidney disease or renal replacement therapy. Trials that did not include Kaplan–Meier plots, or where the extracted hazard ratios from the Weibull models diverged significantly from the originally reported values, were excluded.

All were high-quality, international, randomised controlled trials published in high-impact journals. SGLT2is were examined in nine studies and GLP-1 RAs in three. Renal outcomes were the primary endpoint in three studies, which all investigated an SGLT2i. 

Random-effects meta-analyses were carried out for each monthly follow-up time point and summarised to generate meta-numbers needed to treat (NNTs) for the two classes of drug. The overall median follow-up time was 35.8 months (range 13.0–63.6) and the mean eGFR at baseline ranged from 37.3 to 85.3 mL/min/1.73 m².

This study’s method of extracting individual patient data from Kaplan–Meier plots has been developed by this group in two previous studies, with the express aim of reporting treatment effects on an absolute scale (i.e. as number needed to treat), and with the hope of improving assessment of the utility of offered treatments.^5,6 However, the authors accept that NNTs are necessarily time-dependent and that their method means that they are not using original patient data, thus preventing further insight into associations of patient characteristics with outcomes other than that specified. 

A similar study seeking to inform the use of different SGLT2is uses the novel concept of years of drug administration (YoDA), calculated as a product of NNT and medial duration in years of the trial.⁷ Although it did not include GLP-1 RAs, this latter study also recognised the need to better determine absolute costs and benefits to inform clinicians how best to target these novel therapeutics to the most appropriate patient population and in the most cost-effective manner. 

In the present meta-analysis, the authors could not identify a greater advantage on composite renal outcomes for either class of drug, thus implying that SGLT2is may be equally as renoprotective as GLP-1 RAs. However, comparison of SGLT2i studies that differed in mean baseline eGFR showed a higher absolute efficacy in patients with a lower eGFR and, therefore, higher risk of kidney disease progression. For example, CANVAS (mean eGFR, 76.5 mL/min/1.73 m²) and CREDENCE (mean eGFR, 56.2 mL/min/1.73 m²) had similar relative treatment effects (HR, 0.60 vs 0.66, respectively), but markedly different absolute effects: 3-year meta-NNT in CANVAS was 110, and 25 in CREDENCE. It is possible, therefore, that any superior effect of SGLT2is was dissipated in the heterogenous nature of the cumulative populations studied. 

In contrast to DAPA-CKD and EMPA-KIDNEY, similar trials of GLP-1 RAs where pre-existing impaired renal function is the primary inclusion criteria are not currently available and represent an important area of future research. The FLOW trial, investigating the ability of semaglutide to reduce composite primary renal endpoint, has recruited 3534 participants, and is expected to publish its results later this year; the REMODEL trial seeks to elucidate the mechanistic effect of semaglutide on kidney inflammation and fibrosis.^8,9 The results of these studies are eagerly awaited.

A digest of the study can be read here.

1. Keener AB (2023) SGLT2 inhibitors breathe life into kidney-disease care. Nature 615: S2–S4
2. Palmer BF, Clegg DJ (2023) Kidney-protective effects of SGLT2 inhibitors. Clin J Am Soc Nephrol 18: 279–89
3. Michos ED, Bakris GL, Rodbard HW, Tuttle KR (2023) Glucagon-like peptide-1 receptor agonists in diabetic kidney disease: A review of their kidney and heart protection. Am J Prev Cardiol 24: 100502
4. Brockmeyer M, Parco C, Vargas KG et al (2024) Absolute treatment effects of novel antidiabetic drugs on a composite renal outcome: meta-analysis of digitalized individual patient data. J Nephrol 18 Jan [Epub ahead of print]
5. Wolff G, Lin Y, Akbulut C et al (2023) Meta‐analysed numbers needed to treat of novel antidiabetic drugs for cardiovascular outcomes. ESC Heart Fail 10: 552–67
6. Kuss O, Akbulut C, Schlesinger S et al (2022) Absolute treatment effects for the primary outcome and all-cause mortality in the cardiovascular outcome trials in type 2 diabetes: a meta-analysis of individual patient data. Eur Heart J 43(Suppl 2): ehac544.2685
7. Varadhan L, Saravanan P, Ali SN et al (2022) Informing and empowering patients and clinicians to make evidence-supported outcome-based decisions in relation to SGLT2 inhibitor therapies: the use of the novel years of drug administration (YoDa) concept. Clin Drug Investig 42: 113–25
8. Rossing P, Baeres FM, Bakris G et al (2023) The rationale, design and baseline data of FLOW, a kidney outcomes trial with once-weekly semaglutide in people with type 2 diabetes and chronic kidney disease. Nephrol Dial Transplant 38: 2041–51
9. Bjornstad P, Cherney D, Lawson J et al (2022) MO399: Remodel: A mechanistic trial evaluating the effects of semaglutide on the kidneys in people with type 2 diabetes and chronic kidney disease. Nephrol Dial Transplant 37(Suppl 3): gfac070-013