1.5.1 Aims & recommendation types
1.5.2 Evidence grading
In general, we followed the principles set out in the UK Kidney Association’s “Clinical Practice Guideline Development Manual” and grade “Recommendations for Use” and “Recommendations for Implementation” according to its two-tier grading system (see Table 1.2). We use the term “recommend” within the guideline text where Recommendations are based on Grade 1 evidence, and prefer the term “suggest” for those based on Grade 2 evidence. Recommendations for Implementation could be considered a Practice Point but we avoid using this term for clarity. Our Recommendations for Research are not graded, and we offer Audit Measures for Recommendations with Grade 1 levels of evidence.
Table 1.2: UK Kidney Association’s grading system for recommendations’ strength and evidence quality
1.5.3 Guideline structure
We recognise that the use of SGLT 2 inhibition is subject to a significant amount of ongoing research and there is likely to be further evidence that may influence the recommendations made within these guidelines. As in the previous version of the guideline, we retain a modular structure to facilitate efficient revisions as the evidence base continues to expand.
Recommendations for Use are provided, separately, for individuals with type 2 DM (section 2) and people without DM (section 3). In the present update, though our recommendations for people with and without diabetes have begun to converge, we maintain this division to acknowledge the differences in available evidence in these two populations. Section 4 summarises the current licensing of SGLT 2 inhibitors to support selection of SGLT 2 inhibitors in people with CKD. Section 5 focuses on the information on safety of SGLT 2 inhibitors, including considerations for older or multi-comorbid individuals. This section provides a series of Recommendations for Implementation. Section 6 provides patients’ perspectives and template Patient Information Leaflets. Lastly, section 7 provides consideration for populations of specific interest in which trial evidence is more limited currently. These populations include: (i) type 1 DM, (ii) kidney transplant recipients, and (iii) acute decompensated heart failure.
1.5.4 Evidence synthesis by systematic literature review
The generation of Recommendations was supported by a systematic literature search of relevant SGLT 2 inhibitor randomised controlled trials (see Methodological appendix for full details of the search strategy and results), which was updated ahead of this Guideline update. In brief, a search of MEDLINE and Embase bibliographic databases via OVID from 29th August 2021 to 5th September 2022 was performed and combined with the previous database search, which comprised records from database inception to 28th August 2021. Eligible trials were randomised parallel-group SGLT 2 inhibitor trials irrespective of size or duration. Trials which were placebo-controlled or offered comparisons with non-SGLT 2 inhibitor treatments (e.g. a sulfonylurea) were included, but trials randomizing participants to two different SGLT 2 inhibitors without a control group were excluded. The following other types of trials were also excluded: non-English language reports, purely pharmacokinetic/pharmacodynamics studies (e.g. in healthy volunteers or in phase 1), and duplicates.
Trials were subcategorised into large placebo-controlled trials (i.e. those with >1000 participants randomised and with >500 participants in each arm), and into groups of specific interest relevant to specific guideline sections (i.e. type 1 DM, kidney transplant recipients, and acute decompensated heart failure). Large trials were subject to a trial quality assessment using the Cochrane Risk of Bias 2 (ROB2) tool, with main and relevant subsidiary publications reviewed. Separate searches of pooled analyses from trials, meta-analyses and registries of ongoing trials were also performed, and relevant guidelines from UK stakeholders and elsewhere (e.g. KDIGO) reviewed along with regulatory licences for SGLT 2 inhibitors. Note that the 2021 Association of British Clinical Diabetologists-Renal Association (ABCD-RA) Clinical Practice Guidelines for the Management of Hyperglycaemia in Adults with Diabetic Kidney Disease is particularly relevant to this guideline, and we cross-reference relevant sections. However, our guidance was developed independently, and is consequently not identical.
1.5.5 Guideline update methodology
In the present updated guideline, guideline sections were reviewed in light of new evidence from published trials and updated database search. Updated evidence-based recommendations were drafted by a subgroup of the Guideline Working Group and presented to the wider Guideline Working Group. Once consensus was reached among Working Group members, relevant modular sections were revised and circulated to the Working Group. All members had the opportunity to review proposed updates and final revised guidelines.
1.5.6 Terminology used in this guideline
In this guideline, terminology used to describe kidney disease and relevant outcomes has been chosen in line with KDIGO guidelines on nomenclature for kidney function and disease, which emphasises patient-centred and precise language (84). Where possible, the term ‘kidney’ has been used in preference to the term ‘renal’, and the term ‘kidney failure’ has been used in preference to ‘end-stage kidney disease’. However, where such terms are used to describe outcomes studied in clinical trials, the terms originally used by the trial authors have been preserved as presented in published trial reports.