3.2 Recommendations For Use

In people without type 2 DM:

1. We recommend initiating SGLT 2 inhibition in people with chronic kidney disease, irrespective of primary kidney disease,* for any of the following clinical scenarios (Grade 1A):

a.     eGFR of ≥20 mL/min/1.73m² and a urinary albumin-to-creatinine ratio (uACR) of ≥25 mg/mmol†
b.     Symptomatic heart failure, irrespective of ejection fraction

* excludes people with polycystic kidney disease, type 1 diabetes, or a kidney transplant 
† urinary protein-to-creatinine ratio of 35 mg/mmol can be considered equivalent

Rationale: SGLT 2 inhibition has been shown to be effective in people with albuminuric chronic kidney disease across broad population, including people with and without type 2 diabetes, and down to an eGFR of 20 mL/min/1.73m². Meta-analysis of CKD trials and all SGLT 2 inhibitor trials demonstrates that the kidney benefits of SGLT 2 inhibition are not modified by the presence or absence of diabetes. Furthermore, DAPA-CKD and EMPA-KIDNEY both indicate consistent benefits irrespective of primary kidney disease, with benefits observed in glomerular disease of a similar magnitude to those seen in diabetic kidney disease.

SGLT 2 inhibition has been demonstrated to reduce the risk of heart failure hospitalisation in people with stable established symptomatic HFrEF by the DAPA-HF and EMPEROR-REDUCED trials, with relative effects similar in people with and without DM. Data from EMPEROR-PRESERVED and DELIVER confirm benefits on heart failure complications in people with HFpEF, including people without DM. The four large trials recruited a substantial proportion of people with CKD, with cardiac benefits appearing to be unmodified by moderately reduced levels of eGFR. We therefore provide a grade 1A recommendation for use of SGLT 2 inhibition in people without DM with an eGFR ≥20 mL/min/1.73m² and uACR ≥25 mg/mmol, or those with symptomatic heart failure. Note that the 25 mg/mmol threshold for uACR was chosen pragmatically, given that this value is expected to be easier to recall for practicing clinicians than a cut-off of 23 mg/mmol, as is commonly used in the CKD trials.

2. We recommend initiating SGLT 2 inhibition to slow rate of kidney function decline in people with an eGFR of 20-45 mL/min/1.73m² and a uACR of <25 mg/mmol* (Grade 1B)

* urinary protein-to-creatinine ratio of 35 mg/mmol can be considered equivalent

Rationale: The excellent safety profile of SGLT 2 inhibition in people with CKD without DM has been established in nearly 5000 such people from DAPA-CKD and EMPA-KIDNEY (see Section 5 for further details). DAPA-CKD and EMPA-KIDNEY demonstrated beneficial effects across the spectrum of eGFR in terms of progression of kidney disease in people with and without diabetes. Furthermore, EMPA-KIDNEY also showed that among people without albuminuria rate of kidney function decline (chronic eGFR slope) was reduced by 0.78 mL/min/1.73m² per year in participants with A1 levels of albuminuria (to a rate of -0.11 mL/min/1.73m² per year), and by 1.20 mL/min/1.73m² per year in participants with A2 levels. Such absolute benefits would be predicted to translate into clinically meaningful reductions in progression of kidney disease, even among people with low albuminuria at baseline (9). Among those with low levels of albuminuria and low eGFR at initiation, such effects on eGFR decline could translate into delay in the onset of kidney failure if used for a few/several years. Furthermore, SGLT 2 inhibition has been shown to reduce the risk of AKI and cardiovascular risk. Given the clear magnitude of benefit of SGLT 2 inhibition in this population and the reassuring safety profile, we provide a grade 1 recommendation for this statement. However, at present only EMPA-KIDNEY provides direct evidence in this population, with further supporting evidence obtained from eGFR slopes of the trials in heart failure (i.e. grade B level of evidence).

3. We suggest clinicians consider initiating SGLT 2 inhibition in people with an eGFR below 20 mL/min/1.73m² to slow progression of kidney disease (Grade 2B)

Rationale: Two of the four clinical trials of SGLT 2 inhibition conducted in people with CKD have enrolled people without diabetes (DAPA-CKD and EMPA-KIDNEY), and in both trials SGLT 2 inhibition has been continued below an eGFR of 20 mL/min/1.73m² without evidence of increased adverse events. In EMPA-KIDNEY, in which over half of the participants did not have diabetes, SGLT 2 inhibition was shown to have consistent relative benefits across the spectrum of eGFR, including among people with eGFR <20 mL/min/1,73m² (see section 2 for details; Figure 2.5). Given that people with low eGFR are at high risk of progression to kidney failure, the absolute benefit is likely to be considerable for this population, irrespective of diabetes status. We therefore provide a grade 2B recommendation for initiation of use of SGLT 2 inhibition for people without type 2 DM with eGFR <20 mL/min/1.73m².

Section 3: Recommendations for Use Footnote

All recommendations in sections 2 & 3 exclude people with type 1 DM (see section 7a) and exclude those with a kidney transplant (see section 7b).

*See section 4 for summary of indications/licenced uses