Due to the benefits of SGLT 2 inhibitors on kidney outcomes (CKD and AKI) and cardiovascular risk:
- We recommend initiating SGLT 2 inhibition in people with chronic kidney disease and type 2 diabetes, irrespective of primary kidney disease,* for any of the following 4 clinical scenarios (Grade 1A):
(a) eGFR of 20-45 mL/min/1.73m2
(b) eGFR of >45 mL/min/1.73m2 and a urinary albumin-to-creatinine ratio (uACR) of ≥25 mg/mmol†
(c) Symptomatic heart failure, irrespective of ejection fraction
(d) Established coronary disease
*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: CREDENCE, DAPA-CKD and EMPA-KIDNEY have consistently shown that SGLT 2 inhibition significantly and importantly reduces the risk of progression of CKD in a broad CKD population, including in people with diabetic kidney disease and kidney disease of non-diabetic aetiology. SGLT 2 inhibitors also reduce risk of acute kidney injury and cardiovascular disease. Participants were enrolled down to an eGFR of 20 mL/min/1.73m2, and there is no evidence that the beneficial effects of SGLT 2 inhibition on kidney disease progression or cardiovascular risk are attenuated across the spectrum of eGFR studied. In EMPA-KIDNEY, participants were enrolled with eGFR 20-45 mL/min/1.73m2 irrespective of uACR, or eGFR >45 mL/min/1.73m2 with uACR ≥23 mg/mmol. EMPA-KIDNEY and DAPA-CKD both demonstrated consistent benefits irrespective of primary kidney diagnosis subdivided by diabetic kidney disease, ischaemic and hypertensive nephropathy, and glomerular disease. Among non-albuminuric kidney disease, data from eGFR slope analyses in EMPA-KIDNEY demonstrates reductions in rate of eGFR decline of a magnitude that would be expected to translate into meaningful reductions in progression of CKD, which is supported by similar findings in eGFR slope analyses from EMPEROR-REDUCED, EMPEROR-PRESERVED, DAPA-HF and DELIVER. We therefore provide grade 1A recommendation for use in people with eGFR 20-45 mL/min/1.73m2 or with eGFR ≥45 mL/min/1.73m2 and uACR ≥25 mg/mmol. 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.
Consistent findings from five SGLT 2 inhibitor trials in people with symptomatic heart failure have demonstrated that SGLT 2 inhibition reduces the risk of cardiovascular death or hospitalisation for heart failure among this population. These findings have been demonstrated in people with reduced and preserved ejection fraction, and in people with recent hospitalisation for worsening heart failure. There has been no evidence that the cardiac benefits of SGLT 2 inhibition are modified by diabetes status or by eGFR. Among CKD populations, cardiovascular death or hospitalisation for heart failure has been shown to be reduced by SGLT 2 inhibition in CREDENCE, SCORED and DAPA-CKD. The totality of evidence indicates a reduction of these outcomes of approximately one quarter in people treated with SGLT 2 inhibition compared to placebo. We therefore provide grade 1A recommendation for use in people with CKD for this indication. Those with prior coronary disease are at high risk of MACE and heart failure and are included in this recommendation based on the totality of the evidence (see Figure 2.7).
2. We suggest initiating SGLT 2 inhibition to modify cardiovascular risk and slow rate of kidney function decline in people with an eGFR >45-60 mL/min/1.73m2 and a uACR of <25 mg/mmol, recognising effects on glycaemic control will be limited (Grade 2B)
Rationale: Meta-analysis of large randomised clinical trials of SGLT 2 inhibition indicates that cardiovascular benefits of SGLT 2 inhibition, particularly reducing the risk of cardiovascular death or hospitalisation for heart failure, are present irrespective of trial-level average eGFR. The benefits of SGLT 2 inhibition in terms of reducing progression of kidney disease are also not modified by eGFR in individual trials. eGFR slope analyses from heart failure and CKD trials consistently demonstrate reduced rates of kidney function decline among people treated with SGLT 2 inhibition, including those without significant albuminuria, as demonstrated in EMPA-KIDNEY. EMPEROR-REDUCED, EMPEROR-PRESERVED, DAPA-HF and DELIVER all show reductions in the rate of kidney function decline with SGLT 2 inhibition compared to placebo, while in EMPEROR-REDUCED this reduction in rate of eGFR decline is present in the presence and absence of CKD and across the spectrum of albuminuria. Therefore, while this population has not been directly studied in randomised trials, there is indirect evidence to support reduction in cardiovascular risk and reduced rate of kidney function decline in this group, for which we provide a grade 2B recommendation.
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: Clinical trials of SGLT 2 inhibition conducted in populations with CKD have continued SGLT 2 inhibition until the initiation of kidney replacement therapy, providing indirect evidence to support the use of this SGLT 2 inhibition in this population. Furthermore, data from EMPA-KIDNEY indicates that the benefit of SGLT 2 inhibition in terms of progression of kidney disease is not attenuated in people with an eGFR <20 mL/min/1.73m2. There is no suggestion from the data that kidney benefits of SGLT 2 inhibition begin to attenuate down to an eGFR of 15 mL/min/1.73m2, and those with decreased eGFR are at particularly high risk. We therefore provide a 2B recommendation for use in people with eGFR <20 mL/min/1.73m2.
Section 2: 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).