Page 50 - Read Online

Kalloo et al. Metab Target Organ Damage 2023;3:7 https://dx.doi.org/10.20517/mtod.2022.26 Page 11 of 19

[57]
primary endpoint . This trial will look at a broader spectrum of CKD (mild to severe stages and underlying
causes) in those with and without type 2 diabetes, including those with normal urine albuminuria, and will
therefore expand the understanding of the effects of SGLT2 inhibitors.

There are a few unanswered questions with regards to SGLT2 inhibitors in CKD management which
perhaps will be addressed with EMPA-KIDNEY results; however, one area of consideration for SGLT2
inhibitors is, as with heart failure, whether inpatient initiation is considered in this group. Additionally, with
the presence of finerenone now being recommended by the FDA and EMA for the treatment of CKD in
those with T2DM, the potential benefits of SGLT2 inhibitor therapy in addition to non-steroidal
mineralocorticoid antagonists (ns-MRAs) remains to be evaluated. The FIDELIO and FIGARO-DKD trials
both had a small proportion of patients on dual therapy with SGLT2i and ns-MRAs (6.7% across both
trials), with the pooled analysis FIDELITY showing that finerenone effects were independent of the
presence of SGLT2i use [58-60] . Additionally, another interesting finding was that those on dual therapy had a
lower incidence of hyperkalaemia. In fact, this finding of reduced hyperkalaemia with SGLT2 inhibitors has
been noted from analyses with SGLT2s reducing the risk of serious hyperkalaemia in those with high CV
[61]
risk or CKD and type 2 diabetes . This may provide reassurance for combination therapy with ACEi/
ARBs/nsMRAs and SGLT2is though more specific trials would be required to fully reassure.

A phase II trial CONFIDENCE assessing the effect of finerenone in combination with empagliflozin on
urine ACR compared with each agent on their own may help address this knowledge gap and guide more
[62]
support for the positioning of either agent in CKD and the role of combination therapy .

INCRETINS
GLP-1 RAs
GLP-1 receptor agonists have been shown to be very effective glucose-lowering and weight-lowering
medications in those with type 2 diabetes. In addition, their cardiovascular benefits, especially for the
human analogue based GLP-1s such as dulaglutide and semaglutide, further support their clinical benefits,
especially in stroke reduction - a benefit which the SGLT2 class has not particularly shown [63,64] . The other
benefit of GLP-1 RAs in the management of type 2 diabetes is their efficacy at lower eGFR thresholds, with
the three mainly used therapies (liraglutide, dulaglutide, and semaglutide) all licensed for eGFR over 15 mL/
min. The areas where they perhaps have not shown clear benefit and require further evidence have been on
renal and heart failure outcomes - especially in the setting of preserved ejection fraction and their effect on
obesity/weight loss. Post-hoc analysis of the REWIND cardiovascular outcome trial with dulaglutide
revealed a reduction in a composite renal outcome of new macroalbuminuria, and a decline in eGFR by 30%
or more from baseline or chronic renal replacement therapy. This benefit was predominantly with a
reduction in new-onset macroalbuminuria (HR 0.77); however, this alone is not sufficient to recommend
their use specifically for renal protection and the gold standard primary renal outcome trials with GLP-1
[65]
RAs are still awaited . This may well be answered in the FLOW trial, a randomized, double-blinded,
placebo-controlled trial assessing the effect of semaglutide on renal outcomes in participants at high risk of
CKD progression. Baseline characteristics of participants include those with type 2 diabetes, eGFR 25-75
mL/min/1.73 m , and urine ACR > 100 to < 5,000 mg/g with the primary endpoint being time to first
2
occurrence of renal or cardiovascular death, >/= 50% persistent eGFR reduction from baseline and kidney
failure (eGFR< 15 mL/min/1.73 m or chronic dialysis or kidney transplantation). This trial is the first
2
dedicated renal outcome trial for the GLP-1 class and may help define the role of GLP-1s in those with renal
disease and type 2 diabetes beyond glycaemia .
[66]