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Page 10 of 19 Kalloo et al. Metab Target Organ Damage 2023;3:7 https://dx.doi.org/10.20517/mtod.2022.26

The DAPA-HF, DAPA-CKD, and EMPEROR-REDUCED trials all showed benefits of the respective SGLT2
classes across the spectrum of Hba1c and also with regard to reduction in new-onset type 2 diabetes, thereby
suggesting possible added benefits of this class in these populations. Whether this would be a consideration
seems unlikely, but a cardiovascular outcome trial in those with pre-diabetes on these medications would be
an interesting consideration to test this hypothesis.

Uric acid and gout
The reduction in uric acid levels by SGLT2 inhibitors has long been noted and even considered one of the
[47]
possible mechanisms of their cardiovascular benefit . Recent post hoc analysis from the EMPA-REG
OUTCOME trial has shown that empagliflozin reduced uric acid levels and a composite of gout and gout
[48]
medications in the study population . This uric acid reduction effect has also been shown with
dapagliflozin in the DAPA-HF trial and with canagliflozin [49,50]

In keeping with their multitude of effects, added benefits of SGLT2is in those with type 2 diabetes,
hyperuricaemia, and/or gout could be another treatment consideration.

Recommendation of SGLT2 Inhibitors in NAFLD
Non-alcoholic fatty liver disease (NAFLD) or Metabolic associated fatty liver disease (MAFLD) is becoming
an increasing concern for patients with type 2 diabetes, not just from a progression to cirrhosis but also due
[51]
to the association of cardiovascular disease . There is increasing push toward screening and managing
patients with type 2 diabetes for NAFLD; however, the pharmacological treatment options beyond
pioglitazone are yet to be determined. There have been a number of studies looking at SGLT2 inhibitors in
this population, with benefits seen in liver transaminases, liver fat on imaging, and body weight though
there are minimal studies looking at those without type 2 diabetes and limited histological studies .
[52]

Real-world registries such as the ABCD National Audits have also shown reductions in ALT with SGLT2s
suggesting potential benefit in NAFLD, though again, there are arguments for its correlation with
histological benefits. Though limited data on histological benefits, a trial involving ipragliflozin did show
resolution of NASH in 66.7% of patients treated with Ipragliflozin . Similarly, a small 6-patient study
[53]
looking at liver biopsies in patients treated with canagliflozin suggested favourable histological impact .
[54]
Perhaps the most convincing trial to date looked at metabolic and histological parameters of another SGLT2
inhibitor, tofogliflozin, compared to glimepiride and identified improvements in hepatocellular ballooning,
lobular inflammation and steatosis with tofogliflozin as well as biochemical findings .
[55]
Future studies are considering the use of SGLT2s in NAFLD, though to truly appreciate benefit, there would
need to be specifically designed hepatic outcome trials ‘HOTs’ to determine the benefit of medication in this
comorbidity. Until then, recommendations of SGLT-2 inhibitors in NAFLD will centre around
improvements in surrogate markers.

SGLT2 Inhibitors and CKD
Just as with heart failure, SGLT2 inhibitors have now been recommended as one of the key pillars in the
management of CKD in those with and without type 2 diabetes, as seen in the recent ADA-EASD and
KDIGO guidelines . Specifically, in those with established CKD, regardless of the presence or absence of
[56]
diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage
kidney disease, or death from renal or cardiovascular causes was significantly lower with dapagliflozin than
[26]
with placebo . More recently, the EMPA-KIDNEY trial was halted early due to the achievement of the