Page 48 - Read Online

Kalloo et al. Metab Target Organ Damage 2023;3:7 https://dx.doi.org/10.20517/mtod.2022.26 Page 9 of 19

events, time to first heart failure event, and additionally a five-point change in KCCQ score at 90 days. The
trial achieved its primary outcome (win ratio 1.36 CI 1.09-1.68, P = 0.0054) with good tolerability and safety
profile and no ketoacidosis events in either group, thereby suggesting that inpatient initiation is a valid and
[37]
safe consideration . Additionally, quality of life as well as physical limitations and symptoms were also
improved with empagliflozin as early as day 15 and benefits persisted for the 90 days of the trial .
[38]
The initiation of SGLT2 inhibitors in an inpatient setting may already occur in current practice; however,
driven by the aforementioned trials, the conversations around inpatient cessation of SGLT2s during
intercurrent illness will also be debated with recent consensus suggesting the consideration that the DKA
risk must be balanced with the harms of not restarting these medications [39,40] . This is also supported by
findings from the DARE-19 trial, which assessed the organ protective effects of dapagliflozin 10mg in
patients hospitalized with COVID-19. Though not achieving its primary outcome, it did show a numerical
tendency and, more importantly, no increased safety signals in the dapagliflozin group, suggesting that
[41]
potentially these medications are safe to be continued in some inpatients . Although from an evidence
base perspective, the risk of DKA in patients with diabetes has been shown, the risk of inpatient cessation in
terms of harms has yet to be revealed and with patient safety a key consideration, it is hard to see risk
mitigation in current non-trial based care - although future pragmatic controlled trials might provide real-
world answers to this consideration.

SGLT2s and other considerations
Older adults and frailty
The use of SGLT2 inhibitors is fairly ubiquitous in many guidelines and clinical practices across the world,
with their cardiovascular outcome data and clinical efficacy one of the key reasons. Their benefits have been
seen across the age spectrum, but their use in frailty and in older individuals balancing the risks versus
benefits remains undecided with the potential for harm in such individuals with their side effect profile of
[42]
genitourinary infections and DKA risk as well as weight loss and blood pressure reduction . A recent
presentation looking at 1-year follow-up of individuals over 70 years old on SGLT-2 inhibitors for type 2
diabetes found good tolerance and safety, although with some caveats around frailty status, which, as
mentioned, is a key area for future trials to gather evidence .
[43]

The EMPA-ELDERLY trial is a 52-week trial assessing empagliflozin 10 mg over 52 weeks in an elderly
(> 65yrs) Japanese population. It will be the first SGLT2 inhibitor randomized controlled trial to assess
effects specifically in this older population with secondary outcomes of physical performance, skeletal
muscle mass and muscle strength, which may provide evidence in this rapidly evolving area . Additionally,
[44]
the potential benefit for heart failure must also be considered in the setting of older adults and frailty, with
recent consensus perhaps suggesting this benefit may offset the potential risks . Recently the implications
[18]
of frailty in heart failure have been considered in cardiology fields, and there would be interesting
considerations for the use of SGLT2 inhibitors and their impact on frailty in those with heart failure though
this area is yet to be explored.

Pre-diabetes, gestational diabetes and cardiovascular risk
Recent data is starting to highlight the evolving continuum of the impact of dysglycaemia on cardiovascular
disease, with observational studies in pre-diabetes suggesting that they are at higher risk of poorer outcomes
[45]
with heart failure . A recent meta-analysis of studies with gestational diabetes also noted an increased risk
of postpartum cardiovascular events regardless of the development of type 2 diabetes, thereby suggesting
[46]
risk factor management and closer follow-up for cardiovascular disease .