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Page 14 of 19 Kalloo et al. Metab Target Organ Damage 2023;3:7 https://dx.doi.org/10.20517/mtod.2022.26

Stroke and cognition
The cardiovascular beneficial effects of human analogue GLP-1s have been established with perhaps more
focus on the cardiac benefits compared to the cerebrovascular findings. In fact, with such strong data for
stroke prevention from the dulaglutide and semaglutide cardiovascular outcome trials, it is perhaps
surprising that there has not been more focus on this area in guidelines or in practice. An exploratory
analysis of the REWIND trial revealed a reduction in ischaemic but not haemorrhagic stroke in those with
type 2 diabetes but no impact on stroke severity . Similarly, a post hoc analysis of the semaglutide
[80]
cardiovascular outcome trials (SUSTAIN-6 and PIONEER 6) also revealed that semaglutide reduced the risk
of stroke irrespective of prior stroke at baseline . Prioritisation of such GLP-1 molecules in those with type
[81]
2 diabetes at high risk of stroke (including prior TIA) and increased awareness amongst neurologists and
stroke physicians remains one of the future considerations for these medications and future guidelines.
Additionally, given the beneficial effects on stroke and the impact of stroke on cognitive function, it may
also be considered that these molecules may also have an impact on cognitive impairment. Additionally, the
atherosclerotic impact, insulin resistance effects, and glycaemic benefits of this class may be further
mechanisms whereby their beneficial effects on cognition may be seen. This has been somewhat considered
in small trials, but stands to be further assessed in a larger population with the upcoming trial of oral
[82]
semaglutide in Alzheimer’s disease to provide more insight into this area .

The role of incretins in obesity is another rapidly developing area and beyond the scope of this article;
however, it is important to note that amylin analogues such as cagrilintide have been combined with GLP-1
semaglutide with trials in progress and cardiovascular outcome trials of these molecules in those with
obesity such as SELECT for semaglutide ongoing and already reports of benefits of dual incretin Tirzepatide
in obesity [83-85], . Together with the recent update to ADA-EASD guidance highlighting weight loss in type 2
diabetes management, the future of therapeutic options and focus on diabetes and obesity care with these
molecules seems numerous.

GLP-1s and NAFLD
As with SGLT2s, the effect of GLP-1s in those with NAFLD continues to be of interest. The recent D-LIFT
randomized controlled trial assessed MRI parameters of liver fat content in patients on dulaglutide and
found that dulaglutide significantly reduced liver fat content and gamma GT in subjects with NAFLD with
non-significant reductions in ALT, AST, and liver stiffness . A recent phase 2 trial assessed semaglutide 0.1
[86]
mg, 0.2 mg and 0.4 mg against placebo in patients with biopsy-proven NASH and liver fibrosis. Semaglutide
resulted in a higher percentage of participants with NASH resolution than placebo (40%, 36%, and 59% with
the semaglutide doses compared to 17% with placebo) . A larger, more specific study is in progress to
[87]
further assess semaglutide in those with NASH to further explore and support evidence in this area, but
completion is not expected until 2028 . Although an increasingly developing area of assessment for the
[88]
GLP-1 molecule, it is likely that with the newer incretin molecules, specifically double and triple agonists,
the role of GLP-1s, specifically in NAFLD or obesity, may soon be superceded by these molecules.

Recently the development of once-weekly insulins has been seen as an interesting addition to the treatment
landscape - with ease of use and reduced number of injections being the main reason for positivity.
Confidence still remains unclear around the safety aspects with regard to hypoglycaemia, especially in the
older adult population. The combination of once-weekly GLP-1 with the once-weekly insulin provides hope
for further simplification of management options in those with type 2 diabetes, especially with the
hypoglycaemia and weight gain effects of insulin being reduced by the GLP-1 component. Trials are
underway, with the most advanced being the semaglutide/insulin icodec combination in the COMBINE 3
[89]
trial, which is due to report in 2023 .