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2
empagliflozin) for people with T2DM and CKD if eGFR ≥ 20 mL/min per 1.73m . Once an SGLT-2
inhibitor is commenced, it is reasonable to continue even if the renal function declines (i.e., eGFR falls
2
[33]
below 20 mL/min per 1.73m ) unless it is poorly tolerated or RRT is initiated .
When SGLT inhibitors were first launched, there were concerns about the safety profile regarding adverse
events such as acute kidney injury, volume depletion, hypotension, amputation, and fractures. However,
long-term prospective studies did not support these concerns and have not demonstrated a significantly
increased risk [34,35] . Dedicated renal outcome studies subsequently confirmed a reno-protective effect. The
CREDENCE study did not confirm an increased risk of amputation with canagliflozin as reported by the
CANVAS program. In fact, people with T2DM and peripheral arterial disease (PAD) benefit more from
[36]
SGLT-2 inhibitors, compared with those without PAD . Regarding GLP-1RAs, the adverse events of
interest included medullary thyroid cancer, pancreatitis, and pancreatic cancer but data from the CVOTs
did not indicate that there is an increased risk of these outcomes . Worsening of diabetic retinopathy
[37]
events observed in the SUSTAIN-6 trial (only) is thought to be related to the magnitude and rapidity of
glucose reduction in people with higher baseline HbA1c and pre-existing retinopathy .
[38]
CONCLUSIONS
There is unequivocal evidence for CV benefits of SGLT-2 inhibitors and GLP-1RAs from CVOTs, and this
has led to major changes in the management of hyperglycaemia in people with T2DM). Both GLP-1RAs
and SLGT-2 inhibitors have illustrated a role beyond the glucose-lowering effect. They both have
demonstrated a beneficiary effect on CV risk factors such as weight and blood pressure [39,40] . With regard to
lipid metabolism, GLP-1RAs were associated with slight reductions in total cholesterol, triglycerides, and
[41]
LDL cholesterol but no significant impact on HDL cholesterol , whereas SGLT-2 inhibitors were
associated with a reduction in triglycerides and an increase in HDL cholesterol and LDL cholesterol .
[42]
International guidelines recommend these agents for people with T2DM and established CVD/ or multiple
CV risk factors, independent of HbA1c level and metformin use. However, there is clinical inertia that has
slowed the adoption of SGLT-2 inhibitors and GLP-1RAs into routine clinical practice . The effective
[43]
translation of CVOT evidence and modern guidelines into routine clinical practice will need educational
tools, implementation programmes and raising awareness amongst healthcare professionals of the potential
benefit for patients.

DECLARATIONS
Authors’ contributions
Made substantial contributions to the conception and design of the review article: Min T, Bain SC
Drafting the work or revising it critically for important intellectual content and final approval of the version
to be published: Min T, Bain SC, Crockett E, Pavlou A

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.

Conflicts of interest
E Crockett and A Pavlou have nothing to disclose. SC Bain reports grants and personal fees from
AstraZeneca, Novo Nordisk, and Sanofi-Aventis; personal fees from Boehringer Ingelheim, Eli Lilly, and
Merck Sharp & Dohme; grants from Medscape; expert advice provided to All-Wales Medicines Strategy
Group and National Institute for Health and Care Excellence UK; and partnership in Glycosmedia. T Min