ABSTRACT
Purpose
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel drugs that
have proven efficacy in improving cardiovascular outcomes. Roles for the PCSK9 molecule
in metabolic pathways beyond LDL receptor processing and cholesterol homeostasis are
well established. PCSK9 genetic variants associated with lower LDL-C levels correlate
with a higher incidence of type 2 diabetes (T2DM), calling into question the appropriateness
of these drugs in patients with T2DM and those at high risk of developing diabetes,
and whether cardiovascular benefit seen with PCSK9 inhibitors might be offset by resultant
dysglycemia. The purpose of this review was to examine the role of PCSK9 protein in
glucose homeostasis, the impact of PCSK9 inhibition in relation to glucose homeostasis,
and whether some of the cardiovascular benefit seen with PCSK9 inhibitors and statins
might be offset by resultant dysglycemia.
Methods
Comprehensive literature searches of electronic databases of PubMed, EMBASE, and OVID
were conducted by using the search terms hyperlipidaemia, PCSK9, diabetes, and glucose as well as other relevant papers of interest collected by the authors. The retrieved
papers were reviewed and shortlisted most relevant ones.
Findings
Genetically determined lower circulating LDL-C and PCSK9 concentrations may have an
incremental effect in increasing T2DM incidence, but any perceived harm is outweighed
by the reduced risk of atherosclerotic cardiovascular disease achieved through lower
lifetime exposure to LDL-C. PCSK9 monoclonal antibodies are effective and safe in
patients with T2DM and those at high risk of developing it. The number-needed-to-treat
to prevent one atherosclerotic cardiovascular disease event in the FOURIER (Further
Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk)
study in the subgroup with diabetes is significantly lower than for those without.
Therefore, T2DM or being at high risk to develop it should not be a reason to avoid these
agents. The safety of PCSK9 inhibition in relation to glucose homeostasis may depend
on the method of inhibition and whether it occurs in circulation or the cells. Data
from experimental studies and randomized controlled trials suggest no detrimental
effect of PCSK9 monoclonal antibodies on glucose homeostasis. More data and large
randomized controlled studies are needed to assess the impact of other methods of
PCSK9 inhibition on glucose homeostasis.
Implications
PCSK9monoclonal antibodies markedly reduce LDL-C and consistently reduce cardiovascular
mortality in patients with and without diabetes. Current evidence does not suggest
an adverse effect of PCSK9 monoclonal antibodies on glycemic parameters.
Keywords
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Article info
Publication history
Published online: March 01, 2022
Accepted:
December 9,
2021
Identification
Copyright
© 2021 Published by Elsevier Inc.
