Increases in circulating levels of ketone bodies and cardiovascular protection with SGLT2 inhibitors: Is low‐grade inflammation the neglected component?
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Abstract
Recent clinical trials have demonstrated a strong cardiovascular (CV) protective effect
of sodium/glucose cotransporter (SGLT) 2 inhibitors, a recently introduced class of
hypoglycaemic agents. The improvement in glycated haemoglobin and other conventional
risk factors explains only a portion of the observed reduction in CV risk. A relevant
feature of SGLT2-inhibitor-treated diabetic patients is the increase in circulating
levels of ketone bodies, which has been proposed to mediate part of the beneficial
effects of this class of drugs, mainly through their bioenergetic properties. However,
ketone bodies are emerging as potent anti-inflammatory molecules, and inflammation
is a recognized risk factor for the development of CV events. In this framework, we
hypothesize that, through their unique mechanism of action and by increasing circulating
ketone bodies, SGLT2 inhibitors indirectly target the IL-1β pathway and thus produce
a consistent amelioration of low-grade inflammation, a clinically relevant phenomenon
in diabetic patients with high CV risk. This attenuation could slow the progression
of CV disease and especially the atherosclerotic process, which is sensitive to environmental
changes, even over a short time period. To test this conceptual structure, it would
be necessary to measure circulating pro-inflammatory molecules in patients treated
with SGLT inhibitors. The addition of inflammatory markers to the list of clinical
data measured in FDA-requested, large CV outcome trials could provide supplementary
information regarding potential secondary effects of new anti-hyperglycaemic drugs,
considering that the inflammatory process is an often neglected cornerstone of CV
diseases.