23 / 24
an association with diabetes was demon-
strated for a genetic score composed of
variants in many different genes involved
in LDL-C metabolism supports a more
diffused diabetogenic effect of LDL-C low-
ering.
3
Further studies are needed to settle
this issue. It would be interesting to see
whether the prediction of ezetimibe being
diabetogenic based on the NPC1L1 genetic
prediction, or if more potent LDL-C lower-
ing with PCSK9 inhibitors can be confirmed
in clinical practice.
One caveat about these Mendelian ran-
domization findings is that most of the
variants considered are in non-cod-
ing regions and could affect expression
of additional genes that do not impact
LDL-C metabolism but may nonetheless
affect diabetes risk. Transcriptomic stud-
ies analyzing the genome-wide impact of
these variants in tissues relevant to diabe-
tes could help address this concern. Using
genetic markers as proxies of pharmaco-
logical interventions has intrinsic limitations.
While genetic variants start acting at con-
ception, lipid-lowering interventions are
usually introduced later in life and for a
few decades at most. Whether effects of
lifelong exposures to genetic variants are
representative of those associated with
shorter exposure to LDL-C–lowering drugs
remains to be determined.
While these findings mechanistically
support the diabetogenic potential of
lipid-lowering drugs through LDL-C low-
ering, risk must always be interpreted
alongside benefit. Although statins are
associated with an approximate 9%
increased risk of incident type 2 diabe-
tes, the risk of death from any cause is
reduced by 10% for each 1-mmol/L reduc-
tion in LDL-C with statins over a period of
4 years, and of similar magnitude in those
with or without diabetes.
4,5
The net clini-
cal benefit for people at moderate or high
cardiovascular risk strongly favors LDL-C
lowering. Thus, providers should continue
to prescribe statins and other lipid-lowering
therapy according to established guide-
lines to improve cardiovascular and total
mortality in patients with established ather-
osclerotic disease or multiple risk factors.
Nevertheless, recognizing and confirm-
ing a direct role of LDL-C lowering with
diabetes risk, as supported by this body
of work, and subsequently understand-
ings the potential mechanisms for which
low LDL-C promotes diabetes may lead to
new treatment or prevention approaches.
References
1. Lotta LA, Sharp SJ, Burgess S, et al.
association between low-density lipoprotein
cholesterol-lowering genetic variants and risk
of type 2 diabetes: a meta-analysis.
JAMA
2016;316(13):1383-1391.
2. Swerdlow DI, Preiss D, Kuchenbaecker KB, et
al. HMG-coenzyme A reductase inhibition, type
2 diabetes, and bodyweight: evidence from
genetic analysis and randomised trials.
Lancet
2015;385(9965):351-361.
3. White J, Swerdlow DI, Preiss D, et al. Association
of lipid fractions with risks for coronary
artery disease and diabetes.
JAMA Cardiol
2016;1(6):692-699.
4. Sattar N, Preiss D, Murray HM, et al. Statins and
risk of incident diabetes: a collaborative meta-
analysis of randomised statin trials.
Lancet
2010;375(9716):735-742.
5. Cholesterol Treatment Trialists, Baigent
C, Blackwell L, et al. Efficacy and safety of
more intensive lowering of LDL cholesterol:
a meta-analysis of data from 170,000
participants in 26 randomised trials.
Lancet
2010;376(9753):1670-1681.
Recognizing and confirming
a direct role of LDL-C
lowering with diabetes risk,
as supported by this body of
work, and subsequently
understanding the potential
mechanisms for which low
LDL-C promotes diabetes
may lead to new treatment or
prevention approaches.
MY PERSPECTIVE
23
VOL. 1 • NO. 1 • 2017