PracticeUpdate: Cardiology

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Reading our blueprints – nature’s lessons in
pathophysiology found within our DNA
Written by Allison B Goldfine MD and Alessandro Doria MD, PhD, MPH
3-Hydroxy-3-methylglutaryl
coenzyme A (HMG-CoA)
reductase inhibitors –
statins – have profound
beneficial effects on
cardiovascular event rates
but are also associated
with a higher risk of
incident type 2 diabetes.
Whether this is attributable
to low-density lipoprotein
cholesterol (LDL-C)
lowering, per se, or to
direct or indirect off-target
effects of statins remains
poorly understood.
In a study recently published
in JAMA, Lotta and colleagues
addressed this question by
exploiting nature’s own experiments
through a Mendelian randomisation
study. 1 Specifically, LDL-lowering
alleles in or near the HMGCR,
NPC1L1, and PCSK9 gene
encoding targets of LDL-lowering
drugs (statins, ezetimibe, and
PCSK9 inhibitors, respectively)
and other LDL-C-related variants
near the ABCG5/G8 and LDLR
genes were used as proxies to
assess whether associations between
pharmacological LDL-C lowering
and risk of diabetes is causal. In
a meta-analysis of United States
and European cohorts within
large genetic association studies,
each LDL-lowering variant was
associated with a lower odds ratio for
coronary artery disease, with similar
effect sizes per 1 mmol/L (39 mg/
dL) reduction in LDL-C. However,
consistent with the working
hypothesis, variants in NPC1L1,
and to a lesser extent HMGCR
and PCSK9, were also significantly
associated with an increased risk
of diabetes. A nonsignificant trend
toward a similar effect was also
observed for ABCG5/G8 and LDLR.
These findings agree with those by
Swerdlow et al, who also found an
association between HMGCR and
increased risk of type 2 diabetes, and
those by White et al, who described
a similar diabetes-predisposing effect
with a genetic risk score based on
130 LDL-C-associated SNPs.2,3
Taken together, these studies provide
strong support for LDL-C lowering
contributing to development of
diabetes. However, whether the
culprit is LDL-C lowering, per se,
or how this goal is achieved, remains
unclear. Because not all the genes
hosting variants associated with
lower LDL-C showed statistically
robust associations with diabetes in
the study by Lotta et al, it is possible
the molecule or metabolic function
targeted by the LDL-C-lowering
drug matters most for development
of diabetes.1 On the other hand, the
fact that an association with diabetes
was demonstrated for a genetic score
composed of variants inmany different
genes involved in LDL-Cmetabolism
supports amore diffused diabetogenic
effect of LDL-C lowering.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 lowering with
PCSK9 inhibitors can be confirmed
in clinical practice.
One caveat about theseMendelian
randomisation findings is that most
of the variants considered are in
non-coding regions and could affect
expression of additional genes that
do not impact LDL-C metabolism
but may nonetheless affect diabetes
risk. Transcriptomic studies analysing
the genome-wide impact of these
variants in tissues relevant to diabetes
could help address this concern.
Using genetic markers as proxies of
pharmacological interventions has
intrinsic limitations. While genetic
variants start acting at conception,
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 thesefindingsmechanistically
support the diabetogenic potential
of lipid-lowering drugs through
LDL-C lowering, risk must always
be interpreted alongside benefit.
Although statins are associated
with an approximate 9% increased
risk of incident type 2 diabetes,
the risk of death from any cause is
reduced by 10% for each 1-mmol/L
reduction 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 clinical benefit
for people at moderate or high
cardiovascular risk strongly favours
LDL-C lowering. Thus, providers
should continue to prescribe statins
and other lipid-lowering therapy
according to established guidelines
to improve cardiovascular and total
mortality in patients with established
atherosclerotic disease or multiple
risk factors. Nevertheless, recognising
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.
References
1. Lotta LA, Sharp SJ, Burgess S, et al.
JAMA 2016;316:1383-1391.
2. Swerdlow DI, Preiss D, Kuchenbaecker
KB, et al. Lancet 2015;385:351-361.
3. White J, Swerdlow DI, Preiss D, et al.
JAMA Cardiol 2016;1:692-699.
4. Sattar N, Preiss D, Murray HM, et al.
Lancet 2010;375:735-742.
5. Cholesterol Treatment Trialists,
Baigent C, Blackwell L, et al. Lancet
2010;376:1670-1681.
Dr Goldfine is Associate Professor,
Harvard Medical School,
Co-Head, Section of Clinical
Research, Joslin Diabetes Center
in Boston, Massachusett.
Dr Doria is Associate Professor in
the Department of Epidemiology,
Department of Epidemiology,
Joslin Diabetes Center and
Harvard Medical School in Boston.
New drugs and devices listing
THERAPEUTIC GOODS ADMINISTRATION (TGA)
Adalimumab (Humira), Abbvie – uveitis
Saxagliptin (Onglyza), AstraZeneca - type 2 diabetes
Saxagliptin/dapagliflozin (Qtern 5/10), AstraZeneca – type 2 diabetes mellitus
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Armodafinil (Nuvigil), Teva Pharma – narcolepsy, improve wakefulness
Auranofin (Ridaura), Amdipharma Mercury – rheumatoid arthritis
Dexamethasone (Ozurdex), Allergan – diabetic macular oedema
Imatinib (Imatinib-DRLA), Dr Reddy’s Laboratories – chronic myeloid leukaemia, Ph+ acute lymphoblastic leukaemia,
myelodysplastic/myeloproliferative diseases, aggressive systemic mastocytosis, hypereosinophilic syndrome, chronic
eosinophilic leukaemia, dermatofibrosarcoma protuberans
Ruxolitinib (Jakavi), Novartis – disease-related splenomegaly or symptoms in myelofibrosis, polycythemia vera
Please consult the full Product Information before prescribing.
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FEATURE ARTICLE
VOL. 1 • No. 3 • 2016
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