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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.
I
n a study recently published in
JAMA
,
Lotta and colleagues addressed this
question by exploiting nature’s own
experiments through a Mendelian rand-
omization study.
1
Specifically, LDL-lowering
alleles in or near the HMGCR, NPC1L1, and
PCSK9 gene encoding targets of LDL-low-
ering 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 dis-
ease, 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 diabe-
tes. A nonsignificant trend toward a similar
effect was also observed for ABCG5/G8
and LDLR.
These findings agree with those by Swerd-
low 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-pre-
disposing 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 con-
tributing to development of diabetes.
However, whether the culprit is LDL-C low-
ering, 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 associa-
tions 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
Reading our blueprints –
nature’s lessons in pathophysiology
found within our DNA
By Allison B Goldfine
MD
& Alessandro Doria
MD, PhD, MPH
Dr Goldfine is Associate Professor at
Harvard Medical School, and Co-Head
of the Section of Clinical Research
at Joslin Diabetes Center in Boston.
Dr Doria is Associate Professor in
the Department of Epidemiology,
Department of Epidemiology, Joslin
Diabetes Center and Harvard Medical
School, Boston.
MY PERSPECTIVE
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