JAMA: The frequency of type 2 diabetes among 25,000 patients with familial
hypercholesterolemia (a genetic disorder characterized by high
low-density lipoprotein [LDL] cholesterol levels) was significantly
lower than among unaffected relatives, with the prevalence varying by
the type of gene mutation, according to a study in the March 10 issue of
JAMA.
Statins have been associated with increased risk for diabetes, but
the cause for this is not clear. One theory is that statins
increase expression of LDL receptors and increase cholesterol uptake
into cells including the pancreas, which could cause pancreatic
dysfunction. Familial hypercholesterolemia causes decreased LDL
transport into cells. Researchers have hypothesized that with familial
hypercholesterolemia, decreased pancreatic LDL transport would lessen
cell death and ultimately lead to lower rates of diabetes.
John J. P. Kastelein, M.D., Ph.D., of the Academic Medical Centre,
Amsterdam, the Netherlands, and colleagues assessed the prevalence of
type 2 diabetes between patients with familial hypercholesterolemia and
their unaffected relatives. The study included all individuals (n =
63,320) who underwent DNA testing for familial hypercholesterolemia in
the national Dutch screening program between 1994 and 2014.
The prevalence of type 2 diabetes was 1.75 percent in familial
hypercholesterolemia patients (n = 440/25,137) vs 2.93 percent in
unaffected relatives (n = 1,119/38,183), with adjusted figures
indicating that patients with familial hypercholesterolemia had a 51
percent lower odds of having type 2 diabetes. Prevalence varied by the
type of gene mutation. The researchers observed an inverse dose-response
relationship between the severity of the familial hypercholesterolemia
causing mutation and prevalence of type 2 diabetes.
“The small absolute difference in prevalence of type 2 diabetes
between patients with familial hypercholesterolemia and unaffected
relatives will not have a major influence on individual risk for type 2
diabetes. However, the substantial relative difference of 50 percent,
together with previous findings, might suggest an effect of
intracellular cholesterol metabolism on pancreatic beta cell function.
Nevertheless, a plethora of pathways contribute to development of type 2
diabetes, and therefore, the mechanism we discuss here can only be 1
part of the pathogenesis of this highly complex disease,” the authors
write.
“If these findings are confirmed in longitudinal studies, they might
provide support for development of new approaches to the prevention and
treatment of type 2 diabetes by improving function and survival of
pancreatic beta cells.”
(doi:10.1001/jama.2015.1206; Available pre-embargo to the media at http://media.jamanetwork.com)
Editor’s Note:
Please see the article for additional information, including other
authors, author contributions and affiliations, financial disclosures,
funding and support, etc.
Editorial: Does the LDL Receptor Play a Role in the Risk of Developing Type 2 Diabetes?
David Preiss, M.D., Ph.D., and Naveed Sattar, M.D., Ph.D., of the
University of Glasgow, United Kingdom, comment on the findings of this
study in an accompanying editorial.
“What are the implications of these findings? This report adds to the
growing literature of a complex interplay between lipids, glycemia, and
adiposity, in which statins and other lipid-modifying agents appear to
affect diabetes risk. The study also provides mechanistic insight into
the potential roles of the LDL receptor and intracellular cholesterol
accumulation. From a clinical perspective, the findings should allay any
concerns about the potential diabetogenic effect of statins when
treating patients with familial hypercholesterolemia from childhood or
young adulthood given that these patients appear to be at a low risk for
diabetes.”
“The study by Besseling et al contributes important evidence to
strengthen the previously observed relationship between statin therapy
and diabetes risk. However, this does not, and should not, alter
guidance regarding the use of these important medications in patients at
elevated cardiovascular risk given the clear overall benefit of statin
therapy.”
(doi:10.1001/jama.2015.1275; Available pre-embargo to the media at http://media.jamanetwork.com)
Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc.