Rafael Carmena, MD, PhD
Department of Medicine,
University of Valencia, Spain
Clinical Research Foundation
(INCLIVA) University Clinic Hospital, Valencia
CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)
Instituto de Salud Carlos III, Madrid
El profesor Carmena, Patrono de la Fundación Salud 2000, comparte con todos los lectores del blog, un interesante artículo de candente actualidad:
¿Pueden las estatinas inducir la aparición de
nuevos casos de diabetes?
Las estatinas son los fármacos más utilizados para
reducir el colesterol y prevenir el infarto de miocardio por lo que este tema
despierta ahora gran interés y bastante controversia
Introduction
Statins
are among the most widely prescribed of drugs. A wealth of evidence from randomized
control trials (RCT) demonstrates that statins reduce atherosclerotic
cardiovascular disease events in both primary and secondary prevention,
including diabetic persons, and improve survival in patients with established
disease[i],[ii].
Recommendations virtually mandate statin use in secondary prevention and widely
advocate use for primary prevention2,[iii].
Statins have proven to be safe for most patients. They
do not cause liver disease, cataracts or hemorrhagic stroke[iv],[v],[vi].
Nonetheless, up to 10% of patients taking statins complain of muscle aches,
weakness or other symptoms, and rare patients develop rhabdomyolisis and must
discontinue treatment[vii].
Statins and new onset diabetes (NOD)
Concerning statin diabetogenicity, a recent meta-analysis
of RCT of statins has shown a higher incidence of NOD in the treatment arm5.
That notwithstanding, so far no randomized prospective clinical trials have
been specifically designed to evaluate statin therapy and subsequent risk of
diabetes. Subgroups, post hoc, and meta-analysis of randomized trials and
observational studies, however, have offered insightful information that will
be discussed in this paper.
Interestingly enough, the first report of a possible direct
association between statins and diabetes came from the randomized,
placebo-controled West of Scotland Coronary Prevention Study (WOSCOPS) trial
published in 2001[viii]. The
study showed that treatment with pravastatin resulted in a 30% reduction (p=0.042)
in the hazard of becoming diabetic. It was speculated that the
anti-inflammatory effects of pravastatin were partially responsible for this inverse
association[ix].
, Be that as it may, the criteria used to define diabetes in this trial were
criticized, and the results could not be reproduced using standard criteria for
the definition of diabetes[x].
Moreover, in the PROSPER trial[xi],
using pravastatin, an increase in NOD was observed in the elderly. Other trials
using simvastatin, as in the HPS[xii],
or atorvastatin, like in ASCOT-LLA[xiii]
, CARDS[xiv]
, and TNT[xv] showed
no significant change in diabetes status. Furthermore, in a meta-analysis of
five prospective, randomized controlled trials, conducted by Coleman et al.[xvi],
it was concluded that use of a statin did not significantly alter a patient’s
risk of developing NOD (relative risk, 1.03; 95% CI 0.89-1.19).
With this in mind, the JUPITER trial[xvii]
was launched hypothesizing that treatment with rosuvastatin, a potent new
statin, would decrease the risk of NOD among participants. To the contrary, the
results showed an increase in physician-reported NOD and in HbA1c in 3% of patients
taking rosuvastatin vs. 2.4% of those on placebo (p=0.01). An analysis of the
characteristics in patients who went on to be diagnosed with diabetes showed an
important prevalence at baseline of elevated body mass index (BMI) and metabolic
syndrome[xviii],[xix].
Despite this, a post-hoc analysis carried out recently by the JUPITER’s investigators
concluded that the positive cardiovascular benefits outweighed the risk of
developing diabetes[xx].
Subsequently, several meta-analyses of RCTs, reviewed
by Sattar et al.10 support the notion that statin therapy,
compared to placebo, modestly and significantly increases the risk of NOD by
roughly 9%-13%, with no evidence of heterogeneity across trials10,17,[xxi].
An observational study by Culver et al. [xxii],
including 161 808 postmenopausal women aged 50-79 years followed for 12 years,
found that statin use (simvastatin, fluvastatin, atorvastatin, and pravastatin)
was associated with a substantially increased risk of NOD (HR 1.48; 95% CI
1.38.1.59). There were no significant differences between the types of statin
used. The HR for NOD is higher than it is in any previously reported
meta-analysis. The study, however, has been criticized[xxiii]
for its observational nature and the numerous confounders in the data, making its
results highly questionable at best and simply wrong at worst.
Altogether, the balance of evidence now available,
derived from experimental studies and meta-analyses of RCTs, suggests that
statins are associated with a small absolute risk for the development of
diabetes. According to Preiss et al.21, the number needed to treat
to yield 1 case of NOD per year with intensive-dose statin therapy is 498,
while the number needed to treat per year of intensive-dose statin therapy is
155 for cardiovascular events. Thus, the risk of NOD is clearly outweighed by
the cardiovascular benefits provided by statins. Still, the concerns about the
safety of statins in relation to the development of NOD has prompted the Food
and Drug Administration in the United States and the European Medicines Agency to
add an adverse event warning to statin labels, stating that statins have been
associated with increased glycosylated hemoglobin and fasting blood glucose
levels[xxiv][xxv].
Before closing this section, two comments are
necessary: (a) Diabetes is a cause of cardiovascular morbidity and mortality[xxvi],
and statin therapy significantly decreases the development of coronary artery
disease, morbidity and mortality from heart disease and overall mortality in
this population20. (b) Recent trial data have suggested that the use
of statins causes a modest increase in the risk of NOD, and they do so in a
dose-dependent manner[xxvii].
Are there differences between
statins?
Statin-induced diabetes appears to be a class effect,
although study design differences make definitive conclusions challenging this assumption. The impact of different types and doses of statins on
NOD has been studied in a recent meta-analysis[xxviii]
including 17 RCTs and 113 394 patients. Among different statins, pravastatin 40
mg/day was associated with the lowest risk (7%) while rosuvastatin 20 mg/day
was associated with 25% risk of NOD, compared to placebo. These findings should
be confirmed in powered head-to-head comparisons. A review of 16 trials by
Baker et al.[xxix] in non-diabetic
subjects treated with different statins showed than when pooled as a class,
statins had no significant impact on insulin sensitivity compared with
placebo/control. Nevertheless, when comparing the individual statins
(atorvastatin, pravastatin, rosuvastatin and simvastatin) pravastatin
significantly improved insulin sensitivity, while simvastatin worsened it. Yet a previous network meta-analysis[xxx]
of 170255 patients from 76 randomized trials confirmed a 9% increased risk of
development of NOD , but did not find differing treatment effects among
statins. Since changes in insulin sensitivity do not necessarily increase the
risk of impaired glucose tolerance it is possible that the effect of statins on
NOD may originate from altered islet beta-cell insulin secretion[xxxi].
The association of statin
therapy and NOD seems to be directly
related to the intensity of therapy, presence of risk factors for diabetes, age
and ethnicity of the subjects. Clinical trial evidence suggests that statin
therapy increases the risk of NOD in middle-aged men by 1-2 cases and in
elderly women by 5-6 cases for every 1000 subjects treated for a year, and Asian
subjects appear to be at increased risk of statin induced diabetes[xxxii].
The results of a recent analysis[xxxiii]
indicated that high-doses of statin, compared with lower doses, increased the
risk of NOD among patients with 2 to 4 diabetes risk factors, i.e., fasting
blood glucose >100 mg/dl, fasting triglycerides >150 mg/dl, BMI >30
kg/m2, and a history of hypertension.No increased risk of NOD was
seen, however, with high-dose statin treatment in patients with 0 to 1 risk
factors for diabetes. Compared with low-dose statin, atorvastatin 80 mg reduced
the number of CV events both in patients at low and high risk of diabetes.
These results should reassure physicians treating patients at low risk for
diabetes.
Proposed or hypothetical mechanisms
of statin diabetogenicity
The mechanism by which statins increase the risk of
NOD has been the subject of speculation, but it is currently unknown. As
recently reviewed by Goldstein et al.32, there are
numerous putative mechanisms by which statin therapy might cause diabetes (Table 1).
Type 2 diabetes is characterized by a combination of beta-cell dysfunction and
peripheral insulin resistance, and it is likely that a combination of
mechanisms is involved for a given individual. The muscular side effects from
statins could play a role, via increased insulin resistance, which might be of
particular relevance in the aging population.
One important outcome of the concern about the role of
statins in NOD has been the recognition of the multiple potential effects of
cholesterol on insulin secretion and beta cell physiology, mentioned in Table 1
as another putative mechanism for statin-induced NOD. We will review these
aspects in the following section.
Cholesterol homeostasis in the beta cell: the possible
role of HDL/Apo AI
Cholesterol accumulation in the
cytoplasm of the pancreatic beta-cell has been recently identified as an
important cause of beta cell failure and reduced insulin secretion[xxxiv],[xxxv].
Several mechanisms could be behind such an impairment of beta-cell function. To begin
with, statin inhibition of HMG-CoA reductase causes upregulation of the LDL receptors, leading to an enhanced uptake of LDL
cholesterol in an effort to replenish intracellular beta-cell cholesterol
stores[xxxvi].
An excess of cholesterol in the
beta-cell inhibits the enzyme glucokinase, blocking an important step in the
synthesis of insulin. In addition, the
oxidation of LDL cholesterol may initiate an inflammatory cascade that compromises
the structural integrity of the beta-cell and its insulin secretion apparatus[xxxvii].
Another side effect of excess cholesterol in the cytoplasm of the beta-cell is
a disrupted voltage-gated calcium channel function, leading to impaired insulin
secretion[xxxviii]. Finally,
recent evidence suggests that cholesterol accumulation in the beta-cells can be
alleviated by depleting the cells of cholesterol34,[xxxix].
Thus, cholesterol homeostasis in the beta-cell is dependent on LDL and HDL
cholesterol combined action[xl].
As a consequence, the role of HDL particles in the regulation of insulin
secretion has received much attention in recent years.
Emerging
evidence suggests that low HDL levels might contribute to the pathophysiology
of type 2 diabetes mellitus through direct effects on plasma glucose[xli],[xlii].
In the past decade, animal and clinical studies have uncovered a previously
undescribed spectrum of HDL actions. In fact, HDL might influence glucose homeostasis through
mechanisms including increased insulin secretion, enhanced insulin sensitivity
and direct glucose uptake by muscle via activation of AMP protein-kinase. These
effects might be mediated via mechanisms including the preservation of cellular
function through lipid removal from beta-cells. A
paradigm shift has been suggested42, from HDL being a bystander to
being an active player in diabetic pathophysiology, raising the possibility
that HDL elevation could be a novel therapeutic avenue for type 2 diabetes.
Clinical relevance for an effect of HDL on insulin
secretion has been demonstrated in type 2 diabetic patients in whom an acute
infusion of reconstituted HDL increased plasma insulin levels and reduced
plasma glucose levels39,41,42. Moreover, lipid-free
and lipid-associated apoA-I and apoA-II induced an
increase in insulin secretion; the optimal response was dependent on the expression
of ABCA1 transporter, SR-B1 and ABCG139,42. In
addition, ApoA-I increases mRNA and transcription of the insulin gene in the beta-cell. Thus, HDL seems to protect beta
cells from cholesterol-induced dysfunction, enhancing the beta-cell insulin
secretory function. Moreover, carriers of loss-of-function mutations in the
cholesterol transporter ABCA1, who have decreased HDL levels, have impaired
beta-cell function40.
The hypothesized protective effects of HDL and ApoA-I
on beta-cell function, and the beneficial impact shown on glucose metabolism in
humans could have therapeutic potential in type 2 diabetes in the future. Among
statins, one of the most striking characteristics of pitavastatin, as shown in
the LIVES study, is the significant and persistent HDL cholesterol and ApoA-I
increase[xliii].
Martin et al. have shown that pitavastatin increases ApoA-I gene expression in
the liver through the activation of PPARα[xliv]. When compared
with atorvastatin 10 mg/d, pitavastatin 2 mg/d gave greater increases in HDL
cholesterol and Apo A-I after 1 year of treatment[xlv].
A recent review of different studies comparing pitavastatin with other statins
has shown that pitavastatin has no negative effects on plasma glucose, HbA1c,
insulin, glycoalbumin or HOMAS-R[xlvi] Recently, the unpublished results of the
J-PREDICT Study, conducted in Japanese subjects with impaired glucose tolerance
randomized to pitavastatin or placebo were presented at the 2013 ADA Congress[xlvii].
The primary outcome was the cumulative incidence of diabetes mellitus. After
2.8 years, the incidence of NOD in those treated with pitavastatin was 18%
lower than that in the control group (p=0.041). These results, as well as the
aforementioned studies, suggest that pravastatin may not necessarily be
associated with a diabetogenic effect. The results should be confirmed by other
more robust prospective trials in different populations, and a head-on
comparison with other statins seems logical. Until then, caution is currently
needed.
Conclusions
- The risk of incident diabetes with statin
therapy seems small, of little clinical relevance, and far outweighed by
the CV benefits of this life-saving class of drugs10,20. The
benefit of high-dose statins in preventing cardiovascular events in high-risk
patients with diabetes, stage 3 renal failure, and metabolic syndrome have
been well established15,[xlviii].
Moreover, as evidenced by the
Bradford Hill criteria, a true causal relationship between statins and
diabetes cannot be established with the present data.23
- New
cases of diabetes occur especially at high doses of potent statins in
patients with metabolic syndrome, prediabetes, and in elderly subjects. Besides
endorsing lifestyle changes, lower doses should be considered, patients
should be adviced about the diabetes risk and glucose or glycated
hemoglobin should be monitored in these groups27,33.
- The
risk is greatest among people in whom diabetes is more likely to develop
anyway, at which point they would be treated with statins as part of their
routine care. In considering the balance between NOD and cardiovascular
prevention, it is worth noting that the micro- and macrovascular
complications of diabetes occur relatively uncommonly during the first
decade after diagnosis. Many patients with established vascular disease
will die from an atherosclerotic event before they develop complications
from diabetes32,33.
- When
comparing statins with other cardiovascular drugs known to increase the
risk of diabetes, such as beta-blockers and thiazide diuretics, statins
are much less likely to cause diabetes. The HR of incidence of diabetes
for statins vs beta-blockers and thiazide diuretics is 1.09 (95% CI
1.02-1.17) vs 2.22 (95% CI 1.39-3.57) and 1.43 (95% CI 1.37-3.57),
respectively[xlix].
- Final
message: Statin precribing practice is unlikely to change due to the
modest effect on diabetes risk. Therefore,
clinical practice with statin therapy in patients with existing
cardiovascular disease or at moderate-to-high risk of such disorders
should not change[l]. Patients
being prescribed statins should be informed of potential diabetes risk, thus
giving them an additional incentive to undertake lifestyle changes.
TABLE 1
Putative mechanisms of the
diabetogenic effects of statins
a) Incident diabetes with statin therapy may associate
with risk genotype and/or phenotype predisposing to intrinsic beta-cell
dysfunction. On-going research into the combined effect of risk alleles on insulin
secretion[li]
should be able to identify if there is a specific group at particular
risk. Genetic predisposition to type 2 diabetes may be a trigger for the
diabetogenic effect of statins in the presence of risk factors associated with insulin
resistance.
b) Decrease in expression of adipocyte insulin-responsive
glucose transporter GLUT-4 leading to increased peripheral insulin resistance
and to hyperglycemia.[lii],[liii]
c) Disruption of mitochondrial function in the myocyte,
adipocyte and pancreatic beta-cell, resulting in increased peripheral insulin
resistance and diminished insulin secretion, leading to beta-cell apoptosis and
cell death31,[liv],[lv],[lvi].
d) As a consequence
of the muscle-related side effects of statins7 , muscle fatigue,
reduced exercise potential, and induction of skeletal muscle wasting of aging
could lead to increased peripheral insulin resistance47,[lvii]
e) Dysregulation of beta-cell cholesterol homeostasis,
leading to impaired insulin secretion, as discussed in detail in the text.
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