viernes, 10 de abril de 2015

Are statins diabetogenic?

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

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 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.

  • 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.

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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