EJINME-02689; No of Pages 6 European Journal of Internal Medicine xxx (2014) xxx–xxx
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European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Review Article
Statin therapy and related risk of new-onset type 2 diabetes mellitus Massimiliano Ruscica a,b, Chiara Macchi a,b, Beatrice Morlotti b, Cesare R. Sirtori a,b, Paolo Magni a,b,⁎ a b
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Italy Centro Dislipidemie, Ospedale Niguarda Cà Granda, Milan, Italy
a r t i c l e
i n f o
Article history: Received 23 December 2013 Received in revised form 3 March 2014 Accepted 7 March 2014 Available online xxxx Keywords: Cardiovascular risk New-onset diabetes risk Statins
a b s t r a c t The use of statins for cardiovascular disease (CVD) prevention is clearly supported by clinical evidence. Although statin therapy is rather well tolerated, recent data from prospective and retrospective clinical trials and related meta-analyses suggest an increased incidence of new-onset type 2 diabetes mellitus (T2DM) in association with such treatment. The incidence of this adverse effect is not negligible, especially for specific subsets of patients, such as women, elderly, presence of familial history of T2DM and Asian ethnicity. Statin-driven T2DM appears to be a medication class-effect, mostly not related to potency nor to individual statin, as well as to be independent of previous history of CVD. Therefore, implementation of strategies for identification of patients using statins and at specific risk of incident T2DM, as well as of different therapeutic options is important and is discussed in this article. As most authors emphasized that benefits of CVD reduction by statin therapy seem to far exceed the risk of T2DM development itself, these medications remain the cornerstone for primary and secondary CVD prevention, although a specific attention to glucose metabolism and metabolic syndrome features should be payed before and during statin treatment, especially in cohorts at greater risk. © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Statins are widely used cholesterol-lowering drugs and have shown excellent benefits in reducing cardiovascular diseases (CVDs) and related mortality in patients with and without a past history of CVD. The use of these drugs for primary and secondary CVD prevention is supported by randomized controlled trials [1]. Statins are well tolerated by most patients, but in some cases can produce a variety of relevant adverse effects mostly muscle associated. Among them, one recently emerging risk, which is the topic of this review article, is the increased incidence of new-onset insulin resistance and type 2 diabetes mellitus (T2DM) in association with statin treatment [2]. The mechanisms explaining the potentially higher incidence of T2DM with statin therapy have not yet been identified, although some effects of statins on insulin secretion and sensitivity have been known since the 1990s [3,4]. Interestingly, such risk seems limited to a group of patients already at high risk of developing diabetes, as well as in the elderly [5], in women [6] and Asians [7]. According to several authors, it should be emphasized that the benefits of CVD reduction by statin therapy may exceed the risk of T2DM development [8]. However, implementation of strategies for identification of patients using statins and at specific risk of incident
⁎ Corresponding author at: Dipartimento di Scienze Farmacologiche e Biomolecolari, Via Balzaretti 9, 20133 Milano, Italy. Tel.: +39 0250318229. E-mail address:
[email protected] (P. Magni).
T2DM, as well as of different therapeutic options is important and is discussed in this article. To this regard, by using PubMed.gov, we revised all studies with an acceptable quality, published from January 2001 to December 2013, and relevant to the key clinical question discussed in this narrative review article. 2. Therapeutic use of statins Cardiovascular disease (CVD) related to atherosclerosis and thrombosis is the leading cause of morbidity and mortality in industrialized countries [9]. Among the various determinants that contribute to CVD (i.e., lifestyle, tobacco smoking and dietary habits), atherogenic dyslipidemia represents the most important modifiable risk factor [10] and is frequently present in patients affected by T2DM, which in turn appears to accelerate the progression of atherosclerotic lesions towards CVD. Several studies have established that there is a 1% to 1% relationship between CVD event reduction and reduction of low-density lipoprotein cholesterol (LDL-C) through specific lipid-lowering therapy [11]. A widely used pharmacological approach for lowering total cholesterol and LDL-C is statins [12]. These compounds competitively inhibit the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA), which represents the rate-control step in cholesterol biosynthesis. Indeed, statins are the first-choice class of drugs for reducing CVD and related mortality in patients with and without a past history of CVD. Worldwide, there are seven currently available statins (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and
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Please cite this article as: Ruscica M, et al, Statin therapy and related risk of new-onset type 2 diabetes mellitus, Eur J Intern Med (2014), http:// dx.doi.org/10.1016/j.ejim.2014.03.003
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simvastatin). Almost all of them are predominantly metabolized in the liver microsomal compartment through the cytochrome P450 enzyme system, exhibiting a high degree of first-pass clearance [13]. However, the risk of liver dysfunction upon statin treatment has been recently reconsidered and the Food and Drug Administration (FDA) concluded that serious liver injury with statins is rare and routine periodic liver enzyme monitoring is not necessary [14]. The effectiveness of statin therapy in primary and secondary prevention of CVD has been strongly demonstrated, although some known adverse effects (i.e., myalgia, myopathies, fatigue and the more severe rhabdomyolysis) may be associated with some cases to their use. In addition, another emerging new statin-related side effect is the increased incidence of new-onset insulin resistance and T2DM, which has been reported in some, but not all clinical studies. Two large randomized controlled trials (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin, JUPITER; West of Scotland Coronary Prevention Study, WOSCOPS) indeed reported conflicting data on the correlation between statin therapy and the development of T2DM [8,15]. Although this issue is still partially controversial and needs further clarification, its potential relevance led in early 2012 the European Medicines Agency (EMA) [16] and the Food and Drug Administration (FDA) [17] to require a warning on statin product information (including package leaflets) underlining the need to monitor glucose levels and possible onset of diabetes. 3. Use of statins in primary prevention and risk of insulin-resistance, hyperglycemia and incident diabetes mellitus Although early-onset and late-onset T2DM are notoriously associated with a higher risk of CVD morbidity and mortality, only long-duration (N10 years) T2DM appears to be related to a CVD risk equivalent [18]. Consequently, statins are widely used to treat dyslipidemia for primary and secondary CVD prevention and also in patients with already diagnosed T2DM [19], resulting in reduced CVD risk and occurrence (am diab assoc. diabetes care 2011). In parallel with this information, as mentioned above, recent data from important studies have highlighted the risk of new-onset insulin resistance or T2DM in patients using statins [5,20–22]. The first trial reporting a link between statin use and diabetes is the JUPITER trial, conducted in 17,802 subjects over a 1.9year period, showing an overall 27% increase in investigator-reported T2DM in patients treated with 20 mg/day rosuvastatin compared to patients receiving placebo and a moderate but significant increase of median hemoglobin A1c levels in the rosuvastatin arm compared to the control arm [20]. Very interestingly, this increase may be attributed to the female subgroup (+ 50% new-onset diabetes vs. control, P = 0.008) rather than to men (+ 13%, P = 0.29) [6]. For this specific study, authors concluded that positive cardiovascular benefits of statintreated subjects outweighed the risk of new-onset diabetes [8]. 3.1. Meta-analyses A further evaluation of this issue has been carried out both with novel studies (see paragraphs below) and with some meta-analyses. In particular, Rajpathak et al. [23], evaluating a set of 6 statin trials with a total of 57,593 participants, reported a small increase in diabetes risk (relative risk [RR] 1.13), without evidence of any protective role of statin treatment. Notably, this meta-analysis included also data from the WOSCOPS, which, differently to all other available trials, showed a 30% reduction of T2DM risk by pravastatin [15]. Another metaanalysis including 91,140 participants from 13 statin trials highlighted that new-onset T2DM was found in 4278 (9%) subjects, with no apparent difference between hydrophilic and lipophilic statins [5]. According to a meta-regression analysis of baseline data, the authors concluded that this risk seemed higher in trials with older patients, whereas basal body mass index and LDL-C effect were neutral. A recent metaanalysis included 17 randomized controlled trials with a total of
113,394 patients, comparing either a statin vs. placebo or high-dose vs. moderate-dose statin therapy [24]. All statins were administered once daily and the odds ratio of new-onset T2DM was adjusted for percentage of LDL-C reduction as a covariate. When compared with placebo, the risk for T2DM was greater for 20 mg daily rosuvastatin (+ 25%), and decreased with other statins to +21% (40 mg simvastatin), +15% (80 mg atorvastatin) and + 7% (40 mg pravastatin). With lower statin doses, again vs. placebo, the higher risk for T2DM was + 11% with 10 mg/day rosuvastatin and it decreased to +4% with 10 mg atorvastatin, whereas 10–20 mg pravastatin resulted even protective (− 10%). Compared to higher doses, lower statin doses were associated with only moderate advantage in the induction of new-onset T2DM risk (80 vs. 10 mg atorvastatin: + 1%; 40 vs. 10–20 mg pravastatin: + 7%; 20 vs. 10 mg rosuvastatin: + 12%). According to this meta-analysis, different types and doses of statins show different potential to increase the incidence of T2DM, depicting a new scenario of statin treatment that emphasizes a personalized therapeutic strategy [24] (Fig. 1).
3.2. Retrospective studies The observation that different statins (at different doses) are associated with higher or lower new-onset T2DM risk is also supported by important retrospective studies. Using data from the Women's Health Initiative on a very large population of postmenopausal women, it was observed that 7.04% of the participants used statins and that such treatment was associated with an increased risk of new-onset T2DM (hazard ratio [HR], 1.71). Moreover, statin-driven T2DM appeared to be a class-effect, not related to potency nor to individual statin, as well as to be independent of previous history of CVD [25]. A large retrospective study on 239,628 patients newly treated with statins evaluated the association of statin treatment with subsequent prescription of antidiabetic drugs [26]. A significant increase of treated T2DM was observed with monotherapy with rosuvastatin, simvastatin, and atorvastatin, but not with fluvastatin and pravastatin. Interestingly, in addition to statin type and dose, a significant effect of treatment duration was also observed for all statins except fluvastatin [26]. Another retrospective cohort study was conducted in Taiwan and was aimed at investigating the relative risk for new-onset T2DM in 15,637 elderly hypertensive and dyslipidaemic Taiwanese patients receiving different statins. The study found, in this specific cohort, that patients taking atorvastatin or rosuvastatin were at lower risk to develop new-onset T2DM, whereas lovastatin and simvastatin were linked to a higher risk. No changes were observed in patients taking pravastatin and fluvastatin [27]. Another study by the same authors differently showed that patients with hypertension and dyslipidaemia taking fluvastatin, lovastatin and rosuvastatin were at lower risk of new-onset T2DM, while those taking pravastatin were at higher risk. Simvastatin and atorvastatin seemed to have a neutral effect. Notably, the authors underline that these findings may not be generalized to subjects in other geographic areas, due to potentially different diagnostic criteria and other issues related to the construction of the data set [28]. A recent report describes the analyses conducted, over a 14-year study period, on 471,250 patients with no history of T2DM and new statin treatment for both primary and secondary prevention [29]. It was found that, compared to the reference HMGCR pravastatin, T2DM risk was significantly increased by treatment with rosuvastatin, simvastatin and atorvastatin, but not with fluvastatin and lovastatin [29]. A large retrospective population-based case–control study was conducted in 11,715 Taiwanese women to assess the relationship between statin-associated new-onset T2DM and age and allowed to conclude that overall statin use is indeed linked to an increased T2DM risk in women, significantly higher in the 40–64 year age range, compared to N65 years. When considering a cDDDs (calculated as total amount of drug/defined daily dose) N 60, the risk to develop newonset T2DM was highest among the 40–54 year-olds for rosuvastatin,
Please cite this article as: Ruscica M, et al, Statin therapy and related risk of new-onset type 2 diabetes mellitus, Eur J Intern Med (2014), http:// dx.doi.org/10.1016/j.ejim.2014.03.003
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Fig. 1. Association between different statins and development of new-onset diabetes. Reprinted from [5], with permission from Elsevier.
and highest among the 55–64 year-olds for atorvastatin, simvastatin and pravastatin [30]. 3.3. Additional data on specific statins Some additional information pertaining to each statin, in relationship to new-onset T2DM risk, are discussed below. 3.4. Pravastatin From the above-reported information, it seems that incident T2DM is indeed increased by all statins at most doses (with 10–20 mg pravastatin being possibly even protective from T2DM). Indeed, as mentioned above, in the WOSCOPS, 40 mg daily pravastatin was found to reduce the risk of developing T2DM by 30% (P = 0.042) [15]. Conversely, in the subsequent prospective study of pravastatin in the elderly at risk (PROSPER) trial, 40 mg daily pravastatin for 3.2 years resulted in a +30% new-onset diabetes [31]. Subsequently, in The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) trial, a 6-year treatment with 40 mg daily pravastatin in patients with T2DM or impaired fasting glucose did not affect the incidence of T2DM [32]. 3.5. Simvastatin Among the trials evaluating the effects of simvastatin, we need to additionally mention here the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH). This large trial conducted in 12,064 survivors of myocardial infarction compared 80 vs. 20 mg daily simvastatin and found a comparable risk of new-onset T2DM in both dose subgroup [22]. 3.6. Atorvastatin A worsening glycemic control was shown in the high-dose atorvastatin in the Pravastatin or Atorvastatin Evaluation and Infection
Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE-IT TIMI 22) substudy [33]. More recently, a re-analysis of three large randomized trials (Treating to New Targets, TNT; Incremental Decrease in Endpoints through Aggressive Lipid Lowering, IDEAL; Stroke Prevention by Aggressive Reduction in Cholesterol Levels, SPARCL) was focused on the incidence of new-onset T2DM, an end-point that was not originally included in these trials [34]. During follow-up, in the subjects randomized to high dose atorvastatin (80 mg daily), this analysis showed a trend towards an increase in the incidence of new-onset T2DM in the TNT and IDEAL studies (+ 8.68% vs. 10 mg atorvastatin (p = 0.087); + 5.99% vs. 20 mg simvastatin (p = 0.144); respectively), and a slight but significant increase of such risk in the SPARCL trial, where the comparator was placebo (7.39%, p = 0.002) [34]. 3.7. Pitavastatin Pitavastatin has been introduced more recently in the market in some but not all countries and no references are available so far when PubMed is searched with “pitavastatin” + “new-onset diabetes”, whereas some information are available on its impact on glycometabolic parameters. Overall, pitavastatin appears to be at least neutral [35] and possibly able to improve specific biomarkers, like hemoglobin A1c levels, in patients with T2DM and dyslipidemia [36,37]. On the basis of these promising data, the inclusion of new-onset T2DM as an end-point in future trials with pitavastatin is strongly recommended. 4. Statin use and risk of T2DM: individual risk factor assessment and T2DM-focused monitoring Although no defined explanation for raised T2DM risk following statins is available, the involvement of some different mechanisms has been put forward (Fig. 2) [38]. Statins may potentially reduce insulin secretion by inhibiting adenosine triphosphate (ATP)-dependent potassium channels, depolarization and calcium influx and by inhibiting ubiquinone synthesis and consequent reduced ATP formation. Increased
Please cite this article as: Ruscica M, et al, Statin therapy and related risk of new-onset type 2 diabetes mellitus, Eur J Intern Med (2014), http:// dx.doi.org/10.1016/j.ejim.2014.03.003
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Fig. 2. Hypothetical mechanisms underlying statin-driven glucose impairment (adapted from [38], with permission from Elsevier). (1) Inhibition of ATP-dependent potassium channels, depolarization and calcium influx, reducing insulin secretion; (2) increased intracellular import of LDL-C by LDL-R activation may facilitate oxidation processes, ultimately leading to altered structural integrity of the β cells; (3) inhibition of ubiquinone synthesis; (4) inhibition of isoprenoids synthesis; (5) upregulation of LDL-R expression; (6) oxidation products and inflammation; and (7) overproduction of nitric oxide by cytokines.
intracellular import of LDL-C by LDL-R activation may facilitate oxidation processes, ultimately leading to altered structural integrity of the β cells. Oxidation products may also lead to overproduction of nitric oxide (NO) by cytokines, again potentially inducing β cell apoptosis and impairing insulin secretion. In addition, inhibition of isoprenoids by reduced HMGCR activity may cause down-regulation of glucose transporter type 4 (GLUT4) expression on adipocytes, leading to impaired glucose uptake [38]. Once established the specific statin molecules at defined doses are to some extent associated with increased new-onset T2DM, it is important (i) to assess individual risk of patients assigned to statin therapy (Table 1) and (ii) to evaluate whether diabetes may be diagnosed (Table 2). The attempt to validate a score for stratifying the risk for new-onset T2DM is an important issue and, in this regard, Water and Coll. [34,39], on the basis of the above-mentioned TNT, IDEAL and SPARCL trials, proposed the following four main predictors upon statin treatment: fasting plasma glucose (FPG) N 100 mg/dl, triglycerides N150 mg/dl, body mass index N 30 kg/m2 and history of hypertension, thus producing a score ranging from 0 to 4 (Table 1). Interestingly, the HR for incident T2DM increased in parallel with the score in all of the three studies, independent of the comparator chosen in each trial. For example, considering TNT and IDEAL studies, 80 mg atorvastatin was
Table 1 Statin use and risk of T2DM: individual risk factors assessment. Score calculation (0–4) (Water and coll. [34,39]) Fasting plasma glucose N100 mg/dl Plasma triglycerides N150 mg/dl Body mass index N30 kg/m2 Arterial hypertension Additional features Familial history of T2DM Female gender Older age (especially with high-dose statins) Asian ethnicity Duration of statin treatment Concomitant diabetogenic medications Polycystic ovary syndrome
associated with an increased risk of new-onset T2DM by 24% in patients with 2 to 4 risk factors. In any case, high dose therapy significantly reduced the number of major CVD events [39]. Additional features that may be associated with greater risk of new-onset T2DM, as already mentioned, are familial history of diabetes mellitus, female gender, older age (especially with high-dose statins), Asian ethnicity, duration of statin treatment. Other associated factors possibly leading to enhance new-onset T2DM risk are related to concomitant drug treatment. In the NAVIGATOR Study, evaluating the effect of valsartan and nateglinide on the conversion to T2DM in patients with impaired glucose tolerance and other cardiovascular risk factors over a 5-year follow-up, the concomitant use of diuretics and statins was associated with a significantly increased risk of new-onset T2DM. No effect of beta-blockers or calcium-channel blockers was observed [40]. Interestingly, in a prospective controlled study, atorvastatin therapy resulted in a significantly worsened insulin resistance in women with polycystic ovary syndrome [41]. Taking into consideration all these features, it appears important that, within this context, the physician should also encourage patients Table 2 Individual T2DM screening during statin treatment (according to international guidelines [43–45]). HbA1c b5.7% (39 mmol/mol) ≥5.7% (30 mmol/mol) and b6.5% (48 mmol/mol) ≥6.5% (48 mmol/mol)
Normal Prediabetes Diabetes
Fasting plasma glucose (FPG) b100 mg/dl ≥100 mg/dl and b126 mg/dl ≥126 mg/dl
Normal Prediabetes Diabetes
Oral glucose tolerance test (OGTT, 2 h blood glucose) b140 mg/dl ≥140 mg/dl and b200 mg/dl ≥200 mg/dl
Normal Prediabetes Diabetes
Note 1: if a diagnostic test is abnormal, it should be repeated. Note 2: when two different tests (HbA1c and FPG) are done and are abnormal, the diagnosis is made. Note 3: HbA1c measurement should be performed in a certified laboratory or otherwise not used for diagnosis.
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to follow an appropriate diet program (i.e., the Mediterranean diet), to avoid sugary drinks and fructose, and to practice endurance exercise. In particular, Ballard et al. [42] highlighted that carbohydrate restricted diet may favorably affect markers of inflammation and altered vascular endothelial function and, in a randomized trial of statin users, found that a reduction of total caloric intake by approximately 415 Kcal/day for 6 weeks, predominantly reducing carbohydrates (from 46 to 11% of total calories) reduced systolic and diastolic blood pressures, raised forearm blood flow and reduced serum triglyceride and insulin levels. Clinical assessment for new-onset T2DM needs to be conducted periodically in statin treated patients, especially when the abovementioned features are present, following the current ADA and WHO guidelines [43–45]. In particular, HbA1c, FPG and oral glucose tolerance test are the three diagnostic criteria to be considered (please refer to Table 2 for further details). 5. Statin use and risk of new-onset T2DM: therapeutical implications and options According to most authors, it should be emphasized that the benefits of CVD reduction by statin therapy appear to far exceed the risk of newonset T2DM development. However, the increased risk of incident T2DM in at least a subset of patients upon statin treatment suggests the opportunity to both monitor glycemic control and related parameters in these subjects, as indicated above, and to consider different therapeutical options that may reduce the risk of T2DM without compromising CVD reduction. More specifically, it would be clearly optimal to lower LDL-C in order to achieve the target biomarker levels, promoting at the same time insulin-sensitivity and preventing T2DM development. Since only some of the observations here reported were fully validated in comparative studies vs. regular statin regimens, they should be considered as potential suggestions for a personalized therapeutic approach in the clinical routine as well as for future clinical trials. 5.1. Changes in statin regimen In many patients, one reasonable option, in the presence of adverse effects like musculoskeletal pain, may be to reduce the drug load with, for example, an alternate-day statin use [46,47]. The efficacy of intermittent dosing of statins is related to the observation that the duration of the total cholesterol and LDL-C lowering effects of these drugs is not related to the pharmacokinetics of each individual statin. In light of the above-reported lesser impact of lower statin doses, compared to higher doses, on new-onset T2DM, one may speculate some advantage in this respect also by alternate-day statin, although large-scale clinical trials seem required to validate this hypothesis. It also needs to be underlined that the effect of alternate-day statin regimen on the pleiotropic effects of these drugs is still unknown [48]. Another way to combine reduction of statin dose and a satisfactory lipid profile with CVD risk reduction is the addition of other drugs acting through mechanisms different from statins. For example, statins may be in some instances associated with ezetimibe [49] or colesevelam [50]. Another similar potential approach, that however still requires full clinical validation, is the addition, to statin therapy, of appropriate nutraceutical compounds (i.e., berberine) able to improve insulin resistance and to some extent the lipid profile [51, 52]. The clinical availability of new pharmacological agents also offers other options, although in some cases the use of these drugs is limited, at least for the moment, to very restricted cohorts of patients. Examples of these drugs are microsomal triglyceride transfer protein inhibitors, like lomitapide, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, cholesterol ester transfer protein inhibitors and several others still in the industry pipeline [49]. As mentioned above, pitavastatin appears to have a more favorable profile in terms of glucose metabolism and, in the countries where it is marketed, may be considered for the substitution of current statin treatment in patients at potential risk of new-onset T2DM.
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6. Concluding remarks According to the evidence discussed in this review article, the risk of new-onset T2DM in relationship with statin treatment is not negligible, especially for specific subset of patients. However, most authors emphasized that the benefits of CVD reduction by statin therapy seem to far exceed the risk of T2DM development itself. In any case, statin-driven T2DM appeared to be a medication class-effect, mostly not related to potency nor to individual statin, as well as to be independent of previous history of CVD [25]. Clinical trials with a prolonged follow-up appear necessary to better evaluate the impact of this issue [53]. Baseline fasting glucose and other features of the metabolic syndrome, along with the use of high-dose statins in the elderly, seem to be the strongest predictors of new-onset T2DM. As a practical suggestion for the day-byday clinical activity, it may be concluded that statins remain the cornerstone for primary and secondary CVD prevention, but, in light of the available data, a specific attention to glucose metabolism and metabolic syndrome features should be payed when evaluating a patient for such therapy as well as after statin treatment has been started. Learning points • Statin therapy is rather well tolerated, but an increased incidence of new-onset type 2 diabetes mellitus (T2DM) in association with this treatment has been recently reported. • Incidence of statin-driven T2DM is not negligible, especially for presence of familial history of T2DM, female gender, elderly, Asian ethnicity and duration of statin treatment. • Statin-driven T2DM appears to be a medication class-effect, mostly not related to potency nor to individual statin and independent of previous history of CVD. • Features associated with specific risk of incident T2DM: fasting plasma glucose N 100 mg/dl, plasma triglycerides N 150 mg/dl, body mass index N30 kg/m2, history of arterial hypertension • As a general consideration, the benefits of CVD reduction by statin therapy seem to far exceed the risk of T2DM development. Conflict of interest The authors have no conflict of interest. References [1] Taylor FC, Huffman M, Ebrahim S. Statin therapy for primary prevention of cardiovascular disease. JAMA 2013;310:2451–2. [2] Preiss D, Sattar N. Pharmacotherapy: statins and new-onset diabetes—the important questions. Nat Rev Cardiol 2012;9:190–2. [3] Metz SA, Rabaglia ME, Stock JB, Kowluru A. Modulation of insulin secretion from normal rat islets by inhibitors of the post-translational modifications of GTPbinding proteins. Biochem J 1993;295:31–40. [4] Ohrvall M, Lithell H, Johansson J, Vessby B. A comparison between the effects of gemfibrozil and simvastatin on insulin sensitivity in patients with non-insulin-dependent diabetes mellitus and hyperlipoproteinemia. Metabolism 1995;44:212–7. [5] Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010;375:735–42. [6] Mora S, Glynn RJ, Hsia J, MacFadyen JG, Genest J, Ridker PM. Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity Creactive protein or dyslipidemia: results from the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) and metaanalysis of women from primary prevention trials. Circulation 2010;121:1069–77. [7] Chan JC, Malik V, Jia W, Kadowaki T, Yajnik CS, Yoon KH, et al. Diabetes in Asia: epidemiology, risk factors, and pathophysiology. JAMA 2009;301:2129–40. [8] Ridker PM, Genest J, Boekholdt SM, Libby P, Gotto AM, Nordestgaard BG, et al. HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial. Lancet 2012;376:333–9. [9] Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, et al. ESC/ EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32:1769–818. [10] Reiner Z. Combined therapy in the treatment of dyslipidemia. Fundam Clin Pharmacol 2010;24:19–28.
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[11] Poli A, Corsini A. Reversible and non-reversible cardiovascular risk in patients treated with lipid-lowering therapy: analysis of SEAS and JUPITER trials. Eur J Intern Med 2010;21:372–3. [12] Singh N, Tamariz J, Chamorro G, Medina-Franco JL. Inhibitors of HMG-CoA reductase: current and future prospects. Mini Rev Med Chem 2009;9:1272–83. [13] Corsini A, Jacobson TA, Ballantyne CM. Fluvastatin: clinical and safety profile. Drugs 2004;64:1305–23. [14] Sugerman DT, Livingston EH,Lynm C. JAMA patient page. Statins. JAMA; 309:1419 [15] Freeman DJ, Norrie J, Sattar N, Neely RD, Cobbe SM, Ford I, et al. Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation 2001;103:357–62. [16] (EMA) EMA. HMG-CoA reductase inhibitors—Risk of new onset diabetes. 22 March 2012 [cited; Available from: http://www.ema.europa.eu/docs/en_GB/document_ library/Report/2012/01/WC500120115.pdf; 2012. [17] (FDA) TUSFaDA. FDA Drug Safety Communication: important safety label changes to cholesterol-lowering statin drugs. [cited; Available from: http://www.fda.gov/ drugs/drugsafety/ucm293101.htm; 2012. [18] Wannamethee SG, Shaper AG, Whincup PH, Lennon L, Sattar N. Impact of diabetes on cardiovascular disease risk and all-cause mortality in older men: influence of age at onset, diabetes duration, and established and novel risk factors. Arch Intern Med 2011;171:404–10. [19] Chehade JM, Gladysz M, Mooradian AD. Dyslipidemia in type 2 diabetes: prevalence, pathophysiology, and management. Drugs 2013;73:327–39. [20] Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto Jr AM, Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated Creactive protein. N Engl J Med 2008;359:2195–207. [21] Mills EJ, Wu P, Chong G, Ghement I, Singh S, Akl EA, et al. Efficacy and safety of statin treatment for cardiovascular disease: a network meta-analysis of 170,255 patients from 76 randomized trials. QJM 2011;104:109–24. [22] Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a metaanalysis. JAMA 2011;305:2556–64. [23] Rajpathak SN, Kumbhani DJ, Crandall J, Barzilai N, Alderman M, Ridker PM. Statin therapy and risk of developing type 2 diabetes: a meta-analysis. Diabetes Care 2009;32:1924–9. [24] Navarese EP, Buffon A, Andreotti F, Kozinski M, Welton N, Fabiszak T, et al. Metaanalysis of impact of different types and doses of statins on new-onset diabetes mellitus. Am J Cardiol 2013;111:1123–30. [25] Culver AL, Ockene IS, Balasubramanian R, Olendzki BC, Sepavich DM, WactawskiWende J, et al. Statin use and risk of diabetes mellitus in postmenopausal women in the Women's Health Initiative. Arch Intern Med 2012;172:144–52. [26] Zaharan NL, Williams D, Bennett K. Statins and risk of treated incident diabetes in a primary care population. Br J Clin Pharmacol 2012;75:1118–24. [27] Ma T, Chang MH, Tien L, Liou YS, Jong GP. The long-term effect of statins on the risk of new-onset diabetes mellitus in elderly Taiwanese patients with hypertension and dyslipidaemia: a retrospective longitudinal cohort study. Drugs Aging 2012;29:45–51. [28] Ma T, Tien L, Fang CL, Liou YS, Jong GP. Statins and new-onset diabetes: a retrospective longitudinal cohort study. Clin Ther 2012;34:1977–83. [29] Carter AA, Gomes T, Camacho X, Juurlink DN, Shah BR, Mamdani MM. Risk of incident diabetes among patients treated with statins: population based study. BMJ 2013;346:f2610. [30] Chen CW, Chen TC, Huang KY, Chou P, Chen PF, Lee CC. Differential impact of statin on new-onset diabetes in different age groups: a population-based case–control study in women from an Asian country. PLoS One 2013;8:e71817. [31] Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360:1623–30. [32] Keech A, Colquhoun D, Best J, Kirby A, Simes RJ, Hunt D, et al. Secondary prevention of cardiovascular events with long-term pravastatin in patients with diabetes or impaired fasting glucose: results from the LIPID trial. Diabetes Care 2003;26:2713–21.
[33] Sabatine MS, Wiviott SD, Morrow DA, McCabe CH. High dose atorvastatin associated with worse glycemic control: a PROVE-IT TIMI 22 substudy. Cannon CP,834 HdaawwgcAP-ITsCS Circulation 2004;110 [SIII]. [34] Waters DD, Ho JE, DeMicco DA, Breazna A, Arsenault BJ, Wun CC, et al. Predictors of new-onset diabetes in patients treated with atorvastatin: results from 3 large randomized clinical trials. J Am Coll Cardiol 2011;57:1535–45. [35] Hounslow N, Robillard P, Suzuki M, Betting P, Giral P, Chapman MJ. Pitavastatin is without effect on glycaemic parameters in metabolic syndrome (CAPITAIN Study). Abstract presented at World Diabetes Congress; 2012. [36] Teramoto T, Shimano H, Yokote K, Urashima M. New evidence on pitavastatin: efficacy and safety in clinical studies. Expert Opin Pharmacother 2010;11:817–28. [37] Ginsberg H. Statins in cardiometabolic disease: what makes pitavastatin different? Cardiovasc Diabetol 2013;12:S1. [38] Sattar N, Taskinen MR. Statins are diabetogenic—myth or reality? Atheroscler Suppl 2012;13:1–10. [39] Waters DD, Ho JE, Boekholdt SM, DeMicco DA, Kastelein JJ, Messig M, et al. Cardiovascular event reduction versus new-onset diabetes during atorvastatin therapy: effect of baseline risk factors for diabetes. J Am Coll Cardiol 2013;61:148–52. [40] Shen L, Shah BR, Reyes EM, Thomas L, Wojdyla D, Diem P, et al. Role of diuretics, beta blockers, and statins in increasing the risk of diabetes in patients with impaired glucose tolerance: reanalysis of data from the NAVIGATOR study. BMJ 2013;347:f6745. [41] Puurunen J, Piltonen T, Puukka K, Ruokonen A, Savolainen MJ, Bloigu R, et al. Statin therapy worsens insulin sensitivity in women with polycystic ovary syndrome (PCOS): a prospective, randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab 2013;98:4798–807. [42] Ballard KD, Quann EE, Kupchak BR, Volk BM, Kawiecki DM, Fernandez ML, et al. Dietary carbohydrate restriction improves insulin sensitivity, blood pressure, microvascular function, and cellular adhesion markers in individuals taking statins. Nutr Res 2013;33:905–12. [43] WHO. Use of Glycated Haemoglobin (HbA1c) in the Diagnosis of Diabetes Mellitus. WHO Publication; 2011 [cited; Available from: http://www.who.int/diabetes/ publications/report-hba1c_2011.pdf. [44] Association. AD. Diagnosis and classification of diabetes mellitus. Diabetes Care 2012;35:S64–71. [45] Gillett MJ. International Expert Committee report on the role of the A1c assay in the diagnosis of diabetes: diabetes care 2009; 32(7): 1327–1334. Clin Biochem Rev 2009;30:197–200. [46] Reindl EK, Wright BM, Wargo KA. Alternate-day statin therapy for the treatment of hyperlipidemia. Ann Pharmacother 2010;44:1459–70. [47] Li JJ, Yang P, Liu J, Jia YJ, Li ZC, Guo YL, et al. Impact of 10 mg rosuvastatin daily or alternate-day on lipid profile and inflammatory markers. Clin Chim Acta 2012;413:139–42. [48] Marcus FI, Baumgarten AJ, Fritz WL, Nolan Jr PE. Alternate-day dosing with statins. Am J Med 2013;126:99–104. [49] Wierzbicki AS, Viljoen A, Hardman TC, Mikhailidis DP. New therapies to reduce lowdensity lipoprotein cholesterol. Curr Opin Cardiol 2013;28:452–7. [50] Florentin M, Liberopoulos EN, Rizos CV, Kei AA, Liamis G, Kostapanos MS, et al. Colesevelam plus rosuvastatin 5 mg/day versus rosuvastatin 10 mg/day alone on markers of insulin resistance in patients with hypercholesterolemia and impaired fasting glucose. Metab Syndr Relat Disord 2013;11:152–6. [51] Derosa G, Maffioli P, Cicero AF. Berberine on metabolic and cardiovascular risk factors: an analysis from preclinical evidences to clinical trials. Expert Opin Biol Ther 2012;12:1113–24. [52] Ruscica M, Gomaraschi M, Mombelli G, Macchi C, Bosisio R, Pazzucconi F, et al. Nutraceutical approach to moderate cardiometabolic risk: results of a randomized, double-blind and crossover study with armolipid plus. J Clin Lipidol 2014;8:61–8. [53] Axsom K, Berger JS, Schwartzbard AZ. Statins and diabetes: the good, the bad, and the unknown. Curr Atheroscler Rep 2013;15:299.
Please cite this article as: Ruscica M, et al, Statin therapy and related risk of new-onset type 2 diabetes mellitus, Eur J Intern Med (2014), http:// dx.doi.org/10.1016/j.ejim.2014.03.003