Clinical Review Statin-Associated Incident Diabetes: A Literature Review Zoon H. Park, Alicia Juska, Detelin Dyakov, Ramesh V. Patel Objective: To evaluate available evidence for incident

diabetes associated with statin use and offer some practical management considerations. Data Sources: A literature search was performed using MEDLINE from 2000 to October 2013. The following MESH terms and text key words alone or in combination were included: 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, HMG-CoA reductase inhibitors, statins, incident diabetes, new-onset diabetes, insulin resistance, impaired insulin secretion, meta-analysis, cohort study, and observational study. Study Selection: Analyzed studies were published in English and investigated incident diabetes associated with statin use. Data Extraction: Author consensus determined study inclusion in this review, focusing on observational studies and meta-analyses. Data Synthesis: Since the report of incident diabetes associated with rosuvastatin, an unexpected finding in the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin, safety concerns with statins have emerged. Results of observational studies and meta-analyses show association of incident diabetes with statin use in patients with concomitant risk factors for diabetes. A pharmacodynamic mechanism has yet to be delineated, and individual statins may behave differently. Whether cardiovascular (CV) risk will increase with statin-associated incident diabetes remains unclear. Conclusion: Review of current, available clinical data suggest a possible association between statin use and incident diabetes in patients with underlying diabetes risk factors. Although study data may be insufficient to change the current practice paradigm, clinicians should vigilantly monitor for incident diabetes in patients on statins. Patients with a low risk of CV disease and high risk of diabetes should reconsider statin use and focus on lifestyle management. Key words: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, Elderly, HMG-CoA reductase inhibitors, Incident diabetes, New-onset diabetes, Statins.

Abbreviations: BMI = Body mass index, CHIBA =

Collaborative Study on Hypercholesterolemia Drug Intervention and their Benefits for Atherosclerosis Prevention, CI = Confidence interval, CORONA= Controlled Rosuvastatin Multinational Trial in Heart Failure, CrI = Credible interval, CV = Cardiovascular, CVD = Cardiovascular disease, DM = Diabetes mellitus, FCH = Familial combined hyperlipidemia, FPG = Fasting plasma glucose, GLUT1 = Glucose transporter type 1, GLUT4 = Glucose transporter type 4, HbA1C = Glycosylated hemoglobin, HMG-CoA = 3-Hydroxyl-3methylglutaryl coenzyme A, HOMA = Homeostasis model assessment, HOMA-IR = Homeostasis model assessmentinsulin resistance, HR = Hazard ratio, IGT = Impaired glucose tolerance, ISG = Insulin-secreting granules, JUPITER = Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin, LDL = Low-density lipoprotein, MESH = Medical subject headings, MI = Myocardial infarction, NNH = Number needed to harm, NNT = Number needed to treat, NS = Not significant, ODB = Ontario Drug Benefit Database of Canada, OMID = Ontario Myocardial Infarction Database of Canada, OR = Odds ratio, PROSPER = Prospective Study of Pravastatin in the Elderly at Risk, QUICKI = Quantitative Insulin Check Index, RR = Relative risk, STELLAR = Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin, WHI = Women’s Health Initiative, WOSCOPS = West of Scotland Coronary Prevention Study. Consult Pharm 2014;29:317-34.

Introduction Elevation of low-density lipoprotein (LDL) is recognized as a major risk factor for cardiovascular disease (CVD). 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, commonly known as statins, possess a potent LDL-lowering effect. Evidence for the past 30 years has shown that statins reduce all-cause mortality, prevent or slow down CVD, and are considered a breakthrough medication of the century.1 Statins are the most prescribed medications worldwide, with 16.2% of Americans aged 20 years and older taking a statin.1,2 Advocates are lobbying to make statins available to the public as over-the-counter medications as a way to improve adherence.1,3 However,

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Clinical Review since the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) unexpectedly reported a positive association between rosuvastatin and the incidence of diabetes, the impact of statins on glucose homeostasis has been debated.4 Observational studies and meta-analyses suggest that statins may be associated with a risk of incident diabetes mellitus (DM) (Tables 1, 2).5-21 The significance and magnitude of the trade-off between the benefits of statin treatment and potentially detrimental effects on glucose homeostasis are of great clinical concern. Literature on the association of statin use with incident diabetes will be reviewed.

Data Sources A literature search was performed using MEDLINE from 2000 to October 2013, using the following MESH terms and text key words alone or in combination: 3-hydroxy3-methylglutaryl coenzyme A reductase inhibitors, HMG-CoA reductase inhibitors, statins, incident diabetes, new-onset diabetes, insulin resistance, impaired insulin secretion, meta-analysis, cohort study, and observational study. Clinical trials were included in the review if they were conducted in humans, published in English, and investigated incident DM associated with statin use. Citations in the retrieved studies were examined to identify other relevant studies. Each author independently reviewed the retrieved references. Author consensus determined studies to be included in this review, focusing on observational studies and meta-analyses. Also, references to pharmacodynamic studies associated with incident diabetes and animal studies relating to the mechanism of statin-induced dysglycemia were included.

Mechanism and Experimental Studies Statins demonstrate various beneficial or detrimental pleiotropic effects.22-30 Several mechanisms have been proposed for the observed deleterious effects of statins on glucose homeostasis. One proposed for atorvastatin is that it interferes with glucose metabolism by decreasing adipocyte maturation leading to decreased expression of glucose transporter type 4 (GLUT4) and up-regulation

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of glucose transporter type 1 (GLUT1). In an animal model, this interference decreased insulin sensitivity and exacerbated glucose intolerance.31,32 Statins may also alter calcium (Ca2+) channel signaling cascades. In a rat model, simvastatin blocked L-type Ca2+ channels because of the inhibition of glucose-induced cytoplasmic Ca2+ signaling, leading to decreased insulin secretion.25,33 Endogenous LDL is needed for proper functioning of pancreatic β-cells and glucose homeostasis.34 Cholesterol has secretory and antisecretory effects on β-cells, both of which are dependent on concentration and location of cholesterol. For example, a relatively high concentration of cholesterol is needed in the insulin-secreting granules (ISG) for their proper formation, transport, and docking beneath the plasma membrane. For proper exocytosis of ISG, a low cholesterol concentration in the cytoplasm is required.34 When statins interfere with β-cell functions that require a high cholesterol concentration, the net result is impaired insulin secretion (Figure 1).34,35 Lipophilicity and hydrophilicity of statins may also contribute to insulin resistance. Upregulation of a β-cell membrane LDL receptor may lead to impairment of the exocytosis of matured ISG in the plasma membrane. This effect occurs with lipophilic statins (i.e., atorvastatin, simvastatin). Data suggest that hydrophilic statins (i.e., pravastatin, rosuvastatin) in hypercholesterolemic patients would not deplete intracellular cholesterol for ISG synthesis and therefore should result in improved insulin sensitivity.34,36 However, rosuvastatin did not demonstrate improved insulin sensitivity in a later study.37 Additional studies are required to investigate this effect. Various biomarkers have been used to assess statinassociated incident diabetes. In most experimental studies, insulin sensitivity indices such as the homeostasis model assessment (HOMA) indices, quantitative insulin sensitivity check index (QUICKI), whole-body insulin sensitivity index, fasting plasma glucose (FPG), or HbA1C were measured. A few studies also reported serum adiponectin and leptin levels, impaired glucose tolerance (IGT), or the euglycemic clamp method. Experimental studies suggest that statins, as a class, increase the risk of incident diabetes; however, individual

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Figure 1. Hypothetical Paradigm for Statin-Induced Impairment of Glucose Metabolism

(1) Intracellular arrival of glucose via glucose transporter (Glut2 in β-cells) leads to phosphorylation by glucokinase, and routing to the metabolic pathway. The resulting cascade of closure of ATP-dependent potassium channel, depolarization, and calcium influx leads to insulin secretion; this process may be inhibited by statins. (2) Glucokinase is inhibited by abundance of plasma cholesterol, and thus is conceivably affected by statin-induced inhibition of de novo cholesterol synthesis with increased uptake of plasma LDL. (3) Statin inhibition of HMG-CoA reductase suppresses synthesis of ubiquinone (CoQ10), an essential factor in the mitochondrial electron-transfer system, resulting in inhibition of insulin secretion due to reduced production of ATP. (4) Statin inhibition of HMG-CoA reductase suppresses the synthesis of isoprenoids, thus causing down regulation of Glut4 expression on adipocyte cells, leading to impaired glucose uptake. (5) The inhibition of HMG-CoA reductase causes upregulation of LDL receptors, leading to enhanced uptake of LDL-cholesterol in an effort to replenish intracellular stores. However, the intracellular fate of plasma-derived LDL-cholesterol may be distinct from that of de novo synthesized cholesterol. (6) The oxidation of LDL cholesterol may incite an inflammatory cascade that compromises the functional – for example, insulin secretion apparatus – and ultimately structural integrity of the islet β-cells. (7) Furthermore, cytokine-induced over-production of nitric oxide (NO) has been shown to induce β-cell apoptosis via the activation of calpain – a calcium-dependent protease. Abbreviations: ATP = Adenosine triphosphate, Glut2 = Glucose transporter 2, Glut4 = Glucose transporter 4, HMG-CoA = 3-hydroxymethylglutaryl coenzyme A, LDL = Low-density lipoprotein, NO = Nitric oxide. Source: Reference 35. Adapted with permission.

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Clinical Note statin data showed that statins have a variable effect.37,38 One study showed improvement of insulin sensitivity with atorvastatin; however, the others did not.39-41 The effect of doses and risk factors may not be ruled out. A post hoc analysis of three large, randomized, clinical trials suggested higher doses of atorvastatin may increase the risk of incident diabetes in patients with more than two risk factors.42,43 Variable results have also been reported with pravastatin. Post hoc analyses of clinical trials showed conflicting results, despite both using pravastatin 40 mg.16,36 The conflict appears to result from a difference in study population. While the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) enrolled elderly patients with or at risk for CVD, the West of Scotland Coronary Prevention Study (WOSCOPS) enrolled middle-aged men.16,36 In healthy, nondiabetic volunteers, pravastatin 40 mg for 12 weeks did not affect insulin sensitivity, but in patients with coronary artery disease and IGT, pravastatin improved insulin sensitivity.44,45 After findings with pravastatin were reported from WOSCOPS, it was speculated that aggressively lowering LDL with potent or higher-dose statins would reduce the development of diabetes.36 However, data from clinical trials and experimental investigations were inconclusive. Contrary to positive results reported from WOSCOPS, the JUPITER trial used a potent statin, rosuvastatin, and found a significant increase in physician-reported diabetes.4 The negative result was not replicated in a later study.46 In a randomized, placebo-controlled, clinical trial, 5,011 ischemic systolic heart failure patients 60 years of age and older were followed for a median of 32.8 months. This study suggested that rosuvastatin may not increase the risk of newly diagnosed diabetes as a prespecified outcome measure compared with placebo.46 Experimental studies neither support nor refute the previously mentioned speculation.47,48 Thongtang et al. evaluated 76 blood samples from the atorvastatin 80 mg and rosuvastatin 40 mg groups of the Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin (STELLAR) clinical trial. Both statins significantly increased insulin levels from baseline.47 However, a double-blind, randomized, crossover study of patients

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with familial combined hyperlipidemia (FCH) found rosuvastatin 40 mg did not significantly change the insulin sensitivity indices when compared with placebo.48 A recent post hoc analysis of the JUPITER trial, by Ridker et al., reported a favorable benefit/risk ratio for rosuvastatin. For every 54 new cases of diabetes diagnosed, 134 total cardiovascular (CV) events or 16 deaths were avoided with rosuvastatin treatment in patients with at least one risk factor for developing diabetes at baseline (hazard ratio [HR] = 0.63, 95% confidence interval [CI] 0.25-1.60).49 Several studies using simvastatin 80 mg doses also yielded conflicting results.50,51 A study conducted in 156 nondiabetic Asian patients with hypercholesterolemia (LDL ≥ 100 mg/dL and body mass index [BMI] ≥ 23 kg/m2) found simvastatin doses of 10 mg, 20 mg, 40 mg, and 80 mg significantly reduced insulin sensitivity (QUICKI), by 5%, 8%, 6%, and 6%, respectively, when compared with baseline, and the 80 mg dose significantly increased fasting plasma glucose (FPG).50 No significant correlations were found between changes in other biomarkers and lipoproteins with any simvastatin doses.50 Conversely a study of 20 participants with type 2 DM and hypercholesterolemia showed simvastatin did not affect whole-body insulin sensitivity as measured by glycemic clamp tests.51 Data evaluating incident diabetes with earlier statins (mevastatin, fluvastatin, or lovastatin) are lacking. The newest statin approved in 2010, pitavastatin, appeared not to affect glucose homeostasis as it showed no significant effect on FPG, HbA1C, or HOMA indices.52-54 Results from a study in 279 Japanese diabetic patients found pitavastatin did not significantly affect FPG or HbA1C, whereas atorvastatin significantly increased those levels.54 Similarly, a post hoc subgroup analysis of the Collaborative Study on Hypercholesterolemia Drug Intervention and their Benefits for Atherosclerosis Prevention (CHIBA) study in 204 Japanese hypercholesterolemic patients with diabetes showed similar results.53 Further clinical data with pitavastatin are required to evaluate any association with incident diabetes. Although clinical and experimental data on individual statins yielded mixed results, observational studies and meta-analyses of clinical trials demonstrated an

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association between statins, as a class, and incident diabetes. Evaluation of observational studies indicated a strong association of atorvastatin and simvastatin with incident diabetes.6-8,10,13 Two meta-analyses strongly implicated rosuvastatin association with incident diabetes.19,21

Observational Studies The literature search identified nine observational studies. Except for one study, all studies were conducted outside of the United States (Table 1).5-13 A nested, case-control study was conducted using the General Practice Research Database, which contains data for more than three million United Kingdom residents.5 A total of 588 incident diabetes cases were identified and matched with 2,063 controls. The odds of developing diabetes between statin users and nonexposed patients were not significant (NS) (odds ratio [OR] = 1.1, 95% CI 0.8-1.4). However, BMI and hypertension were independently associated with an increased risk of diabetes, with ORs of 10.1 (95% CI 6.2-16.3) and 1.8 (95% CI 1.4-2.2), respectively.5 As BMI and hypertension are already DM risk factors, it is unclear how much statin treatment contributed to the risk. Another retrospective cohort study evaluated 16,195 patients in the Central Regional Branch Database of the National Health Insurance in Taiwan, for new-onset diabetes with statin use.6 All patients were followed for 3.5 years and at baseline had hypertension and dyslipidemia, but no diabetes. Contrary to results from a previous study by Freeman et al., investigators found the highest hazard for new-onset diabetes in pravastatin (HR = 1.34, 95% CI 1.15-1.55) and atorvastatin (HR = 1.29, 95% CI 1.16-1.44) groups, compared with nonusers.36 Simvastatin was not associated with any risk of newonset diabetes. Fluvastatin (HR = 0.45, 95% CI 0.34-0.60), lovastatin (HR = 0.71, 95% CI 0.61-0.84), and rosuvastatin (HR = 0.54, 95% CI 0.39-0.77) users had a lower hazard of developing incident diabetes than nonusers. Of note, most patients took atorvastatin (37.1%) or lovastatin (32.8%), and only 3.9% of patients took rosuvastatin, which may have varied the results of this study in comparison with others. As the database contained only three diagnostic

data fields, data might have been missed in patients with more than three comorbidities and who then developed incident diabetes.6 Using data from Women’s Health Initiative (WHI) on 153,840 postmenopausal women with and without diabetes, a prospective, observational study by Culver et al., with an average follow-up of 6.5 years, found an increased risk of incident diabetes with statin use.7 Of 10,834 women taking statins, 1,076 (9.93%) reported new-onset DM, whereas of 143,006 nonstatin users, only 9,166 (6.41%) reported new-onset DM. The multivariate-adjusted HR was 1.48 (95% CI 1.38-1.59). This trend was observed for all studied statins. Diabetes was identified by patient’s self-report of new physician diagnosis or treatment with antidiabetic medications. Of interest, women with a BMI < 25 kg/m2 had a significantly increased risk for incident diabetes with statin use, compared with women with higher BMIs of 25-29 kg/m2 or ≥ 30 kg/m2. Additionally, investigators found that patients with self-reported CVD had a similar risk of incident diabetes with statin use as patients without CVD. This finding poses a question of whether hyperlipidemic women without CVD should be treated with statins, if needed, considering the risk of incident diabetes.7 Another large, retrospective, cohort study, investigating statin effects on developing incident diabetes, was conducted using the Irish Health Services Executive Primary Care Reimbursement Services Claim Database.8 Zaharan et al. identified a total of 239,628 patients who received a statin between January 1, 2002 and December 31, 2007. Of patients on statins, 5.9% were initiated on antidiabetic medications, compared with 2.5% in the cohort never treated with a statin (HR = 1.20, 95% CI 1.17-1.23). This increased hazard for incident diabetes was statistically significant for atorvastatin, rosuvastatin, and simvastatin, but was not statistically significant for pravastatin or fluvastatin. All statins showed significant linear association between cumulative dose, duration of therapy, and incident diabetes (P < 0.0001).8 Previous findings were supported by another large, retrospective cohort study by Wang et al., which used the Taiwan National Health Insurance Research Database.9

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Clinical Review

Table 1. Observational Studies: Statin-Associated Incident Diabetes Studies

Data Set

Study Design

Case Criteria

Incident DM

Jick et al. (2004)5

Patients with hyperlipidemia in UK-based General Practice Research Database (January 1991-March 2002)

Nested case-control study Duration of followup: minimum 2 yrs Sample: n = 69,848 Case: n = 588 Control: n = 2,063

Diagnosis by general practitioners with ≥ 2 prescriptions of hypoglycemic agents or 3 recorded entries of management with diet

Overall OR = 1.1 (95% CI 0.8-1.4)

Ma et al. (2012)6

Central Regional Branch Database of National Health Insurance in Taiwan (July 2006December 2009)

Retrospective cohort study in patients with hypertension and hyperlipidemia without diabetes at baseline Duration of followup: 3.5 yrs Sample: n = 16,195

ICD-9 code for diabetes or prescription of antidiabetic drugs (patients with a diabetes diagnosis or prescription for antidiabetic drugs during the 2-year period before receiving a statin were excluded)

Overall HR1 = not reported Atorvastatin HR = 1.15 (95% CI 0.96-1.35) Fluvastatin HR = 0.46 (95% CI 0.33-0.61) Lovastatin HR = 0.70 (95% CI 0.59-0.83) Pravastatin HR = 1.30 (95% CI 1.13-1.56) Rosuvastatin HR = 0.54 (95% CI 0.39-0.76) Simvastatin HR = 1.11 (95% CI 0.92-1.32)

Culver et al. (2012)7

WHI: postmenopausal women (19932005)

Self-report of a new Prospective cohort physician diagnosis study Duration of followup: mean 6.5 yrs3 Sample: n = 153,840 Statin: n = 10,834 Control: n = 143,006 Case: n = 10,242

Overall HR2 = 1.48 (95% CI 1.38-1.59) Atorvastatin HR = 1.61 (95% CI 1.26-2.06) Fluvastatin HR = 1.61 (95% CI 1.35-1.92) Rosuvastatin HR = 1.35 (95% CI 1.19-1.55) Pravastatin HR = 1.63 (95% CI 1.43-1.87) Simvastatin HR = 1.41 (95% CI 1.25-1.61)

Zaharan et al. (2013)8

Irish Health Service Executive Primary Care Reimbursement Services national pharmacy claims database (20022007)

Retrospective cohort Patients newly treated study with antidiabetic Duration of followmedications up: assessed up to 720 DDD4 exposure Sample: n = 1,235,671 Statin: n = 239,628 Control: n = 996,043 Case: n = 38,503

Overall HR2 = 1.20 (95% CI 1.17-1.23) Atorvastatin HR = 1.25 (95% CI 1.20-1.28) Fluvastatin HR = 1.04 (95% CI 0.91-1.18) Pravastatin HR = 1.02 (95% CI 0.98-1.06) Rosuvastatin HR = 1.42 (95% CI 1.33- 1.52) Simvastatin HR = 1.14 (95% CI 1.06-1.23)

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Table 1. Observational Studies: Statin-Associated Incident Diabetes (continued) Studies

Data Set

Wang et al. (2012)9

Retrospective cohort Taiwan National study Health Insurance Research Database Duration of follow(1997-2009) up: median 7.2 yrs Sample: n = 42,060 Statin: n = 8,412 Control: n = 33,648 Case: n = 5,754

Danaei et al. (2013)10

The Health Improvement Network (THIN) of UK (January 2000-December 2010)

Study Design

Case Criteria

Incident DM

ICD-9 codes for diabetes and antidiabetic medications ≥ 30 days

Overall HR = 1.15 (95% CI 1.08-1.22) No data for individual statins reported

Read diabetic Emulated randomized trial with classification code or use of hypoglycemic the database drugs or insulin Sample: n = 285,864 (3,813,919 persontrials with 131 emulated trials)

The study examined the role of survival bias for incident DM with statins: no evidence for the survival bias was found Statin initiators vs. noninitiators: HR = 1.14 (95% CI 1.09-1.19)5 The study observed simvastatin and atorvastatin increased incident DM by 14%

Control: peptic ulcer with statin use Diagnostic code for diabetes and prescriptions of oral antidiabetic drugs or insulin, confirmed with FPG ≥ 126 mg/dL

Izzo et al. (2013)11

Campania Salute Network of Italy (1997-2011)6

Prospective cohort study Duration of followup: mean 4.65 yrs Sample: n = 4,750 Control: n = 4,074 Statin: n = 676

Ko et al. (2013)12

Ontario Myocardial Infarction Database (OMID) of Canada (April 2004-March 2010)

The Ontario Diabetes Retrospective Mellitus Database propensity scoreCriteria8 matched cohort study Duration of follow-up: 5 yrs Sample: n = 17,080 Moderate-dose statin: n = 8,540 Intensive-dose statin: n = 8,450

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Primary prevention in patients with hypertension Overall incident diabetes7: 10.2% vs. 8.7%; P = NS Statins included: atorvastatin 10 or 20 mg, rosuvastatin 10 mg, and simvastatin 20 or 40 mg The study compared incident diabetes rates between intensive statin doses vs. moderate statin doses in post-MI, elderly (mean age 78 yrs) patients Intensive statin dose: doses to achieve about 50% reduction in LDL Moderate statin dose: less than the intensive statin doses In both groups, majority of patients received atorvastatin (92% and 61%, respectively). No difference in rates at 5 yrs (13.6% vs. 13.0%, respectively)

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Clinical Review

Table 1. Observational Studies: Statin-Associated Incident Diabetes (continued) Studies

Data Set

Study Design

Carter et al. (2013)13

Ontario Drug Benefit Database (ODB) of Canada (August 1997March 2010)

Retrospective cohort The Ontario Diabetes Mellitus Database study Sample: n = 471,250 Criteria8 Control: patients on pravastatin

Case Criteria

Incident DM More than 50% of patients received atorvastatin Elderly patients (median age of 73 yrs) on various statins were compared with the pravastatin group, an active comparator Atorvastatin HR = 1.22 (95% CI 1.15-1.29) Fluvastatin HR = 0.95 (95% CI 0.81-1.11) Rosuvastatin HR = 1.18 (95% CI 1.10-1.26) Simvastatin HR = 1.10 (95% CI 1.04-1.17)

Adjusted for age, gender, concomitant medication usage, and mean dose for each statin. Multivariate adjusted HR. 3 Estimated from data reported. 4 Defined daily doses: atorvastatin 10 mg, fluvastatin 40 mg, pravastatin 20 mg, rosuvastatin 10 mg, and simvastatin 15 mg. 5 HR weighted and adjusted for baseline variables. 6 Extrapolated from the Figure 1. 7 Unadjusted risk (adjusted risk was not reported but investigators claimed “NS”). 8 Used a validated administrative data algorithm. 1 2

Abbreviations: CI = Confidence interval, DM = Diabetes mellitus, FPG = Fasting plasma glucose, HR = Hazard ratio, ICD-9 = International Classification of Diseases, Ninth Revision, NS = Not significant, OR = Odds ratio, UK = United Kingdom. Source: References 5-13.

This study also found an increased hazard of incident diabetes with statin use (HR = 1.15, 95% CI 1.08-1.22; P < 0.001). Follow-up comparison demonstrated that patients who did not develop incident diabetes had significantly less major CV events than those who did.9 Of note, this study excluded patients with established coronary events, who were most likely to benefit from statin therapy. An emulated randomized trial, by Danaei et al., with more than three million person-trials, was conducted using data from the Health Improvement Network of the United Kingdom.10 The majority of patients used simvastatin (79%), and 15.5% used atorvastatin. After an average follow-up of 28 months, a 14% increased hazard of diabetes with atorvastatin and simvastatin was found after potential confounder adjustment (HR = 1.14, 95% CI 1.10-1.19).10

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A recent small prospective cohort study (n = 4,750) in Italy investigated statin-associated incident diabetes among hypertensive, nondiabetic outpatients.11 At the end of the follow-up, a mean of 4.65 years, the prevalence of DM was 18.1% in patients on statins and 7.2% among nonusers. However, the incidence of diabetes was similar in statin- vs. nonstatin groups (10.2% vs. 8.7%; P = NS). The cohort received daily atorvastatin 10 mg or 20 mg, rosuvastatin 10 mg, or simvastatin 20 mg or 40 mg.11 Individual statin association with diabetes was not investigated. This study used low-moderate statin doses for primary prevention, which did not show an association of statin therapy with incident diabetes. However, the small sample size may limit validity of the results. Two most recent Canadian studies investigated statin-associated incident diabetes in elderly patients.12,13

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Ko et al. compared intensive vs. moderate doses of statins in post-myocardial infarction, elderly (mean age of 78 years) patients using the Ontario Myocardial Infarction Database (OMID) of Canada. There was no difference in risk of statin-associated incident diabetes between intensive doses vs. moderate doses after five years of follow-up (13.6% vs. 13.0%; P = NS).12 Intensive doses were defined as doses required to achieve about 50% reduction of LDL in the study. These results support a favorable benefit/risk ratio of statin use in the elderly in secondary prevention. In a population-based cohort study, Carter et al. analyzed the Ontario Drug Benefit Database (ODB) of Canada (n = 471,250), comparing other statins to pravastatin in elderly (median age of 73 years) patients, to assess for statin-associated incident diabetes.13 After adjustment for multiple confounders, the greatest increased hazard of incident diabetes (22%) was found among patients treated with atorvastatin, followed by rosuvastatin (18%) and simvastatin (10%). Conversely, fluvastatin and lovastatin showed decreased risk compared with pravastatin.13 The numbers needed to harm (NNH) are estimated to be 172 (atorvastatin), 210 (rosuvastatin), and 363 (simvastatin). Subgroup analyses found the results were consistent in the primary- and secondary-prevention cohorts. Compared with low statin doses (pravastatin, fluvastatin, and lovastatin at all doses; atorvastatin < 20 mg, rosuvastatin < 10 mg, simvastatin < 80 mg), moderate and high statin doses were associated with higher risks.13 This study suggests that low doses of statins or low-potency statins might mitigate the risk. Large numbers of subjects involved in observational studies make it more likely to detect a difference of incident diabetes with statin use if it exists. Five observational studies reported incident diabetes associated with individual statins. Atorvastatin was associated with incident diabetes in all five studies, simvastatin in four studies, rosuvastatin in three studies, pravastatin in two studies, and fluvastatin in one study (Table 1).6-8,10,13 Of interest, the prospective U.S. women’s study implicated all reported statins.7 Of note, health care utilization databases created for reimbursement purposes may impact the validity of reported data as they do not distinguish between disease

severity, statin doses, or patient compliance.55 To reduce bias in health care utilization data analysis, a priori selection strategies of covariates are recommended.56 However, the majority of observational studies reviewed did not report these strategies.

Meta-Analyses A summary of the meta-analyses is presented in Table 2.14-21 A 2008 meta-analysis of five primary and secondary prevention, randomized, placebo-controlled trials by Coleman et al. reported that statin use did not significantly prevent the development of incident diabetes (relative risk [RR] = 1.03, 95% CI 0.89-1.19).14 This meta-analysis was conducted to confirm the beneficial effect of statins in preventing incident diabetes as demonstrated by WOSCOPS; however, the validity of the meta-analysis to conclude no effect was questionable given the degree of heterogeneity (I2=51.1%; Q statistic P = 0.08). Additionally, publication bias could not be ruled out. Subgroup sensitivity analyses were performed for individual statins, with no change in final outcome. However, when pravastatin was excluded from the evaluation, the relative risk for developing incident diabetes was significant (RR = 1.14, 95% CI 1.021.28), with little or no heterogeneity for all subgroups (Q statistic P > 0.13).14 A 2009 meta-analysis by Rajpathak et al. included six large statin trials with a mean follow-up duration of 3.9 years.15 Three studies relied on physician-reported diabetes, and three studies incorporated standardized diagnostic criteria for diabetes diagnosis. Only two of the studies, WOSCOPS and JUPITER, reported a significant association between statin use and incident diabetes. WOSCOPS demonstrated a decreased hazard of incident diabetes with pravastatin (HR = 0.70, 95% CI 0.50-0.99; P = 0.042). Conversely, JUPITER findings showed a significant positive association of rosuvastatin with incident diabetes (RR = 1.25, 95% CI 1.05-1.49; P = 0.01). When all studies were combined and analyzed, no significant correlation between statin use and diabetes incidence was seen (RR = 1.06, 95% CI 0.93-1.23; P = 0.38) with significant heterogeneity driven largely by WOSCOPS data. Taking this into account, five trials were analyzed excluding WOSCOPS

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Clinical Note

Table 2. Meta-analyses: Statin-Associated Incident Diabetes Meta-analysis

Study Inclusion Criteria

Results

Coleman et al. (2008)14

Inclusion (n = 5) Randomized, doubleblinded, placebocontrolled trials

Overall RR = 1.03 (95% CI 0.89-1.19)

Rajpathak et al. (2009)15

Inclusion (n = 6) Randomized, doubleblinded, placebocontrolled trials with Jadad score ≥ 3

Overall RR = 1.06 (95% CI 0.93-1.23; P = 0.38)

Inclusion (n = 13) Placebo and standardcare controlled trials on cardiovascular endpoints in stable individuals

Overall OR = 1.09 (95% CI 1.02-1.17)

Sattar et al. (2010)16

Exclusion: 1. Organ transplant or hemodialysis 2. Comparing either different statins or doses of the same statin

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Statins Included

Comments

Atorvastatin Pravastatin Rosuvastatin Excluding WOSCOPS Simvastatin (pravastatin), RR = 1.14 (95% CI 1.021.28)

• Criteria used to determine incident rates of diabetes differed in each trial • Moderate heterogeneity: (I2 = 51.5%; Q statistic P = 0.08) • Publication bias could not be ruled out (Funnel plots) but less likely by Egger’s • Duration of follow-up: ranges 2.7-6 yrs • Average statin dosing intensity: 35%-40% LDL reduction

Atorvastatin Pravastatin Rosuvastatin Simvastatin

• Criteria used to determine incident rates of diabetes differed in each trial • Significant heterogeneity: (I2 = 57.7%; Q statistic = 11.8; P = 0.03) • No evidence of heterogeneity without WOSCOPS (I2 = 1.6%; Q statistic = 4.06; P = 0.40) • Duration of follow-up: mean 3.9 yrs, median 1.9-5 yrs • Female sex was associated with higher risk • 3 studies were primary cardiovascular prevention trials and 3 studies were secondary prevention trials

Atorvastatin Lovastatin Pravastatin Rosuvastatin Simvastatin

• Although criteria used to determine incident rates of diabetes differed in each trial, this meta-analysis used standard diabetes diagnostic criteria • No evidence of heterogeneity (I2 = 11.2%) • Analysis was not designed to test dose effects of statins • Duration of follow-up: mean 4 yrs • 2 extra diabetes cases per 1,000 patient yrs • No clear difference between statins • Old age was associated with higher risk

Excluding WOSCOPS study (pravastatin), RR = 1.13 (95% CI 1.03-1.24; P = 0.007)

Only trials with placebo: OR = 1.10 (95% CI 1.01-1.20; I2 = 21%)

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Table 2. Meta-analyses: Statin-Associated Incident Diabetes (continued) Meta-analysis

Study Inclusion Criteria

Sattar et al. (2010)16

3. Assessing changes in surrogate markers 4. Participants ≤ 1,000 5. Mean follow-up < 1 yr 6. Uneven follow-up between statins and standard care

Mills et al. (2011)17

Inclusion (n = 17) OR = 1.09 (95% Randomized, controlled CI 1.02-1.16; trials comparing P = 0.008) placebo, standard-care, or no treatment for cardiovascular events

Preiss et al. (2011)18

Inclusion (n = 5)

Results

Statins Included

Comments

Atorvastatin Fluvastatin Lovastatin Pitavastatin Pravastatin Rosuvastatin Simvastatin

• A network meta-analysis • Sub meta-analysis of 76 RCTs included in the meta-analysis for efficacy and safety of statins • Heterogeneity: I2 = 26% • n =111,003 • Incident diabetes rates for individual statins were not reported

Intensive statin vs. Atorvastatin 80 mg moderate statin: vs. 1. Trials to assess the Atorvastatin 10 mg intensive dose statin tx OR = 1.12 (95% vs. moderate-dose statin CI 1.04-1.22) Atorvastatin 80 mg NNH: 498/yr tx on cardiovascular vs. outcomes Pravastatin 40 mg 2. Trials with identical follow-up >1 yr Atorvastatin 80 mg 3. Participants ≥ 1,000 vs. Simvastatin 40 mg or 20 mg Simvastatin 40 mg followed by 80 mg vs. placebo followed by Simvastatin 20 mg Simvastatin 80 mg vs. Simvastatin 20 mg

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• The PRISMA recommendations for meta-analysis were followed • Diabetes diagnostic criteria: o Reported as an ADE o Initiation of anti-diabetic medications o 2 FPG ≥ 126 mg/dL • Quality of trials: high with mean Delphi score of 9 (assessed via Delphi score by the two authors) • No significant heterogeneity: I2 = 0% (95% CI 0%-79%) • Included published and unpublished data • Criteria of intensive and moderate statin treatments were used in each trial • Duration of follow-up: mean 4.9 yrs • Cardiovascular benefits: o OR = 0.84 (95% CI 0.75-0.94) o NNT: 155/yr • All-cause mortality: o OR = 0.93 (95% CI 0.81-1.05)

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Clinical Review

Table 2. Meta-analyses: Statin-Associated Incident Diabetes (continued) Meta-analysis

Study Inclusion Criteria

Alberton et al. (2012)19

Navarese et al. (2013)20

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Statins Included

Comments

Inclusion (n = 72) Overall OR = 1.09 Randomized, controlled (95% CI 1.02-1.16) trials comparing placebo, standard-care, or no treatment for cardiovascular events

Atorvastatin Fluvastatin Lovastatin Pravastatin Rosuvastatin Simvastatin

• Analysis to identify differing adverse event risks across statins • A diagnosis of diabetes was one of covariates chosen a priori and individual studies reported diabetic diagnostic criteria were used • No evidence of heterogeneity (I2 = 11%) for overall analysis • Atorvastatin, Fluvastatin, Lovastatin: insufficient studies for meta-analysis • Pravastatin: OR = 1.04 (95% CI 0.91 1.19; I2 = 35%) • Rosuvastatin: OR = 1.14 (95% CI 1.01-1.29; I2 = 1.5%) • Simvastatin: OR = 1.10 (95% CI 0.97 1.25; I2 = N/A)

Inclusion (n = 17) 1. Randomized, controlled trials comparing high-dose statins versus placebo or no treatment and high- dose statins versus moderate statins, which reported incident diabetes in both groups. 2. Trials had longer than 1 year of follow- up 3. Participants > 1,000

Atorvastatin Lovastatin Pravastatin Rosuvastatin Simvastatin

• Network meta-analysis • PRISMA recommendations for meta- analysis were followed • CIs with Bayesian hierarchical random-effect model • Diabetes diagnostic criteria: o Reported as an ADE o Initiation of antidiabetic medications o 1 or 2 FPG ≥ 126 mg/dL (7 mmol/L) • Higher doses of statins increased incident DM • Potency of statins to reduce LDL may not affect rate of incident DM • Rosuvastatin and simvastatin were associated with highest odds of incident DM among statins • Rates of incident DM with each statin varied

Results

No overall rate reported OR compared highdose statins with placebo: Atorvastatin: 1.15 (95% CI 0.90-1.5) Lovastatin: 0.98 (95% CI 0.59-1.61) Pravastatin: 1.07 (95% CI 0.86-1.30) Rosuvastatin: 1.25 (95% CI 0.82-1.90) Simvastatin: 1.21 (95% CI 0.94-1.56)

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Table 2. Meta-analyses: Statin-Associated Incident Diabetes (continued) Meta-analysis

Study Inclusion Criteria

Naci et al. (2013)21

Inclusion (n = 135) Overall OR1 = 1.09 1. Open or double- (95% CrI 1.02-1.16; blinded randomized I2 = 2.8%) controlled trials comparing one statin with another at any dose or with control (placebo, diet, or usual care for adults with, or at risk of developing CVD. 2. Duration of > 4 weeks based on prespecified inclusion and exclusion criteria 3. Trials had > 50 participants per trial arm

Results

Statins Included

Comments

Atorvastatin Fluvastatin Lovastatin Pitavastatin Pravastatin Rosuvastatin Simvastatin

• Analysis to estimate the comparative harm of individual statins • Individual study reported diabetic diagnostic criteria were used • Rosuvastatin was associated with the highest odds of incident DM among statins (OR = 1.16, 95% CI 1.02-1.31; I2 = 0%) in pairwise comparison from the placebo-controlled trials • Rosuvastatin did not achieve statistical significance in the network meta-analysis, even if effect size estimates in both analyses were similar as a result of wider 95% CrI • The network meta-analysis did not demonstrate a statistically detectable difference of incident DM between individual statins

Pairwise meta-analysis from placebo-controlled trials including 113,698 participants.

1

Abbreviations: ADE = Adverse drug event, CI = Confidence interval, CrI = Credible interval, CVD = Cardiovascular disease, DM = Diabetes mellitus, FPG = Fasting plasma glucose, LDL = Low-density lipoprotein, NNH = Number needed to harm, NNT = Number needed to treat, OR = Odds ratio, PRISMSA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses, RCT = Randomized controlled trial, RR = Relative risk, tx = Therapy, WOSCOPS = West of Scotland Coronary Prevention Study. Source: References 14-21.

and an increased RR of incident diabetes with statin use was found (RR = 1.13, 95% CI 1.03-1.24; P = 0.007).15 The included studies used various diabetes diagnostic criteria and the analysis was unable to rule out survival bias. Another meta-analysis, published in 2010 by Sattar et al., investigated 13 published and unpublished statin vs. placebo trials to determine whether any relationship existed between statins and diabetes development.16 Out of 91,140 nondiabetic participants who received a statin, 4,278 developed diabetes during a mean follow-up of four years (OR = 1.09, 95% CI 1.02-1.17) (NNH = 255 with four years’ treatment) with little heterogeneity between

trials. The meta-regression showed that the odds of developing incident diabetes with statins was highest in trials with older participants, but neither baseline BMI nor changes in LDL accounted for residual variation in risk. The study also found that lipophilic (OR = 1.10, 95% CI 0.99-1.22; I² = 0%) and hydrophilic (OR = 1.08, 95% CI 0.98-1.20;I² = 36%) statins were associated with very similar risks.16 Mills et al. conducted a network meta-analysis with 76 randomized trials to evaluate efficacy and safety of statin treatment for CVD. In the safety analysis with 17 trials (n = 111,003), statin treatment increased the odds of

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Clinical Review incident diabetes by 9% (OR 1.09, 95% CI 1.02-1.16; P = 0.008).17 A 2011 meta-analysis by Preiss et al. investigated intensive vs. moderate-dose effects of statins on the development of incident diabetes.18 Five randomized clinical trials were included, with a mean follow-up duration of 4.9 years. The quality of included trials was assessed using nine characteristics and assigning Delphi scores.57 The median Delphi score was nine, indicating that trials with high quality were selected.18 Out of 32,752 participants without diabetes included in this analysis, 2,749 developed diabetes (OR = 1.12, 95% CI 1.04-1.22), or in absolute terms, two additional cases of diabetes per 1,000 patient years for those treated with intensive-dose statin therapy. This translated into NNH of 498 per year. No significant heterogeneity was detected between trials for incident diabetes (χ2 for heterogeneity = 2.59; P = 0.60; I2 = 0%; 95% CI 0%-79%). No evidence for publication bias was observed (P = 0.54).18 To understand the clinical implications from the results of this meta-analysis, it is important to note that patients who received higher doses of statins are most likely to have risk factors for developing diabetes. Also, intensive statin therapy has yet to be clinically well defined. Alberton et al. conducted an indirect comparison meta-analysis for statin-associated adverse events. This analysis used clinical trials similar to the previous network meta-analysis, including 159,458 patients in 72 randomized controlled trials that compared statin-associated adverse events with placebo, standard treatment, or no treatment for CV event prevention.17,19 Overall risk and risk for individual statin-associated incident diabetes were evaluated. Investigators found increased odds of incident diabetes of 9% (OR = 1.09, 95% CI 1.02-1.16), similar to the previous meta-analyses.16,17 A lack of data for atorvastatin, fluvastatin, or lovastatin prevented their individual statin evaluation. No significant association of incident diabetes was found with pravastatin or simvastatin; however, the association with rosuvastatin was significant compared with controls. A recent network meta-analysis of 17 randomized, controlled trials by Navarese et al. evaluated the

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association of statin treatment with either high or moderate doses or placebo with incident diabetes.20 High doses were defined as atorvastatin 80 mg, lovastatin 20 mg to 40 mg, pravastatin 40 mg, rosuvastatin 20 mg, and simvastatin 40 mg. This meta-analysis supported the hypothesis that the rate of incident diabetes may vary with each statin or doses of statins. Compared with placebo, rosuvastatin 20 mg increased the odds of incident diabetes by 25% (OR = 1.25, 95% CI 0.75-2.01), whereas 10 mg increased the odds by only 10% (OR = 1.10, 95% CI 0.78-1.58).20 A most comprehensive network meta-analysis included 135 trials and investigated the tolerability and harm of individual statins.21 This meta-analysis replicated the incident diabetes rates reported by previous metaanalyses.16,17,19 In the placebo-controlled trials with 113,698 participants, the pair-wise comparison showed that statins as a class statistically significantly increased the odds of incident diabetes by 9% (OR = 1.09, 95% credible interval [Crl] 1.02-1.16; I2 = 2.8%). Rosuvastatin was implicated with significantly higher odds of incident diabetes in the pair-wise comparison of the placebo-controlled trials; however, the drug-level network analysis did not achieve statistical significance for any individual statin because of wider 95% CrIs. Overall, in this analysis, simvastatin and pravastatin showed comparatively favorable side effect profiles, particularly at low-to-moderate doses.

Discussion Experimental studies assessed the risk of statin-associated incident diabetes with biomarkers; however, biomarker significance depends on the degree of specificity for a disease process as a whole. Reliance solely on biochemical markers to determine clinical outcomes may lead to discrepancies in trial results.16,36,37,44,45 Limitations of observational studies and post hoc data analyses, such as meta-analyses, have been well recognized. Data synthesis by those analyses are vulnerable to bias that is not easily overcome even by the best statistical adjustments.55,56 First and foremost, incident diabetes was not a prespecified outcome measure in the clinical trials; therefore, statistical power to detect statin-associated incident diabetes is lacking. Also, the trial follow-up

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duration might be insufficient to detect the emergence of incident diabetes and to rule out survival bias. Another important limitation is that criteria for detecting incident diabetes in clinical trials were quite diverse. Uniform criteria for statin-associated incident diabetes have not been developed. Although researchers tested for heterogeneity, this cannot substitute for the validity that only an objective diagnosis could bestow upon a clinical trial.56 Reviewed observational studies and meta-analyses indicated that as a class, statin treatment carries potential risk for incident diabetes. However, clinical significance of the incident rates is unknown as most patients already had risk factors for diabetes. Patients with a higher BMI (> 30 kg/m2), history of hypertension, elevated FPG (> 100 mg/dL), or fasting triglycerides (> 150 mg/dL) at baseline or older age seem to be prone to developing incident diabetes.5,7,13,16,42,43 Given the consensus on the efficacy of statins in secondary prevention of CV events, the benefits continue to outweigh the risk in nondiabetic patients. However, practical relevance of statin-associated incident diabetes should be considered with tailored treatment explored in primary prevention of CV events.

Implications for Clinical Practice First, will continued statin treatment benefit patients who develop statin-associated incident diabetes? Available data suggest that incident diabetes with statin use is calculated to be about 352,000 cases per year.1,16 Compared with CV benefits of statin treatment, the number may look small. However, it may not be trivial, particularly in primary prevention of CVD when statin treatment can be used for decades in relatively low-risk patients.32 Of note, primary prevention benefits of statin treatment have not been clearly proven in type-2 diabetic patients.58,59 Although the current guidelines recommend statin treatment, based on newly emerging evidence, clinicians may need to explore alternative strategies for managing dyslipidemia in healthy patients for primary prevention. Second, are there patient subgroups in whom statin use may need to be revisited? WHI data demonstrated hypercholesterolemic, postmenopausal women without CVD and with a BMI < 25 kg/m2 may be at a higher risk

for statin-associated incident diabetes.7 Also, patients with a higher BMI (> 30 kg/m2), history of hypertension, elevated FPG (> 100 mg/dL), or fasting triglycerides (> 150 mg/dL) at baseline are prone to develop incident diabetes.5,42 Age above 65 years was also suggested as a risk factor.13,16 An atorvastatin 80 mg dose, in patients with more than two risk factors at baseline, was associated with higher rates of incident diabetes.43 Also, Asian patients appear to have increased sensitivity to statins, causing glucose homeostasis disturbances as demonstrated by low doses of either rosuvastatin or atorvastatin, increasing HbA1C and insulin levels while decreasing insulin sensitivity.40,41 Additionally WHI data showed a trend for greater risk of statin-associated incident diabetes in Asian women.7 Limited evidence exists for glycemic control deterioration in diabetic Japanese patients on atorvastatin.60 Also, heart failure patients may not gain as much benefit with statin therapy as expected. The Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) showed that rosuvastatin 10 mg did not significantly decrease CV mortality compared with placebo; however, it did significantly reduce CV hospitalizations.46 As suggested, it appears that patients with more pronounced dyslipidemia, as in FCH, are at lower risk for statin-induced diabetes.48 Also, opinions may differ in the treatment of otherwise healthy hypercholesterolemic men.61 Some clinicians recommend stratifying statin-induced adverse effect risks with tools such as the Cambridge risk score or coronary-artery calcium scan to determine the risk of CVD before prescribing a statin.61,62 Others advocate lifestyle modification over statins as primary prevention.61 Narrowing the selection of target patients will help derive maximum benefit with minimization of adverse effects. Third, is there a dose-relationship with developing incident diabetes? Intensive statin doses might be associated with higher risk than lower doses.13,18,20,42 Intensive doses should be defined based on lipid-lowering potency, as this varies with each statin.12 For primary prevention, use of the lowest effective dose should reduce incident diabetes risk.

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Clinical Review Fourth, are there any differences among statins? Experimental data with biomarkers and a meta-analysis suggested that each statin may behave differently.20,37,38,47 However, clinical data failed to demonstrate clear differences among statins. Potent statins such as atorvastatin, rosuvastatin, or simvastatin have been implicated more in statin-associated incident diabetes. Fifth, should statin treatment be continued in elderly patients (65 years of age or older) who developed statinassociated incident diabetes? The controversial debate on whether dyslipidemia should be managed aggressively in older patients continues.63 Sufficient clinical trials with statin treatment in older patients have not been conducted to support a consensus, especially for primary prevention. A critique of data from a meta-analysis estimated that the NNT per year to prevent CV events was 450, and the NNT to prevent vascular death ranged from 1,250 to 5,000, suggesting a majority of older patients (older than 60 years of age) may not benefit directly despite taking lifelong statin therapy.64,65 Even though recent post hoc trial analyses suggested that older patients still benefit from statin treatment, direct evidence from clinical trials does not exist.66,67 Older patients have an increased risk of CVD; however, some data suggest that the relative risk for coronary heart disease associated with higher cholesterol decreases with age.63 Recent observational studies and a meta-analysis implicated statins with an increased risk of incident diabetes in elderly patients.12,13,16 Potential benefits gained from continuation or initiation of statin treatment may not be clinically relevant, given multiple comorbidities, organ dysfunction, limited physical reserve, or polypharmacy found in frail elderly patients. Clinicians must find a justified balance between clinical relevancy and treatment benefit in elderly patients. Evidence supporting a negative effect of statins on glucose homeostasis was recently addressed in a Food and Drug Administration safety communication requiring that statin labeling now include information about reports of increased blood glucose and HbA1C levels.68 The Canadian Health Products and Food Branch Inspectorate also issued a similar directive this year.69

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Conclusion Current dyslipidemia guidelines recommend treatment with statins. However, the emergence of mixed results in recent available clinical evidence prompted FDA to issue a warning and change statin labeling to include the risk of hyperglycemia reported with the use of statins. Therefore, clinicians need to be aware of and monitor for statin-associated incident diabetes. Current evidence is insufficient to strongly recommend a change in clinical practice, especially for secondary prevention and high-CV risk patients in whom the benefits of statin use may outweigh the risk of incident diabetes. However, the potential for development of incident diabetes should be considered in 1) low-risk and primary prevention patients, especially those started on high-dose statin regimens, 2) patients with more than two risk factors for statin-associated incident diabetes, 3) elderly, 4) hypercholesterolemic, postmenopausal women without CVD and with a BMI < 25 kg/m2, 5) patients with a higher BMI (≥ 30 kg/m2), history of hypertension, elevated FPG (> 100 mg/dL), or triglycerides (> 150 mg/dL) at baseline, and 6) Asian patients. Future studies are required to determine 1) whether statin effects on glucose metabolism are permanent, 2) if there are differences among individual statins and doses, 3) which risk factors in patients prescribed statins make them more or less susceptible for developing incident diabetes, 4) how to manage statin-induced diabetes, and 5) whether patients with statin-induced diabetes have increased risk for CVD morbidity and mortality.

Zoon H. Park, PharmD, BCPS, CGP, is assistant director, Department of Pharmacy Services, Swedish Covenant Hospital, Chicago, Illinois. Alicia Juska, PharmD, BCPS, is PGY1 pharmacy residency program director, Swedish Covenant Hospital. Detelin Dyakov, PharmD, BCPS, is clinical staff pharmacist, Swedish Covenant Hospital. Ramesh V. Patel, PharmD, is senior director, Pharmacy Services and Clinical Research, Swedish Covenant Hospital. For correspondence: Zoon H. Park, PharmD, BCPS, CGP, Swedish Covenant Hospital, 5145 N. California Avenue, Chicago, IL 60625; Phone: 773-989-3810; Fax: 773-506-0085; E-mail: [email protected].

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The Consultant Pharmacist  MAY 2014   Vol. 29, No. 5