Statin therapy and cataract in type 2 diabetes

Diabetes & Metabolism 37 (2011) 139–143

Original article

Statin therapy and cataract in type 2 diabetes M.P. Hermans a,∗ , S.A. Ahn b , M.F. Rousseau b a

Service d’endocrinologie et nutrition, cliniques universitaires St.-Luc, avenue Hippocrate 10, 1200 Bruxelles, Belgium b Département de cardiologie, cliniques universitaires St.-Luc, université catholique de Louvain, avenue Hippocrate 10, 1200 Brussels, Belgium Received 3 June 2010; received in revised form 5 September 2010; accepted 6 September 2010 Available online 8 December 2010

Abstract Background. – It was recently reported that the prolonged use of statins may predispose to incident cataract in the general population. Cataract is a frequent comorbidity of diabetes, and statins are widely prescribed in patients with type 2 diabetes (T2D) both for primary and secondary cardiovascular prevention. For this reason, this study aimed to assess whether or not the use of statins was associated with an increased prevalence of cataract in such a high-risk population and, conversely, whether or not there was greater usage of statins, or any other lipid-lowering drugs, in T2D patients with cataract. Patients and methods. – This was a cross-sectional analysis of 780 T2D outpatients, with a mean age (± 1 SD) of 64 ± 12 years and diabetes duration of 13 ± 9 years. Diabetic retinopathy (DR) was found in 23%, and cataract was diagnosed in 16.8% (n = 131). Age and diabetes duration of the patients with cataract were significantly higher than those of patients without cataract (n = 649): 75 ± 9 vs 62 ± 11 years, and 20 ± 11 vs 12 ± 8 years, respectively (both P < 0.0001). HbA1c was non-significantly higher in the cataract group: 7.75 ± 1.55% vs 7.57 ± 1.49% (NS). Results. – Statins, fibrates and/or ezetimibe use did not differ between patients with and without cataract, nor was cataract prevalence higher in statin users (n = 435) vs non-users (n = 345). Statin use in patients with cataract was not higher than in cataract-free subgroups with mean age (n = 218) or with both mean age and diabetes duration (n = 161) similar to those of patients with cataract. Conclusion. – In this cross-sectional analysis of a large diabetic population at very high risk of both DR and cataract, chronic therapy with statins was not cataractogenic, and the presence of cataract was not associated with more statin or other lipid-lowering drug use. This suggests that the benefits of statin therapy in T2D may far outweigh any potential ocular drawbacks as a side effect which, in any case, were not supported by our findings. © 2010 Elsevier Masson SAS. All rights reserved. Keywords: Statin; Fibrate; Ezetimibe; Side-effects; Cataract; Retinopathy; Type 2 diabetes

Résumé Traitement par statine et cataracte dans le diabète de type 2. But. – Il a été récemment rapporté que l’usage prolongé de statines pourrait prédisposer à la survenue de cataractes dans la population générale. La cataracte est une co-morbidité fréquente du diabète, et la prescription de statines largement recommandée aux patients diabétiques de type 2 (DT2), tant en prévention cardiovasculaire primaire que secondaire. Nous avons analysé si l’utilisation de statines était associée à une prévalence accrue de cataracte dans cette population à haut risque, et inversement, si les patients DT2 souffrant de cataracte étaient plus souvent traités par statines ou par d’autres agents hypolipémiants. Méthodes. – Analyse transversale de 780 patients ambulatoires avec DT2; l’âge moyen (± 1 DS) était de 64 ± 12 ans, et la durée du diabète de 13 ± 9 ans. Une rétinopathie diabétique (RD) était présente chez 23 % des patients. Une cataracte était diagnostiquée dans 16,8 % de la cohorte (n = 131). L’âge et la durée du diabète des patients avec cataracte étaient significativement supérieurs à ceux des patients sans cataracte (n = 649), respectivement 75 ± 9 versus 62 ± 11 ans, et 20 ± 11 versus 12 ± 8 ans (P à chaque fois inférieur à 0,0001). L’HbA1c était non-significativement plus élevée dans le groupe avec cataracte: 7,75 ± 1,55 % versus 7,57 ± 1,49 %.

∗

Corresponding author. Tel.: +32 0 2 764 54 75; fax: +32 0 2 764 54 18. E-mail address: [email protected] (M.P. Hermans).

1262-3636/$ – see front matter © 2010 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.diabet.2010.09.005

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Résultats. – L’utilisation de statines, de fibrates et/ou d’ézétimibe n’était pas différente entre les patients avec ou sans cataracte. La prévalence de cataracte n’était pas plus élevée chez les utilisateurs de statines (n = 435) versus les non-utilisateurs (n = 345). La prescription de statines chez les patients avec cataracte n’était pas supérieure à celle de sous-groupes de patients sans cataracte d’âge moyen similaire (n = 218), ou à la fois d’âge et de durée de diabète similaires (n = 161) à ceux des patients avec cataracte. Conclusions. – Dans cette étude transversale d’une population de patients avec DT2 à haut risque à la fois de RD et de cataracte, l’usage chronique de statines ne paraît pas cataractogène, et la présence de cataracte n’est pas associée à une utilisation accrue de statines ou d’autres hypolipémiants. Ces observations suggèrent que les bénéfices d’un traitement par statines chez des patients DT2 dépassent largement le risque théorique d’effet délétère sur le cristallin, qui n’est d’ailleurs pas étayé dans cette étude. © 2010 Elsevier Masson SAS. Tous droits réservés. Mots clés : Statine ; Fibrate ; Ézétimibe ; Effets secondaires ; Cataracte ; Rétinopathie ; Diabète de type 2

1. Introduction

2. Patients and methods

Lens opacification leading to cataract is a frequent comorbidity of diabetes, as adults with type 2 diabetes (T2D) are five times more often affected than the general population (60% vs 12%). While juvenile diabetic cataract is rare, adult-onset, mostly cortical cataract in T2D patients is similar to age-related cataract in the general population, except for an earlier onset and greater prevalence [1,2]. Major risk factors for cataract in T2D include hyperglycaemia, diabetes duration and the presence of diabetic retinopathy (DR), although specific risk factors or markers may differ according to cataract subtype. Smoking, for example, is associated with nuclear opacities, whereas ultraviolet radiation increases the risk for cortical opacities, and high blood pressure (BP) and corticosteroids raise the odds for subcapsular cataract. Various pathophysiological mechanisms are involved in cataract formation, including osmosis-driven lens overhydration triggered by the polyol pathway (mostly ascribed to juvenile cataract), lens protein glycation and an excess of free radicals, with the latter being particularly associated with the nuclear subset of age-related cataract [3–5]. The presence of statins in the human lens following lipidlowering therapy has been demonstrated, although the effects of statins on cataract genesis/protection are poorly documented and widely debated [6,7]. Klein et al. [3] reported an inverse association between statin use and nuclear cataract incidence, but not cortical or posterior subcapsular cataract, in a general US population. Recently, an increased risk of all-type cataract was suggested in a group of new statin users of both genders, who were relatively young at baseline and mostly without diabetes, followed over a 6-year observational period in UK-based general practices [8]. T2D is an ideal condition in which to assess the potential beneficial/detrimental effects of statins or other lipid-lowering drugs (LLD) on cataract, as T2D patients have a high prevalence of atherogenic dyslipidaemia as part of the associated metabolic syndrome, and also exhibit an increased incidence/prevalence of both hyperglycaemia- and age-related cataract(s). Also, most T2D patients are de facto eligible for low-density lipoprotein (LDL)-lowering therapy with statins as per the current standards of care [9]. Thus, the aim of the present study was to assess whether or not the use of statins is associated with an increased prevalence of cataract and, conversely, whether or not T2D patients with cataract are more often using a statin and/or other LLD.

This was a cross-sectional analysis of medical records from 780 consecutive adult (aged > 18 years; 84% Caucasian) outpatients with T2D, defined according to the Expert Committee on the Diagnosis and Classification of Diabetes [10]. The diagnosis of cataract (cortical, nuclear and/or subcapsular) was established by an ophthalmologist during annual or biannual retinal checkups. Patients receiving chronic therapy with systemic corticosteroids were excluded from the analysis. In patients with previous lens surgery for cataract, lens extraction was considered a surrogate for cataract prevalence. Cataract was diagnosed in 16.8% of the total study cohort (n = 131; Catar(+) group). DR was diagnosed following mydriatic fundus examination, with conventional fluorescein (fluo) angiography if deemed necessary by an in-house ophthalmologist. DR was classified as mild, moderate or severe and as non-proliferative or proliferative. Mean age and diabetes duration of patients in the Catar(+) group were significantly higher than those of patients without cataract (n = 649): 75 ± 9 vs 62 ± 11 years, and 20 ± 11 vs 12 ± 8 years, respectively (both P < 0.0001). Age and diabetes duration are major confounders of cataract incidence, as both increase the likelihood of statin treatment for primary, secondary or equivalent-secondary cardiovascular disease (CVD) prevention. For this reason, Catar(+) patients were compared with a cataract-free group [Catar(–), n = 218], representing the upper tertile of the age distribution of those without cataract (n = 216), plus two adjacent patients from the 66th percentile for rounding. The following parameters were recorded: age; gender; known diabetes duration; family history (diabetes, CVD); CVD medications; and body mass index (BMI). The presence of the metabolic syndrome (MetS) was defined according to American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) criteria [11]. Hypertension was defined as systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg and/or treatment with BP-lowering drug(s) for high BP. Coronary artery disease (CAD) was defined as a medical history of myocardial infarction, angioplasty, stents, revascularization surgery and/or significant coronary stenosis confirmed by angiography. Peripheral artery disease (PAD) was defined as a medical history of lower-limb claudication and/or ischaemic diabetic foot, angioplasty, stents, revascularization surgery and/or significant lower-limb artery stenosis, confirmed by Doppler ultrasonography and/or angiography. Stroke was defined according to UK Prospective Diabetes Study (UKPDS) criteria: any neurologi-

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cal deficit lasting ≥ 1 month, with no distinction made between ischaemic, embolic and haemorrhagic strokes [12]. In patients with multiple CVD events, only the first was considered in the prevalence data. The following biological variables were also measured: HbA1c (measured by chromatography; normal range: 4–6%); fasting lipids; apolipoproteins A-I and B100 (with LDL cholesterol [LDL-C] calculated by Friedewald’s formula, and non-high-density lipoprotein (HDL)-C calculated by subtracting HDL-C from total C); high-sensitivity C-reactive protein (hs CRP); fibrinogen; serum urate; serum cystatin C; plasma homocysteine; and albuminuria. Normo-, micro- and macroalbuminuria were defined as urinary albumin excretion < 30 (normoalbuminuria), 30–299 (microalbuminuria) and ≥ 300 (macroalbuminuria) ␮g.mg creatinine−1 . Glomerular filtration rate was estimated (eGFR) using the Modified Diet in Renal Disease (MDRD) formula [13]. The computer-based homoeostasis model assessment (HOMA) model (see www.dtu.ox.ac.uk) was used to assess insulin sensitivity, ␤-cell function, and the hyperbolic product and its loss rate, as previously described [14–18]. The study was performed in accordance to the World Health Organization’s standards of Good Clinical Practice. 3. Statistical analyses Results were presented as means ± 1 standard deviation (SD) or as proportions. The significance of differences between means was assessed by Student’s t test or by Welch’s test for datasets with significant differences in SD, and by Fisher’s exact test for differences in proportions (using GraphPad InStatTM software). Results were considered significant or non-significant (NS) for P < or ≥ 0.05, respectively. 4. Results The mean age of our total T2D cohort (n = 780) was 64 ± 12 years, with a diabetes duration of 13 ± 9 years. The MetS was present in 78%, and a history of hypertension in 84%. Mean HbA1c was 7.6 ± 1.5%, total C was 176 ± 40 mg.dL−1 , LDLC was 97 ± 34 mg.dL−1 , HDL-C was 47 ± 14 mg.dL−1 and triglycerides were 169 ± 119 mg.dL−1 . LLD were prescribed to 67% as statins (56%), fibrates (21%) and/or ezetimibe (3%). In statin users, pravastatin was being used by 4%, simvastatin by 54%, atorvastatin by 22% and rosuvastatin by 20%. Macroangiopathy was present in 32% as CAD (23%), PAD (9%) and/or stroke (8%). With microangiopathy, DR was diagnosed in 23% (n = 182), of whom 21% were non-proliferative (n = 163) and 2% (n = 19) were proliferative. Lower-limb diabetic neuropathy was documented in 26%. Age and diabetes duration are major confounders for cataract incidence, as they increase the odds of being treated with statins for primary, secondary or equivalent-secondary CVD prevention. On comparing Catar(+) patients with cataract-free Catar(–) subjects of similar mean age (n = 218; Table 1), there were no significant differences in smoking history, BMI, insulin sensitivity, hypertension, MetS prevalence, BP values or eGFR. There were, however, significant differences between the groups in

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Table 1 Patients’ characteristics. No cataract

Cataract

P

n Age (years) Males:females (%) Diabetes duration (years) Smokinga BMI (kg.m−2 ) HOMA S (%) Metabolic syndromeb (%) Hypertension (%) Systolic BP (mmHg) Diastolic BP (mmHg) Retinopathy (%) Background (%) Proliferative (%)

218 75 (6) 62:38 16 (10) 51 - 40 - 9 28.5 (5.5) 59 (37) 80 91 143 (20) 77 (10) 25 23 2

131 75 (9) 57:43 20 (11) 51 - 40 - 9 28.1 (5.3) 56 (31) 81 92 144 (21) 77 (11) 42 38 5

∼ ∼ NS 0.0006 NS NS NS NS NS NS NS 0.0009 0.0070 NS

Peripheral polyneuropathy (%) Creatinine (mg.dl−1 ) eGFRc (ml.min−1 1.73 m2 ) Albuminuria (alb.) (␮g.mg creatinine−1 ) Normo- vs. micro-/macro-alb. (%) IIEF-5 erectile function (score/25)

27 1.12 (0.46) 70 (23) 72 (211) 67–33 11 (8)

43 1.25 (0.79) 66 (27) 149 (305) 49–51 8 (8)

0.0022 NS NS 0.0116 0.0007 0.0099

Results are expressed as means (1 SD) or proportions (%); BMI: body mass (Quetelet’s) index; BP: blood pressure; eGFR: estimated glomerular filtration rate; HOMA: homeostatic model assessment; HOMA-S: insulin sensitivity; IIEF-5: International Index of Erectile Function 5-items questionnaire; NS: non significant. a Never - former - current smokers. b NCEP ATP III definition. c Modified diet in renal disease (MDRD) formula.

diabetes duration [longer by a mean of 4 years in Catar(+)], and in DR and polyneuropathy prevalence [1.7 and 1.6 times higher, respectively, in Catar(+)]. The degree and prevalence of albuminuria were also higher in the Catar(+). HbA1c was non-significantly higher (by a mean of 0.3%) in Catar(+): 7.75 ± 1.55% vs 7.57 ± 1.49% in Catar(–). Men with cataract also scored lower (by a mean of 3 points) on the five-item version of the International Index of Erectile Function (IIEF-5) questionnaire. For glucose-lowering therapies, 56%, 47%, 5% and 47% of the Catar(–) group were being treated with metformin, ␤-cell stimulant, glitazone and/or insulin, respectively, vs 54%, 42%, 8% and 58% of Catar(+) patients (NS except for insulin, which was P = 0.0364; Table 1). HOMA for ␤-cell function (HOMA-B) was higher in the Catar(–): 61 ± 41% vs 53 ± 33% in the Catar(+) (P = 0.0465), as was also (but not significantly) the hyperbolic product (BxS): 29 ± 17% vs 26 ± 16% in Catar(+) (NS). The BxS loss rate was significantly lower in the Catar(–): 1.05 ± 0.28%/year vs 1.13 ± 0.29%/year in the Catar(+) (P = 0.0112). Neither lipid values nor systemic CVD risk biomarkers (fibrinogen, urate, cystatin C and homocysteine) differed significantly between groups, except for hs CRP, which was higher by a mean of 55% in the Catar(+) (Table 2). LLD use in the entire cohort was analyzed according to cataract status and ongoing statin therapy. No significant differences were found in statin, fibrate or ezetimibe use between the Catar(–) and Catar(+) groups (Fig. 1, left). Intraclass distributions of statin use in the Catar(–) vs Catar(+) groups were: fluvastatin: 2% vs 0%; pravastatin: 6% vs 2%; simvastatin: 47%

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Table 2 Laboratory values. No cataract

Cataract

P

n HbA1c (%)

218 7.45 (1.25)

131 7.75 (1.55)

∼ NS

Cholesterol (mg.dl−1 ) LDL-C (mg.dl−1 ) Non-HDL-C (mg.dl−1 ) HDL-C (mg.dl−1 ) Apolipoprotein A-I (mg.dl−1 ) Apolipoprotein B100 (mg.dl−1 ) Triglycerides hsCRP (mg.dl−1 ) Fibrinogen (mg.dl−1 ) Uric acid (mg.l−1 ) Cystatin C (mg.dl−1 ) Homocysteine (␮mol.l−1 )

175 (43) 94 (35) 127 (41) 48 (13) 151 (30) 90 (27) 170 (110) 0.31 (0.42) 331 (85) 5.7 (1.6) 0.96 (0.36) 14.2 (5.7)

175 (35) 95 (29) 126 (35) 49 (14) 154 (29) 87 (24) 155 (109) 0.48 (0.85) 330 (70) 5.6 (1.8) 1.03 (0.37) 15.3 (5.5)

NS NS NS NS NS NS NS 0.0340 NS NS NS NS

Results expressed as means (1 SD); C: cholesterol; hsCRP: high-sensitivity Creactive protein; HDL: high density lipoprotein; LDL: low-density lipoprotein; NS: non significant.

vs 55%; atorvastatin: 22% vs 25%; and rosuvastatin: 23% vs 18% (all NS). On analyzing the cohort by statin therapy, cataract prevalence was non-significantly lower—by an absolute 4%—in statin users (Fig. 1, right). LLD use was also assessed in Catar(–) subgroups of those with comparable mean age (n =218) or with both comparable age and diabetes duration (n = 161). In the agecomparable subgroup, statin use was significantly higher in the Catar(–) vs Catar(+): 63% vs 51%, respectively (P = 0.0327), whereas fibrate and ezetimibe use did not differ between these groups. Also, LLD use did not differ between the age- and diabetes duration-comparable Catar(–) vs Catar(+): 58%, 22% and 3% vs 51%, 22% and 4% for statin, fibrate and ezetimibe use, respectively (data not shown). 5. Discussion This cross-sectional study of a large cohort of T2D patients failed to suggest any association between statin therapy and the presence of cataract. In addition, the type of statin used did

Fig. 1. Use of lipid-lowering drugs (LLD) in 780 type 2 diabetic (T2D) patients without (n = 649) and with (n = 131) cataract (all non-significant, NS) (left); and prevalence of cataract in T2D patients treated with (n = 435) and without (n = 345) a statin drug (right).

not differ between patients with and without cataract. In fact, in the age-comparable cataract-free subgroup, statin use was significantly higher than in patients with cataract. Such an anticataractogenic association with statins may be a reflection of beneficial pleiotropic effects with statins such as antioxidant activities [19]. As expected, significant associations were found between cataract prevalence and age, diabetes duration, DR, polyneuropathy, erectile dysfunction and/or albuminuria, which is in keeping with the present paradigm of shared underlying risk factors for cataract, diabetic eye disease and microangiopathy in non-ocular target organs [1–5,20,21]. However, conflicting associations between statin use and cataract have been reported, albeit in mostly non-diabetic populations [3,8,22,23]. Patients with cataract had longer diabetes duration and nonsignificantly higher HbA1c , a combination likely to have brought about a greater risk of hyperglycaemia over time. This may partly explain the more frequent end-organ damage seen in patients with cataract, who also presented with significantly higher prevalences of DR, albuminuria, polyneuropathy and erectile dysfunction. In addition, residual ␤-cell function was lower in patients with cataract, who also had significantly lower hyperbolic product, both of which are likely to raise HbA1c and, consequently, prompt the initiation of aggressive glucoselowering therapies. More frequent use of exogenous insulin in cataract patients may have contributed to reducing the discrepancy in current metabolic control between groups. Otherwise, there were no differences in inflammatory or lipid markers between groups, except for a significantly higher hs CRP level observed in T2D patients with cataract, as has been previously reported for age-related cataract in the general population [4]. The findings of our present study in T2D adults do not support an association between the use of statins and presence of cataract, nor do they demonstrate a different pattern of distribution of currently used LLD in T2D patients with or without cataract. Curiously, however, Hippisley-Cox and Coupland [8] mentioned that statin use was linked to cataract risk, and cited a report by Klein et al. [3] in which the sole significant difference between statin users and non-users was a lower odds ratio for developing nuclear cataracts. Furthermore, their comparison of statin users and non-users did not adjust for the plausible likelihood of unequal distribution/exposure to major risk factors for newonset cataract at either baseline or during the observation period. Thus, comorbidities associated with impaired fasting glucose, impaired glucose tolerance, the MetS, T2D or an age-related increase in CVD all had the potential to promote new-onset statin therapy as well as to contribute to cataract incidence. The overall prevalence of documented cataract in the present study was low, despite the fact that most of our patients were elderly and, therefore, had substantial exposure to hyperglycaemia over their mean diabetes duration. Other than biases due to gross misdiagnoses and markedly reduced life expectancy associated with cataract affecting the cross-sectional demographics, both of which are unlikely or implausible scenarios, such low prevalences of documented cataract in the medical record may arise, in part, from less extensively reported findings of subclinical lens opacities in an older population referred

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by endocrinologists who are focused on DR or maculopathy screening and treatment. However, the present study has several limitations related to its cross-sectional design, heterogeneity of the statins prescribed and/or statin exposures, lack of data on the time intervals between statin prescription and cataract diagnosis or vice versa, and the restricted applicability of these observations to a Caucasian T2D population. In addition, the retrospective diagnosis of cataract was based on ophthalmologists’ records, and not systematically diagnosed according to a protocol-defined, gold standard classification. This may also have contributed to the relatively low cataract prevalence in spite of the mean age of the cohort [20]. Furthermore, no subanalyses were performed between cataract subtypes and statin use although, based on the demographics of our T2D cohort, the majority of patients most likely had cortical subtypes of lens opacities [21]. Finally, the size of our cohort did not allow adjusting for other, non-agerelated risk factors for cataract such as previous steroid use, occupation and myopia. T2D is an ideal condition for assessing the potentially detrimental and beneficial effects of statins on cataract, as the current guidelines recommend prescribing a statin in most cases for primary and secondary CVD prevention. Also, T2D patients have high incidences and prevalences of both hyperglycaemiaand age-related cataracts. Nevertheless, our present data do not demonstrate an association between statins and cataract. Thus, from this large cross-sectional analysis of a diabetic population at high risk for both DR and cataract, it is possible to conclude that chronic therapy with statins is not cataractogenic, and that the presence of cataract is not associated with greater use of statins or any other LLD. Conflict of interest statement The authors report no conflict of interest. References [1] Massin P, Angioi-Duprez K, Bacin F, Cathelineau B, Cathelineau G, Chaine G, et al. Detection, monitoring and treatment of diabetic retinopathy. Recommendations of ALFEDIAM. Committee of above-mentioned experts and validated by the board of directors and scientific board of ALFEDIAM. Diabetes Metab 1996;22:203–9. [2] Massin P. Oeil et diabète. In: Grimaldi A, editor. Traité de diabétologie. Paris: Médecine-Sciences Flammarion; 2005. p. 536–55. [3] Klein BE, Klein R, Lee KE, Grady LM. Statin use and incident nuclear cataract. JAMA 2006;295:2752–8.

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