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Low prevalence of fibrate use in adults with type 1 and type 2 diabetes and established diabetic retinopathy

  • Justin Morein
    Affiliations
    Division of Endocrinology & Metabolism, Department of Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ont., Canada
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  • Artem Uvarov
    Affiliations
    Department of Epidemiology & Biostatistics, Schulich School of Medicine & Dentistry, Western University, London, Ont., Canada
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  • Tamara Spaic
    Affiliations
    Division of Endocrinology & Metabolism, Department of Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ont., Canada

    St. Joseph's Health Care London, London, Ont., Canada
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  • Jeffrey L. Mahon
    Affiliations
    Division of Endocrinology & Metabolism, Department of Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ont., Canada

    Department of Epidemiology & Biostatistics, Schulich School of Medicine & Dentistry, Western University, London, Ont., Canada

    St. Joseph's Health Care London, London, Ont., Canada
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  • Irene Hramiak
    Affiliations
    Division of Endocrinology & Metabolism, Department of Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ont., Canada

    St. Joseph's Health Care London, London, Ont., Canada
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  • Selina L. Liu
    Correspondence
    Correspondence to Selina L. Liu, MD, St. Joseph's Health Care London, 268 Grosvenor St, London ON Canada N6A 4V2
    Affiliations
    Division of Endocrinology & Metabolism, Department of Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ont., Canada

    St. Joseph's Health Care London, London, Ont., Canada
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Published:January 29, 2021DOI:https://doi.org/10.1016/j.jcjo.2021.01.002
      Diabetic retinopathy (DR) is common, with estimated prevalences of 25% (type 2 diabetes [T2D]) and 77% (type 1 diabetes [T1D]).
      • Yau J.W.
      • Rogers S.L.
      • Kawasaki R.
      • Lamoureux E.L.
      • Kowalski J.W.
      • Bek T.
      • et al.
      Global prevalence and major risk factors of diabetic retinopathy.
      The estimated 10-year cumulative incidence of DR is 67% (T2D not on insulin), 79% (T2D on insulin), and 89% (T1D)
      • Klein R.
      • Klein B.E.
      • Moss S.E.
      • Cruickshanks K.J.
      The Wisconsin Epidemiologic Study of diabetic retinopathy. XIV. Ten-year incidence and progression of diabetic retinopathy.
      and at 25 years is 97% (T1D).
      • Klein R.
      • Knudtson M.D.
      • Lee K.E.
      • Gangnon R.
      • Klein B.E.
      The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XXII the twenty-five-year progression of retinopathy in persons with type 1 diabetes.
      DR comprises 3 processes: (i) nonproliferative DR (microaneurysms, intraretinal hemorrhages, intraretinal microvascular anomalies) and proliferative DR (neovascularization, vitreous hemorrhage, tractional retinal detachment); (ii) diabetic macular edema (ME), from vessel leakage within the macula; and (iii) macular ischemia.
      Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada.
      Because DR may be asymptomatic, routine screening is recommended.
      Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada.
      ,
      • Hooper P.
      • Boucher M.C.
      • Cruess A.
      • Dawson K.G.
      • Delpero W.
      • Greve M.
      • et al.
      Excerpt from the Canadian Ophthalmological Society evidence-based clinical practice guidelines for the management of diabetic retinopathy.
      Early DR identification is important as effective treatments exist to prevent or delay DR-related vision loss: optimal glycemic and blood pressure control, laser photocoagulation, anti-vascular endothelial growth factor therapy, and fenofibrate.
      Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada.
      Evidence from the FIELD
      • Keech A.C.
      • Mitchell P.
      • Summanen P.A.
      • O'Day J.
      • Davis T.M.E.
      • Moffitt M.S.
      • et al.
      Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomized controlled trial.
      and ACCORD-Eye
      The ACCORD Study Group and ACCORD Eye Study Group
      Effects of medical therapies on retinopathy progression in type 2 diabetes.
      studies support fenofibrate use to improve eye outcomes. Thus, Diabetes Canada recommends that “fenofibrate, in addition to statin therapy, may be used in people with T2D to slow the progression of established retinopathy” (grade A level 1A recommendation).
      Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada.
      Although the Canadian Ophthalmological Society does not formally recommend fenofibrate, it notes Diabetes Canada's recommendation for lipid control.
      • Hooper P.
      • Boucher M.C.
      • Cruess A.
      • Dawson K.G.
      • Delpero W.
      • Greve M.
      • et al.
      Excerpt from the Canadian Ophthalmological Society evidence-based clinical practice guidelines for the management of diabetic retinopathy.
      There is a dearth of studies assessing fibrate utilization in DR. We hypothesized that people with DR are underprescribed fenofibrate. The primary study objective was to determine prevalence of fibrate use in DR at our tertiary care centre. The secondary objective was to determine fibrate use predictors. This was a single-centre cross-sectional study at St. Joseph's Healthcare London in London, Canada. Data were extracted in November 2018 from WebDR, a diabetes-specific electronic medical record database in routine clinical use since 2011, housing ∼25,000 unique patient records. Adults aged ≥18 years with T1D or T2D with DR were eligible for inclusion. DR was defined as the presence in WebDR of ≥1 of: retinopathy, ME, clinically significant ME, laser photocoagulation, vitrectomy, or blindness/vision loss, ascertained via patient self-report during routine clinical care and/or optometrist/ophthalmologist report. Fibrate use was defined as inclusion of fenofibrate, bezafibrate, or gemfibrozil in the current medications. Descriptive statistics were compared using Welch's t test or Fisher's exact test as appropriate. Hierarchical logistic regression was performed to determine fibrate use predictors. Estimated odds ratios and 95% confidence intervals were calculated using Firth's correction and the profile likelihood approach to minimize effect of bias caused by the rarity of fibrate use with a 5% level of significance. Statistical analyses were performed using SAS software, Version 9.4 (SAS Institute, Inc., Cary, NC). The study was approved by the Western University Health Sciences Research Ethics Board.
      Of 24,736 patients, 1532 (6.2%) had DR, including 589 (43.9%) with severe DR. Of the 1532, 46 (3.0%) were on a fibrate. Patient characteristics are in Table 1. Factors predictive of fibrate use are in Table 2.
      Table 1Univariate analyses—patient characteristics
      Total

      (n = 1341)
      No Fibrate

      (n = 1301)
      Fibrate

      (n = 40)
      p Value
      Male sex736 (54.9)714 (54.9)22 (55.0)0.988
      Age (y), mean (SD)63.0 (15.5)62.8 (15.6)69.2 (13.1)0.004
      p < 0.05 (Welch's t test or Fisher's exact test).
      Type 1 diabetes506 (37.7)502 (38.6)4 (10.0)<0.001
      p < 0.05 (Welch's t test or Fisher's exact test).
      Duration of diabetes (y), mean, (SD)29.7 (12.8)29.7 (12.8)28.4 (10.9)0.450
      Followed by family physician diabetologist296 (22.1)282 (21.7)14 (35.0)0.053
      HbA1c (%), mean (SD)8.2 (2.6)8.2 (2.6)8.0 (1.7)0.500
      LDL-cholesterol (mmol/L), mean (SD)1.90 (0.82)1.90 (0.82)1.83 (0.94)0.640
      Triglyceride (mmol/L), mean (SD)1.61 (1.11)1.59 (1.10)2.30 (1.02)<0.001
      p < 0.05 (Welch's t test or Fisher's exact test).
      HDL-cholesterol (mmol/L), mean (SD)1.32 (0.46)1.33 (0.46)1.01 (0.32)<0.001
      p < 0.05 (Welch's t test or Fisher's exact test).
      Nonproliferative DR375 (28.0)358 (27.5)17 (42.5)0.120
      Severe DR
      Severe DR (one or more of proliferative DR, clinically significant macular edema, prior laser photocoagulation or vitrectomy or vision loss).
      589 (43.9)574 (44.1)15 (37.5)
      DR/macular edema not otherwise specified377 (28.1)369 (28.4)8 (20.0)
      Hypertension924 (68.9)886 (68.1)38 (95.0)<0.001
      p < 0.05 (Welch's t test or Fisher's exact test).
      Dyslipidemia (other than hypertriglyceridemia)983 (73.3)946 (72.7)37 (92.5)0.003
      p < 0.05 (Welch's t test or Fisher's exact test).
      Coronary artery disease333 (24.8)319 (24.5)14 (35.0)0.14
      Cerebrovascular disease145 (10.8)138 (10.6)7 (17.5)0.19
      Chronic kidney disease504 (37.6)486 (37.4)18 (45.0)0.053
      End-stage renal disease or renal transplant128 (9.5)126 (9.7)2 (5.0)
      Peripheral vascular disease102 (7.6)95 (7.3)7 (17.5)0.028
      p < 0.05 (Welch's t test or Fisher's exact test).
      Statin use1023 (76.3)993 (76.3)30 (75.0)0.850
      ACE-I or ARB use946 (70.5)911 (70.0)35 (87.5)0.020
      p < 0.05 (Welch's t test or Fisher's exact test).
      ASA use599 (44.7)582 (44.7)17 (42.5)0.087
      Intensive insulin therapy
      Multiple daily insulin injections or subcutaneous insulin pump therapy.
      848 (63.2)828 (63.6)20 (50.0)0.070
      Basal insulin only171 (12.8)166 (12.8)5 (12.5)
      Split mixed insulin154 (11.5)144 (11.1)10 (25.0)
      SD, standard deviation; HbA1c, glycated haemoglobin; LDL, low-density lipoprotein; HDL, high-density lipoprotein; DR, diabetic retinopathy; ACE-I, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; ASA, acetylsalicylic acid.
      Data are presented as n, % unless otherwise specified.
      low asterisk Severe DR (one or more of proliferative DR, clinically significant macular edema, prior laser photocoagulation or vitrectomy or vision loss).
      Multiple daily insulin injections or subcutaneous insulin pump therapy.
      p < 0.05 (Welch's t test or Fisher's exact test).
      Table 2Multivariate analyses—factors independently associated with fibrate use
      Odds Ratio (95% CI)
      Dyslipidemia (other than hypertriglyceridemia)3.53 (1.26–13.48)
      p < 0.05.
      Type 2 diabetes3.30 (1.03–12.57)
      p < 0.05.
      ACE-I/ARB use2.79 (1.17–8.05)
      p < 0.05.
      Serum triglyceride (per mmol/L)1.36 (1.11–1.64)
      p < 0.05.
      Severe DR
      Versus nonproliferative diabetic retinopathy (reference).
      ,
      Severe DR (one or more of proliferative DR, clinically significant macular edema, prior laser photocoagulation, vitrectomy or vision loss).
      0.47 (0.22–0.95)
      p < 0.05.
      DR or macular edema not otherwise specified
      Versus nonproliferative diabetic retinopathy (reference).
      0.41 (0.16–0.96)
      p < 0.05.
      Male sex1.07 (0.56–2.08)
      Age (per year)1.01 (0.98–1.04)
      Duration of diabetes (per year)1.01 (0.98–1.04)
      HbA1C (per %)1.02 (0.75–1.06)
      Serum LDL cholesterol (per mmol/L)0.80 (0.50–1.23)
      ASA use0.59 (0.30–1.15)
      Statin use0.45 (0.20–1.07)
      CI, confidence interval; ACE-I, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; DR, diabetic retinopathy; HbA1c, glycated haemoglobin; LDL, low-density lipoprotein; ASA, acetylsalicylic acid.
      low asterisk p < 0.05.
      Versus nonproliferative diabetic retinopathy (reference).
      Severe DR (one or more of proliferative DR, clinically significant macular edema, prior laser photocoagulation, vitrectomy or vision loss).
      To our knowledge, this is the first study examining fibrate use in DR. This study's strength is the inclusion of detailed real-world clinical data of patients with a full range of DR severity, though as a cross-sectional study, it is limited by potential misclassification and ascertainment biases caused by reliance on self-reported fibrate use. Other limitations are: assessment of current (vs ever) fibrate use, absence of indication for fibrate (dyslipidemia or DR), and absence of formal validation of DR (likely contributing to fewer than expected patients with DR). We attempted to minimize selection bias by including all eligible adults with DR in WebDR, though the single-centre design precludes generalizability.
      Despite strong evidence supporting fenofibrate to delay DR progression, fibrate use in DR at our centre is extremely low. This observation, if widely confirmed elsewhere, highlights an important care gap in DR management that should be addressed.

      Acknowledgements

      The authors acknowledge the assistance of Ms. Selam Mequanint, WebDR Database Manager, Centre for Studies in Family Medicine, Western University, London, Ontario, Canada.

      Footnotes and Disclosure

      The authors have no proprietary or commercial interest in any materials discussed in this article.

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