Disertasi

Efek Fenofibrat Oral pada Ketebalan Retina dan Volume Makula: Kajian terhadap Disfungsi Endotel Vaskular Retina, Inflamasi dan Angiogenesis pada Retinopati Diabetik dengan Dislipidemia. = Effects of Oral Fenofibrate on Retinal Thickness and Macular Volume: Assessments on Retinal Endothelial Vascular Dysfunction, Inflammation, and Angiogenesis in Diabetic Retinopathy with Dyslipidemia.

Retinopati diabetik (DR) merupakan komplikasi mikrovaskular diabetes melitus (DM). Fenofibrat oral dapat mencegah progresivitas DR dengan mekanisme pengaturan kadar lipid (lipid-related) dan mekanisme lain (nonlipid-related), antara lain dengan mencegah disfungsi endotel, mengurangi inflamasi, dan angiogenesis. Penelitian ini bertujuan mengetahui efek fenofibrat oral terhadap ketebalan makula sentral (CMT) dan volume makula, serta pengaruhnya pada kadar penanda biologis serum disfungsi endotel (eNOS), inflamasi (VCAM-1), dan angiogenesis (VEGF) pada penyandang DR dengan dislipidemia. Penelitian prospektif ini menggunakan disain uji klinis acak tersamar ganda dengan membagi subjek menjadi kelompok intervensi (simvastatin dan fenofibrat) dan kontrol (simvastatin dan plasebo). Penelitian berlangsung sejak Nopember 2016 hingga Oktober 2017, di Klinik Vitreo-retina, Departemen Medik Mata–RSCM Kirana, melibatkan 60 mata dari 30 pasien penyandang DR non-proliferatif (NPDR) dengan dislipidemia. Penelitian pada tiap subjek dilakukan selama tiga bulan dengan evaluasi klinis, foto fundus, dan spectral domain optical coherence tomography (SD-OCT) makula tiap bulan. Pengukuran kadar eNOS, VCAM-1, dan VEGF, serta HbA1c dan profil lipid dilakukan sebelum dan setelah tiga bulan pengobatan. Sebelum intervensi, pada kedua kelompok tidak didapatkan perbedaan karakteristik demografik, klinik, dan penanda biologis serum. Tidak didapatkan perbedaan bermakna pada CMT kelompok simvastatin+fenofibrat (248,0 ± 40,4µm) dibandingkan kelompok simvastatin+plasebo (265,8 ± 40,8 µm), namun CMT lebih rendah secara bermakna pada bulan ke-1 pada kelompok simvastatin+fenofibrat. Pada subjek dengan edema makula diabetik (DME) pemberian simvastatin+fenofibrat setelah tiga bulan menunjukkan CMT lebih rendah secara bermakna. Volume makula setelah tiga bulan pemberian obat 10086 ± 886,4 µm 3 pada kelompok simvastatin+fenofibrat dan 10307 ± 1058,6 µm 3 pada simvastatin+plasebo. Perbedaan tersebut tidak bermakna, namun pada subjek dengan regulasi glukosa darah yang baik (HbA1c ≤ 7%) didapatkan volume makula lebih rendah pada bulan ke-2. Kadar penanda biologis serum setelah tiga bulan pemberian obat menunjukkan rerata kadar eNOS dan median VEGF sebesar 3878,8 ± 873,33 pg/mL dan 242,8 (86 - 1123,3) pg/mL pada kelompok simvastatin+fenofibrat, dibandingkan 4031,2 ± 742,56 pg/mL dan 370 (134,8 - 810,6) pg/mL pada kelompok simvastatin+plasebo, yang tidak berbeda bermakna, namun penurunan kadar VCAM-1 serum lebih besar secara bermakna pada kelompok simvastatin+fenofibrat (50,7 pg/mL, 32,5 - 223,4 pg/mL vs. 40,4 pg/mL, 27,9 - 94,2 pg/mL). Pada subjek dengan kontrol glukosa darah ketat (HbA1c ≤ 6,5%) kadar VEGF 128,7 (114,5 - 145,2) pg/mL, lebih rendah secara bermakna dibandingkan 423 (86 - 1233,3) pg/mL pada subjek dengan HbA1c > 6,5%. Disimpulkan pemberian simvastatin+fenofibrat selama tiga bulan pada subjek DR dengan dislipidemia secara umum tidak menurunkan CMT dan volume makula, namun menurunkan CMT khusus pada subjek DR dengan DME. Pemberian simvastatin+fenofibrat pada subjek DR tidak mencegah penurunan kadar eNOS, peningkatan kadar VCAM-1 dan VEGF, namun pengendalian gula darah yang baik dapat mencegah peningkatan kadar VEGF. Simvastatin+fenofibrat dapat dipertimbangkan sebagai terapi ajuvan pada penyandang DR dengan DME yang disertai dislipidemia. Pengontrolan glukosa yang baik merupakan manajemen utama pada DR.
Kata kunci: diabetes melitus, dislipidemia, fenofibrat, retinopati diabetik.


Diabetic retinopathy (DR) is a microvascular complication of diabetes mellitus (DM) due to structural and biochemical changes. Previous studies showed that oral fenofibrate prevents the progression of DR through lipid-regulating mechanism and by other mechanisms (nonlipid-related), including preventing endothelial dysfunction, and reducing inflammation and angiogenesis. This study aims to investigate the effects of oral fenofibrate on central macular thickness (CMT) and macular volume, as well as on specific biomarkers of endothelial dysfunction (eNOS), inflammation (VCAM-1), and angiogenesis (VEGF) in DR individuals with dyslipidemia. This is a prospective, double-blind randomized clinical trial, with the subjects divided into intervention group (simvastatin and fenofibrate) and control group (simvastatin and placebo). This study was conducted from November 2016 to October 2017 at the Vitreo- retina Clinic, Department of Ophthalmology–RSCM Kirana, involving 60 eyes from 30 non-proliferative DR patients (NPDR) with dyslipidemia that met inclusion criteria. Each subject was observed for three months, with monthly clinical evaluation, fundus photo, and macular spectral domain optical coherence tomography (SD-OCT). Serum eNOS, VCAM-1, and VEGF biomarkers, as well as HbA1c and lipid profile examinations, were performed before and after three months of intervention. Before intervention, there were no differences in demographic and clinical characteristics, and in serum biomarker levels between the two groups. After three months of treatment, there was no significant difference between CMT in the simvastatin+fenofibrate group and the simvastatin+placebo group (248 ± 40.4 µm vs. 265.8 ± 40.8 µm), but a significantly lower CMT was observed in the simvastatin+fenofibrate group at the first month. In eyes with diabetic macular edema (DME), three months treatment with simvastatin+fenofibrate showed a significantly lower CMT compared to the simvastatin+placebo group. Macular volume after three months of treatment was 10086 ± 886.4 µm 3 in the simvastatin+fenofibrate group and 10307 ± 1058.6 µm 3 in the simvastatin+placebo group, this difference was not significant, but in all subjects with good blood glucose regulation (HbA1c ≤ 7%), macular volume in the second month was significantly lower compared to subjects with HbA1c > 7%. Serum biologic marker levels after three months treatment showed mean eNOS and median VEGF levels of 3878.8 ± 873.33 pg/mL and 242.8 (86 - 1123.3) pg/mL in simvastatin + fenofibrate group, compared to 4031.2 ± 742.56 pg/mL and 370 (134.8 - 810.6) pg/mL in simvastatin+placebo group, which was not significantly different, however, decrease in VCAM-1 level was significantly higher in the simvastatin+fenofibrate group (50.7 pg/mL, 32.5 - 223.4 pg/mL vs. 40.4 pg/mL, 27.9 - 94.2 pg/mL). In subjects with tighter blood glucose control (HbA1c ≤ 6.5%), serum VEGF level was 128.7 (114.5 - 145.2) pg/mL, which was significantly lower compared to 423 (86 - 1233.3) pg/mL in subjects with HbA1c > 6.5%. In conclusion, three months treatment with simvastatin+fenofibrate in overall DR subjects with dyslipidemia does not reduce CMT and macular volume, but more reduces CMT in specifically DME subjects. Simvastatin+fenofibrate treatment in DR subjects does not prevent lowering of serum eNOS levels, elevation of VCAM-1 levels and elevation of VEGF levels, but tight blood sugar control prevents elevation of serum VEGF. Simvastatin+fenofibrate may be considered as adjuvant therapy in DR subjects with DME and dyslipidemia. Good glucose control remains most essential in the management of DR.
Key words: diabetes mellitus, diabetic retinopathy, dyslipidemia, fenofibrate.