September 16, 2007
The Effect of Long-Term Treatment With Sulindac on the Progression of Diabetic Retinopathy*
By Hattori, Yukiko Hashizume, Kiyoshi; Nakajima, Kazuo; Nishimura, Yoshihiro; Et al
Key words: Diabetic retinopathy - Long-term treatment - Sulindac - Type 2 diabetes ABSTRACT
Research design and methods: 40 Japanese patients with type 2 diabetes were enrolled in a randomized, single-blind controlled trial in which the effects of sulindac (200 mg/day, 100 mg twice a day; n = 16 patients) on the progression of DR were compared to controls (24 patients) for 3 years. All patients were comparable in their age, gender, duration of disease, body mass index, dipstick proteinuria, insulin therapy, glycemic control, and clinical stages of DR. Outcome was determined by comparing parameters of retinopathy in fundus photographs that were taken at time 0 to those taken 1 , 2, and 3 years after the initiation of treatment.
Results: Patients in the sulindac group did not develop DR during the course of treatment nor was there progression of pathology in those who began the study with mild non-proliferative DR (NPDR). On the other hand, six patients progressed to mild NPDR in the control group - three at year 1 and three at year 3 - and an additional patient progressed to severe NPDR from mild NPDR by year 1 and to proliferative DR by year 2. The findings at year 3 in the sulindac group were significantly (p
Conclusions: Long-term treatment with sulindac was clinically effective in decreasing the progression of mild DR in type 2 diabetic patients in this pilot study.
Diabetic retinopathy (DR) is one of the chronic complications of type 2 diabetes. The pathogenesis is complex, with risk factors including hyperglycemia and hypertension1. Glycemie control is the most important factor to prevent occurrence or progression of DR1. It is also reported that tight blood pressure control reduces the risk of DR23. The renin-angiotensin system has been implicated in DR, and angiotensin-converting enzyme inhibitors were shown to decrease the progression of mild DR4. However, to date there have been few reports of other preventive drug treatments for DR, although photocoagulation and vitrectomy are well-established surgical treatments for advanced DR.
Sulindac, which is used clinically for the treatment of pain and arthritis5, and is structurally related to indomethacin, is a prodrug which is metabolized to sulfide and sulfone derivatives in the liver and by colonic bacteria6. The non-steroidal anti- inflammatory drugs (NSAIDs), such as sulindac and acetylsalicylic acid, have aldose reductase (AR) inhibitory activity7. The activity of sulindac is greater than that of other classes of anti- inflammatory agents8,9. Sulindac sulfide is the drug's most active metabolite, which blocks prostaglandin synthesis by non-selective inhibition of cyclooxygenase (COX)-1 and -2. Sulindac also inhibits the production of inflammatory cytokines by blocking the nuclear factor-kappaB (NF-kappaB) pathway10. Sulindac was reported to prevent retinal capillary basement membrane thickening in early DR in cats" and dogs12, but was ineffective in preventing disease progression over a short, 6-month clinical course13.
We proposed that long-term treatment with sulindac would be effective in blocking the progression of DR when begun at an earlier stage, since AR is thought to be principally involved in the development of early stage complications"4. In the present pilot study, we tested the hypothesis that longer-term treatment with sulindac might be more effective in decreasing the progression of early DR.
Patients and methods
The study was carried out between October 1997 and October 2000. We intended to set up a larger study based on this pilot study. Forty middle-aged Japanese patients with type 2 diabetes, all seen at Asama General Hospital, were enrolled in this randomized, single blind, controlled trial. All patients had been diabetic for more than 5 years and exhibited poor glycemie control (glycosylated hemoglobin [HbA^sub 1c^] > 8.0%); they were all normotensive (
The patients were then randomized with stratification to the following two groups: (1) a sulindac group (n = 16) in which patients took 100 mg of sulindac twice a day; and (2) a control group (n = 24) in which patients took no additional medications. The patients remained on their medications for 3 years. Safety was assessed by the recording of treatment-emergent adverse events, and by systemic physical examinations. Laboratory tests included a hematologic panel and measurements of liver and kidney function. HbA^sub 1c^ values were determined at monthly intervals. In addition, patients were examined by seven-field stereoscopic retinal photography at baseline and at yearly intervals; all of these photographs were evaluated by the same ophthalmologist who was unaware of the study design. Patients were classified as exhibiting no apparent retinopathy, mild non-proliferative DR (NPDR), moderate NPDR, severe NPDR, or proliferative DR (PDR), as per the International Clinical Diabetic Retinopathy Disease Severity Scale. During the course of the study, patients were considered to have reached an endpoint if they were diagnosed with PDR or if they exhibited a dipstick proteinuria of >/= 1 +, which was taken as a sign of nephropathy.
Continuous variables are presented as mean +- SD. The significance of the differences between baseline patients' data in the two groups was estimated by Student's t-test or the Mann- Whitney U test. Parameters of retinopathy were compared using the Mann-Whitney U test. The significance value was set at 0.05.
Informed consent was obtained from all patients prior to initiation of the study. The study was conducted in accordance with the principles of the Declaration of Helsinki, and was approved by the Institutional Review Board of Asama General Hospital.
The baseline characteristics of the randomized patients are presented in Table 1. Patients in the two groups were comparable in age, duration of disease, body mass index, dipstick proteinuria, and clinical stages of DR. They had also had similar insulin treatment regimens and levels of glycemie control; the gender frequencies in both groups were also comparable. At the initiation of the trial, patients either exhibited no apparent retinopathy or mild NPDR; there were no significant differences in retinal pathology between groups at baseline (Table 2).
None of the patients in the sulindac group exhibited any progression of disease during the course of the study. On the other hand, three control patients developed mild NPDR after 1 year which persisted through year 3, while another patient's mild NPDR progressed to severe NPDR after 1 year. This severe NPDR of the latter patient progressed to PDR in year 2, after which she dropped out of the study and received photocoagulation therapy. Finally, three additional control patients developed mild NPDR at year 3 (Table 3). This resulted in a statistically significant decrease in the progression of clinically apparent DR at year 3 (p = 0.0284), but no differences at year 1 and year 2 (both p = 0.0895).
Table 1. Patients' baseline data
Table 2. Baseline ophthalmohgic evaluation
Neither blood pressure nor HbAlc levels changed in any of the patient groups, nor did they suffer any adverse effects of treatment. One patient did drop out of the study because she had reached a defined end point.
The polyol pathway, the formation of advanced glycation end products (AGEs), oxidative stress, and the activation of protein kinase C (PKC) have all been implicated in the development of diabetic complications' and interact with one another15,16. AR is the first and rate-limiting enzyme in the polyol pathway. In its native form, AR has a low affinity for glucose but sorbitol production is enhanced in a hyperglycemic environment14.
Table 3. Effects of treatment on the progression of retinopathy
Recent findings have suggested that DR may represent a chronic inflammatory disease. Activation of the polyol pathway leads to activation of PKC which further increases cytosolic phospholipase A^sub 2^ activity. Activation of this enzyme increases the production of two inhibitors of Na^sup +^-K^sup +^ ATPase- arachidonate and prostaglandin E^sub 2^17. The expression of retinal intercellular adhesion molecule-1 (ICAM-1) and the leukocyte integrin CD18 is up-regulated in DR; proinflammatory cytokines such as vascular endothelial growth factor (VEGF) are known to drive the up-regulation of ICAM-1, most likely via nitric oxide- and NF- kappaB-dependent pathways18. The production of tumor necrosis factor- alpha (TNF-alpha), a vasoactive cytokine, is also elevated in DR19.
It was recently shown that COX, especially COX-2, interacts with VEGF20. COX-1 is a constitutively expressed isoform that is found in most tissues. In contrast, COX-2 is not normally expressed but is induced by pro-inflammatory and mitogenic stimuli such as VEGF, TNF- alpha, and interleukins-1 a and -1beta. COX-2 is also thought to interact with NF-kappaB, interleukin 6, and cyclic adenosine monophosphatase21. Numerous reports have suggested that aldose reductase inhibitors (ARIs) can prevent the occurrence and progression of experimental DR11,12,22. In contrast to the success seen in animal models, ARIs have not been shown to provide appreciable clinical benefit for the treatment of human DR23,24. The diabetic animal models only show the early signs of DR14, and are generally carried out in severely hyperglycemic conditions to induce DR at higher rates and more rapidly14. In contrast, the diabetic patients in the human trials are usually well- to moderately- controlled.
We planned our pilot study in the light of the above considerations. At baseline, the patients in our study all had no apparent retinopathy or mild NPDR. Patients in the sulindac group took the drug for 3 years. Our data showed that 3-years' treatment with sulindac resulted in a statistically significant decrease in the progression of DR in type 2 diabetic patients. On the other hand, we were not able to show that sulindac significantly suppresses the progression of DR because of the small size of the study.
While sulindac prevented retinal capillary basement membrane thickening in diabetic dogs, it had no effect on the activity of the polyol pathway, the accumulation of AGEs, or oxidative stress12. Thus, the suppression of inflammatory cytokines and COX by sulindac might also be important. It is likely that the other effects of sulindac also contribute to its ability to prevent DR. Our study has unavoidable limitations because of its small size, and we therefore now plan to conduct investigations, including a comparison of the effects of sulindac with specific ARIs or other NSAIDs on DR, and to explore the mechanisms underlying sulindac 's effect. To this end, a much larger study population will be required.
We found that treatment with sulindac for 3 years was clinically effective in decreasing the progression of early DR in type 2 diabetic patients in this pilot study. Larger scale clinical trials will be required to confirm these findings. In order to define the action mechanisms of sulindac, further studies are needed. But the beneficial effect of sulindac is important to decrease the progression of DR.
Declaration of interest: No conflict of interest was declared.
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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com
Paper CMRO-3921_3, Accepted for publication: 11 June 2007
Published Online: 06 July 2007
Yukiko Hattori(a), Kiyoshi Hashizume(b), Kazuo Nakajima(a), Yoshihiro Nishimura(a), Motoji Naka(a) and Kazuto Miyanaga(c)
a Department of Internal Medicine, Asama General Hospital, Saku, Japan
b Department of Aging Medicine and Geriatrics, Institute of Aging and Adaptation, Shinshu University Graduate School, Matsumoto, Japan
c Department of Ophthalmology, Tatsuno General Hospital, Tatsuno, Japan
Address for correspondence: Yukiko Hattori, Department of Molecular Oncology, Division of Molecular and Cellular Biology Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan. Tel.: +81 263 37 2723; Fax: +81 263 37 2724; [email protected]
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