Effect of calcium dobesilate on progression of early diabetic retinopathy: a randomised double-blind study

  • Maria L. Ribeiro
  • Andras I. Seres
  • Angela M. Carneiro
  • Michael Stur
  • Alain Zourdani
  • Patricia Caillon
  • José G. Cunha-Vaz
  • on behalf of the DX-Retinopathy Study Group
Clinical Investigation

Abstract

Background

The study was carried out to confirm the effect of calcium dobesilate (CaD) compared to placebo (PLA) on the blood-retinal barrier (BRB) permeability in early diabetic retinopathy (DR).

Methods

Adults with type II diabetes and early diabetic retinopathy (below level 47 of ETDRS grading and PVPR between 20 and 50×10−6/min, plasma-free fluorescein) were included in this double-blind placebo-controlled study. Treatment was 2 g daily for 24 months. The primary parameter, posterior vitreous penetration ratio (PVPR), was measured every 6 months by fluorophotometry. Secondary parameters were fundus photography, fluorescein angiography and safety assessments. Metabolic control was performed every 3 months.

Results

A total of 194 patients started the treatment (98 CaD, 96 PLA) and 137 completed the 24-month study (69 CaD, 68 PLA). Both treatment groups were comparable at baseline, with ETDRS level 10 in about 59% of patients. Mean PVPR change from baseline after 24 months was significantly (P=0.002) lower in the CaD group [−3.87 (SD 12.03)] than in the PLA group [+2.03 (SD 12.86)], corresponding to a 13.2% decrease in the CaD group and a 7.3% increase in the PLA group. PVPR evolution was also analysed by HbA1c classes (<7%, between 7 and 9%, ≥9%) and results confirmed the superiority of CaD independently of the diabetes control level. A highly significant difference [CaD: −3.38 (SD 13.44) versus PLA: +3.50 (SD 13.70)] was also obtained in a subgroup of patients without anti-hypertensive and/or lipid-lowering agents (P=0.002 at 24 months). A further analysis of the secondary parameters showed significant changes in favour of CaD in the evolution from baseline to the last visit of haemorrhages (P=0.029), DR level (P=0.0006) and microaneurysms (P=0.013). Regarding safety, only 2.5% (n=5 patients/events) of all adverse events reported were assessed as possibly or probably related to the test drug, while all serious adverse events were reported as unlikely. There was no statistical difference between groups.

Conclusion

Calcium dobesilate 2 g daily for 2 years shows a significantly better activity than placebo on prevention of BRB disruption, independently of diabetes control. Tolerance was very good.

Keywords

Diabetic retinopathy Blood-retinal barrier Posterior vitreous penetration ratio Calcium dobesilate 

References

  1. 1.
    Bailey CC, Sparrow JM (2001) Visual symptomatology in patients with sight-threatening diabetic retinopathy. Diabet Med 18:883–888PubMedCrossRefGoogle Scholar
  2. 2.
    Bergerhoff K, Clar C, Richter B (2002) Aspirin in diabetic retinopathy. A systematic review. Endocrinol Metab Clin N Am 31:779–793CrossRefGoogle Scholar
  3. 3.
    Berthet P, Farine JC, Barras JP (1999) Calcium dobesilate: pharmacological profile related to its use in diabetic retinopathy. Int J Clin Pract 53:631–636PubMedGoogle Scholar
  4. 4.
    Binkhorst PG, Van Bijsterveld OP (1976) Calcium Dobesilate versus placebo in the treatment of diabetic retinopathy: a double-blind cross-over study. Curr Ther Res Clin Exp 20:283–288PubMedGoogle Scholar
  5. 5.
    Brunet J, Farine JC, Garay RP et al (1998) In vitro antioxydant properties of calcium dobesilate. Fundam Clin Pharmacol 12:205–212PubMedCrossRefGoogle Scholar
  6. 6.
    Brunet J, Farine JC, Garay RP et al (1998) Angioprotective action of calcium dobesilate against reactive oxygen species-induced capillary permeability in the rat. Eur J Pharmacol 358:213–220PubMedCrossRefGoogle Scholar
  7. 7.
    Buch H, Vinding T, La Cour M et al (2004) Prevalence and causes of visual impairment and blindness among 9980 Scandinavian adults: The Copenhagen City Eye Study. Ophthalmology 111:53–61PubMedCrossRefGoogle Scholar
  8. 8.
    Bursell SE, Delori Fac, Yoshida A et al (1984) Vitreous fluorophotometric evaluation of diabetics. Invest Ophthalmol Vis Sci 25:703–710PubMedGoogle Scholar
  9. 9.
    Chaturvedi N, Sjolie AK, Stephenson JM et al (1998) Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID Study Group. EURODIAB Controlled Trial of Lisinopril in Insulin–Dependent Diabetes Mellitus. Lancet 351:28–31PubMedCrossRefGoogle Scholar
  10. 10.
    Chaturvedi N, Sjoelie AK, Svensson A (2002) The Diabetic Retinopathy Candesartan Trials (DIRECT) Programme, rationale and study design. J Renin Angiotensin Aldosterone Syst 3:255–261PubMedGoogle Scholar
  11. 11.
    Cunha-Vaz JG, Gray JR, Zeimer RC, Mota MC, Ishimoto BH, Leite EB (1985) Characterization of the early stages of diabetic retinopathy by vitreous fluorophotometry. Diabetes 34:53–59PubMedGoogle Scholar
  12. 12.
    Cunha-Vaz JG, Leite E, Castro Sousa JP, Faria de Abreu JR (1993) Blood-retinal barrier permeability and its relation to progression of diabetic retinopathy. A four year follow-up study. Graefe’s Arch Clin Exp Ophthalmol 231:141–145CrossRefGoogle Scholar
  13. 13.
    Cunha-Vaz J, Lobo C, Sousa JC et al (1998) Progression of retinopathy and alteration of the blood-retinal barrier in patients with type 2 diabetes: a 7-year prospective follow-up study. Graefe’s Arch Clin Exp Ophthalmol 236:264–268CrossRefGoogle Scholar
  14. 14.
    Cunha-Vaz JG (2000) Diabetic retinopathy: surrogate outcomes for drug development for diabetic retinopathy. Ophthalmologica 214:377–380PubMedCrossRefGoogle Scholar
  15. 15.
    DAMAD Study Group (1989) Effect of aspirin alone and aspirin plus dipyridamole in early diabetic retinopathy. A multicenter randomized controlled clinical trial. The DAMAD Study Group. Diabetes 38:491–498Google Scholar
  16. 16.
    Davis MD, Hubbard LD, Trautman J, Klein R (1985) Studies of retinopathy. Methodology for assessment and classification with fundus photographs. Diabetes 34 (suppl. 3):42–49PubMedGoogle Scholar
  17. 17.
    ETDRS Research Group (1991) Classification of diabetic retinopathy from fluorescein angiograms. ETDRS report number 11. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 98 (5 Suppl):807–822Google Scholar
  18. 18.
    Feman SS, Leonard-Martin TC, Andrews JS, Armbruster CC, Burdge TL, Debelak JD, Lanier A, Fischer AG (1995) A quantative system to evaluate diabetic retinopathy from fundus photographs. IOVS 36:174–181Google Scholar
  19. 19.
    Frank RN (2002) Potential new medical therapies for diabetic retinopathy: protein kinase C inhibitors. Am J Ophthalmol 133:693–698PubMedCrossRefGoogle Scholar
  20. 20.
    Freyler H (1974) Microvascular protection with calcium dobesilate (Doxium) in diabetic retinopathy. Ophthalmologica 168:400–416PubMedGoogle Scholar
  21. 21.
    Frison LJ, Pocock SJ (1997) Linearly divergent treatment effects in clinical trials with repeated measures: efficient analysis using summary statistics. Stat Med 16:2855–2872PubMedCrossRefGoogle Scholar
  22. 22.
    Garay P, Hannaert P, Chiavaroli C (2005) Calcium dobesilate in the treatment of diabetic retinopathy. Treat Endocrinol 4:221–232PubMedCrossRefGoogle Scholar
  23. 23.
    Gilbert RE, Krum H, Wilkinson-Berka J, Kelly DJ (2003) The renin-angiotensin system and the long-term complications of diabetes: pathophysiological and therapeutic considerations. Diabet Med 20:607–621PubMedCrossRefGoogle Scholar
  24. 24.
    Giusti C (2002) Is medical treatment for diabetic retinopathy still an unreal dream? Med Hypoth 59:706–709CrossRefGoogle Scholar
  25. 25.
    Gloviczki P, Fowl RJ, Hollier LH et al (1985) Prevention of platelet deposition by ibuprofen and calcium dobesilate in expanded polytetrafluoroethylene vascular grafts. Am J Surg 150:589–592PubMedCrossRefGoogle Scholar
  26. 26.
    Haas A (1995) Einfluss von Kalziumdobesilat auf die Progression der diabetischen Retinopathie. Klin Monatsbl Augenheilkd 206:17–21Google Scholar
  27. 27.
    Harper CA (1999) Treatment of diabetic retinopathy. Clin Exp Optom 82:98–101PubMedGoogle Scholar
  28. 28.
    Klein BEK, Davis MD, Segal P et al (1984) Diabetic retinopathy. Assessment of severity and progression. Ophthalmology 91:10–17PubMedGoogle Scholar
  29. 29.
    Knudsen ST, Bek T, Poulsen PL et al (2003) Effects of losartan on diabetic maculopathy in type 2 diabetic patients: a randomized, double-masked study. J Intern Med 254:147–158PubMedCrossRefGoogle Scholar
  30. 30.
    Leite EB, Mota MC, Faria de Abreu JR, Cunha-Vaz JG (1990) Effect of calcium dobesilate on the blood-retinal barrier in early diabetic retinopathy. Int Ophthalmol 14:81–88PubMedCrossRefGoogle Scholar
  31. 31.
    Lobo CL, Bernardes RC, de Abreu JR, Cunha-Vaz JG (2001) One-year follow-up of blood-retinal barrier and retinal thickness alterations in patients with type 2 diabetes and mild nonproliferative retinopathy. Arch Ophthalmol 119:1469–1474PubMedGoogle Scholar
  32. 32.
    Lobo CL, Bernardes RC, Figueira JP et al (2004) Three-year follow-up of blood-retinal barrier and retinal thickness alterations in patients with type 2 diabetes mellitus and mild nonproliferative diabetic retinopathy. Arch Ophthalmol 122:211–217PubMedCrossRefGoogle Scholar
  33. 33.
    Nakagami T, Kawahara R, Hori S, Omori Y (1997) Glycemic control and prevention of retinopathy in Japanese NIDDM patients. A 10-year follow-up study. Diabetes Care 20:621–622PubMedGoogle Scholar
  34. 34.
    Narayan KM, Boyle JP, Thompson TJ et al (2003) Lifetime risk for diabetes mellitus in the United States. JAMA 290:1884–1890PubMedCrossRefGoogle Scholar
  35. 35.
    Parving HH, Larsen M, Hommel E, Lund-Andersen H (1989) Effect of antihypertensive treatment on blood-retinal barrier permeability to fluorescein in hypertensive type 1 (insulin-dependent) diabetic patients with background retinopathy. Diabetologia 32:440–444PubMedCrossRefGoogle Scholar
  36. 36.
    Pearson AR, Keightley SJ, Casswell AG (1998) How good are we at assessing driving visual fields in diabetics? Eye 12:938–942PubMedGoogle Scholar
  37. 37.
    Polak BC, Crijns H, Casparie AF, Niessen LW (2003) Cost-effectiveness of glycemic control and ophthalmological care in diabetic retinopathy. Health Policy 64:89–97PubMedCrossRefGoogle Scholar
  38. 38.
    Pradhan R, Fong D, March C, Jack R et al (2002) Angiotensin-converting enzyme inhibition for the treatment of moderate to severe diabetic retinopathy in normotensive type 2 diabetic patients. A pilot study. J Diabetes Complications 16:377–381PubMedCrossRefGoogle Scholar
  39. 39.
    Ratzmann KP, Raskovic M, Thoelke H (1989) Significance of proteinuria and hypertension in the prognosis of type 1 diabetes. Results of a 10-year follow-up study on micro- and macrovascular disease mortality[Article in German]. Dtsch Med Wochenschr 114:1311–1315PubMedCrossRefGoogle Scholar
  40. 40.
    Rota I, Chiavaroli C, Garay RP et al (2004) Reduction of retinal albumin leakage by the antioxidant calcium dobesilate in streptozotocin-diabetic rats. Eur J Pharmacol 495:217–224PubMedCrossRefGoogle Scholar
  41. 41.
    Russell PW, Sekuler R, Fetkenhour C (1985) Visual function after pan-retinal photocoagulation: a survey. Diabetes Care 8:57–63PubMedGoogle Scholar
  42. 42.
    Salama-Benarroch I, Nano H, Perez H et al (1977) Assessment of calcium dobesilate in diabetic retinopathy. A double-blind clinical investigation. Ophthalmologica 174:47–51PubMedCrossRefGoogle Scholar
  43. 43.
    Saum SL, Thomas E, Lewis AM, Croft PR (2002) The effect of diabetic control on the incidence of, and changes in, retinopathy in type 2 non-insulin dependent diabetic patients. Br J Gen Pract 52:214–216PubMedGoogle Scholar
  44. 44.
    Schmidt M, Michal M (1989) Inhibition of sorbitol formation in human erythrocytes by calcium dobesilate. Arzneimittleforschung/Drug Res 39:493–495Google Scholar
  45. 45.
    Sjolie AK, Chaturvedi N (2002) The retinal renin-angiotensin system: implications for therapy in diabetic retinopathy. J Hum Hypertens 16 (Suppl 3):S42–S46PubMedCrossRefGoogle Scholar
  46. 46.
    Snoek FJ (2000) Barriers to good glycaemic control: the patient’s perspective. Int J Obes Relat Metab Disord 24(Suppl 3):S12–S20PubMedGoogle Scholar
  47. 47.
    Stovring H, Andersen M, Beck-Nielsen H et al (2003) Rising prevalence of diabetes: evidence from a Danish pharmaco-epidemiological database. Lancet 362:537–538PubMedCrossRefGoogle Scholar
  48. 48.
    Szabo ME, Haines D, Garay E et al (2001) Antioxydant properties of calcium dobesilate in ischemic/reperfused diabetic rat retina. Eur J Pharmacol 428:277–286PubMedCrossRefGoogle Scholar
  49. 49.
    Ubink-Veltmaat LJ, Bilo HJ, Groenier KH et al (2003) Prevalence, incidence and mortality of type 2 diabetes mellitus revisited: a prospective population-based study in the Netherlands (ZODIAC-1). Eur J Epidemiol 18:793–800PubMedCrossRefGoogle Scholar
  50. 50.
    Van Schaik HJ, Benitez del Castillo JM, Caubergh MJ et al (1998–99) Evaluation of diabetic retinopathy by fluorophotometry. European concerted action on ocular fluorometry. Int Ophthalmol 22:97–104CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Maria L. Ribeiro
    • 1
  • Andras I. Seres
    • 2
  • Angela M. Carneiro
    • 3
  • Michael Stur
    • 4
  • Alain Zourdani
    • 5
  • Patricia Caillon
    • 6
  • José G. Cunha-Vaz
    • 1
  • on behalf of the DX-Retinopathy Study Group
  1. 1.AIBILIClinical Trial CentreCoimbraPortugal
  2. 2.Department of OphthalmologySemmelweis UniversityBudapestHungary
  3. 3.Department of OphthalmologyHospital de São JoãoPortoPortugal
  4. 4.Department of OphthalmologyMedical University of ViennaViennaAustria
  5. 5.Department of OphthalmologyUniversity-Paris XII-CreteilCreteilFrance
  6. 6.OM PHARMAMeyrin/GenevaSwitzerland

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