Ординатура / Офтальмология / Английские материалы / Diabetes and Ocular Disease Past, Present, and Future Therapies 2nd edition_Scott, Flynn, Smiddy_2009

344 Diabetes and Ocular Disease

(RR, 0.53; P < .001). Cotton-wool spots increased in both groups but less so in the tight BP control group which had fewer cotton-wool spots at 7.5 years (RR, 0.53; P < 0.001). A two-step or more deterioration on the ETDRS scale was significantly different at 4.5 years with fewer people in the tight BP control group progressing two steps or more (RR, 0.75; P = 0.02). Patients assigned to tight BP control were less likely to undergo photocoagulation (RR, 0.65; P = 0.03). This difference was mainly in photocoagulation for diabetic macular edema (RR, 0.58; P = 0.02). There was a 50% reduction in the risk of moderate vision loss as well as with decrease in blindness or vision of 20/200 or worse. The decreased vision of 20/200 or worse in one eye was found in 18/758 for the tight BP control group compared with 12/390 for the less tight BP control group. The absolute risks of such poor vision was of the order of 3.1 to 4.1 per 1000 patient-years, respectively (P = 0.046; RR, 0.76; 99% confidence interval [CI], 0.29–1.99).

A previously published study of BP medication in patients with diabetic retinopathy suggested that there might be a specific benefit of angiotensin-converting enzyme (ACE) inhibition and BP reduction, even in “normotensive” persons, on the progression of diabetic retinopathy [22]. The UKPDS included a randomized comparison of beta-blockers and ACE inhibitors in the tight BP control arm of that study. Benefits from tight BP control were present in both the ß-blocker and ACE inhibitor treatment groups, with no statistically significant difference between them. The results of the UKPDS suggest that the treatment effect is more likely to be secondary to BP reduction than to a specific effect of ACE inhibitors [20].

ELEVATED SERUM LIPID LEVELS

The Wisconsin Epidemiologic Study of Diabetic Retinopathy, a population-based study, and the Early Treatment Diabetic Retinopathy Study (ETDRS) found that elevated levels of serum cholesterol were associated with increased severity of retinal hard exudates (Fig. 17.3) [23,24]. A study of diabetic retinopathy in African Americans with type 1 diabetes also showed the association of macular edema and retinal hard exudates with elevated serum lipids [25]. Patients with a total cho- lesterol/high-density lipoprotein cholesterol (HDL-C) ratio of 4.5 or greater were almost twice as likely to have retinal hard exudates compared to those with a ratio of less than 4.5. Patients with higher quartile of total cholesterol or low-density lipoprotein cholesterol (LDL) levels were five to six times more likely to have retinal hard exudates than those in the lowest quartiles. In the ETDRS, elevated total cholesterol (240 mg/dL or 6.21 mmol/L) was twice as likely to have retinal hard exudates at baseline (odds ratio [OR]: 2.00, 99% CI: 1.35–2.95). Similar results were found when comparing elevated LDL levels (160 mg/dL or 1.14 mmol/L) with the lowest level of LDL (130 mg/dL or 3.37 mmol/L) and the OR was 1.97, 99% CI: 1.3–2.96. Patients with elevated cholesterol and triglyceride levels were 50% more likely to develop retinal hard exudates. Independent of the accompanying macular edema, the severity of retinal hard exudates at baseline was associated with decreased visual acuity in the ETDRS (Fig. 17.4). The severity of retinal hard exudates was also a significant risk factor for moderate visual loss (15 or more

346 Diabetes and Ocular Disease

trend = 0.03). Similar findings were found for association of serum lipids with the development of retinal hard exudates. After adjusting for all known potential risk factors, the following were statistically significant predictors of retinal hard exudates: total cholesterol: RR= 2.37, P for trend = 0.001; LDL cholesterol: 2.77, P for trend = 0.002; total-to-HDL cholesterol ratio: 2.44, P for trend = 0.0004; and triglycerides: 3.20, P for trend = 0.006. These findings were similar to those found in the ETDRS.

In a study of the risk factors associated with the development of subretinal fibrosis in ETDRS patients with diabetic macular edema, the presence of severe hard exudates was the strongest risk factor [27]. Elevated serum triglyceride levels were also associated with a greater risk of developing high-risk proliferative diabetic retinopathy in the ETDRS patients [28]. In a study in Pittsburgh, elevated triglycerides, as well as elevated LDL cholesterol, were found to be associated with proliferative diabetic retinopathy [3].

Although these are all observational findings, the data are compelling to recommend lowering elevated serum lipids in patients with diabetic retinopathy to reduce the risk of vision loss. In addition to reducing the risk of cardiovascular disease, reducing the risk of vision loss should be another motivating factor for patients to lower elevated serum lipids. Currently, the National Heart, Lung, and Blood Institute (NHLBI) of National Institutes of Health (NIH) is addressing this question in the Actions to Control Cardiovascular Risk in Diabetes (ACCORD) Study, a randomized controlled clinical trial of glycemic control, BP control, and management of dyslipidemia in 10,000 subjects with type 2 diabetes. The results from this study will hopefully answer the particular question of possible association of serum cholesterol with progression of diabetic retinopathy and development of diabetic macular edema.

DIABETES AND PREGNANCY

The effects of pregnancy on the development and the rate of progression of underlying diabetic retinopathy have been controversial. Although a number of studies have suggested a worsening of retinopathy during pregnancy [29–32], others have not [33,34]. Diabetic retinopathy can worsen during pregnancy because of the pregnancy itself or the changes in metabolic control, usually a marked improvement in glucose control [29–30].

The DCCT is the largest prospective study to assess the effect of pregnancy on the development and progression of diabetic retinopathy and other microvascular abnormalities [35]. The women in the DCCT were generally younger and had shorter duration of diabetes with fewer or less severe diabetic complications than those reported previously in other studies. Women in the intensive treatment group had HbA1c levels that were near normal for a mean of 3 years prior to conception. When the analyses were stratified by the treatment group, both the intensive and the conventional groups showed a short-term deterioration of retinopathy during pregnancy that persisted through the first year postpartum. In the conventional treatment group, there was a 2.5-fold increase in the risk of retinopathy

progression when compared with nonpregnant women. This was statistically significant and not affected by other risk factors. In the intensive treatment group, the adjusted risks were not as great while the risk of retinopathy progression was nominally statistically significant. However, there were fewer events in the early treatment group.

There was a significant trend toward greater worsening of retinopathy with greater reductions in HbA1c. This progression may be similar to that of the early worsening that has been shown to be related to the magnitude of the decrease of HbA1c level with the intensive therapy for glycemic control. However, when the recent changes in retinopathy were compared between the pregnant and nonpregnant women, adjusted for the recent changes in HbA1c, the increased worsening of retinopathy during pregnancy persisted. It would appear that both the effects of pregnancy as well as the effects of intensive therapy are important in the progression (worsening) of retinopathy. The follow-up examinations showed that the effects of pregnancy on retinopathy continued to increase over the first year following delivery of the baby. The cause for this continued effect of accelerated progression following delivery is not known. It is possible that factors other than glucose control may be involved, such as changes in hormones (e.g., growth hormone or cortisol). However, there were no long-term consequences of this worsening of retinopathy as both pregnant and nonpregnant women had similar severity of retinopathy at the end of the study.

Patients with diabetes who are planning to become pregnant are encouraged to achieve glucose control as tight as possible to reduce the risk of malformations and other genetic abnormalities. Patients with diabetes who are planning to become pregnant are encouraged to have their eyes examined prior to conception, to be counseled on the risk of development and/or progression of diabetic retinopathy. During the first trimester, another eye examination should be performed; subsequent follow-up will depend on the level of retinopathy found; and postpartum examination may also be important.

DIABETES AND PUBERTY

The effect of puberty on the progression of diabetic retinopathy has been investigated in a number of epidemiologic studies. Some have found puberty to be not a risk factor for the progression of diabetic retinopathy [36,37], while other investigators have determined puberty to be a significant risk factor [38–40]. Children who were postpubescent had a greater prevalence of retinopathy than those who were not sexually mature. The relative odds of having retinopathy in the postpubescent group compared to prepubescent or pubescent group was 4.8 (95% CI: 1.5–15.3). This study also suggested that minimal retinopathy in children is not rare and that postpubescent children have a greater prevalence of diabetic retinopathy than do prepubescent children with similar duration of diabetes. In the Wisconsin Epidemiologic Study of Diabetic Retinopathy, prepubescent patients had no progression in the 10 year study follow-up [41]. Puberty may increase the risk of progression of diabetic retinopathy.

348 Diabetes and Ocular Disease

DIABETIC NEUROPATHY

The risk of proliferative diabetic retinopathy was 5 times more common in patients with diabetic neuropathy compared with those without neuropathy in a crosssectional analysis of approximately 2500 European patients [42]. In a case-control study of patients with or without proliferative diabetic retinopathy after 15 to 21 years of insulin-dependent diabetes at the Joslin Clinic, the odds of having cardiovascular autonomic neuropathy were about thirty to forty fold greater for those with proliferative diabetic retinopathy than those without [43]. In the ETDRS, the presence of neuropathy increased the risk of development of proliferative diabetic retinopathy by 26 to 32% (P < 0.0009) [28].

ANEMIA

In the ETDRS, a progressive increase in the risk of developing high-risk proliferative diabetic retinopathy was associated with decreasing hematocrit [28]. In the lowest category of hematocrit for both men and women, there was a 52% increased risk (P < 0.0038). Similar findings were seen in a cross-sectional study of patients in a diabetes clinic in Finland [44].

FIBRINOGEN AND ALBUMIN

In the DCCT, elevated fibrinogen and decreased albumin were associated with increased risk of diabetic retinopathy progression [45]. In the ETDRS, elevated fibrinogen increased the risk of proliferative diabetic retinopathy and this was of borderline statistical significance [28]. Fibrinogen is a marker of inflammation and recent studies have suggested that inflammation may play a critical role in the pathogenesis of diabetic retinopathy [46].

SUMMARY

Following years of debate, randomized, controlled clinical trials of intensive treatment compared with conventional treatment of hyperglycemia demonstrated the important role of glucose control in the development and progression of diabetic retinopathy. In addition to intensive treatment of hyperglycemia, the reduction of elevated blood pressure significantly reduced the risk of progression of diabetic retinopathy and moderate vision loss. The data regarding the association of elevated cholesterol and its components with macular edema, retinal hard exudates, and moderate vision loss are observational but nevertheless compelling. Recommendations to lower elevated cholesterol are important for other macrovascular diseases that are common in the population of persons with diabetes.

States of hormonal changes such as pregnancy and perhaps puberty are associated with progression of retinopathy. Other microvascular complications, neuropathy and nephropathy, are often correlated with retinopathy and may share common risk factors [47]. Another systemic condition that may have an impact on

the course of diabetic retinopathy is anemia. There are emerging data to suggest the importance of inflammation in the pathogenesis of diabetic retinopathy and future research in this area will provide important information.

All patients with diabetes should be educated on the importance of tight glycemic control and reduction of elevated blood pressure and of elevated cholesterol levels. These medical measures may prevent the development of, and retard the progression of, diabetic retinopathy. Prevention is preferable to the current treatments, which include laser photocoagulation and other surgical procedures.

REFERENCES

1.The Eye Diseases Prevalence Research Group. Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol. 2004;122:477–485.

2.Klein R, Klein BEK, Moss SE, Cruickshanks KJ. Relationship of hyperglycemia to the long-term incidence and progression of diabetic retinopathy. Arch Intern Med. 1994;154:2169–2178.

3.Lloyd CE, Klein R, Maser RE, Kuller LH, Becker DJ, Orchard TJ. The progression of retinopathy over 2 years: the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study. J Diab Complic. 1995;3:140–148.

4.Janka HU, Warram JH, Rand LI, Krolewski AS. Risk factors for progression of background retinopathy in long-standing IDDM. Diabetes. 1989;38:460–464.

5.Teuscher A, Schnell H, Wilson PWF. Incidence of diabetic retinopathy and relationship to baseline plasma glucose and blood pressure. Diabetes Care. 1988;11:246–251.

6.Krolewski AS, Barzilay J, Warram JH, Martin BC, Pfeifer M, Rand LI. Risk of earlyonset proliferative diabetic retinopathy in IDDM is closely related to cardiovascular autonomic neuropathy. Diabetes. 1992;41:430–437.

7.The Diabetes Control and Complications Trial Research Group (1993). The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977–986.

8.The Diabetes Control and Complications Trial Research Group. The effect of intensive diabetes treatment on the progression of diabetic retinopathy in insulin-dependent diabetes mellitus. Arch Ophthalmol. 1995;113:36–51.

9.The Diabetes Control and Complications Trial Research Group. The relationship of glycemic exposures (HbA1C) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial. Diabetes. 1995;44:968–983.

10.The Diabetes Control and Complications Trial Research Group. Perspectives in Diabetes. The absence of a glycemic threshold for the development of long-term complications: the perspective of the Diabetes Control and Complications Trial. Diabetes. 1996;45:1289–1289.

11.Reichard P, Nilsson BY, Rosenqvist U. The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Eng J Med. 1993;329:304–309.

12.The Diabetes Control and Complications Trial Research Group. Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol. 1998;116:874–886.

13.The Diabetes Control and Complications Trial Research Group. Progression of retinopathy with intensive versus conventional treatment in the Diabetes Control and Complications Trial. Ophthalmology. 1994;103:647–661.

350 Diabetes and Ocular Disease

14.The Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med. 2000;342: 381–389.

15.The Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complications Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA. 2002;287:2563–2569.

16.Klein R, Klein B, Moss S. Relation of glycemic control to diabetic microvascular complications in diabetes mellitus. Ann Intern Med. 1996;124:90–96.

17.Ohkubo Y, Hideke K, Eiichi A, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin- dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract. 1995;28:103–117.

18.UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with Type 2 diabetes (UKPDS 33). Lancet. 1998;352:837–853.

19.UK Prospective Diabetes Study Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with Type 2 diabetes (UKPDS 34). Lancet. 1998;352:854–865.

20.UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in Type 2 diabetes (UKPDS 38). BMJ. 1998;317:703–713.

21.Matthews DR, Stratton IM, Aldington SJ, Holman RR, Kohner EM, UK Prospective Diabetes Study Group. Risks of progression of retinopathy and vision loss related to tight blood pressure control in type 2 diabetes mellitus: UIKPDS 69. Arch Ophthalmol. 2004;122:1631–1640.

22.Chaturvedi N, Sjolie AK, Stephen JM, et al. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. Lancet. 1998;351:28–31.

23.Klein BEK, Moss SE, Klein R, Surawicz TS. The Wisconsin Epidemiologic Study of Diabetic Retinopathy, X: relationship of serum cholesterol to retinopathy and hard exudates. Ophthalmology. 1991;98:1261–1265.

24.Chew EY, Klein ML, Ferris III FL, et al. Association of elevated serum lipid levels with retinal hard exudates in diabetic retinopathy. Arch Ophthalmol. 1996;114: 1079–1084.

25.Roy MS, Klein R. Macular edema and retinal hard exudates in African Americans with type 1 diabetes. The New Jersey 725. Arch Ophthalmol. 2001;119:251–259.

26.Miljanovic B, Glynn RJ, Nathan Dm, Manson JE, Schaumberg DA. A prospective study of serum lipids and risk of diabetic macular edema in type 1 diabetes. Diabetes. 2000;53:2883–2892.

27.Fong DS, Segal PP, Myers F, Ferris FL, Hubbard LD, Davis MD. Subretinal fibrosis in diabetic macular edema, ETDRS Report No. 23. Arch Ophthalmol. 1997;115:873–877.

28.Davis MD, Fisher MR, Gangnon RE, et al. Risk factors for high-risk proliferative diabetic retinopathy and severe visual loss: Early Treatment Diabetic Retinopathy Study Report #18. Invest Opthalmol Vis Sci. 1998;39:233–252.

29.Phelps RL, Sakol P, Metzger BE. Jampol LM, Freinkel N. Changes in diabetic retinopathy during pregnancy: correlation with regulation of hyperglycemia. Arch Ophthalmol. 1986;104:1806–1810.

30.Klein BE, Moss SE, Klein R. Effect of pregnancy on progression of diabetic retinopathy. Diabetes Care. 1990;13:34–40.

31.Chew EY, Mills JL, Metzger BE, et al. Metabolic control and progression of retinopathy. The Diabetes in Early Pregnancy Study. National Institute of Child Health and Human Development Diabetes in Early Pregnancy Study. Diabetes Care. 1995;18:631–637.

32.Axer-Stegel R, Hod M, Fin k-Cohen A, et al. Diabetic retinopathy during pregnancy. Ophthalmology. 1996;103:1815–1819.

33.Lovestam-Adrian M, Agardh C-D, Aberg A, Agardh E. Pre-eclampsia is a potent risk factor for deterioration of retinopathy during pregnancy in type 1 diabetic patients. Diabet Med. 1997;14:1059–1065.

34.Lapolla A, Cardone C, Negrin P, et al. Pregnancy does not induce or worsen retinal or peripheral nerve dysfunction in insulin-dependent diabetic women. J Diabetes Complications. 1998;12:74–80.

35.The Diabetes Control and Complications Trial Research Group. Effect of pregnancy on microvascular complications in the Diabetes Control and Complications Trial. Diabetes Care. 2000;23:1084–1091.

36.Bognetti E, Calori G, Meschi F, Macellaro P, Bonfanti R, Chiumello G. Prevalence and correlations of early microvascular complications in young type I diabetic patients: role of puberty. J Pediatr Endocrinol Metab. 1997;10:587–592.

37.Donaghue KC, Fung AT, Hing S, et al. The effect of prepubertal diabetes duration on diabetes. Microvascular complications in early and late adolescence. Diabetes Care. 1997;20:77–80.

38.Porta M, Sjoelie AK, Chaturvedi N, et al. Risk factors for progression to proliferative diabetic retinopathy in the EURODIAB Prospective Complications Study. Diabetologia. 2001;44(12):2203–2209.

39.R Klein BE, Moss SE, Klein R. Is menarche associated with diabetic retinopathy? Diabetes Care. 1990;13:1034–1038.

40.Murphy RP, Nanda M, Plotnick L, Enger C, Vitale S, Patz A. The relationship of puberty to diabetic retinopathy. Arch Ophthalmol. 1990;108:215–218.

41.Klein R, Klein BE, Moss SE, Cruickshanks KJ. The Wisconsin Epidemiologic Study of diabetic retinopathy. XIV. Ten-year incidence and progression of diabetic retinopathy. Arch Ophthalmol. 1994;112:1217–1228.

42.Tesfaye S, Stevens LK, Stephenson JM, et al. Prevalence of diabetic peripheral neuropathy and its relation to glycaemic control and potential risk factors: the EURODIAB IDDM Complications Study. Diabetologia. 1995102:647–661.

43.Krolewski AS, Warram JH, Rand LJ, Christlieb AR, Busick EJ, Kahn CR. Risk of proliferative diabetic retinopathy in juvenile-onset type 1 diabetes: a 40 year follow-up study. Diabetes Care. 1986;9(5):443–552.

44.Qiao Q, Keinänen-Kiukaanniemi S, Läärä E. The relationship between hemoglobin levels and diabetic retinopathy. J Clin Epidemiol. 1997;50:153–158.

45.McMillan DE, Malone JI, Rand LJ, Steffes MW. Hemorheological plasma proteins predicts future retinopathy and nephropathy in the DCCT. Diabetologia. 1986;29:23–29.

46.Miyamoto K. Khorsrof S, Bursell SE, et al. Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion mol- ecule-1 inhibition. Proc Natl Aca Sci USA. 1999;96:10836–10841.

47.Cusick M, Meleth AD, Agron E, et al. Associations of mortality and diabetes complications in patients with type 1 and type 2 diabetes: Early Treatment Diabetic Retinopathy Study Report no. 27. Diabetes Care. 2005;28:617–625.

This page intentionally left blank