Article Date: 11/1/2010

Diabetic Retinopathy as a Prognostic Tool

Diabetic Retinopathy as a Prognostic Tool

Yasir J. Sepah, MB, BS • Brian Cho, MS-II • Diana V. Do, MD

Diabetes mellitus (DM) is growing at an astonishing rate, affecting over 240 million people worldwide, including 20 million people in the United States.7 As the prevalence of DM increases, diabetic retinopathy (DR) remains a leading cause of vision loss, especially in the working-age population of the US.5,7 DR can be categorized into two groups: nonproliferative (NPDR) and proliferative (PDR). Among the 240 million people with DM, approximately one-third have signs of DR,5 and a third of this group will eventually develop vision-threatening retinopathy.5

Recently, it has been noted that DR may be one of the early signs of an increased risk of life-threatening systemic vascular complications.1,5 There is growing evidence of an association between DR and cardiovascular diseases, such as stroke and coronary artery disease.10 It has been proposed that signs of DR could reflect generalized microangiopathic processes that affect not only the eyes but also organs elsewhere in the body.1,10 This includes cerebral microvascular disease and other thromboembolic events as well.4

DIABETIC RETINOPATHY: RISK FACTORS

Major risk factors for DR include the overall duration of DM and poor glycemic control.5,7,8 The greater the duration of disease, the greater the risks are of developing DR. Almost all patients with more than 20 years of DM develop some degree of DR. Glycemic control also plays an important role in the development of DR. Studies have demonstrated that a 1% decrease in HbA1c levels roughly equates to a decreased risk of retinopathy by 40%, progression to vision-threatening retinopathy by 25%, need for laser therapy by 25%, and risk of blindness by 15%.5

In the case of hypertension, epidemiologic studies have not found it to be a consistent risk factor for DR incidence and progression; however, many randomized control trials indicate that tight control of blood pressure is a major modifiable factor.7 Some studies have suggested that a decrease in systolic blood pressure of 10 mm Hg roughly equates to a decreased risk of retinopathy progression by 35%, need for laser therapy by 35%, and vision loss by 50%.5 Dyslipidemia is also a possible risk factor for DR. Observational studies suggest that dyslipidemia increases the risk of DR and, in particular, diabetic macular edema.7

DR AND THROMBOEMBOLIC EVENTS

Understanding the relationship between DR and systemic vascular diseases is important for the physician caring for diabetic patients. DR specifically represents the micro-angiopathic burden of DM in the eyes and, in general, its adverse effects on the body's vascular system. Current evidence suggests that the presence of retinopathy, even in its mildest form, is associated with a two- to threefold increased risk of stroke, coronary heart disease and heart failure, independent of cardiovascular risk factors.5

Diabetic retinopathy is associated with increased risk of stroke in both type 1 and 2 diabetes. The Atherosclerosis Risk in Communities (ARIC) study showed that signs of retinopathy are associated with a two- to fourfold risk of clinical stroke.1,8 The Blue Mountain Eye Study (BMES), the Cardiovascular Health Study (CHS) and the Beaver Dam Eye study (BDES) have all shown an increased risk of stroke in patients with DR.8

In the general population, the primary cause of ischemic stroke is macrovascular disease; however, in diabetic patients, microvascular disease plays an important role toward the development of stroke. Scientists have suggested that disruption of the blood-brain barrier is a possible pathophysiologic feature in the development of cerebrovascular disease.1,5,8 Retinal signs of microangiopathy (ie, retinal hemorrhages, microaneurysms and cotton wool spots) seen in DR represent breakdown of the blood-brain barrier and likely increase the risk of cerebrovascular disease in patients with DR.1,5,8

In addition, DR has been recently associated with a twofold increased risk of coronary heart disease and myocardial infarction.8 The ARIC study showed an association between DR and an increased risk of myocardial infarction and coronary heart disease.1,8 These associations are independent of diabetes duration, glycemic control, smoking, lipid profile and other risk factors. The population-attributable risk of retinopathy to heart failure has been estimated to be 30.5% in diabetic patients without a previous history of myocardial infarction and hypertension.1

Furthermore, DR has been consistently associated with microalbuminuria and clinical nephropathy. There is not only a high correlation between changes in the retinal and renal vasculature in DM patients, but the severity of retinopathy has also been demonstrated to correlate with biopsy-proven glomerulopathy.11 Patients with type 1 DM and severe DR at baseline have been shown to have an elevated four-year risk of nephropathy.

Diabetic retinopathy has also been reported as a risk factor for venous thromboembolic events (VTEs).6 However, Heit et al. reported that both DM and DM complications (retinopathy, nephropathy, neuropathy and ketoacidosis) are not independent risk factors for incident VTE. They attributed the increased incidence of VTE in DM patients to hospitalization and confinement to nursing homes. No significant association was found between DM and incidence of VTE when controlled for the mentioned risk factors.6

DR SEVERITY AND THROMBOEMBOLIC EVENTS

Both NPDR and PDR have been linked with diseases such as stroke, coronary heart disease, heart failure and nephropathy,1 leading to an increase in mortality rate among DM patients. Overall, the age-adjusted mortality rate in diabetic patients is twice that of the normal population.

A recent population-based study in the US11 concluded that the ratio of the mortality rates (MR) for individuals with type 2 diabetes was highest for younger patients and declined with increasing age (25-44 years, MR=3.6; 45-64 years, MR=2.2; 64-74 years, MR=1.5). This trend was noted in both sexes and across all ethnicities studied (ie, Hispanic, non-Hispanic, Caucasian, African American).12

The association between DR and mortality is mainly attributed to an increased risk of cardiovascular disease (CVD), and it is suggested that there is a "dose-dependent" relationship between increasing severity of retinopathy and an increased CVD risk.12-19 However, when controlling for CVD risk factors, the increased risk of mortality in type 1 diabetic patients with NPDR disappears, while it still remains twice as high in type 1 diabetics with PDR. If CVD is included, the all-cause mortality in PDR increases by 400% compared to NPDR.9

In patients with type 2 diabetes, the Wisconsin Epidemiological Study of Diabetic Retinopathy (WESDR) study demonstrated that both NPDR and PDR are associated with a 34% to 89% excess risk of death after a 16-year follow-up period.17 These findings were independent of age, sex, diabetes duration, glycemic control and other survival-related risk factors. The ARIC study also reported that the presence of type 2 diabetes in middle-aged white and black Americans with mild NPDR was associated with a two to three times higher risk of ischemic stroke,2 consequently leading to an increase in morbidity and mortality.

CONCLUSIONS

Diabetic retinopathy is a common and vision-threatening complication of DM. Understanding the relationship between DR and systemic vascular diseases is important for healthcare professionals caring for diabetic patients. According to epidemiologic studies, individuals with DM are at higher risk of stroke, myocardial infarction and mortality than non-DM subjects. Age, cardiovascular profile and other variations in susceptibility might contribute to the increased risk of morbidity and mortality in DM patients. RP

REFERENCES

1. Cheung N, Wong TY. Diabetic retinopathy and systemic vascular complications. Prog Retin Eye Res. 2008;27:161-176.
2. Cheung N, Wang JJ, Klein R, Couper DJ, Sharrett AR, Wong TY. Diabetic retinopathy and the risk of coronary heart disease: the Atherosclerosis Risk in Communities Study. Diabetes Care. 2007;30:1742-1746. Erratum in: Diabetes Care. 2007; 30:2762.
3. Targher G, Bertolini L, Zenari L, et al. Diabetic retinopathy is associated with an increased incidence of cardiovascular events in Type 2 diabetic patients. Diabet Med. 2008;25:45-50.
4. Cheung N, Rogers S, Couper DJ, Klein R, Sharrett AR, Wong TY. Is diabetic retinopathy an independent risk factor for ischemic stroke? Stroke. 2007; 38:398-401.
5. Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. Lancet. 2010;376:124-136.
6. Heit JA, Leibson CL, Ashrani AA, Petterson TM, Bailey KR, Melton LJ 3rd. Is diabetes mellitus an independent risk factor for venous thromboembolism?: a population-based case-control study. Arterioscler Thromb Vasc Biol. 2009;29:1399-1405.
7. Mohamed Q, Gillies MC, Wong TY. Management of diabetic retinopathy. JAMA. 2007;298:902-916.
8. Nguyen TT, Wong TY. Retinal vascular changes and diabetic retinopathy. Curr Diab Rep. 2009;9:277-283.
9. van Hecke MV, Dekker JM, Stehouwer CD, et al. Diabetic retinopathy is associated with mortality and cardiovascular disease incidence: the EURODIAB prospective complications study. Diabetes Care. 2005;28:1383-1389.
10. Cheung N, Wang JJ, Rogers SL, et al.; ARIC Study Investigators. Diabetic retinopathy and risk of heart failure. J Am Coll Cardiol. 2008;51:1573-1578.
11. Panzram G. Mortality and survival in type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia. 1987;30:123-131.
12. Gu K, Cowie CC, Harris MI. Mortality in adults with and without Diabetes in a national cohort of the U.S population, 1971-1993. Diabetes Care. 1998;21:1138-1145.
13. Klein R, Zinman B, Gardiner R, et al. The relationship of diabetic retinopathy to pre-clinical diabetic glomerulopathy lesions in type 1 diabetic patients: the Renin-Angiotensin System Study. Diabetes. 2005;54:527-533.
14. Henricsson M, Nilsson A, Heijl A, Janzon L, Groop L. Mortality in diabetic patients participating in an ophthalmological control and screening programme. Diabet Med. 1997;14:576-583.
15. Jager A, van Hinsbergh VW, Kostense PJ, et al. Prognostic implications of retinopathy and a high plasma von Willebrand factor concentration in type 2 diabetic subjects with microalbuminuria. Nephrol Dial Transplant. 2001;16:529-536.
16. Juutilainen A, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Retinopathy predicts cardiovascular mortality in type 2 diabetic men and women. Diabetes Care. 2007; 30:292-299.
17. Klein R, Klein BE, Moss SE, Cruickshanks KJ. Association of ocular disease and mortality in a diabetic population. Arch Ophthalmol. 1999;117:1487-1495.
18. Rajala U, Pajunpää H, Koskela P, Keinänen-Kiukaanniemi S. High cardiovascular disease mortality in subjects with visual impairment caused by diabetic retinopathy. Diabetes Care. 2000;23:957-961.
19. Targher G, Bertolini L, Tessari R, Zenari L, Arcaro G. Retinopathy predicts future cardiovascular events among type 2 diabetic patients: The Valpolicella Heart Diabetes Study. Diabetes Care. 2006;29:1178.
20. Van Hecke MV, Dekker JM, Nijpels G, et al. Retinopathy is associated with cardiovascular and all-cause mortality in both diabetic and nondiabetic subjects: the hoorn study. Diabetes Care. 2003;26:2958.
21. Wong TY, Klein R, Couper DJ, et al. Retinal microvascular abnormalities and incident stroke: Atherosclerosis Risk in Communities Study. Lancet 2001;358:1134-1140.

Yasir J. Sepah, MB, BS, and Brian Cho, MS-II, are medical students at the Johns Hopkins and Georgetown medical schools, respectively. Diana V. Do, MD, is assistant professor of ophthalmology and assistant director of the Retina Fellowship Training Program at Wilmer Eye Institute at John Hopkins. None of the authors reports any financial interest in any products mentioned in this article. Dr. Do can reached at ddo@jhmi.edu.


Retinal Physician, Issue: November 2010