Chang and Sarraf patients (Barber et al 1998). However, it is unclear whether this increased cell death directly causes retinal dysfunction or represents loss of hypo- or non-functional cells. Pathogenesis Hyperglycemia leads to microvascular retinal disease through various postulated mechanisms, including the polyol pathway (Robinson et al 1983), advanced glycation end products (AGE) pathway (Brownlee et al 1988), the renin-angiotensinogen pathway (Deinum et al 1990), the angiogenesis pathway (especially that associated with vascular endothelial growth factor or VEGF) (Ferrara 1995), and pathways associated with oxidative damage (Kunisaki et al 1995). The ﬁrst mechanism, the polyol pathway, is no longer considered an important target for the therapy of DR. Hyperglycemia leads to an increase in aldose reductase enzyme activity and increased sorbitol production causing lens and retinal toxicity by various mechanisms including osmotic effects, breakdown of the blood-retina barrier, and loss of pericytes ( Engerman and Kern 1984; Cheung et al 2005). Aldose reductase inhibitors have shown promise in animal models of DR, but human studies have had limited success (Anonymous 1993b). The other pathogenic pathways hold more promise for future therapies and these are discussed later in this review. Risk factors for the progression of diabetic retinopathy Risk factor modiﬁcation is the single most important inter- vention in decreasing the rate of development and progression of DR. Although the duration of diabetes is a signiﬁcant risk factor, hyperglycemia and hypertension are the most critical modiﬁable risk factors (Jain et al 2003). The Wisconsin Epi- demiologic Study of Diabetic Retinopathy (WESDR) con- ducted a cross sectional population survey and found a linear relationship of A1C level correlated with retinopathy ie,the lower the A1C level the lower the prevalence of retinopathy (Klein et al 1988). The Diabetic Control and Complications Trial (DCCT) showed that type I diabetics prospectively ran- domized to intensive glycemic therapy to maintain HgA1C below 7% had a 76% reduction in development of diabetic retinopathy, 47% reduction in the incidence of severe NPDR or PDR, 23% decreased incidence of macular edema, 54% reduction in the rate of progression of pre-existing diabetic retinopathy, and a 56% decrease in the need for laser therapy (Anonymous 1993a). A long-term sustained beneﬁt of initial intensive glycemic control was demonstrated by the Epide- miology of Diabetes Interventions and Complications Trial 426 (EDIC), an extension of the DCCT with study length of over 10 years (Anonymous 2000b). The United Kingdom Prospective Diabetes Study (UKPDS) conﬁrmed a beneﬁt of intensive glycemic control in decreasing the risk of progression of diabetic retinopathy in older type II diabetics (Anonymous 1998). Subsequent analysis showed that among diabetics who also had hypertension, tighter blood pres- sure control ( 150/85) was as important as glycemic control. Diabetic retinopathy progression and visual acuity decline were reduced by 34% and 47% respectively versus those in the con- trol group (blood pressure 180/105) (Anonymous 1998b). A number of reports have identiﬁed elevated serum lipids as a risk factor for the progression of various features of DR. The WESDR and the ETDRS showed an association between elevated total serum lipid and cholesterol levels and increased hard exudates (Klein et al 1991; Chew et al 1996), a signiﬁ- cant risk factor for moderate vision loss. Subsequent analysis showed that the presence of severe hard exudates was the strongest predictive factor in the development of subretinal ﬁbrosis, an adverse clinical ﬁnding, in patients with DME (Fong et al 1997). Elevated serum triglycerides were also found to be a risk factor for development of high-risk PDR (Davis et al 1998). In a cohort of type 1 diabetics, a positive correlation between DR progression and elevated serum tri- glycerides and negative correlation with serum HDL levels was identiﬁed (Lyons et al 2004). Higher serum cholesterol and triglyceride levels increased the risk for progression of retinopathy while total and LDL cholesterol were positively associated with more severe retinal HE (van Leiden et al 2002). In a prospective, double-blind randomized control trial, reduction of total and LDL cholesterol with simvastatin was associated with a reduction in worsening of vision from in type 1 or 2 diabetics (Sen et al 2002). Pregnancy has been linked to the more rapid progression of DR (Chew et al 1995). Either poorer or paradoxically tighter glycemic control during pregnancy may lead to more rapid progression of DR. Systemic changes (eg, hormonal and cardiovascular), may also account for this observation (Anonymous 2000a). Nevertheless, improved blood glucose control and more stringent DR screening criteria are recom- mended for pregnant diabetics. Microalbuminuria and proteinuria indicative of diabetic nephropathy have been identiﬁed as risk factors for DR progression in some, but not all, studies. Importantly, this may not be a causal relationship, but rather two sequelae of generalized angiopathy caused by changes in enzymatic reduction of heparin sulfate proteoglycan side chains (Deckert et al 1989). Danaparoid sodium, a mixture of Clinical Ophthalmology 2008:2(2)