The degree of retinopathy is equally predictive for renal and macrovascular outcomes in the ACCORD Trial
Introduction
Diabetic microvascular complications of the eye and kidney are similar in their risk factor profiles and share some mechanisms in their pathogenesis (Brownlee, 2005, Ravid et al., 1998, Yau et al., 2012). Numerous studies have examined the association of retinopathy with diabetic kidney disease, but the vast majority of these have been of cross sectional design. In type 2 diabetes, the presence versus absence of any diabetic retinopathy (DR) gives an adjusted odds ratio of between 2.5 and 3.3 for the presence of macroalbuminuria (defined as a urine albumin:creatinine ratio > 300 ug/mg) (El-Asrar et al., 2001, Romero-Aroca et al., 2010). Similar results have been obtained in studies examining the association of DR with decreased estimated glomerular filtration rate (eGFR), defined as < 60 ml/min/1.73 m2 (Mottl et al., 2012, Penno et al., 2012). In a step-wise fashion, more severe retinopathy is increasingly associated with diabetic kidney disease. The presence of proliferative retinopathy carries an odds ratio for concurrent macroalbuminuria or decreased eGFR as high as 17-fold (El-Asrar et al., 2001, Mottl et al., 2012).
A strong relationship between DR and cardiovascular (CV) disease has also been well established. In prospective observational cohorts of people with type 2 diabetes, the presence of any DR versus no DR is associated with an adjusted hazard ratios of 2.3 for stroke, (Cheung, Rogers, Couper, et al., 2007) 2.5 for heart failure, (Cheung, Wang, Rogers, et al., 2008) and 2.2–3.3 for cardiovascular death (Cheung, Wang, Klein, et al., 2007, Liew et al., 2009). Longitudinal studies have found more severe retinopathy to result in adjusted hazard ratios of 1.7–3.8 for combined fatal and nonfatal ischemic CV endpoints (Cheung, Wang, Klein, et al., 2007, Gerstein et al., 2012, Gimeno-Orna et al., 2009, Targher et al., 2008).
The similarity in risk estimates for diabetic kidney and CV outcomes in the setting of retinopathy might suggest a similar or shared pathogenesis for micro- and macrovascular complications of diabetes. Although an overlap in their pathobiology likely exists, there are also data to suggest that there is some distinction. The association between retinopathy and CV events has been noted to be of similar magnitude, regardless of diabetes type, (Kramer, Rodrigues, Canani, et al., 2011) however, the link between retinopathy and nephropathy is considered to be significantly greater in type 1 versus type 2 diabetes (Wolf, Muller, Mandecka, et al., 2007). It has been suggested that kidney disease in type 2 diabetes is more heterogeneous than in type 1 diabetes, with a greater prevalence of tubulointerstitial versus glomerular lesions, (Fioretto, Mauer, Brocco, et al., 1996) and a higher prevalence of normoalbuminuric chronic kidney disease (NA-CKD) (Macisaac & Jerums, 2011). Whether these distinctions in the clinical and pathologic characteristics in type 2 diabetes explain the weaker association of retinopathy with kidney disease than in type 1 diabetes is unknown.
Given the uncertainty over the specificity of DR for renal versus CV disease, we sought to compare the relative incidence of these events according to the severity of retinopathy. Detailed analyses of the association of DR with incident CV events in the ACCORD trial have been previously published (Gerstein et al., 2012). Given the assumption that DR has greater overlap in pathogenesis with other diabetic microvascular complications, such as kidney disease, we hypothesized that kidney outcomes should occur at a greater relative frequency compared to CV outcomes in participants with more severe retinopathy. A simplistic approach to this question could include fitting separate survival models for kidney and CV outcomes, using the resulting hazard ratios to compare associations with DR, however, such a comparison ignores the increased risk of CV events associated with the development of chronic kidney disease (CKD) (Hemmelgarn et al., 2010, Weiner et al., 2004). In circumstances where one event modifies the risk for another event, treating the outcomes as competing risks can be more appropriate (Noordzij, Leffondre, van Stralen, et al., 2013). Therefore in the present study, we used competing risks techniques to compare the relative incidence of CV and renal outcomes, focusing on which event occurs first in subgroups of participants from the ACCORD trial, stratified by severity of DR.
Section snippets
Study population
The design of the ACCORD trial and ACCORD Eye Study have been previously reported (Buse et al., 2007, Chew et al., 2007). Briefly, middle-aged and elderly people with type 2 diabetes, hemoglobin A1c (HbA1c) levels ≥ 7.5% and known CV disease or additional CV risk factors were recruited from 77 clinical centers. Exclusion criteria included BMI > 45 kg/m2 and SCr > 132.6 μmol/L (1.5 mg/dL). Participants were randomized to the intensive glucose-lowering trial as well as an intensive blood pressure-lowering
Results
Of the 3,472 participants recruited for the ACCORD Eye Study, 3,210 had complete baseline covariate data and complete follow-up for both kidney and cardiovascular outcomes. At baseline, 1,628, 587, 955 and 40 participants had no, mild, moderate, and severe DR, respectively. Sociodemographic and clinical characteristics of the participants, stratified by category of DR severity are displayed in Table 1. The prevalence of macular edema did not differ amongst the four categories of DR. The
Discussion
The novel finding in this study is that the incidence of CV versus renal endpoints was not different within strata of retinopathy status, indicating a similar strength in the association of retinopathy with renal versus CV outcomes. Comparison of kidney and CV outcomes is complex, as kidney disease is a strong risk factor for CV events (Hemmelgarn et al., 2010) and death often occurs prior to the progression of renal failure (Adler, Stevens, Manley, et al., 2003). The use of a competing risk
Acknowledgments
AKM designed the analyses, interpreted the results and wrote the manuscript. NP designed the analyses, performed all statistical analyses, interpreted the results and reviewed and contributed to the writing of the manuscript. CVF, FIB, EC, WTA, CG, US, JB designed the study, collected the data, reviewed and contributed to the writing of the manuscript. AKM and NP are the guarantors of the manuscript.
Contents of this manuscript appeared in abstract/poster form at the 74th Scientific Sessions of
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The authors have no conflict of interest to report.