In a post hoc analysis of 8,879 participants from a large RCT, we observed a strong association between annual change in kidney function and the future risk of major clinical outcomes in type 2 diabetes. We found that an annual substantial decrease in eGFR over 20 months exhibited a statistically significant association with increased risks of major renal events, major macrovascular events and all-cause mortality, independent of baseline kidney function, albuminuria and other covariates, consistently observed across various patient subgroups of covariates. Although an annual substantial increase in eGFR did not significantly predict the risk of these outcomes, our results from multiple analyses supported the utility of eGFR slopes for predicting the subsequent vascular outcomes and all-cause death in type 2 diabetes.
A limited number of studies have shown the relationship between eGFR slopes and the subsequent risk of ESKD [10, 21], cardiovascular disease [11, 22] and all-cause mortality [12,13,14]. Results from a meta-analysis of 13 CKD cohorts showed that an eGFR slope of −3 vs 0 ml min−1 (1.73 m)−2 year−1 over 3 years was associated with the risk of ESKD (HR 1.73 [95% CI 1.50, 2.00]) after adjusting for last measurement of eGFR . In a cohort of 529,312 adults in the Alberta Kidney Disease Network, an eGFR slope of −4 ml min−1 (1.73 m)−2 year−1 was associated with 74%, 16% and 21% higher risks of congestive heart failure, acute myocardial infarction and stroke, respectively, compared with no change in eGFR . In a cohort of French individuals with type 2 diabetes, annual eGFR decline over 6.3 years of follow-up was greater in individuals with major cardiovascular events compared with those without (−3.0 vs −1.7 ml min−1 [1.73 m]−2 year−1) . Furthermore, a meta-analysis of 12 CKD cohorts within the CKD Prognosis Consortium showed that an eGFR slope of −6 vs 0 ml min−1 (1.73 m)−2 year−1 over 3 years was associated with an adjusted HR for all-cause mortality of 1.25 (95% CI 1.09, 1.44) after adjusting for last measurement of eGFR . However, these results were mostly based on general or CKD populations. Therefore, the current study was notable for evaluating the composite outcome of major renal and macrovascular events and all-cause mortality in a large population with type 2 diabetes after adjusting for important risk factors of kidney disease progression.
Various mechanisms have been suggested to explain why declining kidney function is associated with increased risk of cardiovascular disease and all-cause mortality as well as renal outcome. Decrease in eGFR may exacerbate cardiovascular risk factors such as BP and lipids . Other possible factors which were not measured in our cohort include activation of the RAAS, endothelial dysfunction, inflammation and oxidative stress [24, 25]. On the other hand, these risk factors and progression of cardiovascular disease certainly accelerate the progression of CKD . In addition, worsening kidney function may cause decreased appetite, decreased physical function and overall frailty, and indirectly result in higher mortality risk .
There has been increasing interest in the utility of eGFR slope as a surrogate endpoint for predicting subsequent ESKD in clinical trials, but a clear definition of the magnitude of eGFR slope as a surrogate endpoint has not been established. The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guideline defined rapid eGFR decline as a sustained decline in eGFR of greater than −5 ml min−1 (1.73 m)−2 year−1 , which was supported by other studies [10, 21]. A number of studies already used eGFR slope greater than −5 ml min−1 (1.73 m)−2 year−1 as a substitute for kidney outcome, which suggested the potential of eGFR slope of −5 ml min−1 (1.73 m)−2 year−1 as a surrogate endpoint. However, in the present study (approximately 80% had early-stage diabetic kidney disease at baseline with eGFR ≥60 ml min−1 [1.73 m]−2 and UACR <300 μg/mg), only 1.4% of participants developed eGFR decline greater than −5 ml min−1 (1.73 m)−2 year−1. Instead, more than fivefold participants developed eGFR slopes of −3 vs −5 ml min−1 (1.73 m)−2 year−1 and their risks of major renal events were weaker but still robustly increased. Therefore, the potential of using eGFR slopes less than −5 ml min−1 (1.73 m)−2 year−1 may be a future subject to be assessed for seeking more practical surrogate endpoints in people with type 2 diabetes.
The standard duration for estimating eGFR slopes is also unknown. We excluded the first 4 months after randomisation from the eGFR slope ascertainment period, in order to remove an acute pharmacological effect of ACEi on eGFR. RAAS blockers, including ACEis and ARBs, are largely known to prevent the onset and progression of diabetic kidney disease and improve survival rate in people with diabetes [28,29,30]. During the initiation of RAAS blockers, there may be an acute fall in eGFR [19, 31], because RAAS blockers inhibit angiotensin 2-mediated renal vasoconstriction which in turn causes a reduction in intraglomerular pressure and filtration fraction. Thus, in people starting RAAS blockers, changes in eGFR over time should be evaluated separately during the initial months when an acute fall in eGFR is observed, and during subsequent periods until the end of follow-up.
Currently, both 30% and 40% declines in eGFR are widely accepted as surrogate endpoints for CKD progression, based on a series of meta-analyses and simulations [8, 9]. In this study, similar associations were observed when using percentage change in eGFR and eGFR slope, and the discrimination statistics in the model including eGFR slope were similar to those using percentage change in eGFR for predicting major clinical outcomes. This may be consistent with a previous report . The eGFR slope can potentially reflect the course of changes in kidney function more accurately than percentage change in eGFR, because the slope takes into account all of the available eGFR measurements of an individual over time. Our study indicated that evaluating eGFR slope in an individual might be a promising alternative to percentage change in eGFR for predicting the progression of diabetic kidney disease.
Recently, a number of clinical trials have assessed the effects of sodium glucose cotransporter 2 inhibitors in people with type 2 diabetes. Among the trials with similar baseline renal characteristics to our cohort, the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program (mean eGFR 77 ml min−1 [1.73 m]−2 [SD 21]) reported that participants allocated to the placebo group had a mean annual long-term decline in eGFR of −0.9 ml min−1 (1.73 m)−2 year−1 . The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose (EMPA-REG OUTCOME) trial (mean eGFR 74 ml min−1 [1.73 m]−2 ) observed a mean annual change in eGFR of −1.46 ml min−1 (1.73 m)−2 year−1 in the placebo group . Our cohort included a lower-risk population showing slower decline in eGFR compared with these trials.
The strengths of our study include the large number and diverse groups of participants, the long duration of follow-up, the sequential measurements of eGFR during the ADVANCE trial and the ability to adjust for multiple important risk factors. Also, we used linear mixed models, which are more robust than ordinary linear regression models, to estimate eGFR slopes and assess changes over time in participants with varying intervals between measurements . However, our study has several limitations. First, as our study cohort was derived from a randomised trial, the results may limit generalisability to broader populations. Second, only 84% of the participants alive at the end of the ADVANCE trial were enrolled in the post-trial follow-up (ADVANCE-ON trial). However, baseline characteristics of those included in the ADVANCE-ON trial were similar to those of the entire trial population . Third, we used eGFR instead of a directly measured GFR to calculate GFR slopes, which may lead to some misclassification of true course of change in kidney function [36, 37]. Finally, our models to estimate eGFR slopes did not consider non-linear and time-varying patterns of eGFR decline. However, a previous study showed that slopes were linear for 83% of individuals with diabetes and normal kidney function . Also, estimating eGFR slope may be subject to measurement error including regression to the mean .
In conclusion, an annual substantial decrease in eGFR over 20 months was strongly associated with the future risk of renal and cardiovascular events and all-cause mortality in type 2 diabetes, supporting the potential for using eGFR slope as a predictor for major clinical outcomes. The present analysis suggests that monitoring eGFR over time is beneficial to identifying individuals with diabetes at high risk of vascular outcomes and all-cause death, requiring close monitoring for early initiation of appropriate preventive and therapeutic strategies.