Reduction of albuminuria in type 1 diabetes does not mean reduction in cardio-renal risk

Once again, the priceless resource that is the DCCT/EDIC study has been used to shed light on a vexed question in diabetic nephropathy research. The association between increasing albuminuria and cardio-renal risk was established in the 1980s, and was confirmed in people without diabetes in recent meta-analyses (Fox et al, 2012). Broadly speaking, cardiovascular mortality is doubled in those with moderately increased albuminuria (≥30 mg/day; previously known as microalbuminuria) and at least doubled again in those with severe albuminuria (≥300 mg/day; previously known as macroalbuminuria or clinical nephropathy).

The risks for end-stage renal disease (ESRD) are even greater with increasing albuminuria, although many die of cardiovascular disease before reaching ESRD. Both improved glycaemic and blood pressure control (mainly with renin–angiotensin system [RAS]-blocking agents) have been shown to reduce cardio-renal risk (Maione et al, 2011; Fullerton et al, 2014), although the results are relatively modest and take many years to become apparent. 

Post hoc analyses of these studies have shown that the greatest benefit is seen in those with (mainly) severe albuminuria, who show the greatest reduction following therapeutic intervention (Heerspink et al, 2015). This has led some to call for reduction in albuminuria to be an accepted surrogate endpoint for intervention trials. This proposition has been debated for many years, and has been the subject of editorials and conferences (Levey et al, 2009). So far, regulatory authorities have been unwilling to adopt the proposal. Does this latest analysis from the DCCT/EDIC Research Group help in any way?

The frontline results from the study are summarised alongside. Essentially, in an original cohort of 1441 people with type 1 diabetes, 355 developed moderate (micro) albuminuria; 171 remitted to normoalbuminuria (normo) and, subsequently, 43 reverted back to moderate. 157 progressed from moderate to severe (macro), 22 from normo, and 1 from remitted moderate to severe. Cardiovascular event rates were no different from those with sustained or remitted moderate albuminuria, with about a two-fold increase in hazard ratio (HR) compared to patients with normoalbuminuria. 

Similarly, HRs for a reduced eGFR of ≤60 mL/min/1.73 m² were the same for sustained and remitted moderate albuminuria, at around 3 compared to normoalbuminuria. Predictably, severe albuminuria had a much higher HR of 25.5 for reduced eGFR (these results being lower than those reported in the abstract as they relate to a fully adjusted model taking into account smoking status, RAS blocker use and achieved HbA_1c). 

The strengths of this analysis are the comprehensive and complete dataset, as well as the long duration of follow-up (>27000 person-years at risk). The main weaknesses are the relatively low number of events (although these rates are consistent with recently published data from other cohorts; Groop et al, 2009), and the limitation to type 1 diabetes. In addition, the analysis concentrated on a categorical change in albuminuria status. This means that a person could be classed as remitting if albumin excretion rate (AER) fell from 31 to 29 mg/day, but not if it reduced from 299 to 31 mg/day. Moreover, the definition of normoalbuminuria is arbitrary and historic; there is a near linear relationship between AER 10–30 mg/day and cardiovascular risk (Fox et al, 2012). It would, therefore, be interesting to repeat the analysis using percent change rather than categorical change in AER.

For practical and ethical reasons, there is unlikely to be a prospective trial with different levels of AER as an outcome. So, we are limited to post hoc analyses of intervention trials, and even those as thorough as DCCT/EDIC can never provide a definitive answer. As a result, this analysis does not support the concept of a reduction of AER as a valid surrogate outcome measure of cardio-renal benefit, at least in type 1 diabetes. The diabetes and nephrology communities need to come up with novel strategies to resolve this question.

To read the article summaries, please download the PDF