Using Albuminuria To Predict CV and Renal Outcomes For T2D

The association between 1-year changes in albuminuria and subsequent risk of cardiovascular and renal events in T2D patients. 

Albuminuria is shown to be a good indicator of cardiovascular and renal events through observational research and clinical trials in diabetes. Albuminuria classification into classes (i.e., normal-, micro-, and macroalbuminuria based on urinary albumin-to-creatinine ratio [UACR] values of 0 to 30 mg/g, 30-300 mg/g, and $300 mg/g) is clinically beneficial in stratifying danger and directing treatment decisions. Comprehensive meta-analyses have reinforced the evolving evidence for the role of albuminuria as a renal risk factor and its reduction as a treatment target for kidney disease. Utilizing findings from the LEADER report, this study tested the hypothesis that a decrease in UACR was associated with a reduction in the CV and renal risk in a cohort treated with GLP-1 RA or placebo against the backdrop of control of known CV risk factors and the continued use of RAAS blockade in most participants. 

In brief, the LEADER study included 32 countries that participated in this randomized, double-blind, placebo-controlled trial to test the CV protection of liraglutide at high CV risk in participants with T2D. In addition to standard-of-care treatment, a total of 9,340 patients were randomized to obtain either subcutaneous liraglutide (1.8 mg/day or the maximum tolerated dose of 0.6-1.8 mg/day) or matching placebo 1:1. The duration of treatment was 3.5-5 years, with a follow-up period of 30 days. The primary outcome was the time from randomization to the first occurrence of a composite of major adverse CV events (MACE) consisting of CV death, non-fatal myocardial infarction, or non-fatal stroke. In this post hoc analysis, researchers investigated the risk of MACE (major adverse cardiac events) and a three-component nephropathy composite (doubling of serum creatinine and eGFR,45 mL/min/ 1.73 m2, renal replacement therapy, or renal death) in contributors with a UACR measurement at baseline and one year after randomization.  

Nearly one-half of the patients had an increase in albuminuria during the 1st year of the trial, of whom 12.1% experienced CV events and 2.7% renal events. The remainder of the population had >30% and 30-0% UACR reduction from baseline UACR during the 1st year. An overall reduction in UACR was 3.5% (95% CI), UACR decreased by 15% in the liraglutide group, and there was an estimated increase of 10% in the placebo group. Compared with any increase in UACR, patients with a decrease of up to 30% had a similar risk of MACE (12.1%) with a hazard ratio (HR) of 0.99 (95% CI). For patients with a 1-year reduction in UACR of >30% from baseline, the HR for MACE was 0.82 (0.71, 0.94; P 5 0.006) and 0.67 (0.49, 0.93; P 5 0.02) for the composite nephropathy outcome. The associations between early change and subsequent MACE and renal outcomes were consistent in the liraglutide and placebo groups (P for interaction 5 0.516 and 0.839 for MACE and renal events, respectively). The data for both endpoints in the UACR change groups from 1 year and onward tended to favor liraglutide.  

The results of this post hoc analysis from the LEADER trial indicate that a reduction in UACR from baseline to 1 year predicts future benefits on CV and renal outcomes. For example, a >30% reduction of UACR from baseline was associated with a reduced risk of the composite nephropathy outcome.  Approximately one-third of the LEADER population experienced a substantial reduction (i.e., >30%) of UACR, which was seen more frequently with liraglutide than with placebo. Nevertheless, no treatment interaction was observed with the association of change in UACR and MACE or renal outcomes, indicating that the renal benefit of UACR reduction was not restricted to liraglutide-treated patients alone.  

In conclusion, the current study’s findings with a median follow-up of 3.8 years in a large, contemporary population of T2D patients support the strong association of reductions in UACR with a reduced risk of significant CV and renal outcomes in the high CV and moderate renal risk patients with T2D. The idea of a randomized controlled trial testing lower and higher UACR target levels on major CV and renal outcomes is strongly supported by these results. This study’s uniqueness is that the LEADER trial did not examine RAAS blockade or antihypertensive therapy but rather a pleiotropic treatment for diabetes. In addition to reducing glycemic regulation, blood pressure, and lipid levels in diabetes treatment recommendations, this supports an emphasis on albuminuria reduction as an overall clinical treatment objective. At present, the downside is that there is a lack of prospective intervention research targeting higher and lower UACR targets and evaluating renal and CV results equivalent to intensive versus normal blood pressure or glycemic control goals. To develop effectively tailored treatments, we need a better mechanistic understanding of the likely harm caused by albuminuria. 

Practice Pearls: 

• There is a need for a better mechanistic understanding of the potential damage caused by albuminuria to develop appropriately targeted therapies.  
• There should be a focus on albuminuria reduction as an overall clinical treatment goal alongside reducing glycemic, blood pressure, and lipid levels in T2D treatment. 
• A reduction in UACR from baseline to 1 year predicts future benefits on CV and renal outcomes.

References for “Using Albuminuria To Predict CV and Renal Outcomes For T2D”:
Persson, Frederik, et al. “Changes in Albuminuria Predict Cardiovascular and Renal Outcomes in Type 2 Diabetes: A Post Hoc Analysis of the LEADER Trial.“ Diabetes Care, American Diabetes Association, January 26, 2021 

Hertzel C. Gerstein, MD. “Albuminuria and Risk of Cardiovascular Events, Death, and Heart Failure in Diabetic and Nondiabetic Individuals.“ JAMA, JAMA Network, July 25, 2001 

Shalonda Kimble, PharmD Candidate, South College School of Pharmacy 

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