Mann JFE;Orsted DD;Brown-Frandsen K;Marso SP;Poult Liraglutide and Renal Outcomes in Type 2 Diabetes. N Engl J Med. 2017 Aug 31;377(9):839-848. doi: 10.1056/NEJMoa1616011.
Area Score
Family Medicine (FM)/General Practice (GP)
General Internal Medicine-Primary Care(US)
Internal Medicine
Cardiology
Endocrine
Nephrology
Abstract

BACKGROUND: In a randomized, controlled trial that compared liraglutide, a glucagon-like peptide 1 analogue, with placebo in patients with type 2 diabetes and high cardiovascular risk who were receiving usual care, we found that liraglutide resulted in lower risks of the primary end point (nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) and death. However, the long-term effects of liraglutide on renal outcomes in patients with type 2 diabetes are unknown.

METHODS: We report the prespecified secondary renal outcomes of that randomized, controlled trial in which patients were assigned to receive liraglutide or placebo. The secondary renal outcome was a composite of new-onset persistent macroalbuminuria, persistent doubling of the serum creatinine level, end-stage renal disease, or death due to renal disease. The risk of renal outcomes was determined with the use of time-to-event analyses with an intention-to-treat approach. Changes in the estimated glomerular filtration rate and albuminuria were also analyzed.

RESULTS: A total of 9340 patients underwent randomization, and the median follow-up of the patients was 3.84 years. The renal outcome occurred in fewer participants in the liraglutide group than in the placebo group (268 of 4668 patients vs. 337 of 4672; hazard ratio, 0.78; 95% confidence interval [CI], 0.67 to 0.92; P=0.003). This result was driven primarily by the new onset of persistent macroalbuminuria, which occurred in fewer participants in the liraglutide group than in the placebo group (161 vs. 215 patients; hazard ratio, 0.74; 95% CI, 0.60 to 0.91; P=0.004). The rates of renal adverse events were similar in the liraglutide group and the placebo group (15.1 events and 16.5 events per 1000 patient-years), including the rate of acute kidney injury (7.1 and 6.2 events per 1000 patient-years, respectively).

CONCLUSIONS: This prespecified secondary analysis shows that, when added to usual care, liraglutide resulted in lower rates of the development and progression of diabetic kidney disease than placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048 .).

Comments from MORE raters

Endocrine rater

CKD is a disease that is chronic and progressive in nature and eventually leads to ESRD. We cannot reverse this process, but reduction of progression from earlier stages to stage V (in eGFR category) remains the main target of CKD management. One of the most important complications of diabetes is CKD. It is good to know that liraglutide, a GLP-1 agonist, along with glucose and cardiovascular disease lowering, reduces progression to ESRD, but the study was funded by the manufacturer of liraglutide. A large-scale multicenter trial is required before applying this to clinical practice.

Endocrine rater

While this study is impressive and, if independently confirmed, probably has important implications for clinical practice, I have my usual concern about any industry-sponsored study. Further, we will need much longer follow-up to see whether gains continue and result in ultimately improved long-term outcomes. While I know it`s just a pipe dream, we need such studies to be vetted and conducted by a central impartial lead.

Family Medicine (FM)/General Practice (GP) rater

These results call for an early administration of this costly agent beyond RAS inhibitors and tight glycemic control in high-risk patients.

Internal Medicine rater

It appears that the results were driven by the composite endpoint.

Internal Medicine rater

Liraglutide is now good for CV risk reduction, renal protection, and weight loss.

Internal Medicine rater

The absolute differences are modest but showed themselves over a fairly short time-frame and are probably important. This coupled with other end-organ benefits, such as in NASH, may play a role in therapeutic selection.

Nephrology rater

This is a secondary analysis of an RCT showing reduction in progression of albuminuria with no progression protection in terms of GFR decline. It remains to be seen whether any of the newer agents protect from progression to ESRD.

Nephrology rater

Ultimately a disappointing result. The effect on albuminuria was not accompanied by an effect on doubling of creatinine or incidence of ESRD, especially given the previous result: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4985288/ For now empagliflozin appears to have a more significant effect on renal outcomes: https://www.ncbi.nlm.nih.gov/pubmed/26378978

Nephrology rater

This is a very well conducted and reported study. These renal results are primarily driven by new macroalbuminuria. This work appears in context of Wanner and colleagues' report on renal effects of empagliflozin, which showed statistically significant decrease in doubling of creatinine or ESRD, and decrease in ESRD (small numbers of outcomes, and borderline statistical significance for the latter). N Engl J Med 2016; 375:323-334July 28, 2016DOI: 10.1056/NEJMoa1515920 It appears that similar numbers of people with GFR <60 (around 2000) were recruited into each study. There were more doubling of creatinine and ESRD events in the liraglutide study than in the empagliflozin study, and the best estimate of effect in the liraglutide study is modest (around 0.89) and not statistically significant, so the reason for no difference in GFR-based events seems unlikely to be power.