May 13, 2020
3 min read

HbA1c likely mediates liraglutide’s CV benefit

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John Buse
John Buse

Change in HbA1c is likely the greatest mediator of the effect of the GLP-1 receptor agonist liraglutide on cardiovascular disease for adults with poorly controlled type 2 diabetes who are at high CV risk, according to findings from an exploratory analysis of the LEADER trial published in Diabetes Care.

“The paper reflects an attempt to understand the mediator of the effect of liraglutide, primarily on cardiovascular disease,” John Buse, MD, PhD, director of the Diabetes Center, director of the North Carolina Translational and Clinical Sciences Institute, and executive associate dean for clinical research at the University of North Carolina School of Medicine in Chapel Hill, told Healio. “A variety of approaches were used. They all came up with the same answer — mediation was largely based on change in HbA1c. There are a multitude of reasons why it is more likely that HbA1c is really a marker of the mediator that was unmeasured in the study. One such mediator could be protocol adherence; however, there are certainly others downstream of the GLP-1 receptor. At the end of the day, the paper leaves us with questions about what is the real mechanism of benefit for liraglutide for CVD.”

Buse and colleagues performed exploratory analyses to identify potential mediators of the effect of liraglutide (Victoza, Novo Nordisk) on major adverse CV events, defined as a composite of CV death, nonfatal myocardial infarction and nonfatal stroke, using data from the LEADER trial, a double-blind, randomized controlled trial assessing data from 9,340 participants aged at least 50 years with poorly controlled type 2 diabetes. As Healio previously reported, researchers randomly assigned participants daily liraglutide 1.8 mg (n = 4,668) or placebo injection (n = 4,672). Participant characteristics were similar across groups (mean age, 64 years; 64% men; mean diabetes duration, 13 years; mean HbA1c, 8.7%; mean BMI, 32.5 kg/m²); 73% had prior CVD. Median follow-up was 3.8 years, and median exposure to the study drug was 3.5 years.

Mediators assessed were HbA1c, body weight, urinary albumin to creatinine ratio, confirmed hypoglycemia, sulfonylurea use, insulin use, systolic blood pressure, and LDL cholesterol.

Change in HbA1c is likely the greatest mediator of the effect of the GLP-1 receptor agonist liraglutide on cardiovascular disease for adults with poorly controlled type 2 diabetes who are at high CV risk.
Source: Adobe Stock

“These candidates were selected as CV risk factors on which liraglutide had an effect in LEADER such that a reduction in CV risk might result,” the researchers wrote.

Researchers used several mediation methods to analyze data, including a new statistical methodology, the Vansteelandt method, designed to integrate sequential confounders.

In analyses using Cox modeling, researchers found that HbA1c mediated the effect of liraglutide on a first major adverse CV event by 41.1% (95% CI, 8.6-161) and urinary albumin to creatinine ratio mediated the effect by 28.6% (95% CI, 12.3-132.8).


Mediation analysis using the Vansteelandt method similarly indicated that HbA1c was the “most promising candidate” among those studied as a potential mediator. In analyses using the Vansteelandt method, researchers found that HbA1c mediated the effect of liraglutide by 82% (95% CI, 11.7-449.3), with the direct effect of liraglutide accounting for the remaining 18% of the total observed CV benefit.

“When adjusted for HbA1c, the survival curve (proportion of patients without a major adverse CV event) for patients randomized to liraglutide treatment shifted down toward the placebo curve,” the researchers wrote. “This indicated a reduced CV benefit in the liraglutide group when the difference in HbA1c between the liraglutide and placebo groups was modeled as a mediator for the major adverse CV events results.”

Mediation effects were small for other candidates, according to researchers.

The researchers noted that the analyses cannot distinguish between the possibilities that HbA1c could be a mediator or a marker of unmeasured factors that are also affected by treatment with liraglutide and that themselves affect CV outcomes.

“For example, a large change in HbA1c could be indicative of adherence to treatment, including concomitant medications,” the researchers wrote. – by Regina Schaffer

For more information:

John Buse, MD, PhD, can be reached at the University of North Carolina School of Medicine, Burnett-Womack 8027, 160 Dental Circle, Chapel Hill, NC 27599-7172; email:

Disclosures: Novo Nordisk funded the LEADER trial and this post hoc analysis. Buse reports he receives research support from or serves as an adviser for Adocia, AstraZeneca, Boehringer Ingelheim, Cirius Therapeutics Inc, CSL Behring, Dance Biopharm, Dexcom, Elcelyx Therapeutics, Eli Lilly, Intarcia, Johnson & Johnson, Lexicon, MannKind, Metavention, NovaTarg, Novo Nordisk, Neurimmune AG, Pendulum Therapeutics, Sanofi, Senseonics, Stability Health, Theracos, Tolerion, vTv Therapeutics and Zafgen and holds stock options in Mellitus Health, Pendulum Therapeutics, PhaseBio and Stability Health. Please see the study for all other authors’ relevant financial disclosures.