Lixisenatide Renal Benefit in Diabetes With Macroalbuminuria

Liam Davenport

October 04, 2018

BERLIN — The injectable glucagon-like peptide (GLP-1) agonist lixisenatide (Lyxumia, Sanofi) may protect patients with type 2 diabetes who have cardiovascular disease from developing kidney damage, although the effect is most pronounced in those who already have macroalbuminuria, suggests a post-hoc analysis of the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial.

Marcel H. A. Muskiet, MD, Diabetes Center, VU University Medical Center Amsterdam, the Netherlands, presented the new data here at the European Association for the Study of Diabetes (EASD) 2018 Annual Meeting, which were also simultaneously published in The Lancet Diabetes & Endocrinology.

The findings indicate that the urinary creatinine-to-albumin ratio was significantly reduced by a 39% in patients with type 2 diabetes and macroalbuminuria who took lixisenatide compared with placebo, and a borderline significant 21% for the same comparison in those with microalbuminuria.

At a press conference, Muskiet said the "effect on albuminuria progression is maintained after adjustment for the traditional risk factors, namely HbA1c, systolic blood pressure, and body weight."

So "in patients with type 2 diabetes without severe renal impairment but with a recent acute coronary syndrome (ACS), the addition of lixisenatide to usual care...improved the burden of micro- and macroalbuminuria beyond glycemic control."

Muskiet believes that this is a promising finding for patients with type 2 diabetes and diabetic kidney disease as novel treatment strategies are required. And he noted that the findings "are very much in line with the data already shown [for other GLP-1 agonists, liraglutide] in LEADER and [semaglutide] in SUSTAIN-6. This effect on the renal system and perhaps also directly or indirectly on the cardiovascular system should be looked into in further trials."

SGLT2 Inhibitors Best for Kidney? Dedicated Renal Trials Needed

In an accompanying comment, Muh Geot Wong, MD, PhD, Meg Jardine, MD, PhD, and Vlado Perkovic, MD, PhD, from The George Institute for Global Health, University of New South Wales, Sydney, Australia, agree that the new findings from ELIXA are "particularly consistent" with those of other GLP-1 agonists.

Asking what this means for the future of type 2 diabetes care, they write that GLP-1 agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors, and sodium glucose cotransporter 2 (SGLT2) inhibitors "all seem to reduce albuminuria levels in people with type 2 diabetes, with potentially greater effects in participants with macroalbuminuria."

"Although growing evidence suggests that this effect will translate into major benefits for kidney function and the risk of kidney failure for SGLT2 inhibitors, no clear and consistent effects of DPP-4 inhibitors or GLP-1 receptor agonists on kidney failure have been reported to date."

The data for SGLT2 inhibitors in this regard are beginning to accumulate, they point out, including results from the CANVAS/CANVAS-R and EMPA-REG OUTCOME studies (of the SGLT2 inhibitors canagliflozin and empagliflozin, respectively), which "demonstrated marked reductions in the risk of secondary composite outcomes comprised of doubling of serum creatinine, end-stage kidney disease, or renal death."

And the CREDENCE trial of canagliflozin in patients with type 2 diabetes and established nephropathy "was recently stopped early for efficacy, supporting the likelihood of an important role for SGLT2 inhibitors in renal protection in type 2 diabetes."

"Further renal outcome trials with dapagliflozin (DAPA-CKD) and empagliflozin (EMPA-KIDNEY) are underway that will also assess effects in people with nondiabetic kidney disease," they note.

Wong and colleagues therefore underline that dedicated trials looking at the effect of DPP-4 inhibitors and GLP-1 agonists on diabetic kidney disease are needed. The results of one such trial, CARMELINA, with the DPP-4 inhibitor linagliptin, will be reported here at the EASD meeting. More than 60% of participants in CARMELINA had chronic kidney disease at baseline.

Studies of combinations of, for example, an SGLT2 inhibitor and GLP-1 receptor agonist, will also be "key," they add.

"Most importantly, the accumulating evidence regarding the relative benefits of different classes of glucose-lowering drugs on the kidney should be incorporated into treatment decisions to produce better outcomes for people with type 2 diabetes," they assert.

Approached for comment, Per-Henrik Groop, MD, DMSc, professor of nephrology, Helsinki University Hospital, Finland, told Medscape Medical News that he believes the evidence is strongest for SGLT2 inhibitors having a greater renal benefit than GLP-1 agonists.

The reason, says Groop, is that SGLT2 inhibitors primarily work in the kidney, blocking glucose and sodium reabsorption in the proximal tubule, thus controlling renal hemodynamics and protecting the kidney from hypoxia.

Although GLP-1 receptor agonists also have a strong effect on sodium–hydrogen transport in the proximal tubule, their effect on kidney function is partially mitigated by the drugs also reducing tone in the afferent renal artery, he explained.

"Yes, GLP-1 agonists have an effect on the kidney, but it might be that we see it only in those with pronounced kidney disease, and the problem with ELIXA is that it had a small number of patients with macroalbuminuria." In addition, lixisenatide "is not the most potent GLP-1 agonist," he observed.

Post-Hoc Renal Analysis of ELIXA

Muskiet began his presentation by pointing out that up to 40% of patients with type 2 diabetes will develop diabetic kidney disease, and despite a range of multifactorial treatment strategies, patients still have a high residual cardiorenal risk.

Moreover, a large proportion of patients do not reach treatment goals, with for example, around 90% not reaching the target HbA1c of less than 6.5% and more than half failing to achieve a systolic blood pressure of less than 130 mmHg.

In the original ELIXA trial, patients with type 2 diabetes and a recent acute coronary event (in the previous 180 days) were randomized in a double-blind fashion to lixisenatide (n = 3034) or placebo (n=3034) in addition to standard cardiovascular and diabetes therapy, alongside diet and lifestyle counseling. The primary endpoint was major adverse coronary events.

Median follow-up was 108 weeks.

For the current post-hoc analysis, the team set out to examine the long-term effect of lixisenatide on renal outcomes, stratified by baseline urinary albumin-to-creatinine ratio (UACR).

Muskeit said that at the beginning of the study 4441 (74%) patients had normoalbuminuria (UACR < 30 mg/g), 1148 (19%) had microalbuminuria (UACR ≥ 30 mg/g to <300 mg/g), and 389 (7%) had macroalbuminuria (UACR ≥ 300 mg/g).

As expected, the duration of type 2 diabetes was longer in patients with macroalbuminuria, at 14.2 years, than in those with microalbuminuria, at 11.5 years, and those with normoalbuminuria, at 8.3 years.

A greater proportion of patients with macroalbuminuria had moderate renal impairment, or an estimated glomerular filtration rate (eGFR) ≥ 30 to < 60 mL/min/1.73 m2, at 52.6%, versus 30.7% for those with microalbuminuria and 18.6% for those with normal albumin.

During the study period, treatment with lixisenatide had no significant impact on eGFR compared with placebo, regardless of albuminuria category at baseline.

The results were different, however, when researchers looked at the effect of lixisenatide on changes in UACR stratified by baseline albuminuria status. The original trial had indicated that the change in UACR across the whole study population was not significant, a finding that was consistent in the 74% of patients who had normoalbuminuria (P = .1974 for trend).

But in patients with microalbuminuria, the reduction in UACR with active [lixisenatide] treatment approached significance (P = .0889 for trend), and for those with macroalbuminuria, it cleared that hurdle (P = .0163).

The effects were more marked when the team looked at percentage change in UACR from baseline to week 108 with lixisenatide versus placebo.

Patients with normoalbuminuria had a negligible reduction in UACR of -1.89 (P = .7398), which increased to a borderline significant -21.10% in patients with microalbuminuria (P= .0502) and a significant -39.18% in those with macroalbuminuria (P = .007).

Overall, lixisenatide was associated with a significant reduction in the incidence of macroalbuminuria versus placebo, at a hazard ratio of 0.815 (P = .0485) when adjusted for baseline and on-trial HbA1c levels.

The editorialists observe that there were too few events of established hard renal endpoints (for example, end-stage kidney disease eGFR < 15 mL/min/1.73m2 or doubling of serum creatinine) "for any meaningful interpretation but no effect in either direction was identified."

CVOTs for Type 2 Diabetes Drugs Designed to Show Safety, not Efficacy

In a discussion following Muskiet's presentation, session co-chair, Samy Hadjadj, MD, professor of endocrinology and diabetes, Centre Hospitalier Universitaire de Poitiers, France, pointed out that, unlike other GLP-1 agonist post-marketing cardiovascular outcomes trials, ELIXA did not show cardiovascular benefits for lixisenatide.

As reported by Medscape Medical News at the time, there was no significant differences in the primary composite outcome of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina between patients taking lixisenatide and placebo, at a hazard ratio of 1.02.

Asked why that could be the case and yet the study now shows renal benefits, Muskiet pointed out that "these studies were set-up primarily by the US Food and Drug Administration mandate to show safety and not a benefit."

"As the ELIXA trial was one of the first trials out there, there was a very high risk at baseline [with patients having had recent ACS]," he explained, adding that the event rate was extremely high and "we believe that this may have driven the neutral effect" of lixisenatide.

The ELIXA trial was sponsored and coauthored by Sanofi. Muskiet has reported receiving consulting fees from Eli Lilly and Novo Nordisk, with all honoraria paid to the VU University Medical Center. Wong has reported receiving honorarium for scientific lectures from AstraZeneca, Amgen, Retrophin, and Baxter. Groop is on the advisory board of Medscape Diabetes & Endocrinology. He has disclosed the following relevant relationships. He serves, or has serv ed as a global advisory board member for AbbVie, AstraZeneca Pharmaceuticals, Boehringer Ingelheim, Eli Lilly, Janssen, Medscape, MSD, Novartis, Novo Nordisk, and sanofi-aventis. Serve(d) as a speaker (within the last 6-7 years) for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Elo Water, Genzyme, Janssen, Medscape, MSD, Novartis, Novo Nordisk, and sanofi-aventis. Received research grant (6-7 years ago) from Eli Lilly and Roche. Received income in an amount equal to or greater than $250 (within the last 6-7 years) from AstraZeneca, Boehringer Ingelheim, Lilly, Elo Water, Genzyme, Janssen, Medscape, MSD, Novartis, Novo Nordisk, and sanofi-aventis.

European Association for the Study of Diabetes (EASD) 2018 Annual Meeting; October 3, 2018; Berlin, Germany. Abstract 77.

Lancet Diabetes Endocrinol. Published online October 3, 2018. Abstract, Comment

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