GLP-1 receptors have been found in the renal vasculature and proximal tubule in animal models. Studies have shown that Liraglutide and other GLP-1 agonists promote natriuresis and diuresis thereby lowering blood pressure. They have vasodilatory effects on the afferent arteriole, inhibit sodium/hydrogen exchanger (NHE3) in the proximal tubule, and inhibit the RAAS system (directly inhibit renin and angiotensin II) to promote loss of sodium and water. This should result in activation of the tubular glomerular feedback, afferent arteriole vasoconstriction and thus, a decline in eGFR. However, the LEAD trials did not show a decline in eGFR in patients treated with Liraglutide. There are some postulated explanations for this. Usually there is a post-prandial glomerular hyperfiltration to facilitate solute and catabolic waste removal; however, Liraglutide delays gastric emptying and might blunt this response. Liraglutide also inhibits diabetes related hyperfiltration via SGLT1/2 and by decreasing reactive oxidative species; therefore perhaps balancing the decline in eGFR from natriuresis and diuresis.
The kidney effects of Liraglutide has been assessed in various trials. Pooled analyses of the LEAD trials from 2009 showed that Liraglutide did not cause a change in eGFR. The SCALE diabetes RCT from 2015 showed an 18% reduction in urine ACR when patients were given 3mg of Liraglutide daily. A small RCT looking at the effects of Liraglutide on renal function showed no change in eGFR with Liraglutide but did show a 32% lower urine albumin excretion rate. The LIRA-Renal trial looked at change in eGFR as part of their safety assessment and found no change in eGFR with Liraglutide use. The LEADER trial was the most recent trial to assess the renal effects of Liraglutide. A separate paper was published in NEJM in August 2017 specifically looking at renal outcomes (secondary outcomes in original LEADER trial). This study showed a lower rate of new onset macroalbuminuria with Liraglutide and a urine ACR increase that is 17% (approximately 5mg of albumin/g of creatinine) less than that of placebo at 3 years. It also showed a 2% less decrease in eGFR at 3 years, which is 7.44 ml/min/1.73 m2 in the liraglutide group compared to 7.82 ml/minute/1.73 m2 in the placebo group. The table is a summary of the renal effects of Liraglutide noted in the aforementioned trials.
Overall no large RCT looking specifically at the renal outcomes of Liraglutide have been published to date. Approximately 2.5% of the participants in the LEADER trial had eGFR less than 30 and 21% had eGFR between 30 and 60, attesting to its safe use in patients with eGFR less than 45 and even eGFR less than 30. This is one advantage Liraglutide potentially has over SGLT2 inhibitors as the use of the latter class is restricted to patients with eGFR less than 45. Other GLP-1 agonists such as Dulaglutide are under study to see if they are safe to use in patients with CKD and to determine if they have any renoprotective effects in diabetes patients.
Study
|
Year
|
N
|
UACR
|
Change in eGFR
|
Progression to ESKD
|
Aug 2017
|
9340
|
Less new onset
macroalbuminuria
HR 0.74
(0.60–0.91)
Est. UACR
increased less. 17% lower in Liraglutide group at 3 years
|
2% less decrease
in eGFR with Liraglutide at 3 years
No doubling of
serum Cr
Stage 3 CKD eGFR
decline 2mL/min less than placebo
|
AKI and kidney
failure rates were the same
|
|
Feb 2016
|
279
|
Not assessed
|
No significant change in eGFR seen
|
Not assessed
|
|
The effect of Liraglutide
on renal function: A randomized clinical trial
|
Sept 2016
|
32
|
32% lower UAER
with Liraglutide
|
No significant
change in eGFR seen
|
Not assessed,
not followed long-term to see effects
|
Aug 2015
|
846
|
18% Reduction with 3mg/d
|
Not assessed
|
Not assessed
|
|
2009
|
4456
|
Not assessed
|
No change seen
in pooled analysis of all 6 trials
|
Not assessed
|
Januvi Jegatheswaran
PGY 4 Nephrology
University of Ottawa
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