Kidney Effects of Liraglutide

Liraglutide (marketed as Victoza or Saxenda) is a glucagon-like peptide -1 (GLP-1) receptor agonist that is dipeptidyl peptidase-4 (DPP-4) resistant. It is a once a day subcutaneous injection with doses ranging from 0.6mg to 1.8mg daily. It is shown to be cardioprotective, reduce HbA1c by 1-1.5% and promote weight loss when used for six months to one year. Other glucose-independent effects of Liraglutide include decrease in blood pressure, dyslipidemia and inflammation/fibrosis.

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
LEADER Trial	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
LIRA-Renal	Feb 2016	279	Not assessed	No significant change in eGFR seen	Not assessed
The effect of Liraglutide on renal function: A randomized clinical trial Scholten et al.	Sept 2016	32	32% lower UAER with Liraglutide	No significant change in eGFR seen	Not assessed, not followed long-term to see effects
SCALE Diabetes RCT	Aug 2015	846	18% Reduction with 3mg/d	Not assessed	Not assessed
LEAD trials	2009	4456	Not assessed	No change seen in pooled analysis of all 6 trials	Not assessed

 

Januvi Jegatheswaran
PGY 4 Nephrology
University of Ottawa