GLP-1 receptor agonists and the kidney – Organised by NOVO NORDISK A/S

Symposium Summary

Written by Jasna Trbojevic-Stankovic
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Brief introduction to symposium, objectives, sessions and speakers

Peter Rossing, Denmark

Diabetes is the leading cause of chronic kidney disease (CKD) worldwide, with estimates that as many as 40% of patients with diabetes will develop CKD. GLP-1 receptor agonists (GLP-1 RAs) are a potent class of glucose-lowering agents. Data from recent clinical trials indicates that GLP-1 RAs may also confer renal benefits in patients with type 2 diabetes (T2D). At a virtual satellite symposium, held during the 2021 ERA-ERA fully virtual congress, Professor Roland Schmieder, Professor Ofri Mosenzon and Professor Hiddo Lambers Heerspink discussed current understanding of CKD in T2D, renal outcome data with GLP-1 RAs in T2D, and GLP-1 RAs’ potential mechanism of action on the kidney.

Chronic Kidney Disease in Type 2 Diabetes: what do we know?

Roland Schmieder, Germany

Elevated blood glucose levels are often seen as defining diabetes, but it is more than a metabolic disease. Diabetes also affects the cardiovascular and vascular systems, and the kidneys. Consequently, effective management of T2D must address not only hyperglycaemia, but also the cardiovascular and renal complications of diabetes. Professor Schmieder reported that this holistic, multidisciplinary approach is reflected in the latest KDIGO guidelines on diabetes management in CKD.

KDIGO’s first step is the combination of lifestyle measures, with glycaemic and blood pressure (BP) control. It is clear that high blood glucose levels must be lowered-at a minimum to <8%-in T2D. However, while strict glycaemic control improves renal and cardiovascular prognosis in type 1 diabetes, the evidence is less clear for T2D: it seems to reduce albuminuria but its effects on serum creatinine are variable.

The randomized, controlled, open-label SPRINT trial assigned participants either to standard treatment to achieve systolic BP <140 mmHg or intensive treatment to achieve systolic BP <120 mmHg. In people with CKD at baseline but without diabetes, there was no significant between-group difference in the composite outcome of decrease in eGFR ≥50% or development of end-stage kidney disease (ESKD). Professor Schmieder commented that SPRINT used a very specific technique: unattended automatic office BP measurement (AOBP). This is not generally used in clinical practice and its results are approximately 10 mmHg lower than office measurement. He therefore advised that, while BP should be controlled to <140/80 mmHg (and in some patients <130/80 mmHg), lowering BP to <120 mmHg is not recommended as it increases risk of adverse effects.

KDIGO’s second step is a combination of a sodium-glucose transport protein 2 inhibitor (SGLT2i) and renin-angiotensin-aldosterone system inhibitor (RAASi) to reduce risk of CKD and cardiovascular disease. In large studies, RAAS blockade resulted in a relative risk reduction in renal outcomes of approximately 40%, but a significant residual risk remains. Finerenone, a selective mineralocorticoid receptor antagonist (MRA), has been shown to reduce the risk of CKD progression and cardiovascular events in people with T2D, and in combination with a RAASi offers a new option for additional risk reduction of CKD.

Turning to antihyperglycemic therapies, Professor Schmieder noted that, after lifestyle management, KDIGO recommends the second-line combination of metformin and SGLT2i, followed by GLP-1 RAs as third line in preference to other glucose-lowering therapies. He concluded that, while there is currently insufficient data to recommend GLP-1 RAs as second-line, this evidence may become available in future.

Kidney Outcomes with GLP1-RAs: what evidence have we seen so far?

Ofri Mosenzon, Israel

According to Professor Mosenzon, cardiovascular outcome trials provide important clues to the potential renal benefits of GLP-1 RAs. For example, in a meta-analysis of seven placebo-controlled trials including a total of 56,004 T2D patients, GLP-1 RAs showed consistent benefit on composite renal outcomes, mainly due to reduction in albuminuria. Furthermore, although composite renal outcomes differed in REWIND (dulaglutide), LEADER (liraglutide) and SUSTAIN 6 (semaglutide), renal risk was reduced in each trial.

A post hoc pooled analysis of renal outcomes in LEADER and SUSTAIN 6 found that, compared to placebo, treatment with liraglutide and semaglutide decreased the risk of an annual 30%, 40%, 50% or 57% reduction in eGFR in patients with eGFR 30-59 ml/min/1.73m2 and micro/macroalbuminuria. Similarly, in a pooled analysis of SUSTAIN 6 (subcutaneous [s.c.] semaglutide once weekly) and PIONEER 6 (oral semaglutide once daily), annual change in eGFR was slower in both active treatment arm than in the placebo group (overall estimated treatment difference [ETD] 0.60mL/min/1.73m2/year (95% CI 0.31-0.90; p<0.0001 at year 2). Patients with baseline eGFR 30-59 ml/min/1.73m2 appeared to benefit most, though the ETD was not statistically significant when considering p-value for interaction.

FLOW (NCT03819153) is an ongoing renal outcomes trial, in which 3508 T2D patients (HbA1c ≤10%) have been randomized to either 1mg semaglutide s.c. once weekly plus standard of care or placebo plus standard of care, including RAASi. The trial includes two groups of patients: eGFR ≤75 to ≥50 ml/min/1.732 plus urine albumin to creatinine ratio (UACR) >300 to <5000 mg/g, and eGFR <50 to ≤25 ml/min/1.732 plus UACR >200 to <5000 mg/g. The primary composite endpoint is the important clinical outcome of persistent ≥50% reduction in eGFR (CKD-EPI) compared to baseline, or onset of persistent eGFR <15, or renal replacement therapy, or cardiovascular or renal death.

Professor Mosenzon noted that, when available, the results of the FLOW trial will fit with other renal outcome trials because the study has randomized a similar population to that in renal outcomes trials with SGLT2is and the MRA finerenone. She concluded that, depending on the results of the FLOW trial, GLP-1 RAs could represent the next frontier in the treatment of diabetic kidney disease.

GLP-1RAs and the Kidney: what might the mechanism(s) of action be?

Hiddo Lambers Heerspink, Netherlands

Professor Heerspink considered that GLP-1 RAs may mediate renal outcomes, not only through indirect effects in terms of improved glycaemic control, reduction in BP and weight loss, but also directly through natriuresis, hemodynamic, endothelial function, anti-inflammatory effects and reduced oxidative stress, or inhibition of the RAAS.

An acute infusion of exenatide increased sodium excretion and urinary pH in a study including both healthy overweight males and T2D patients. This pattern of effect suggests that exenatide blocks the sodium hydrogen exchange transporter in the proximal tubule. This increases natriuresis and decreases proton excretion thereby increasing urinary pH, and may have favourable direct effects on the kidney, as well as by reducing BP and body weight.

SGLT2i produce an acute decline in eGFR that is associated with long-term kidney protection. In contrast, in SAFEGUARD, which included T2D patients without CKD, there was no difference after 12 weeks in the acute effects of liraglutide, sitagliptin or placebo on both estimated and inulin-measured GFR. This suggests that GLP-1 RAs do not have an acute hemodynamic effect on the kidney.

In contrast, GLP-1 RAs appear to improve endothelial function. In a randomized controlled trial including participants with T2D, exenatide increased the resistance hyperemia index compared to placebo. This effect was, however, abolished when exenatide was given in combination with the GLPR-1 antagonist exendin 9, indicating that exenatide has a direct effect on endothelial function that may translate into long-term kidney protection.

Studies have also shown that GLP-1 RAs have anti-inflammatory effects. C-reactive protein (CRP) was assessed as a measure of systemic inflammation in both PIONEER 1 (oral semaglutide versus placebo) and PIONEER 2 (oral semaglutide versus empagliflozin). There was a somewhat dose-dependent reduction in CRP in PIONEER 1 that was greater with the 7 mg and 14 mg doses than with the 3 mg dose. Additionally, in PIONEER 2, reduction in CRP was greater with semaglutide 14 mg than with empagliflozin 5 mg. The results suggest that semaglutide reduced systemic inflammation, which may translate into not only kidney protection, but also cardiovascular protection.

Finally, the effects of GLP-1 RA on RAAS remain uncertain. Several acute studies indicate that GLP-1 RAs reduce plasma renin concentration and activity, decrease angiotensin II and lower angiotensinogen concentration in the urine. These effects may also block the RAAS in the kidney, but studies have not replicated these effects during long-term intervention.

Overall, there appear to be multiple pathways by which GLP-1 RAs protect the kidney, but most mechanistic studies conducted to date are relatively small. REMODEL-Renal mode of action with semaglutide (NCT04865770) is a mechanistic, multinational, randomized controlled trial including 105 patients with T2D, HbA1 ≤9%, eGFR ≥40 to <75 ml/min/1.732, and UACR ≥30 to ≤5000 mg/g. All patients will be treated with maximum tolerated doses of a RAASi.

Patients will be randomized to semaglutide s.c.1 mg once weekly plus standard of care or placebo plus standard of care for 52 weeks, and will be followed up for five weeks at the end of treatment. The main endpoints include clinical, hemodynamic, inflammatory and oxidative parameters. Investigators will also collect kidney biopsies, perform MRI scans, measure GFR and urinary protein excretion, and biomarkers in blood and urine.

Professor Lambers Heerspink concluded that emerging data indicate a kidney protective role for GLP-1 RAs in patients with T2D and CKD. The mechanism of kidney protection remains incompletely understood, but it is likely to involve multiple pathways, both direct and indirect. The results of prospective clinical trials like FLOW and REMODEL will be needed to confirm the renoprotective effects of GLP-1 RAs.

Further reading

CKD in diabetes

International Diabetes Federation. IDF Atlas. 9th edition 2019

KDIGO 2020 Clinical practice guideline for diabetes management in chronic kidney disease. Kidney Int 2020;98(4S):S1-S115

The SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. New Engl J Med 2015; 373:2103-2116

Kidney outcomes with GLP-1 RAs

Kristensen SL, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol 2019;7(10):776-785.

Gerstein HC, et al. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Lancet 2019;394(10193):131-138

Mann JFE, et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med

2017;377(9):839-848

Marso SP, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375(19):1834-1844.

GLP-1 RAs and the kidney: mechanism(s) of action

Muskiet MHA, et al. GLP-1 and the kidney: from physiology to pharmacology and outcomes in diabetes. Nat Rev Nephrol 2017;13(10):605-628.

Tonneijck L, et al. Renal effects of DPP-4 inhibitor sitagliptin or GLP-1 receptor agonist liraglutide in overweight patients with type 2 diabetes: a 12-week, randomized, double-blind, placebo-controlled trial. Diabetes Care 2016;39(11):2042-2050

Koska J, et al. Exenatide protects against glucose- and lipid-induced endothelial dysfunction: evidence for direct vasodilation effect of GLP-1 receptor agonists in humans. Diabetes 2015;64(7):2624-35