Nephroprotective effects of GLP-1 receptor agonists: where do we stand?

Mosterd, Charlotte M.; Bjornstad, Petter; Raalte, Daniël H. van

doi:10.1007/s40620-020-00738-9

Cited by 31 publications

(25 citation statements)

References 65 publications

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“…As recently reviewed, GLP-1RAs reduce progression to macroalbuminuria and lead to (subtle) reductions in the decline in renal function (118). In a recent post-hoc analysis of SUSTAIN 6, semaglutide was associated with less events of nephropathy, independent of baseline blood pressure (119).…”

Section: Acute Kidney Injurymentioning

confidence: 99%

“…In contrast to the incidental cases of AKI, the CVOTs mainly demonstrate a beneficial effect on renal outcomes, likely because of effects on cardiovascular risk factors ( 117 ). As recently reviewed, GLP-1RAs reduce progression to macro-albuminuria and lead to (subtle) reductions in the decline in renal function ( 118 ). In a recent post-hoc analysis of SUSTAIN 6, semaglutide was associated with less events of nephropathy, independent of baseline blood pressure ( 119 ).…”

Section: Adverse Effects Of Semaglutidementioning

confidence: 99%

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Safety of Semaglutide

Smits

Raalte

2021

Front. Endocrinol.

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The glucagon-like peptide-1 receptor agonist (GLP-1RA) semaglutide is the most recently approved agent of this drug class, and the only GLP-1RA currently available as both subcutaneous and oral formulation. While GLP-1RAs effectively improve glycemic control and cause weight loss, potential safety concerns have arisen over the years. For semaglutide, such concerns have been addressed in the extensive phase 3 registration trials including cardiovascular outcome trials for both subcutaneous (SUSTAIN: Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) and oral (PIONEER: Peptide InnOvatioN for the Early diabEtes tReatment) semaglutide and are being studied in further trials and registries, including real world data studies. In the current review we discuss the occurrence of adverse events associated with semaglutide focusing on hypoglycemia, gastrointestinal side effects, pancreatic safety (pancreatitis and pancreatic cancer), thyroid cancer, gallbladder events, cardiovascular aspects, acute kidney injury, diabetic retinopathy (DRP) complications and injection-site and allergic reactions and where available, we highlight potential underlying mechanisms. Furthermore, we discuss whether effects are specific for semaglutide or a class effect. We conclude that semaglutide induces mostly mild-to-moderate and transient gastrointestinal disturbances and increases the risk of biliary disease (cholelithiasis). No unexpected safety issues have arisen to date, and the established safety profile for semaglutide is similar to that of other GLP-1RAs where definitive conclusions for pancreatic and thyroid cancer cannot be drawn at this point due to low incidence of these conditions. Due to its potent glucose-lowering effect, patients at risk for deterioration of existing DRP should be carefully monitored if treated with semaglutide, particularly if also treated with insulin. Given the beneficial metabolic and cardiovascular actions of semaglutide, and the low risk for severe adverse events, semaglutide has an overall favorable risk/benefit profile for patient with type 2 diabetes.

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Section: Acute Kidney Injurymentioning

confidence: 99%

Section: Adverse Effects Of Semaglutidementioning

confidence: 99%

Safety of Semaglutide

Smits

Raalte

2021

Front. Endocrinol.

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“…It is therefore vital to identify those at higher risk of nephropathy to be able to enhance monitoring and possibly to intervene at an early stage to slow down renal decline. Interventions include intensified glycaemic control; nephroprotective glucose lowering drugs, including glucagon-like peptide 1 receptor antagonists and sodium-glucose cotransporter 2 inhibitors; blood pressure control; and renin-angiotensin system inhibition 14151617. More stringent glycaemic control has been suggested to reduce the development and worsening of nephropathy 13.…”

Section: Discussionmentioning

confidence: 99%

Performance of prediction models for nephropathy in people with type 2 diabetes: systematic review and external validation study

Slieker

Heijden

Siddiqui

et al. 2021

BMJ

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Objectives To identify and assess the quality and accuracy of prognostic models for nephropathy and to validate these models in external cohorts of people with type 2 diabetes. Design Systematic review and external validation. Data sources PubMed and Embase. Eligibility criteria Studies describing the development of a model to predict the risk of nephropathy, applicable to people with type 2 diabetes. Methods Screening, data extraction, and risk of bias assessment were done in duplicate. Eligible models were externally validated in the Hoorn Diabetes Care System (DCS) cohort (n=11 450) for the same outcomes for which they were developed. Risks of nephropathy were calculated and compared with observed risk over 2, 5, and 10 years of follow-up. Model performance was assessed based on intercept adjusted calibration and discrimination (Harrell’s C statistic). Results 41 studies included in the systematic review reported 64 models, 46 of which were developed in a population with diabetes and 18 in the general population including diabetes as a predictor. The predicted outcomes included albuminuria, diabetic kidney disease, chronic kidney disease (general population), and end stage renal disease. The reported apparent discrimination of the 46 models varied considerably across the different predicted outcomes, from 0.60 (95% confidence interval 0.56 to 0.64) to 0.99 (not available) for the models developed in a diabetes population and from 0.59 (not available) to 0.96 (0.95 to 0.97) for the models developed in the general population. Calibration was reported in 31 of the 41 studies, and the models were generally well calibrated. 21 of the 64 retrieved models were externally validated in the Hoorn DCS cohort for predicting risk of albuminuria, diabetic kidney disease, and chronic kidney disease, with considerable variation in performance across prediction horizons and models. For all three outcomes, however, at least two models had C statistics >0.8, indicating excellent discrimination. In a secondary external validation in GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland), models developed for diabetic kidney disease outperformed those for chronic kidney disease. Models were generally well calibrated across all three prediction horizons. Conclusions This study identified multiple prediction models to predict albuminuria, diabetic kidney disease, chronic kidney disease, and end stage renal disease. In the external validation, discrimination and calibration for albuminuria, diabetic kidney disease, and chronic kidney disease varied considerably across prediction horizons and models. For each outcome, however, specific models showed good discrimination and calibration across the three prediction horizons, with clinically accessible predictors, making them applicable in a clinical setting. Systematic review registration PROSPERO CRD42020192831.

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“…On the horizon of diabetes therapy, new "players", such as sodium-glucose co-transporter type 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP1RA) are currently emerging. Even though their real role in the future of diabetic therapy is not fully defined, SGLT2i and GLP1RA have great potential for the prevention of cardiovascular (CV) risk and CKD in diabetic patients [8,9]. The recent guidelines of the ESC 2019 and the ADA-EASD 2020 Consensus suggested adding these drugs to metformin to reach the HbA1c target, and in high-risk CV patients regardless of the HbA1c values achieved with metformin treatment [8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Metformin, chronic nephropathy and lactic acidosis: a multi-faceted issue for the nephrologist

Mariano

Biancone

2020

J Nephrol

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Metformin is currently considered a first-line therapy in type 2 diabetic patients. After issuing warnings for decades about the risks of lactic acidosis in patients with chronic nephropathy, metformin is now being re-evaluated. The most recent evidence from the literature has demonstrated both a low, acceptable risk of lactic acidosis and a series of favorable effects, which go beyond its hypoglycemic activity. Patients treated with metformin show a significant mortality reduction and lower progression towards end-stage renal disease in comparison with those treated with other hypoglycemic drugs. Concerning lactic acidosis, in the last few years it has been shown how lactic acidosis almost always developed when patients kept taking the drug in the face of a concomitant disease or situation such as sepsis, fever, diarrhea, vomiting, which reduced metformin renal clearance. Actually, clearance of metformin is mainly renal, both by glomerular filtration and tubular secretion (apparent clearance 933–1317 ml/min, half-life < 3 h). As regards treatment, in cases of lactic acidosis complicated by acute kidney injury, continuous renal replacement therapy (CRRT) plays a crucial role. Besides the elimination of metformin, CRRT improves survival by correcting acidosis, electrolyte alterations, and maintaining fluid balance. Lactic acidosis almost always develops because of preventable drug accumulation. Therefore, prevention is a key factor. Patients should be aware that discontinuation for a limited time does not affect their health, even when it may be inappropriate, but it may avoid a serious, potentially fatal adverse event.

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Nephroprotective effects of GLP-1 receptor agonists: where do we stand?

Cited by 31 publications

References 65 publications

Safety of Semaglutide

Safety of Semaglutide

Performance of prediction models for nephropathy in people with type 2 diabetes: systematic review and external validation study

Metformin, chronic nephropathy and lactic acidosis: a multi-faceted issue for the nephrologist

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