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Review
. 2022 Mar;13(3):389-421.
doi: 10.1007/s13300-021-01198-5. Epub 2022 Feb 17.

Glucagon-Like Peptide-1 Receptor Agonist Use in People Living with Type 2 Diabetes Mellitus and Chronic Kidney Disease: A Narrative Review of the Key Evidence with Practical Considerations

José L Górriz  1 , Irene Romera  2 , Amelia Cobo  3 , Phillipe D O'Brien  4 , Juan F Merino-Torres  5
Affiliations
Review

Glucagon-Like Peptide-1 Receptor Agonist Use in People Living with Type 2 Diabetes Mellitus and Chronic Kidney Disease: A Narrative Review of the Key Evidence with Practical Considerations

José L Górriz et al. Diabetes Ther. 2022 Mar.

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are incretin-mimetic agents that are effective adjuncts in the treatment of diabetes. This class of medications is also associated with promoting weight loss and a low risk of hypoglycemia, and some have been shown to be associated with a significant reduction of major cardiovascular events. Mounting evidence suggests that GLP-1 RAs have benefits beyond reducing blood glucose that include improving kidney function in people living with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD), a common microvascular complication of T2DM. Several large clinical studies, the majority of which are cardiovascular outcome trials, indicate that GLP-1 RA therapy is safe and tolerable for people living with T2DM and compromised renal function, and also suggest that GLP-1 RAs may have renoprotective properties. Although evidence from clinical trials has shown GLP-1 RAs to be safe and efficacious in people living with T2DM and renal impairment, their use is uncommon in this patient population. With continuing developments in the field of GLP-1 RA therapy, it is important for physicians to understand the benefits and practical use of GLP-1 RAs, as well as the clinical evidence, in order to achieve positive patient outcomes. Here, we review evidence on GLP-1 RA use in people living with T2DM and CKD and summarize renal outcomes from clinical studies. We provide practical considerations for GLP-1 RA use to provide an added benefit to guide treatment in this high-risk patient population.

Keywords: Chronic kidney disease; Diabetic kidney disease; Glucagon-like peptide-1 receptor agonists; Renal impairment; Type 2 diabetes mellitus.

Plain language summary

Type 2 diabetes mellitus (T2DM) is a common disorder characterized by insulin resistance and dysfunction of insulin-producing beta cells of the pancreas. People living with T2DM have an increased risk of developing complications, including chronic kidney disease (CKD), which itself is associated with increased mortality. Both the American Diabetes Association and Kidney Disease Improving Global Outcomes organization provide updated pharmacological recommendations for treating T2DM in people with CKD that include the use of sodium-glucose co-transporter-2 inhibitors (SGLT2i) or glucagon-like peptide-1 receptor agonists (GLP-1 RAs). GLP-1 RAs are effective and safe treatments for controlling blood sugar levels and reducing body weight, and evidence from large clinical trials also suggests that GLP-1 RAs may be renoprotective. Despite the benefits of GLP-1 RAs, they are not commonly prescribed in people living with T2DM and CKD. Healthcare practitioners need to be aware of the most recent information so that they can make informed decisions when selecting treatment options. The objective of this review is to summarize the main renal outcomes from clinical studies while providing practical guidance on the use of GLP-1 RAs.

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Figures

Fig. 1
Fig. 1
Classification of CKD based on GFR and albuminuria categories. The risk of CKD progression, morbidity, and mortality are depicted by color (green, low risk; yellow, moderately increased risk; orange, high risk; red, very high risk) and include general decision-making recommendations that are based on expert opinion based on GFR and albuminuria. “Monitor” indicates that eGFR and albuminuria be monitored more frequently. “Refer” indicates referral to a nephrologist; “Refer*” indicates that clinicians may wish to discuss treatment or referral with their nephrology service. CKD Chronic kidney disease, GFR glomerular filtration rate. Figure is reproduced with permission (Kidney Disease: Improving Global Outcomes CKD Work Group [133])
Fig. 2
Fig. 2
Summary of ADA and KDIGO guidelines of use for glucose-lowering medication in people living with T2DM and CKD. Upper panel: ADA guidelines were abbreviated for specific treatment for people living with T2DM and CKD. Proven CVD benefit means it has label indication of reducing CVD events. For more context regarding glucose lowering medication in this population, refer to the Standards of Medical Care in Diabetes—2021 [15]. Lower panel: KDIGO recommend guidelines of glycemic management for people living with T2DM and CKD begin with lifestyle therapy followed by first-line pharmacological therapy with metformin and SGLT2i. For people contraindicated for SGLT2i, GLP-1 RAs are recommended. Additional drug therapy is guided by patient preferences, comorbidities, eGFR, and cost, and includes people with eGFR < 30 ml/min per 1.73 m2 or those treated with dialysis [2]. *: Dapagliflozin; it is not recommended to initiate treatment with dapagliflozin in patients with GFR < 25 ml/min/1.73 m2 [20, 21]. ADA American Diabetes Association, CV cardiovascular, CVOT cardiovascular outcome trial, DPP-4 dipeptidyl peptidase-4, eGFR estimated GFR, GLP-1 RA glucagon-like peptide-1 receptor antagonist, HbAc1 glycated hemoglobin, SGLT2i sodium-glucose cotransporter-2 inhibitor, T2DM type 2 diabetes mellitus, TZD thiazolidinediones. The figure was created by Lilly using the data from the American Diabetes Association [15] and Kidney Disease: Improving Global Outcomes Diabetes Work Group [2]. Permission is not required as only data were used
Fig. 3
Fig. 3
Physiological _targets of GLP-1. GLP-1 exhibits pleotropic attributes that affect various tissues and organs, including the pancreas, stomach, brain, liver, adipose, heart, and kidney. GLP-1 Glucagon-like peptide-1, VLDL very-low-density lipoprotein. The figure was created by Lilly using the data from Muskiet et al. [25]; permission is not required as only data were used
Fig. 4
Fig. 4
Potential direct and indirect renoprotective effects of GLP-1 RAs. cAMP/PKA Cyclic adenosine monophosphate/protein kinase A, ANP atrial natriuretic peptide. The figure was created by Lilly using the data from Greco et al. (see Table 1) [35]. Permission is not required as only data were used
Fig. 5
Fig. 5
Information on the use of GLP-1 RA in people with T2DM and CKD based on USPI and the European Union SmPC. The FDA-approved prescribing information and EMA-approved SmPC summarizing GLP-1RA use in populations with renal impairment. Recommendations are depicted by color (white, no specific recommendation; gray, use with caution; black, not recommended). *: For the purposes of graphically summarizing the information on GLP-1 RA use in people with renal impairment, end-stage renal disease, as described in the SmPC and USPI, is defined as eGFR < 15/mL/min/1.732 when specific eGFR values are not provided in the label information. aInformation is based on FDA-approved label unless superseded by the most recent USPI as of 20 May 2021. bLimited experience exists for liraglutide use in people with end-stage renal disease. cLimited experience exists for lixisenatide in people with an eGFR from 15 to 30 ml/min/1.73 m2. BID twice daily, EMA European Medicines Agency, FDA U.S. Food and Drug Administration, QW once weekly, SmPC Summary of Product Characteristics, USPI U.S. Prescribing Information
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