By Andrea Lenear, PharmD Candidate 2025 and Adenike Atanda-Oshikoya, PharmD, BCACP, CDCES
What is Diabetic Kidney Disease?
Chronic kidney disease (CKD) attributed to diabetes mellitus (DM) may be categorized as diabetic kidney disease (DKD) and is often broadly referred to as diabetic nephropathy. DKD is a microvascular complication of DM that develops in approximately 40% of individuals diagnosed with diabetes during their lifetime.(1) According to the 2024 American Diabetes Association (ADA) Standards of Care in Diabetes guideline, DKD is the leading cause of end-stage kidney disease (ESKD) and is diagnosed by decreased estimated glomerular filtration rate (eGFR) and elevation of urinary albumin to creatinine ratio (UACR).(1) Moderately elevated albuminuria is an early indicator of DKD and is defined by UACR ranging from 30-299 mg/g.(2) Metabolic dysregulation, hemodynamic effects, and inflammation of the kidney are major mechanisms that drive DKD in patients, and without early pharmacologic intervention, approximately 50% of patients diagnosed with DKD will progress to severely elevated albuminuria (UACR ≥ 300 mg/g).(1,2)
Mainstays of Therapy in DKD
According to the 2024 ADA Standards of Care in Diabetes and 2022 KDIGO Clinical Practice Guideline for Diabetes Management of CKD updates, metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors and renin-angiotensin-aldosterone system (RAS) inhibitors (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor blockers [ARBs]) are recommended as first line therapy for all patients with type 2 DM (T2DM) and chronic kidney disease, while non-steroidal mineralocorticoid antagonists (finerenone) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) can be considered for additional risk-based therapy to prevent progression of established DKD.(3,4,5,6) In regards to glucose lowering therapies, metformin provides robust glucose lowering effects, while SGLT2 inhibitors such as canagliflozin, empagliflozin, and dapagliflozin exhibit nephroprotective benefits via risk reduction of ESKD in addition to their glucose lowering effects.(5)
Evidence for GLP-1 RA Use in DKD
GLP-1 RAs lower blood glucose via stimulation of the glucose-dependent release of insulin from beta cells and suppression of glucagon release from alpha cells in the pancreatic islets.(7) GLP-1 RAs are recommended for use in people with T2DM and DKD who require additional glycemic control despite dose optimization of metformin and an SGLT2 inhibitor, or in patients with restrictions preventing their use (e.g. low eGFR, drug allergies, adverse effects, or contraindications).(4) There are currently eight published cardiovascular outcomes trials (CVOTs) for injectable GLP-1 RAs, four of which have shown positive renal benefits through secondary composite outcomes.(6)
The LEADER trial evaluated liraglutide, which reduced the risk of new or worsening nephropathy by 22% (HR: 0.78; 95% CI: 0.67-0.92; P = 0.003) compared to placebo as a secondary composite outcome consisting of renal and retinal microvascular outcomes.(4,8) Of the 9340 trial participants, 25% had CKD with 10.7% presenting with microalbuminuria and/or proteinuria.(4,8)
The REWIND and AWARD-7 trials evaluated dulaglutide cardiovascular outcomes and glycemic lowering efficacy against insulin glargine, respectively. In the REWIND trial, a reduction of 15% in the secondary microvascular composite outcome was found with dulaglutide use compared to placebo (HR: 0.85; 95% CI: 0.77-0.93; P = 0.0004).(9,10) While the AWARD-7 trial was not conducted long enough to assess differences in progression of CKD in patients with T2DM compared to insulin glargine, eGFR was higher following the 52 week trial period in patients that received either 0.5 mg or 1.5 mg once-weekly dulaglutide.(4,10)
The SUSTAIN-6 trial, which evaluated subcutaneous semaglutide, contained a composite renal outcome defined as persistent severe albuminuria, doubling of serum creatinine, or need for continuous renal replacement therapy (CRRT). Compared to placebo, subcutaneous semaglutide led to reduced new or worsening nephropathy (HR: 0.64; 95% CI: 0.46-0.88).(5,11) Overall drug comparisons between liraglutide, dulaglutide, and semaglutide can be found in Table 1.
Table 1: GLP-1 RAs for DKD Comparison Chart (8-11,15,16)
*Note: This list includes GLP-1 RA formulations that showed positive cardiovascular and renal outcomes in their respective CVOTs.
New GLP-1 RA studies seeking to evaluate primary renal outcomes have reported positive results. The FLOW study, which evaluated subcutaneous semaglutide against placebo in patients with T2DM and significant albuminuria, found that semaglutide reduced the risk of major kidney disease events through a composite outcome consisting of onset of kidney failure (long-term use of dialysis), kidney transplantation, or reduced eGFR to less than 15 mL/min for 28 days or more, or a 50% or greater reduction in eGFR compared to baseline. (HR: 0.76; 95% CI: 0.66-0.88; P = 0.0003).(12) In the SURPASS-4 trial, gastric inhibitory polypeptide (GIP) and GLP-1 agonist tirzepatide decreased the risk of a composite renal outcome consisting of eGFR decline ≥ 40% or more compared to baseline, renal death, progression to ESKD or new onset macroalbuminuria by 41% compared to insulin glargine (HR: 0.59; 95% CI: 0.43-0.66), indicating potential in use for patients with DKD.(13)
Areas of Concern
While GLP-1 RAs show promise in the treatment of DKD, cost-effectiveness in target patient populations and side effects are areas of concern. Compared to sulfonylureas, thiazolidinediones, and human insulin, GLP-1 RAs may be harder to obtain for socially disadvantaged patients due to cost concerns.(5) Manufacturer discount cards and copay assistance programs such as the Patient Access Network (PAN) foundation may allow patients to affordably obtain GLP-1 RAs.(14) Furthermore, despite evidence noting higher risk of DKD and progression to kidney failure in male patients of Black, Hispanic/Latino, Native American, and native Alaskan ethnicity, the LEADER, REWIND, AWARD-7, and SUSTAIN-6 clinical trials were composed primarily of Caucasian patients (averaging over 70% of participants), which affects the generalizability of the study results.(8-11) Dose-dependent gastrointestinal side effects and the FDA black box warning for thyroid C-Cell tumors, medullary thyroid tumors, and multiple endocrine neoplasia syndrome type 2 may also prevent GLP-1 RA use in some patients.(4)
Conclusion In conclusion, SGLT2 inhibitors and RAS inhibitors (ACE inhibitors or ARBs) are recommended therapies to prevent progression of established DKD in patients with T2DM. GLP-1 RAs are recommended as additional risk-based therapy to consider in patients who have not met their glycemic goals despite optimized first-line therapies or have restrictions to their use. Both GLP-1 RAs and finerenone can be considered for additional risk-based therapy for prevention of DKD progression. Studies prioritizing renal outcomes of GLP-1 RA agents in patients with diabetes are currently in progress and will provide valuable data to further inform their place in DKD therapy.
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Gerstein HC, Colhoun HM, Dagenais GR, 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. doi:10.1016/S0140-6736(19)31150-X.
Tuttle KR, Lakshmanan MC, Rayner B, et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet Diabetes Endocrinol. 2018;6(8):605-617. doi:10.1016/S2213-8587(18)30104-9.
Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375(19):1834-1844. doi:10.1056/NEJMoa1607141.
Perkovic V, Tuttle KR, Rossing P, et al. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. N Engl J Med. Published online May 24, 2024. doi:10.1056/NEJMoa2403347.
Heerspink HJL, Sattar N, Pavo I, et al. Effects of tirzepatide versus insulin glargine on kidney outcomes in type 2 diabetes in the SURPASS-4 trial: post-hoc analysis of an open-label, randomised, phase 3 trial. Lancet Diabetes Endocrinol. 2022;10(11):774-785. doi:10.1016/S2213-8587(22)00243-1.
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Andrea Lenear
PharmD Candidate 2025
University of North Texas
Health Science Center College of Pharmacy
Fort Worth, TX
Adenike Atanda-Oshikoya, PharmD, BCACP, CDCES
Assistant Dean of Pharmacy Student Success and Academic Performance - Office of Pharmacy Student Success
Director of Introductory Pharmacy Practice Experiences - Office of Experiential Education
Associate Professor of Pharmacotherapy
University of North Texas
Health Science Center College of Pharmacy
Fort Worth, TX
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