Renal Effects of GLP-1RAs in Patients With Diabetic Kidney Disease

In patients with type 2 diabetes mellitus and in those with chronic kidney disease (CKD), the leading causes of death are cardiovascular diseases. Patients with both diabetes and CKD (diabetic kidney disease [DKD]) face increased risk of end-stage kidney disease (ESKD) and the need for dialysis. The rate of cardiovascular mortality in patients with DKD is more than two-fold higher than that in patients with type 2 diabetes with preserved kidney function.

First-line medication for patients with type 2 diabetes is metformin. Recommended medications for patients with established atherosclerotic cardiovascular disease (ASCVD)  or multiple risk factors for ASCVD include glucagon-like peptide-1 receptor agonists (GLP-1RAs), along with sodium-glucose cotransporter 2 inhibitors (SGLT2is). Adding GLP-1RAs to SCLT2is in patients with diabetes and heart failure has resulted in significantly reduced composite cardiovascualr events.

According to Yuan Lin, MD, and colleagues in Taiwan, there are few data available of the effect of GLP-1RAs on cardiovascular outcomes in patients with advanced DKD (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m²). The researchers conducted a cohort study to assess whether GLP-1RAs have cardiovascular and renal protective effects in patients with advanced DKD. Results were reported online in BMC Cardiovascular Diabetology.

The primary outcomes of interest were composite cardiovascular outcomes, including cardiovascular death, myocardial infarction, and ischemic stroke; a composite renal outcome of a decline in eGFR >50%; and progression to ESKD with dialysis; and cardiovascular death. The study cohort included patients with a first prescription for a GLP-1RA or dipeptidyl peptidase-4 inhibitor (DPP-4i) from January 1, 2012, to December 31, 2021.

The date of the first prescription was the index date. GLP-1RAs included liraglutide and dulaglutide, and DPP-4is included sitagliptin, vildagliptin, saxagliptin, and linagliptin. The cardiorenal protective effects in the GLP-1RA and DDP-4i groups were assessed using a Cox proportional hazard model. A propensity score matched cohort was created to compare outcomes.

A total of 125,392 patients had a first prescription during the study period and were enrolled. Following application of exclusion criteria, 759 GLP-1RA users and 8163 DPP-4i users were eligible for analysis. In the matched cohort, 212, 117, 59, and 214 patients in the GLP-1RA group were matched to 1, 2, 3, and 4 counterparts in the DPP-4i group, respectively, resulting in a total of 1479 patients in the DPP-4i group and 602 in the GLP-1RA group.

Overall, mean age was 68 years and 50.6% (n=4516) were male. Mean duration of diabetes mellitus was 6.4 years and baseline hemoglobin A1c (HbA1c) was 62 mmol/mol. Compared with patients in the DPP-4is group, those in the GLP-1RA group were younger, had a higher body mass index, longer duration of diabetes mellitus, higher baseline HBA1c, less CKD stage 5 (eGFR <15 mL/min/1.73 m²), higher prevalence of diabetes mellitus retinopathy and neuropathy, hypertension, hyperlipidemia, coronary heart disease, coronary intervention and myocardial infarction, greater Charlson Comorbidity Index scores, and higher triglyceride level. Patients in the GLP-1RA group were also more likely to take thiazolidinedione, alpha glucosidase, SGLT2is, insulin, statins, and fibrates. Following matching, the two groups were similar in baseline characteristics.

In the matched cohort, mean follow-up was 2.1 years. There was no significant difference between the GLP-1RA and DPP-4i groups in the risk of composite cardiovascular outcome (13% vs 13.8%; hazard ratio [HR], 0.88; 95% CI, 0.68-1.13). The groups were also similar in the risks of myocardial infarction, ischemic stroke, and cardiovascular death.

In analyses of renal outcomes, those in the GLP-1RA group had a greater protective effect than those in the DPP-4i group, including progression to ESKD with dialysis (23.4% vs 27.45%; subdistribution HR, 0.72; 95% CI 0.56-0.93), decline in eGFR >50%, and the composite renal outcomes. In the GLP-1RA group, the median duration to new-onset dialysis was significantly longer than in the DPP-4i group (median, 1.9 years vs 1.3 years).

In secondary outcome analyses, the GLP-1RA group had lower risk of all-cause death compared with the DPP-4i group (18.4% vs 25.2%; HR, 0.71; 95% CI, 0.57-0.88). The risk of all-cause readmission was also lower in the GLP-1RA group. The risk of composite major adverse limb events in the GLP-1RA group was borderline significantly lower than that in the DPP-41 group.

There were no significant differences between the two groups in the common causes of death among patients with advanced DKD, including malignancy, infection, cardiovascular diseases, diabetes mellitus, and kidney disease. Other causes of death were significantly lower in the GLP-1RA group than in the DPP-4i group.

The researchers cited some limitations to the study, including the retrospective design that limited the ability to infer causal associations between GLP-1RAs and cardiovascular or kidney outcomes, background heterogeneity in the GLP-1RA and DPP-4i cohorts, the database research may have had coding errors, only including the human GLP-1-like analogues liraglutide and dulaglutide in the study, and the inability to ensure mediation adherence in each patient.

“GLP-1RAs had no influence on the composite cardiovascualr outcomes but reduced composite kidney events, including a decline in eGFR >50% and progression to ESKD with dialysis, all-cause mortality, and admission in patients with advanced DKD (eGFR <30 mL/min/1.73 m²) compared with DPP-4is,” the authors said.

Takeaway Points

1. Researchers in Taiwan reported results of a study investigating the potential cardiovascular and renal protective effects of glucagon-like peptide 1 receptor agonists (GLP-1RAs) in a population of patients with diabetic kidney disease (DKD) with moderate to severe decline in kidney function.
2. The study compared cardiovascular and renal outcomes in patients with DKD treated with GLP-1RAS with a matched cohort treated with dipeptidyl peptidase-4 inhibitors (DPP-4is).
3. GLP-1RAs had a neutral effect on composite cardiovascular outcomes but reduced composite kidney events compared with DPP-4is.

Source: BMC Cardiovascular Diabetology