Treating Type 2 Diabetes and Advanced CKD

Patients with chronic kidney disease (CKD) or end-stage kidney disease (ESKD) face increased health burdens and are at increased risk for cardiovascular events and mortality. The most common cause of CKD is type 2 diabetes, and both diabetes and CKD are associated with greater risk of  all-cause mortality and increased rates of infection and cardiovascular events. The increased mortality is attributable in part to cardiovascular or infection-related events.

Both glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors are associated with improved blood pressure control, greater reduction in body weight, lower mortality, and lower incidence of cardiovascular events in the general population with diabetes. Guidelines from the American Diabetes Association recommend GLP-1 receptor agonist treatment for patients with diabetes and CKD with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 who are at risk for cardiovascular disease.

The Kidney Disease: Improving Global Outcomes 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease suggests GPL-1 receptor agonist treatment for patients unable to use metformin or SGLT-2 inhibitors; GLP-1 receptor agonists can be used in patients with advanced CKD or ESKD. Results of a recent meta-analysis found potentially different clinical outcomes following use of GLP-1 receptor agonists and use of dipeptidyl peptidase-4 (DPP-4) inhibitors in the general population with diabetes. In that study, there was an association between use of GLP-1 receptor agonists and improved survival compared with use of DPP-4 inhibitors.

According to Jia-Jin Chen, MD, and colleagues, previous randomized clinical trials have excluded or included only small numbers of patients with advanced CKD or ESKD. In addition, there are no real-world data available on comparisons of GLP-1 receptor agonists with DPP-4 inhibitors for the treatment of patients with advanced CKD or ESKD. The researchers conducted a retrospective cohort study among patients with diabetes and advanced stage CKD or ESKD to examine whether use of GLP-1 receptor agonists in that population would be associated with better outcomes compared with the use of DPP-4 inhibitors. Results of the study were reported online in JAMA Network Open [doi:10.1001/jamanetworkopen.2022.1169].

The study utilized data on patients with type 2 diabetes and stage 5 CKD or ESKD from the National Health Insurance Research Database of Taiwan. The study was conducted between January 1, 2012, and December 31, 2018. Data analyses were conducted from June 2020 to July 2021.

The study exposures were treatment with GFLP-1 receptor agonists compared with treatment with DPP-4 inhibitors. The outcomes were all-cause mortality, sepsis- and infection-related mortality, and mortality related to major adverse cardiovascular and cerebrovascular events (MACCE) in patients treated with GLP-1 receptor agonists compared with those in patients treated with DPP-4 inhibitors.

Covariates included age, sex, area of residence (urban or rural), income level, occupation, and 10 comorbidities (hypertension, dyslipidemia, cirrhosis, systemic lupus erythematosus, atrial fibrillation, peripheral arterial disease, coronary artery disease or ischemic heart disease, heart failure, cerebrovascular disease, and ESKD requiring dialysis). The imbalance among covariates between the groups was mitigated using propensity score weighting.

A total of 75,556 patients with type 2 diabetes and stage 5 CKD or ESKD requiring dialysis were identified during the study period. Of those, 48,277 were excluded, resulting in a study cohort of 27,279 patients. Of those, 26,578 were in the DPP-4 group (45.34% [n=14,443] were male; mean age 65 years) and 701 were in the GLP-1 receptor agonist group (49.36% male [n=346], mean age 59 years).

Prior to propensity score weighting, the DPP-4 group was older, concentrated in rural areas, and included fewer patients receiving dialysis and more patients receiving an angiotensin-converting enzyme inhibitor, diuretics, and insulin compared with the GLP-1 group. After propensity score weighting, the two groups were balanced in all analyzed covariates.

After propensity score weighting, the DPP-4 group included 26,568 patients and the GLP-1 receptor group included 603 patients. Mean age was 66 years in the DPP-4 inhibitor group and 65 years in the GLP-1 agonist group. In the DPP-4 group, 54.25% (n=14,414) were male; in the GLP-1 group 52.90% (n=319) were male. The most common comorbidity in the total cohort was hypertension (84.20% [n=22,369] in the DPP-4 inhibitor group and 83.92% [n=506] in the GLP-1 group).

The rate of all-cause mortality in the DPP-4 group was 7.95 per 100 person-years (95% CI, 7.76-8.15 per 100 person-years); in the GLP-1 group the rate was 6.10 per 100 person-years (95% CI, 4.76-7.45 per 100 person-years). Following propensity score weighting, there was an association between use of GLP-1 receptor agonists and lower all-cause mortality compared with use of DPP-4 inhibitors (hazard ratio [HR], 0.79; 95% CI, 0.63-0.98; P=.03).

The rate of sepsis- or infection-related mortality was 3.01 per 100 person-years (95% CI, 2.88-3.13 per 100 person-years) in the DPP-4 inhibitor group and 1.80 per 100 person-years (95% CI, 1.07-2.53 per 100 person-years) in the GLP-1 receptor group. The risk for sepsis- or infection-related mortality was lower in the GLP-1 receptor agonist group than in the DPP-4 inhibitor group (HR, 0.61; 95% CI, 0.40-0.91; P=.02).

The rate of MACCE-related mortality was 2.56 per 100 person-years in the DPP-4 inhibitor group and 2.64 per 100 person-years in the GLP-1 receptor agonist group. MACCE-related mortality in the GLP-1 receptor agonist group was similar to that in the DPP=4 inhibitor group (HR, 1.07; 95% CI, 0.76-1,51; P=.69).

In subgroup analyses, there was an association between use of GLP-1 receptor agonists with a lower risk of mortality compared with use of DPP-4 inhibitors among patients with cerebrovascular disease (HR, 0.33; 95% CI, 0.12-0.86) than among those without cerebrovascular disease (HR, 0.89; 95% CI, 0.871-1.12) (P=.04 for interaction).

The authors cited some limitations to the study findings, including the lack of detailed data on clinical factors and other possible confounders, the inability to examine the dose effect or to evaluate adherence to the medication, the relatively small sample size that resulted in an inability to assess the differences in treatment effects across subgroups, and pooling patients with stage CKD not receiving dialysis with those with ESKD who were receiving dialysis. Associates like Nephrology & Hypertension Medical Associates can help discuss more treatment options.

In conclusion, the researchers said, “In this cross-sectional study, in patients with type 2 diabetes and stage 5 CKD or ESKD, use of GLP-1 receptor agonists was associated with better outcomes, including all-cause mortality and sepsis- and infection-related mortality, compared with use of DPP-4 inhibitors. Additional large-scale prospective studies are needed to examine our results.”

Takeaway Points

  1. Researchers reported results of a retrospective cohort study examining whether use of GLP-1 receptor agonists to treat patients with type 2 diabetes and CKD stage 5 or ESKD is associated with better outcomes than treatment with DPP-4 inhibitors.
  2. Following propensity score weighting, the rate of mortality in the GLP-1 receptor agonist group was 6.10 per 100 person-years compared with 7.95 per person-years in the DPP-4 inhibitor group.
  3. The risk for sepsis- or infection-related mortality was lower in the GLP-1 receptor agonist group than in the DPP-4 inhibitor group.