Glomerular Filtration Rate and Associated Risks of Cardiovascular Events, Mortality, and Severe Hypoglycemia in Patients with Type 2 Diabetes: Secondary Analysis (DEVOTE 11)

Abstract

Introduction: The associations of chronic kidney disease (CKD) severity, cardiovascular disease (CVD), and insulin with the risks of major adverse cardiovascular events (MACE), mortality, and severe hypoglycemia in patients with type 2 diabetes (T2D) at high cardiovascular (CV) risk are not known. This secondary, pooled analysis of data from the DEVOTE trial examined whether baseline glomerular filtration rate (GFR) categories were associated with a higher risk of these outcomes.

Methods: DEVOTE was a treat-to-target, double-blind trial involving 7637 patients with T2D at high CV risk who were randomized to once-daily treatment with either insulin degludec (degludec) or insulin glargine 100 units/mL (glargine U100). Patients with estimated GFR data at baseline (n = 7522) were analyzed following stratification into four GFR categories.

Results: The risks of MACE, CV death, and all-cause mortality increased with worsening baseline GFR category (P < 0.05), with a trend towards higher rates of severe hypoglycemia. Patients with prior CVD, CKD (estimated GFR < 60 mL/min/m²), or both were at higher risk of MACE, CV death, and all-cause mortality. Only CKD was associated with a higher rate of severe hypoglycemia, and the risk of MACE was higher in patients with CVD than in those with CKD (P = 0.0003). There were no significant interactions between randomized treatment and GFR category.

Conclusion: The risks of MACE, CV death, and all-cause mortality were higher with lower baseline GFR and with prior CVD, CKD, or both. The relative effects of degludec versus glargine U100 on outcomes were consistent across baseline GFR categories, suggesting that the lower rate of severe hypoglycemia associated with degludec use versus glargine U100 use was independent of baseline GFR category.

Funding: Novo Nordisk.

Keywords: Basal insulin analogs; Cardiovascular disease; Chronic kidney disease; Glomerular filtration rate; Insulin degludec; Insulin glargine U100; Severe hypoglycemia; Type 2 diabetes.

Fig. 1

Risks of various outcomes by baseline GFR category relative to GFR category G1. *Rate of events/100 patient years of exposure. GFR category G1 (solid circle) was used as the reference for GFR categories G2, G3, and G4–5 (open circles). Time from randomization to first MACE, cardiovascular death, and all-cause mortality were analyzed using Cox proportional hazard regression models with treatment, baseline GFR category, and interaction between treatment and baseline GFR category as fixed factors. The number of severe hypoglycemic events was analyzed using a negative binomial regression model with log-link function and the logarithm of the duration of observation time (100 patient years) as offset in addition to randomized treatment, baseline GFR category, and their interactions. Data on the proportion of patients with events and the rate of severe hypoglycemic events are based on observed numbers. CI confidence interval, CV cardiovascular, GFR glomerular filtration rate, MACE major adverse cardiovascular events

Fig. 2

Kaplan–Meier plots for a time to first MACE,b time to cardiovascular death, c time to all-cause mortality, and d number of severe hypoglycemic events by baseline GFR category. GFR glomerular filtration rate, MACE major adverse cardiovascular events

Fig. 3

Comparisons of associations of treatment with degludec or glargine U100 with the risks of MACE, cardiovascular death, and all-cause mortality and the rate of severe hypoglycemia by baseline GFR category. *P value for the interaction between treatment and baseline GFR category;^†rate of events/100 patient years of exposure. Time from randomization to first MACE, cardiovascular death, and all-cause mortality were analyzed using Cox proportional hazard regression models with treatment, baseline GFR category, and interaction between treatment and baseline GFR category as fixed factors. The number of severe hypoglycemic events was analyzed using a negative binomial regression model with log-link function and the logarithm of the duration of observation time (100 patient years) as offset in addition to randomized treatment, baseline GFR category, and their interactions. Data on the proportion of patients with events and the rate of severe hypoglycemic events are based on observed numbers. The MACE and severe hypoglycemia analyses have already been published [25]. CI confidence interval, GFR glomerular filtration rate,glargine U100 insulin glargine 100 units/mL, MACE major adverse cardiovascular events

Fig. 4

Comparison of associations of prior CVD/CKD and no prior CVD/CKD with the risks of MACE, cardiovascular death, and all-cause mortality and the rate of severe hypoglycemia. *Rate of events/100 patient years of exposure. A more detailed exploration of the impact of a history of CVD or CKD on these outcomes is available in the ESM. Time from randomization to first MACE, cardiovascular death, and all-cause mortality were analyzed using Cox proportional hazard regression models with treatment, baseline GFR category, and interaction between treatment and baseline GFR category as fixed factors. The number of severe hypoglycemic events was analyzed using a negative binomial regression model with log-link function and the logarithm of the duration of observation time (100 patient years) as offset in addition to randomized treatment, baseline GFR category, and their interactions. Data on the proportion of patients with events and the rate of severe hypoglycemic events are based on observed numbers. CI confidence interval, CVD cardiovascular disease,CKD chronic kidney disease, glargine U100 insulin glargine 100 units/mL, MACE major adverse cardiovascular events

Fig. 5

Comparison of the associations of prior CVD/CKD/no prior CVD/CKD and treatment with degludec/glargine U100 with the risks of MACE, cardiovascular death, all-cause mortality and the rate of severe hypoglycemia. *P value for interaction between treatment and baseline CVD and CKD status;^†rate of events/100 patient years of exposure. Times from randomization to first MACE, cardiovascular death, and all-cause mortality were analyzed using Cox proportional hazard regression models with treatment, baseline GFR category, and interaction between treatment and baseline GFR category as fixed factors. The number of severe hypoglycemic events was analyzed using a negative binomial regression model with log-link function and the logarithm of the duration of observation time (100 patient years) as offset in addition to randomized treatment, baseline GFR category, and their interactions. Data on the proportion of patients with events and the rate of severe hypoglycemic events are based on observed numbers. CI confidence interval, CVD cardiovascular disease,CKD chronic kidney disease, glargine U100 insulin glargine 100 units/mL, MACE major adverse cardiovascular events