Fasting substrates predict chronic kidney disease progression in CREDENCE trial patients with type 2 diabetes

Abstract

BACKGROUNDSodium-glucose cotransporter 2 inhibitors slow down progression of chronic kidney disease (CKD). We tested whether the circulating substrate mix is related to CKD progression and cardiovascular outcomes in patients with type 2 diabetes (T2D) and albuminuric CKD in the CREDENCE trial.METHODSWe measured fasting substrates in 2,543 plasma samples at baseline and 1 year after randomization to either 100 mg canagliflozin or placebo and used multivariate Cox models to explore their association with CKD progression, heart failure hospitalization/cardiovascular death (hHF/CVD), and mortality.RESULTSHigher baseline lactate and free fatty acids (FFAs) were independently associated with a lower risk of CKD progression (HR = 0.73 [95% CI: 0.54-0.98] and HR = 0.67 [95% CI: 0.48-0.95], respectively) and hHF/CVD HR = 0.70 [95% CI: 0.50-0.99] and HR = 0.63 [95% CI: 0.42-0.94]). Canagliflozin led to a rise in plasma FFAs, glycerol, β-hydroxybutyrate, and acetoacetate. Changes in substrate between baseline and year 1 predicted an approximately 30% reduction in relative risk of both CKD progression and hHF/CVD independently of treatment. More patients who did not respond to canagliflozin treatment in terms of CKD progression belonged to the bottom lactate and FFA distribution tertiles.CONCLUSIONIn T2D patients with albuminuric CKD, basic energy substrates selectively influenced major long-term endpoints; canagliflozin treatment amplified their effects by chronically raising their circulating levels.

Keywords: Cardiology; Diabetes; Drug therapy; Endocrinology; Intermediary metabolism.

Figure 1. Baseline substrates versus outcomes.

Kaplan-Meier plot of time to first primary composite endpoint (top) and time to composite renal endpoint (bottom) by tertile of baseline fasting plasma lactate concentrations.

Figure 2. Forest plot showing the multivariate Cox proportional hazards model of the association between several covariates, including baseline fasting plasma lactate and free fatty acids, with time to first primary composite endpoint.

Only covariates reaching statistical significance are plotted; additional covariates with no statistically significant differences are not plotted. SD, standard deviation; Ln, natural logarithm; BMI, body mass index; HbA_1c, glycated hemoglobin A1c; eGFR, estimated glomerular filtration rate; UACR, urinary albumin-to-creatinine ratio; LDL-C, low-density lipoprotein cholesterol; FFA, free fatty acids.

Figure 3. Kaplan-Meier plots of time to first composite renal endpoint and time to first hospitalized congestive heart failure by tertile of baseline fasting plasma FFA concentrations.

Figure 4. Forest plots showing the multivariate Cox proportional hazards model of the association between several covariates, including baseline fasting plasma lactate and free fatty acids, with time to first of the composite of hospitalized congestive heart failure (upper panel) or cardiovascular death and time to all-cause death (lower panel).

Only covariates reaching statistical significance are plotted; additional covariates with no statistically significant differences are not plotted. SD, standard deviation; Ln, natural logarithm; HbA_1c, glycated hemoglobin A1c; UACR, urinary albumin-to-creatinine ratio; LDL-C, low-density lipoprotein cholesterol; CVD, cardiovascular disease; HF, heart failure; FFA, free fatty acids.

Figure 5. Kaplan-Meier plot of time to first composite renal endpoint and time to first hospitalized congestive heart failure by treatment responder status in the treatment arm (see text for definition of responder).

Figure 6. Organization of current results into a minimal physiologic model.

A constitutive metabolic blueprint influences long-term cardio-renal outcomes; the metabolic changes that follow SGLT2 inhibition essentially reinforce the constitutive pattern, while hemodynamic and oxygen-delivery effects exert their own influence on outcomes. Subserving molecular pathways (enzyme activities, signaling, redox shifts, etc.) are still under study.