Discussion
CKD, kidney disease, cardio-renal disease, DKD, cardio-renal, diabetes
KIDNEY DISEASE, EVENTS, CELLULAR PROLIFERATION, TYPE 2 DIABETES, INSULIN SENSITIVITY, COMPLICATIONS, DIABETES
In this trial of patients with type 2 diabetes and CKD who were randomized to receive canagliflozin or placebo, we showed that baseline IGF-1 levels and IGF-1/IGFBP-3 ratio (but not IGFBP-3 concentrations) were associated with cardio-renal outcomes. Higher IGF-1 levels (for a given age) were associated with a greater risk of developing renal and all-cause mortality events. 3 years of therapy with canagliflozin did not significantly change IGF-1 and IGFBP-3 concentrations. Lastly, the benefits of canagliflozin to reduce cardio-renal events in this high-risk population were consistent across IGF-1 and IGFBP-3 strata. These findings provide evidence regarding the role of the IGF axis in risk for cardio-renal disease.IGF-1 is an anabolic hormone that regulates cellular proliferation, apoptosis, and several metabolic pathways in the human body. Nearly all 98% of IGF-1 is bound to 1 of 6 IGFBPs in circulation. Owing to its longer half-life, IGFBP-3 is the most abundant member of the IGFBP family and accounts for 80% of all IGFBPs [While enhancing insulin sensitivity, growth-promoting properties of IGF-1 are proposed to play a role in developing complications of diabetes [Despite the proposed mechanistic role of IGF-1 in DKD, results of clinical studies investigating the association between IGF-1 levels and kidney disease are inconclusive. In the NHANES study (National Health and Nutrition Examination Survey), Teppala and colleagues [Findings of our study corroborate studies indicating a detrimental association between elevated IGF-1 (when above age-specific cutoffs) as well as higher IGF-1/IGFBP-3 ratio on kidney function. As IGF-1 levels decrease by age, the findings from this study highlight the importance of considering IGF-1 age-specific cutoffs as well as incorporating the balance of IGF-1 bioactivity (reflected in the IGF-1/IGFBP-3 ratio) when studying IGF biology and cardio-renal risk. On the other hand, IGFBP-3 was not correlated with baseline kidney function and failed to predict any clinical events. IGFBP-3 has several IGF-1–dependent and IGF-1–independent functions [The exact mechanism of the cardio-renal benefit of canagliflozin is still undetermined [This study had several limitations. First, biomarker data were unavailable for all participants; however, those in this post hoc analysis were similar to the main study. Second, more than 70% of study participants were White. A diverse research population can increase generalizability of our findings. Future studies need to implement the National Institutes of Health recommendations to conduct research studies with diverse ethnic backgrounds. Lastly, patients were followed up for 3 years; a longer duration may be required to investigate the association between IGF-1 and incident HF.