SGLT2i attenuates longitudinal rises in CV biomarkers in T2DM patients
Stress Cardiac Biomarkers, Cardiovascular and Renal Outcomes, and Response to Canagliflozin
Introduction and methods
Patients with DM can be efficiently stratified by their risk of future CV events using CV biomarkers for different pathophysiological processes . These biomarkers—either measured alone or in combination—have been projected to identify at-risk persons who may gain greater absolute treatment benefits from SGLT2is .
The CANVAS (CANagliflozin cardio-Vascular Assessment Study) trial was a CV outcomes study in which the effect of canagliflozin in T2DM patients with and without established CVD was evaluated . A diverse panel of biomarkers targeting different axes of risk and pathophysiological abnormalities was assessed in the CANVAS biomarker substudy.
Aim of the study
The primary aims of the CANVAS biomarker substudy were: (1) to examine the effect of canagliflozin on the trajectory of 3 biomarkers for up to 6 years, (2) to analyze the association of baseline measurement of these biomarkers (either alone or collectively) with adverse CV and renal outcomes, and (3) to determine whether the treatment benefits of canagliflozin are modified by baseline levels of these biomarkers.
The CANVAS biomarker substudy was a post-hoc analysis of the CANVAS trial. In this RCT, 4330 T2DM patients with eGFR >30 mL/min per 1.73 m2 and high CVD risk were randomized (1:1:1 ratio) to canagliflozin 100 mg or 300 mg or placebo and followed for up to 6 years. In the substudy, the following biomarkers were studied: high-sensitivity cardiac troponin T (hs-cTnT; marker of myocardial injury), soluble suppression of tumorigenesis-2 (sST2; marker of vascular congestion, tissue inflammation, and fibrosis), and insulin-like growth factor–binding protein 7 (IGFBP7; marker of tissue senescence and remodeling). Availability of baseline measurements of these 3 biomarkers ranged from 71% to 83% of the participants.
The primary endpoint of the CANVAS trial was the occurrence of MACE (composite of CV death, non-fatal MI, and non-fatal stroke). Secondary endpoints included all-cause mortality, CV death, and a composite outcome of CV death or HF hospitalization. The renal composite endpoint comprised eGFR decrease ≥40%, need for kidney replacement therapy, or renal death. The additional renal composite endpoint included all of these components plus CV death.
Effect of canagliflozin on biomarker trajectory
- At baseline, 39% of the patients had an elevated hs-cTnT level (≥14 pg/mL), 6% had sST2 >35 ng/mL, and 49% showed IGFBP7 >96.5 ng/mL.
- Canagliflozin was associated with a significantly lower hs-cTnT concentration (geometric mean ratio (GMR): 93.8%; 95%CI: 88.6–99.3; P=0.027) and a significantly lower sST2 level (GMR: 87.9%; 95%CI: 78.0–99.0; P=0.033) compared with placebo at year 6; there were no significant associations at year 1.
- There was no difference in the IGFBP7 level increase between the canagliflozin and placebo groups after 1 year (measurements were not available at year 6).
Association of baseline biomarker level with CV and renal outcomes
- Each biomarker was significantly associated with several adverse CV and renal outcomes, independent of clinical covariates such as BMI, duration of DM, or history of HF.
- IGFBP7 in particular showed a strong association with the risk of HF hospitalization (adjusted hazard ratio (HR) per unit increase in log-transformed biomarker: 13.9; 95%CI: 7.29–26.4; P<0.001).
Modification of canagliflozin treatment benefits by baseline biomarker levels
- Canagliflozin reduced the incidence of HF and kidney disease events regardless of elevated baseline biomarker concentrations (all P values for interaction >0.10).
- Patients with hs-cTnT ≥14 pg/mL (HR: 0.71; 95%CI: 0.56–0.91) appeared to gain a greater relative benefit of canagliflozin for MACE compared with those with a normal hs-cTnT level (HR: 1.10; 95%CI: 0.81–1.49; P for interaction between canagliflozin and biomarker=0.05).
- There was also an interaction between elevated hs-cTnT level and treatment effect of canagliflozin on non-fatal MI (P for interaction=0.04).
- In patients with sST2 ≥35 ng/mL (HR: 0.53; 95%CI: 0.27–1.05), the relative benefit of canagliflozin for MACE appeared to be larger compared with those with sST2 <35 ng/mL (HR: 0.92; 95%CI: 0.75–1.12; P for interaction=0.04).
- Elevated IGFBP7 levels could have modified the treatment responses to canagliflozin for non-fatal stroke (P for interaction=0.03).
- With a multimarker risk panel comprising the 3 biomarkers, each cardiac and renal outcome could be predicted. Patients with multiple elevated plasma biomarkers appeared to have a greater relative reduction in MACE after canagliflozin treatment compared with placebo (P for interaction trend=0.005).
- Absolute risk reductions for canagliflozin compared with placebo ranged from 0.1 per 100 patient-years in patient with no elevated circulating biomarker levels to 5.4 per 100 patient-years in those with 3 elevated biomarkers.
In this longitudinal study, canagliflozin delayed the increase in hs-cTnT and sST2 levels compared with placebo for up to 6 years. This treatment also reduced the incidence of HF and kidney disease events regardless of the baseline concentrations of the studied biomarkers. Based on their study results, the authors believe “there is a potential future role of biomarkers in more accurate risk stratification and identification of [T2DM] patients who stand to benefit from cardioprotective therapies.”