Background/Introduction: Circulating biomarkers reflecting different mechanistic pathways
may identify patients most likely to benefit from sodium glucose co-transporter 2 (SGLT2)
inhibitors.
Purpose: To determine if 3 biomarkers (high sensitivity cardiac troponin T [hs-cTnT], soluble
ST2 [sST2], and insulin-like growth factor binding protein 7 [IGFBP7]) have prognostic
implications or modify treatment response to canagliflozin in the CANVAS trial.
Methods: Among 3,040 participants in the CANVAS trial with available biomarker data, we
created a multi-marker panel assigning 1 point for each abnormally elevated level of hs-cTnT,
sST2, and IGFBP7. We assessed its association with risk of cardiac and kidney outcomes, and
whether each biomarker alone or as a multi-marker panel modified the treatment response to
canagliflozin. Incremental discrimination was tested by comparing C-statistics of a base clinical
model plus each individual biomarker (or multi-marker panel) vs. the base clinical model alone
(age, eGFR, body mass index, systolic blood pressure, HbA1c, duration of diabetes, urine
albumin:creatinine ratio, history of HF, and diuretic use).
Results: Among placebo-treated participants, 38% had elevated levels of hs-cTnT ≥14 pg/mL,
7% had sST2 >35 ng/mL, and 49% had IGFBP7 >96.5ng/mL. Overall, 1,102 (36%), 1,051
(35%), 819 (27%), and 68 (2%) had 0, 1, 2, and 3 elevated biomarkers. Increasing numbers of
elevated biomarkers independently predicted each cardiac and kidney outcome in a graded
fashion and improved risk discrimination compared with clinical variables alone (C-statistic
improvement by +0.04 to +0.06) (Figure). Canagliflozin reduced heart failure and kidney events
regardless of baseline biomarker concentrations, however patients with elevated hs-cTnT
appeared to derive greater relative benefit for major adverse cardiovascular events (MACE)
compared with those with lower values (hazard ratio [HR] 0.77; 95% confidence interval [CI]
0.61-0.97 vs. HR 1.10; 95% CI 0.83-1.44; Pinteraction=0.05). Similarly, patients with elevated
IGFBP7 >96.5 ng/mL (HR 0.81; 95% CI 0.64-1.01) appeared to derive greater relative treatment
effects for stroke compared with patients with normal IGFBP7 ≤96.5 ng/mL (HR 1.03; 95% CI
0.78-1.36; Pinteraction=0.05). Participants with an increasing number of abnormal circulating
biomarkers appeared to have greatest relative reductions in MACE from canagliflozin treatment:
0 abnormal biomarkers (HR 0.94; 95% CI 0.63-1.39), 1 abnormal biomarker (HR 1.36; 95% CI
0.96-1.92), 2 abnormal biomarkers (HR 0.62; 95% CI 0.46-0.83), and 3 abnormal biomarkers
(HR 0.44; 95% CI 0.19-1.01); Pinteraction trend=0.009.
Conclusions: Circulating markers of myocardial injury and remodeling are frequently abnormal
in patients with type 2 diabetes at high cardiovascular risk and may identify patients who may
derive greater benefit from SGLT2 inhibitors.