In the present study, we incorporated NT-proBNP measurement together with ECG screening into the DM complication screening program. We identified the prevalence and predictors of elevated NT-proBNP concentration, which is indicative of a higher risk of developing HF and therefore could inform further clinical management. First, in our cohort of 1,043 consecutive DM patients without prior history of HF or AF, we showed that the prevalence of elevated NT-proBNP concentration, defined as above the age-specific diagnostic threshold of HF, was relatively high at 4.1%. The prevalence increased progressively with age (from 0.85% in patients aged < 50 years to 7.14% in those aged 70–79 years), as well as with worsening kidney function (from 0.43% in patients with CKD stage 1 to 42.86% in CKD stage 5). Second, in multivariate logistic regression, male gender (OR: 3.67 (1.47–9.16), p = 0.005*), prior stroke (OR: 3.26 (1.38–7.69), p = 0.007*), CKD (p < 0.001*), and newly detected AF (OR: 7.02 (2.65–18.57), p < 0.001*) were associated with elevated NT-proBNP concentration. Third, amongst DM patients with elevated NT-proBNP concentration, 45% of them had an LVEF below 50%, and 31% of them had diastolic dysfunction with left ventricular hypertrophy. Last but not least, AF was newly detected in 4.1% of the current study population.
DM is associated with macrovascular and microvascular complications that can go unnoticed and be left untreated until irreversible damage ensues. The American Diabetes Association (ADA) has recommended a comprehensive list of medical evaluations to detect complications, which has been widely incorporated into DM complication screening programs worldwide.32 On the other hand, despite the high prevalence of HF (~ 28%) amongst DM patients,20–24 early detection or screening of HF and/or asymptomatic left ventricular dysfunction has not been recommended or routinely practiced. This may be partly related to the difficulty to detect HF particularly non-acute HF in primary care setting.33 Plasma natriuretic peptides including NT-proBNP and BNP which have high positive predictive value for HF, are established tests for HF diagnosis,34–36 as well as prognostication.37–39 More recently, the use of plasma natriuretic peptides has been extended for screening of early HF and/or asymptomatic left ventricular dysfunction amongst patients at risk of developing HF.28, 40–42 The screening yield depends on the prevalence of HF and/or asymptomatic left ventricular dysfunction in specific screened population. In the present study involving patients with DM but without prior history of HF and AF, the overall prevalence of elevated NT-proBNP concentration was relatively high at 4.1%, compared with ~ 1% prevalence of HF in the general population. Although NT-proBNP assay has a high positive predictive value to detect early HF and/or asymptomatic left ventricular dysfunction, it is not widely available due to cost. Nonetheless, the prevalence increased disproportionally with age and CKD stage, two independent predictors of elevated NT-proBNP concentration and asymptomatic left ventricular dysfunction in patients with DM. For instance, while the prevalence of elevated NT-proBNP concentration in DM patients aged < 70 years and with CKD stage 1 is negligible and may not justify screening, for those with CKD stage 3–5, the prevalence of elevated NT-proBNP concentration could range from 9.5–14.3%, giving a very high screening yield. Therefore, an age- and kidney function-based screening would be a more efficient strategy to identify patients with early HF or asymptomatic left ventricular dysfunction.
As the purpose to detect early HF and/or asymptomatic left ventricular dysfunction is to prevent HF, there should be a therapeutic intervention effective at this early phase to modify the disease course. In the STOP-HF trial involving 1,374 patients aged 40 years or older with at least one high-risk factor for HF but without HF and/or asymptomatic left ventricular dysfunction,40 a BNP based screening program, together with the collaborative care between primary care physician and cardiovascular specialist, reduced the combined rates of left ventricular dysfunction and HF, which confirmed the role of plasma natriuretic peptides as a HF risk identifier. Furthermore, in the PONTIAC study,41 accelerated up-titration of renin-angiotensin system antagonists and beta-adrenergic blockers amongst DM patients with an elevated NT-proBNP concentration reduced hospitalization or death due to cardiac disease by 64% in 2 years. More recently, in EMPA-REG,26 and CANVAS trials that randomized patients with type 2 DM and history of cardiovascular disease to SGLT2 inhibitors (empagliflozin and canagliflozin, respectively) or placebo, SGLT2 inhibitors substantially reduced cardiovascular mortality and hospitalization for HF. Furthermore, subgroup analyses of these landmark randomized controlled trials revealed that SGLT2 inhibitors reduced HF hospitalization regardless of the presence of documented HF at baseline, suggesting the possibility of utilizing SGLT2 inhibitors to improve HF outcome in DM patients with subclinical HF43, 44. These further strengthens the armamentarium to prevent DM related HF.
There are several limitations in our study. First, the presented data are collected from a single center, therefore local patient characteristics and medical practice may limit the generalizability of the results. Second, since the current study is a single-arm observational study instead of a randomized controlled trial, it remains uncertain whether incorporation of NT-proBNP measurement and ECG to DM complication screening program could reduce the risks of incident HF, hospitalization for HF, and/or mortality. Nonetheless, identification of these at-risk patients by systematic screening is the critical first step that would allow further prospective assessment of whether early intervention is associated with improved clinical outcome.