Author + information
- Dimitrios Farmakis, MD,
- John Parissis, MD and
- Gerasimos Filippatos, MD∗ ()
- ↵∗Heart Failure Unit, Second Department of Cardiology, University of Athens Medical School, Attikon University Hospital, 28 Doukissis Plakentias Street, 11523 Athens, Greece
Cardiovascular (CV) prevention has long been a target of clinical trials in diabetes mellitus (DM). Several of those trials, however, have been unsuccessful. In an effort to address this issue, the recently published PONTIAC (NT-proBNP Guided Primary Prevention of CV Events in Diabetic Patients) trial used natriuretic peptides (NPs) to select patients who had a relatively greater need for CV prevention and hence were probably more prone to improvement (1). This study was successful, but there were some questions that arise from this and previous trials on CV prevention in DM.
First, was the poor patient selection the main reason why the previous trials failed? The interventions used by some of the previous trials also may have not been successful. For example, in the ROADMAP (Randomized Olmesartan and Diabetes Microalbuminuria Prevention) trial, a high dose of an effective angiotensin receptor inhibitor (20 mg olmesartan) was used to prevent microalbuminuria in patients with DM who did not have hypertension, which resulted in high rates of hypotension and other complications and thus treatment failure (2,3). In the PONTIAC trial, a small but significant decline in estimated glomerular filtration rate observed in the intensified treatment group may be of some concern.
Second, what is the underlying pathophysiology for a mild increase in NP levels in symptomatic patients with DM but without known cardiac disease? There are several reasons for false-positive or negative NP results, particularly in a population such as those with DM, characterized by increased rates of comorbidities such as renal dysfunction or obesity. In other words, what is the pathogenetic process that we treat in those patients, and is the neurohormonal blockage a suitable treatment for this process? In the PONTIAC trial, there was no significant reduction in NP levels in the intensified treatment group during the study period, and thus the reason for elevated levels of NP at baseline was probably not addressed by the applied intervention.
Third, how should we titrate and monitor neurohormonal blockade therapy in patients without a clear evidence-based indication for such a therapy, such as arterial hypertension or heart failure? In the PONTIAC trial, treatment titration could not have been guided or followed by NPs, because there was no significant difference in NP levels between the 2 study groups at the end of the study.
Finally, could the positive results of the PONTIAC trial be explained solely by the increased use of health care resources in the intensified treatment group? Those patients were seen regularly not only by diabetologists but also by cardiologists in the cardiac outpatient clinics where they were receiving individualized treatment, and that may be a sufficient reason for a better outcome. In other words, the success of the PONTIAC trial may not lie on the use of NPs for patient selection but instead on the intensification and individualization of their cardiac care. The finding that event rates were similarly low in the intensified group and in patients who had low NP levels and were not included in the study cannot apparently speak against this because the PONTIAC trial was not designed or powered to address this comparison (4). Thus, why not follow a similar “intensified” and individualized approach in all patients with DM? Cost analysis studies are required to address whether such an approach is cost-effective.
Even in the field of heart failure, where NPs are excellent diagnostic and prognostic tools, there is still conflicting evidence regarding their effectiveness to guide therapy; it seems that they are of benefit only when used in the context of a multidisciplinary approach. Given that DM is currently considered a coronary artery disease equivalent, the key to CV prevention in these patients could be the close multidisciplinary follow-up, the individualization of treatment, and the sufficient use of health care resources. NPs or other biomarkers may be of help as part of such an approach.
- American College of Cardiology Foundation
- Huelsmann M.,
- Neuhold S.,
- Resl M.,
- et al.
- Felker G.M.,
- Ahmad T.