Objective To evaluate whether the use of dipeptidyl peptidase-4 (DPP-4) inhibitors and their cardiac tissue distribution profile and anticalcification abilities are associated with risk of aortic stenosis (AS) progression.
Methods Out of the five different classes of DPP-4 inhibitors, two had relatively favourable heart to plasma concentration ratios and anticalcification ability in murine and in vitro experiments and were thus categorised as ‘favourable’. We reviewed the medical records of 212 patients (72±8 years, 111 men) with diabetes and mild-to-moderate AS who underwent echocardiographic follow-up and classified them into those who received favourable DPP-4 inhibitors (n=28, 13%), unfavourable DPP-4 inhibitors (n=69, 33%) and those who did not receive DPP-4 inhibitors (n=115, 54%).
Results Maximal transaortic velocity (Vmax) increased from 2.9±0.3 to 3.5±0.7 m/s during follow-up (median, 3.7 years), and the changes were not different between DPP-4 users as a whole and non-users (p=0.143). However, the favourable group showed significantly lower Vmax increase than the unfavourable or non-user group (p=0.018). Severe AS progression was less frequent in the favourable group (7.1%) than in the unfavourable (29.0%; p=0.03) or the non-user (29.6%; p=0.01) group. In Cox regression analysis after adjusting for age, baseline renal function and AS severity, the favourable group showed a significantly lower risk of severe AS progression (HR 0.116, 95% CI 0.024 to 0.551, p=0.007).
Conclusions DPP-4 inhibitors with favourable pharmacokinetic and pharmacodynamic properties were associated with lower risk of AS progression. These results should be considered in the preparation of randomised clinical trials on the repositioning of DPP-4 inhibitors.
- aortic stenosis
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SL and S-AL contributed equally.
Contributors SL and S-AL participated in the study design and analysis and interpretation of the final data, as well as in the drafting and approval of the final manuscript. BC, Y-JK and SJO were involved in in vivo animal experiments for pharmacokinetic–pharmacodynamic modelling and statistical analysis. H-MC, EKK, D-HK, G-YC, J-MS, SWP and D-HK were involved in the recruitment of participants from clinics. J-KS was responsible for the design and supervision of the study and revision of the manuscript.
Funding This research was supported by the Korea Drug Development Fund, funded by the Ministry of Science and ICT, Ministry of Trade, Industry and Energy, and Ministry of Health and Welfare (KDDF-201609-12, Republic of Korea).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not required.
Ethics approval The respective institutional review boards of each institution approved the protocols of this study. All animal experiments and protocols were performed in accordance with the Guide for the Care and Use of Laboratory Animals and approved by the Institutional Animal Care and Use Committee of Asan Institute for Life Sciences in Asan Medical Center (Seoul, Republic of Korea).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request. Please contact the corresponding author for our data.
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