Dipeptidyl peptidase-4 inhibition to prevent progression of calcific aortic stenosis

Abstract

ObjectiveTo 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.MethodsOut 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%).ResultsMaximal 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).ConclusionsDPP-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.

Evogliptin Suppresses Calcific Aortic Valve Disease by Attenuating Inflammation, Fibrosis, and Calcification

“…This implied that DPP-4 inhibitors may be useful for preventing or delaying CAVD progression. Various DPP-4 inhibitors are currently available and we showed that the distribution of evogliptin in cardiac tissue is considerably higher than the other seven DPP-4 inhibitors, in another report from our laboratory [ 20 ]. We thus speculated that evogliptin, a DPP-4 inhibitor possessing high cardiac tissue distribution profile, may be effective as a disease-modifying agent for CAVD.…”

“…We have previously shown from our laboratory that the DPP-4 inhibitor sitagliptin reduces the mineralization of VICs in vitro, decreases calcific lesion formation in eNOS −/− mice, and improves aortic valve performance accompanied by a reduction in the calcium deposits in a rabbit CAVD model [ 19 ]. Moreover, we also reported that aortic stenosis patients who received DPP-4 inhibitors that have a higher cardiac tissue distribution profile show a significantly lower risk of severe aortic stenosis progression than patients who did not receive DPP-4 inhibitors, or were treated with those having a lower cardiac tissue distribution profile [ 20 ]. We also found that evogliptin had the highest cardiac tissue distribution among the eight known DPP-4 inhibitors (evogliptin, linagliptin, gemigliptin, alogliptin, sitagliptin, vildagliptin, saxagliptin, and teneligliptin) as revealed by pharmacokinetic and pharmacodynamic analysis [ 20 ].…”

“…Moreover, we also reported that aortic stenosis patients who received DPP-4 inhibitors that have a higher cardiac tissue distribution profile show a significantly lower risk of severe aortic stenosis progression than patients who did not receive DPP-4 inhibitors, or were treated with those having a lower cardiac tissue distribution profile [ 20 ]. We also found that evogliptin had the highest cardiac tissue distribution among the eight known DPP-4 inhibitors (evogliptin, linagliptin, gemigliptin, alogliptin, sitagliptin, vildagliptin, saxagliptin, and teneligliptin) as revealed by pharmacokinetic and pharmacodynamic analysis [ 20 ]. In our present study, we have provided several lines of evidence that pharmacological inhibitor evogliptin, which shows the highest cardiac tissue distribution among its class of molecules, also has positive effects on the incidence of CAVD.…”

“…Given our previous evaluation of the cardiac tissue distribution profile of eight different DPP-4 inhibitors, and finding that evogliptin had the highest adjusted heart to plasma concentration [ 20 ], we here studied the effects of evogliptin on aortic valve inflammation, fibrosis, and calcification in CAVD animal models. In our present analyses, we evaluated the efficacy of evogliptin in suppressing the in vitro osteogenesis of VICs, inflammatory cytokine expression, and the formation of calcific lesions in CAVD animal models to elucidate the mechanism by which DPP-4 inhibitor attenuates CAVD.…”

The mechanistic pathways of oxidative stress in aortic stenosis and clinical implications

“…A recent Korean study explored the anti-calcification effects of different DPP-4 inhibitors that were commercially available, and divided them into two groups - favourable (linagliptin and gemigliptin), and unfavourable (alogliptin, sitagliptin and vildagliptin) based on their heart and plasma concentrations after administration 122 . Interestingly, they found that the use of linagliptin and gemigliptin in diabetic patients with mild-moderate AS were associated with a significantly lower rate of increase in the maximal transaortic velocity compared to the patients taking unfavourable DPP-4 inhibitors as well as those not taking DPP-4 inhibitors at all 122 . This was a retrospective study, and whether these results can be replicated in a future prospective study remains to be seen.…”