In the present study, we demonstrate that long-term treatment of the DPP-4 inhibitor vildagliptin in rats with LV remodeling due to MI increases endogenous active plasma GLP-1 levels, via inhibition of DPP-4 activity. However, this did not result in a decreased infarct size nor did it attenuate cardiac remodeling associated with post-MI. No differences in glucose levels and body weight were found in these non-diabetic rats when treated with vildagliptin.
To our knowledge, this is the first study to assess the effects of immediate and late vildagliptin treatment in a non-diabetic rat model. We furthermore aimed to dissect immediate versus late effects of DPP-4 inhibition. We herein show that neither early nor late vildagliptin treatments exert beneficial effects in MI-induced deterioration in cardiac remodeling. Notably, MI size was (non-significantly) smaller in the vildagliptin treated rats. However, this effect was observed both in rats immediately treated with vildagliptin as well as in rats in which treatment with vildagliptin started after 3 weeks, so when the infarction scar is fully organized. From this, we postulate that vildagliptin is unlikely to reduce infarct size. The associated differences in LVEF may be ascribed to the differences in infarct size. Other measures of LV remodeling were also unaffected by vildagliptin. For example, both early and late vildagliptin treatment did not reverse the MI-induced decrease in capillary density, measured at the border zone of the infarcted myocardium. Similarly, both early and late vildagliptin treatment did not counteract MI-induced cardiomyocyte hypertrophy. Furthermore, both early and late vildagliptin treatment had no effects on the MI-induced increases in cardiac expression of ANP, BNP. ANP and BNP cardiac gene expression closely associates with the severity of LV dysfunction , so this finding supports the notion that cardiac remodeling is not affected by vildagliptin. Furthermore, the expression of matricellular proteins collagen I and MMP-9 were also not affected by vildagliptin treatment.
A number of acute studies have been previously performed with DPP-4 inhibitors, GLP-1 or GLP-1 analogues, addressing their role in cardioprotection. A study with the DPP-4 inhibitor PFK275-055, a vildagliptin-analogue, showed a reduced infarct size with activation of the cardioprotective RISK (reperfusion-induced salvage kinase) pathway in pre-diabetic rats , whereas a study with the DPP-4 inhibitor sitagliptin showed that infarct size or short-term cardiac function were not affected by the treatment . The latter study is in line with our study.
Another mean of increasing GLP-1 is direct GLP-1 infusion. Acute GLP-1 infusion studies both in patients and rodents did show beneficial effects. In a clinical study, 3-day infusion of GLP-1 improved LV function in patients after acute MI . Moreover, ischemia/reperfusion experiments in rats showed that GLP-1 administration prior to the ischemia leads to smaller infarct size in the isolated heart [11, 12, 26]. Another ischemia-reperfusion study showed that only the GLP-1 analogue exendin-4, but not GLP-1(9-36) amide exerts infarct-limiting action, while both of them improved LV performance . Apparently, GLP-1 infusion provides a stronger effect than DPP-4 inhibition, probably due to a stronger elevation of GLP-1 levels. The published results from DPP-4 inhibition studies are variable and this might be explained by different levels of inhibition (different inhibitors used, different dosages), and variable levels of GLP-1.
So, although a number of acute studies have been performed, only few chronic studies have addressed the effects of GLP-1 on cardiac function in non-diabetic models. A chronic (3 month) infusion study showed that GLP-1 improved LV systolic function and prolonged survival in spontaneously hypertensive rats by increasing myocardial glucose uptake and reducing myocyte apoptosis . Treatment with either GLP-1 or exenatide analogue AC3174 also demonstrated promising cardioprotective effects, including improved LVEF, LV end-diastolic pressure, and cardiac dimensions in a rat MI model (comparable to the present model) . Our results are not in concert with the observations that cardioprotection is achieved by GLP-1 treatment. The reasons for the discrepancies between the present study and earlier work may be attributable to the dosing regimen, the different analogue utilized, the levels of GLP-1 achieved, and the timing of the treatment and the species studied .
Furthermore, a number of other issues should be considered when discussing the lack of vildagliptin-induced cardioprotection as observed in our study. First, we used a model of non-diabetic rats, with normal glucose levels. Vildagliptin is an antidiabetic agent which exerts its beneficial effects in the cardiovascular system through glycometabolic control. Thus it may be possible that vildagliptin is more beneficial in diabetic models. Second, as a DPP-4 inhibitor, vildagliptin inhibits degradation of GLP-1 and prolongs its half life in vivo; however, its effects are less strong than continuous GLP-1 infusion. The elevations in GLP-1 levels achieved by vildagliptin are likely to be lower than achieved by GLP-1 infusion and thus insufficient to produce cardioprotection. Finally, we do not know if other, hitherto unknown mechanisms, may underpin the effects of vildagliptin in the heart. To date, limited data are available describing the effects of vildagliptin on the cardiovascular system.
In addition, the biological effects of DPP-4 inhibitors appear different from GLP-1 and other GLP-1R agonists . Vildagliptin treatment has no effect on body weight, food intake, energy expenditure and insulin sensitivity [4, 32, 33]. Although it has been shown that vildagliptin reduced plasma cholesterol and triglycerides in diabetic patients [34, 35], no effects of vildagliptin on these parameters were found in our post-MI animal study. However, GLP-1 inhibits glucagon secretion and controls body weight by decreasing food intake, increase insulin sensitivity and improve glucose uptake, which are beneficial cardiovascular factors [36–38]. Moreover, the protective effects of GLP-1 are also mediated through GLP-1R-independent pathways, partially though beneficial effects of its metabolite GLP-1 (9-36) . These differences might explain why we observed only limited improvements in our study with vildagliptin as compared to other studies with GLP-1 and GLP-1 analogues.