The prevention of cardiovascular disease is among our highest priorities in managing patients with diabetes. The concerns that arose from the association between rosiglitazone use and the incidence of myocardial infarction have led drug regulatory authorities to mandate evidence of cardiovascular safety before a new antihyperglycemic agent can be approved. For the dipeptidyl peptidase (DPP)-4 inhibitors, the availability and analysis of these data have, to date, not only shown apparent safety but have also raised the tantalizing possibility of cardiovascular protection. There are, however, numerous caveats to such analyses and their interpretation. Foremost, the trials are primarily designed to determine the glucose-lowering properties of these agents and not their effects on cardiovascular outcomes, which are instead captured as adverse events. In addition, most of these studies are of short duration, have relatively few patients and mostly do not focus on subjects with pre-existing heart disease or at high risk of developing it. These limitations notwithstanding, some interesting findings are evident.
A series of meta-analyses examining the cardiovascular effects of DPP-4 inhibitors have been conducted over recent years. A very recent one of these included all published and unpublished studies in humans, examining a total of 70 trials with 41 959 patients and a mean follow-up of 44.1 weeks. Consistent with previous, smaller studies, this meta-analysis reported Mantel–Haenszel odds ratios of 0.71 (95% confidence intervals [CI] 0.59, 0.86), 0.64 (95% CI 0.44, 0.94) and 0.60 (95% CI 0.41, 0.88) for major adverse cardiovascular events (MACE), myocardial infarction and mortality, respectively. Of note, the effect appeared consistent among individual drugs within the DPP-4 inhibitor class. In addition, the analysis estimated the effects that may be attributable to risk factor modification by examining data on HbA1c, blood pressure and lipids, when available. Here, the authors concluded that the reduction in myocardial infarction was greater than may be predicted on the basis of changes in conventional risk factors, leading them to suggest a role for other mechanisms.
For endocrinologists, familiar with the incretin effect, it is tempting to speculate that the modest increases in glucagon-like peptide-1 may account for the observed cardiovascular effects of DPP-4 inhibitors. However, as described below, other studies (mostly in the cardiac literature) suggest that other mechanisms may be operating, focusing instead on the role of stromal cell-derived factor (SDF)-1α. This chemokine is constitutively expressed by the bone marrow, where it assists in the maintenance and differentiation of hematopoietic and vascular progenitors. However, its expression may also be induced by hypoxia-inducible factor-1-dependent mechanisms in peripheral tissues in response to ischemia. For example, following myocardial infarction, SDF-1α expression in the heart is markedly increased. This upregulation attenuates injury and assists in cardiac repair by protecting cardiac myocytes from apoptosis and enhancing angiogenesis by both bone marrow-derived and local endothelial-based mechanisms (Fig. 1).
Given the newfound importance of the microvasculature in the setting of ischemic heart disease,[4, 5] the potential role of SDF-1α as a therapeutic agent has recently been explored. In a study of mice with experimental myocardial infarction, intracardiac injection of recombinant SDF-1α led to improved cardiac function and reduced scar formation compared with controls. Similar benefits have also been reported using a protease-resistant SDF-1α, with evidence of enhanced progenitor cell recruitment, increased capillary density, and improved cardiac function after myocardial infarction. Indeed, based on the positive findings of such reports, Juventas, a biotechnology company, has developed a non-viral DNA plasmid that expresses SDF-1α to be used for the treatment of ischemic disorders. Their lead product, JVS-100, will be used in STOP-HF, a study to evaluate the safety and efficacy of JVS-100 administered to adults with ischemic heart failure that is currently recruiting participants (see http://clinicaltrials.gov [ClinicalTrials.gov identifier NCT01643590], accessed 14 March 2013).
Because SDF-1α is rapidly inactivated by DPP-4-mediated cleavage, inhibition of this enzyme presents an alternative strategy of augmenting local SDF-1α bioactivity. Consistent with this notion, Zaruba et al. have shown that DPP-4 inhibition reduces cardiac infarct size in mice, an effect that is enhanced by the coadministration of granulocyte colony-stimulating factor (G-CSF) to mobilize bone marrow-derived endothelial progenitor cells. That study not only provides the non-clinical data for a patent asserting the benefit of DPP-4 inhibition in ischaemic heart disease, but also serves as the scientific basis for the Sitagrami Study examining the effects of sitagliptin with G-CSF in patients with acute myocardial infarction (see http://clinicaltrials.gov [ClinicalTrials.gov identifier NCT00650143], accessed 14 March 2013).
In individuals with diabetes, both soluble and cell surface (CD26) DPP-4 activities are increased.[11, 12] These findings provide a plausible explanation, at least in part, for the comparatively poor prognosis for patients with diabetes and ischaemic heart disease even after adjustment for clinical and angiographic variables.[13, 14] In addition, it offers a rational basis for hypothesizing that DPP-4 inhibition may be particularly cardioprotective in the diabetes setting. Indeed, in studies by us and others using diabetic animal models of cardiomyopathy and acute myocardial infarction, DPP-4 inhibition attenuated many of the structural and functional attributes of disease.[4, 12] The effects of DPP-4 inhibition have also been examined in humans with type 2 diabetes, whereby 4 weeks sitagliptin administration increased both plasma SDF-1α concentrations and the number of circulating endothelial progenitor cells.
In conclusion, the SDF-1α hypothesis provides a plausible basis to explain the relatively fewer MACE in subjects treated with DPP-4 inhibitors reported in meta-analyses. However, caution is still needed to avoid overinterpreting the clinical trial data, which, to date, are largely based on adverse event reporting. Fortunately, definitive answers will hopefully soon be forthcoming, with a series of large prospective randomized controlled cardiovascular studies using a range of DPP-4 inhibitors currently in progress that are expected to be completed in 2013–2018 (see http://clinicaltrials.gov [ClinicalTrials.gov identifiers 01107886, 00790205, 01243424 and 00968708], accessed 14 March 2013).