Patients with ischemic heart disease and diabetes are at a particularly high risk for the recurrence of cardiovascular events. Conversely, certain classes of oral antidiabetic medications have been shown to cause hypoglycemia as well as adverse cardiovascular effects [1–3]. Diabetes induces complex vascular changes, promoting accelerated atherosclerosis and hypercoagulability, as can be assessed indirectly by a number of markers. Principal perturbations include endothelial dysfunction, increased inflammatory plaque infiltration, adhesion molecule over-expression and adverse effects of circulating fatty acids and advanced glycosylation end products.
Animal studies have suggested numerous beneficial antiatherosclerotic changes of dipeptidyl peptidase-4 inhibitors (DPP4i), well beyond the effects on blood glucose alone [4, 5]. Additionally, antiremodeling effects are proposed . However, this feature has not been established in a clinical setting. Concomitant treatment with a DPP4i and metformin may offer an attractive glycemic reduction modality with synergistic mechanism of action while exerting additional vascular protective benefits. Reduction of inflammatory marker levels is of great clinical importance and has been shown to correlate with reduction in significant clinical events. Therefore, in the present study we plan to focus on possible anti inflammatory and atherothrombotic protective effects of DPP4i in a clinical setting.
Key representative markers for the present study are chosen in order to correctly represent alterations in: inflammation (hs-CRP), risk of atherosclerotic plaque rupture and matrix turnover (MMP-9), and platelet reactivity (aggregability tests). These markers are further detailed:
Interleukin 6 (IL-6)
This established inflammatory marker has been shown to be increased in individuals with coronary artery disease [7, 8]. Furthermore, diabetes has been referred to as a chronic inflammatory state. Therefore, a reduction in inflammatory markers in this high-risk population is likely to correlate with a corresponding reduction in the risk for atherothrombotic events.
High sensitivity C-reactive protein (hs-CRP)
Marker of inflammation with a strong correlation with cardiovascular events even in normolipemic population . Reduction of hs-CRP has been demonstrated with vildagliptin-pioglitazone combination, but data from patients with cardiovascular disease and vildagliptin-metformin combination are lacking .
Platelet reactivity testing
Platelets are hyper-reactive in diabetic patients, and this heightened activity is closely linked to vascular events [11, 12]. Perturbations in both structure and function have been described [13, 14]. Reduction in reactivity is a viable surrogate of reduced thrombogenic milieu . However, currently there are no human data on the effects of DPP4i on platelet function. We hypothesize that a combined vildagliptin-metformin therapy will be associated with a greater reduction in platelet reactivity as compared with metformin monotherapy.
Hormone with regulatory metabolic function secreted from the adipose tissue. Reduced levels of adiponectin were shown to be associated with obesity, metabolic syndrome, and diabetes, and to promote the atherosclerotic process [16–18]. Higher levels have been found to be protective [18, 19]. Reduction in adiponectin levels induced by fatty diet has recently been shown to be corrected by DPP4i in mice , yet the effect in diabetic humans is unknown.
Matrix metallo-proteinases 9 (MMP-9)
The MMPs are a large family of zinc-dependent, extra-cellularly acting endo-peptidases. Substrates of MMPs are proteins of the extracellular matrix and adhesion proteins. Patients with coronary artery disease were recently shown to have increased levels of MMP-9 . A higher MMP-9 level was also shown to correlate with coronary artery ectasia , and to predict increased mortality in patients with coronary artery disease . Accordingly, we hypothesize that treatment with combined vildagliptin-metformin therapy will be associated with significantly greater reductions in MMP-9 levels as compared with metformin monotherapy.
The effect of DPP4i on the above-mentioned parameters has not been studied in humans. Accordingly, the demonstration of significant improvements in markers of atherothrombosis and inflammation in high-risk diabetic patients is of great clinical importance and novelty that may be employed for the reduction of major cardiovascular events in this population.