The Effects of Dipeptidyl Peptidase-4 Inhibition on Microvascular Diabetes Complications

Diabetes Care, Oct 2014

We performed a review of the literature to determine whether the dipeptidyl peptidase-4 inhibitors (DPP4-I) may have the capability to directly and positively influence diabetic microvascular complications. The literature was scanned to identify experimental and clinical evidence that DPP4-I can ameliorate diabetic microangiopathy. We retrieved articles published between 1 January 1980 and 1 March 2014 in English-language peer-reviewed journals using the following terms: (“diabetes” OR “diabetic”) AND (“retinopathy” OR “retinal” OR “nephropathy” OR “renal” OR “albuminuria” OR “microalbuminuria” OR “neuropathy” OR “ulcer” OR “wound” OR “bone marrow”); (“dipeptidyl peptidase-4” OR “dipeptidyl peptidase-IV” OR “DPP-4” OR “DPP-IV”); and (“inhibition” OR “inhibitor”). Experimentally, DPP4-I appears to improve inflammation, endothelial function, blood pressure, lipid metabolism, and bone marrow function. Several experimental studies report direct potential beneficial effects of DPP4-I on all microvascular diabetes-related complications. These drugs have the ability to act either directly or indirectly via improved glucose control, GLP-1 bioavailability, and modifying nonincretin substrates. Although preliminary clinical data support that DPP4-I therapy can protect from microangiopathy, insufficient evidence is available to conclude that this class of drugs directly prevents or decreases microangiopathy in humans independently from improved glucose control. Experimental findings and preliminary clinical data suggest that DPP4-I, in addition to improving metabolic control, have the potential to interfere with the onset and progression of diabetic microangiopathy. Further evidence is needed to confirm these effects in patients with diabetes.

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The Effects of Dipeptidyl Peptidase-4 Inhibition on Microvascular Diabetes Complications

The Effects of Dipeptidyl Peptidase-4 Inhibition on Microvascular Diabetes Complications 0 Department of Medicine, Division of Metabolic Diseases, University of Padova , Padova , Italy 1 Angelo Avogaro and Gian Paolo Fadini - We performed a review of the literature to determine whether the dipeptidyl peptidase-4 inhibitors (DPP4-I) may have the capability to directly and positively influence diabetic microvascular complications. The literature was scanned to identify experimental and clinical evidence that DPP4-I can ameliorate diabetic microangiopathy. We retrieved articles published between 1 January 1980 and 1 March 2014 in English-language peer-reviewed journals using the following terms: (“diabetes” OR “diabetic”) AND (“retinopathy” OR “retinal” OR “nephropathy” OR “renal” OR “albuminuria” OR “microalbuminuria” OR “neuropathy” OR “ulcer” OR “wound” OR “bone marrow”); (“dipeptidyl peptidase-4” OR “dipeptidyl peptidase-IV” OR “DPP-4” OR “DPP-IV”); and (“inhibition” OR “inhibitor”). Experimentally, DPP4-I appears to improve inflammation, endothelial function, blood pressure, lipid metabolism, and bone marrow function. Several experimental studies report direct potential beneficial effects of DPP4-I on all microvascular diabetes-related complications. These drugs have the ability to act either directly or indirectly via improved glucose control, GLP-1 bioavailability, and modifying nonincretin substrates. Although preliminary clinical data support that DPP4-I therapy can protect from microangiopathy, insufficient evidence is available to conclude that this class of drugs directly prevents or decreases microangiopathy in humans independently from improved glucose control. Experimental findings and preliminary clinical data suggest that DPP4-I, in addition to improving metabolic control, have the potential to interfere with the onset and progression of diabetic microangiopathy. Further evidence is needed to confirm these effects in patients with diabetes. Diabetes increases the incidence of cardiovascular disease (CVD) ( 1 ), but the role of hyperglycemia in the pathogenesis of CVD is still under debate. Recent large trials have shown that, at least for the duration of the trials, glucose lowering has modest or neutral effects on CVD in people with type 2 diabetes (T2D) ( 2–5 ). On the other hand, the relationship between hyperglycemia and microvascular outcomes is very strong, as high glucose promotes activation, dysfunction, and apoptosis of vascular and nonvascular cells (6). Importantly, diabetic microvascular changes affect the retina, kidney, and nerves, but they can also be detected in other organs, such as the heart ( 7,8 ). For instance, we have shown that acute hyperglycemia in T2D significantly alters myocardial microvascular perfusion (9). Although the analogy between site-specific microvascular complications is difficult to assess, the association between retinal disease and nonretinal consequences of diabetes is supported by a fairly relevant amount of clinical and experimental data ( 10 ). For instance, the presence of diabetic retinopathy is associated with a two- to threefold higher risk of incident fatal and nonfatal coronary heart disease, even after adjustment for traditional risk factors, and up to 25-fold higher prevalence of lower limb amputation ( 11,12 ). A relationship between retinopathy and the extent of coronary artery calcium was observed (13), and microangiopathy is independently associated with presence, severity, and composition of carotid atherosclerosis ( 14 ). These data suggest the existence of common, yet unknown, pathogenic mechanisms and mutual relationships between microvascular disease and cardiovascular risk. Diabetic nephropathy is another strong CVD predictor. Microalbuminuria is itself recognized as an independent determinant of mortality and CVD in both the general and diabetic populations ( 15,16 ), and chronic kidney disease, starting from stage 1, is well documented as an amplifier of the cardiovascular risk (17). More recently, diabetes has also been shown to induce microangiopathy in the bone marrow (BM) of mice and humans ( 18,19 ). By providing regenerative vascular stem/progenitor cells, the BM acts as a central housekeeper of cardiovascular health, whereas BM microangiopathy may impair cardiovascular homeostasis (20). Large randomized prospective studies have shown that, despite a neutral effect on macrovascular disease, HbA1c control significantly reduces microvascular end points ( 2,21– 24 ). However, either the short duration of these studies or the adverse effects of glucose-lowering agents do not allow us to (dis)prove the causal relationship between the prevention of microvascular complications and the subsequent improvements in cardiovascular outcomes. So-called incretinergic therapies have boosted enthusiasm in the treatment of patients with T2D since both GLP-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 (DPP-4 (...truncated)


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Angelo Avogaro, Gian Paolo Fadini. The Effects of Dipeptidyl Peptidase-4 Inhibition on Microvascular Diabetes Complications, Diabetes Care, 2014, pp. 2884-2894, 37/10, DOI: 10.2337/dc14-0865