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)