Biomedical Engineering Reference
In-Depth Information
confer cardio-protection via augmentation of these substrates. 97,98 Cardiovas-
cular trials are currently under way which will address the impact of the DPP-4
inhibitor therapies on macrovascular risk.
Inhibition of DPP-4 has been shown to be protective against obesity in
preclinical studies. 99,100 The mechanism for reduced weight gain may involve
decreased appetite and increased energy metabolism. 99 DPP-4 inhibition also
augments postprandial lipid mobilization and oxidation in type 2 diabetic
patients. 101 The role of DPP-4 in appetite control and energy metabolism is
most likely to be primarily via GLP-1. GLP-1 inhibits gastric motility and
secretion, delaying the supply of nutrients for absorption to reduce meal-
induced glucose excursion. GLP-1 also acts centrally within the brain to induce
satiety, and GLP-1 mimetic treatment is generally associated with weight loss. 69
DPP-4 inhibition slows neuropeptide Y (NPY) degradation, which may alter its
orexigenic effect, since intact NPY stimulates food intake. 102 DPP-4-mediated
inactivation of other substrates such as VIP, PACAP, GLP-2, 103 and gastrin-
releasing peptide (GRP) 104 might also influence weight and appetite control.
However, thus far, clinical trials have indicated that DPP-4 inhibitors are body-
weight neutral. 78 The relatively small increases in GLP-1 levels by DPP-4
inhibition might be insucient to measurably alter gastric emptying and sati-
ety, 81 but long-term DPP-4 inhibitor treatment may benefit obese patients. Clinical Safety of DPP-4 Inhibitors
Therapeutic use of DPP-4 inhibitors is considered safe. DPP-4 inhibitors are
well tolerated in humans, and DPP-4 gko mice show no defects, suggesting that
DPP-4 is not essential for normal functions. 105 Long-term studies using DPP-4
inhibitors in clinical trials have, to date, not been associated with any major
side effects. 106,107
DPP-4 inhibitors sitagliptin and alogliptin are primarily excreted by the
kidney and hence have a relatively low risk of drug interaction because of their
limited hepatic metabolism. Overdose of DPP-4 inhibitors are not associated
with any toxicity. However, the drugs that are actively renally cleared need dose
adjustment in patients with moderate/severe renal impairment. 78
Since DPP-4 is ubiquitously expressed and has a large number of potential
substrates, the issue of non-selectivity has to be kept in mind with respect to
long-term safety. There has been an increased incidence of headache, naso-
pharyngitis, and hypersensitivity with DPP-4 inhibitor treatment, although
placebo effects were very similar. 107 Nevertheless, these effects potentially could
be due to inhibition of degradation of DPP-4 substrates such as substance P,
bradykinin, and SDF-1a. However, many DPP-4 substrates are inactivated by
other enzymes. 81 For instance, SDF-1a is degraded by neutral endopeptidase
(NEP), cathepsin G, and matrix metalloproteinase (MMP)-9. 2 Hence, DPP-4
inhibition might not have any effect on the levels of such peptides. Some DPP-4
chemokine substrates are cleaved by DPP-4-related enzymes, but at a much
slower rate. 108
Search WWH ::

Custom Search