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Antidiabetic treatment with gliptins: focus on cardiovascular effects and outcomes.

Fisman EZ, Tenenbaum A - Cardiovasc Diabetol (2015)

Bottom Line: These changes, as an almost general rule, include improved endothelial function, reduction of inflammatory markers, oxidative stress ischemia/reperfusion injury and atherogenesis.Moreover, when employing saxagliptin, while the drug was not associated with an augmented risk for ischemic events, it should be pinpointed that the rate of hospitalization for heart failure was significantly increased.Nonetheless, for the time being, a definite relationship between gliptins treatment and improved cardiovascular outcomes remains uncertain and needs yet to be proven.

View Article: PubMed Central - PubMed

Affiliation: Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 69978, Tel Aviv, Israel. zfisman@post.tau.ac.il.

ABSTRACT
The traditional oral pharmacological therapy for type 2 diabetes mellitus (T2DM) has been based on the prescription of metformin, a biguanide, as first line antihyperglycemic agent world over. It has been demonstrated that after 3 years of treatment, approximately 50% of diabetic patients could achieve acceptable glucose levels with monotherapy; but by 9 years this had declined to only 25%. Therefore, the implementation of a combined pharmacological therapy acting via different pathways becomes necessary, and its combination with a compound of the sulfonylurea group was along decades the most frequently employed prescription in routine clinical practice. Meglitinides, glitazones and alpha-glucosidase inhibitors were subsequently developed, but the five mentioned groups of oral antihyperglycemic agents are associated with variable degrees of undesirable or even severe cardiovascular events. The gliptins-also called dipeptidyl peptidase 4 (DPP4) inhibitors--are an additional group of antidiabetic compounds with increasing clinical use. We review the status of the gliptins with emphasis on their capabilities to positively or negatively affect the cardiovascular system, and their potential involvement in major adverse cardiovascular events (MACE). Alogliptin, anagliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin and vildagliptin are the compounds currently in clinical use. Regardless differences in chemical structure and metabolic pathways, gliptins as a group exert favorable changes in experimental models. These changes, as an almost general rule, include improved endothelial function, reduction of inflammatory markers, oxidative stress ischemia/reperfusion injury and atherogenesis. In addition, increased adiponectin levels and modest decreases in lipidemia and blood pressure were reported. In clinical settings, several trials--notably the longer one, employing sitagliptin, with a mean follow-up period of 3 years--did not show an increased risk for ischemic events. Anyway, it should be emphasized that the encouraging results from basic science were not yet translated into clinical evidence, probably due the multiple and pleiotropic enzymatic effects of DPP4 inhibition. Moreover, when employing saxagliptin, while the drug was not associated with an augmented risk for ischemic events, it should be pinpointed that the rate of hospitalization for heart failure was significantly increased. Gliptins as a group constitute a widely accepted therapy for the management of T2DM, usually as a second-line medication. Nonetheless, for the time being, a definite relationship between gliptins treatment and improved cardiovascular outcomes remains uncertain and needs yet to be proven.

No MeSH data available.


Related in: MedlinePlus

Schematic depiction of the main biochemical and clinical effects of DPP4 (dipeptidyl peptidase-4) inhibition. While both the increasing (green arrows) and decreasing (blue arrows) effects seem to be favorable, the overall influence on MACE (major adverse cardiovascular events) remains uncertain
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Fig1: Schematic depiction of the main biochemical and clinical effects of DPP4 (dipeptidyl peptidase-4) inhibition. While both the increasing (green arrows) and decreasing (blue arrows) effects seem to be favorable, the overall influence on MACE (major adverse cardiovascular events) remains uncertain

Mentions: Which could be the molecular mechanisms for the favorable results of DPP4 inhibition in experimental settings? Several responses can be outlined. DPP4 is a transmembrane glycoprotein that cleaves N-terminal dipeptides from many substrates. It is ubiquitously expressed, including several growth factors, hormones, neuropeptides, and chemokines [30, 33, 131]. Using a proteomics approach, human adipocytes’ secretome has been unveiled, identifying DPP4 as a newfangled adipokine, produced particularly by fully differentiated adipocytes [132, 133]. Anyway, it should be emphasized that the main divergence with many other adipokines is that DPP4 is not directly secreted by adipocytes but released from the plasma membrane as soluble DPP4 following proteolytic cleavage [32, 134]. Soluble DPP4 is a striking activator of both mitogen-activated protein kinases (MAPK) and nuclear factor kappa B (NF-κB); these pro-inflammatory signaling pathways lead to proliferation and atherogenic transformation of VSMC [133]. A DPP-4 inhibitor exerts anti-inflammatory effects on macrophages and adipocytes, being able to suppress NF-κB activation [135]. In this context, soluble DPP4 also induces activation of extracellular-signal-regulated kinases (ERKs, a specific subset of the MAPK family) in VSMC, which was partially blocked by DPP4 inhibition [123]. The main effects of this inhibition are depicted in Fig. 1.Fig. 1


Antidiabetic treatment with gliptins: focus on cardiovascular effects and outcomes.

Fisman EZ, Tenenbaum A - Cardiovasc Diabetol (2015)

Schematic depiction of the main biochemical and clinical effects of DPP4 (dipeptidyl peptidase-4) inhibition. While both the increasing (green arrows) and decreasing (blue arrows) effects seem to be favorable, the overall influence on MACE (major adverse cardiovascular events) remains uncertain
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4587723&req=5

Fig1: Schematic depiction of the main biochemical and clinical effects of DPP4 (dipeptidyl peptidase-4) inhibition. While both the increasing (green arrows) and decreasing (blue arrows) effects seem to be favorable, the overall influence on MACE (major adverse cardiovascular events) remains uncertain
Mentions: Which could be the molecular mechanisms for the favorable results of DPP4 inhibition in experimental settings? Several responses can be outlined. DPP4 is a transmembrane glycoprotein that cleaves N-terminal dipeptides from many substrates. It is ubiquitously expressed, including several growth factors, hormones, neuropeptides, and chemokines [30, 33, 131]. Using a proteomics approach, human adipocytes’ secretome has been unveiled, identifying DPP4 as a newfangled adipokine, produced particularly by fully differentiated adipocytes [132, 133]. Anyway, it should be emphasized that the main divergence with many other adipokines is that DPP4 is not directly secreted by adipocytes but released from the plasma membrane as soluble DPP4 following proteolytic cleavage [32, 134]. Soluble DPP4 is a striking activator of both mitogen-activated protein kinases (MAPK) and nuclear factor kappa B (NF-κB); these pro-inflammatory signaling pathways lead to proliferation and atherogenic transformation of VSMC [133]. A DPP-4 inhibitor exerts anti-inflammatory effects on macrophages and adipocytes, being able to suppress NF-κB activation [135]. In this context, soluble DPP4 also induces activation of extracellular-signal-regulated kinases (ERKs, a specific subset of the MAPK family) in VSMC, which was partially blocked by DPP4 inhibition [123]. The main effects of this inhibition are depicted in Fig. 1.Fig. 1

Bottom Line: These changes, as an almost general rule, include improved endothelial function, reduction of inflammatory markers, oxidative stress ischemia/reperfusion injury and atherogenesis.Moreover, when employing saxagliptin, while the drug was not associated with an augmented risk for ischemic events, it should be pinpointed that the rate of hospitalization for heart failure was significantly increased.Nonetheless, for the time being, a definite relationship between gliptins treatment and improved cardiovascular outcomes remains uncertain and needs yet to be proven.

View Article: PubMed Central - PubMed

Affiliation: Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 69978, Tel Aviv, Israel. zfisman@post.tau.ac.il.

ABSTRACT
The traditional oral pharmacological therapy for type 2 diabetes mellitus (T2DM) has been based on the prescription of metformin, a biguanide, as first line antihyperglycemic agent world over. It has been demonstrated that after 3 years of treatment, approximately 50% of diabetic patients could achieve acceptable glucose levels with monotherapy; but by 9 years this had declined to only 25%. Therefore, the implementation of a combined pharmacological therapy acting via different pathways becomes necessary, and its combination with a compound of the sulfonylurea group was along decades the most frequently employed prescription in routine clinical practice. Meglitinides, glitazones and alpha-glucosidase inhibitors were subsequently developed, but the five mentioned groups of oral antihyperglycemic agents are associated with variable degrees of undesirable or even severe cardiovascular events. The gliptins-also called dipeptidyl peptidase 4 (DPP4) inhibitors--are an additional group of antidiabetic compounds with increasing clinical use. We review the status of the gliptins with emphasis on their capabilities to positively or negatively affect the cardiovascular system, and their potential involvement in major adverse cardiovascular events (MACE). Alogliptin, anagliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin and vildagliptin are the compounds currently in clinical use. Regardless differences in chemical structure and metabolic pathways, gliptins as a group exert favorable changes in experimental models. These changes, as an almost general rule, include improved endothelial function, reduction of inflammatory markers, oxidative stress ischemia/reperfusion injury and atherogenesis. In addition, increased adiponectin levels and modest decreases in lipidemia and blood pressure were reported. In clinical settings, several trials--notably the longer one, employing sitagliptin, with a mean follow-up period of 3 years--did not show an increased risk for ischemic events. Anyway, it should be emphasized that the encouraging results from basic science were not yet translated into clinical evidence, probably due the multiple and pleiotropic enzymatic effects of DPP4 inhibition. Moreover, when employing saxagliptin, while the drug was not associated with an augmented risk for ischemic events, it should be pinpointed that the rate of hospitalization for heart failure was significantly increased. Gliptins as a group constitute a widely accepted therapy for the management of T2DM, usually as a second-line medication. Nonetheless, for the time being, a definite relationship between gliptins treatment and improved cardiovascular outcomes remains uncertain and needs yet to be proven.

No MeSH data available.


Related in: MedlinePlus