Antidiabetic treatment with gliptins: focus on cardiovascular effects and outcomes

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.

Glycemic control and cost-effectiveness attained by the drug utilization of oral antidiabetic agents in a tertiary care hospital in South India

“…DPP-4 inhibitors (n=24) have been advocated as second line agents due to its improved glycemic control over time, pleiotropic cardiovascular effects and pancreatic beta cell protective effects in animal studies. 18,19 Pioglitazone (n=16) prescription has declined in our study compared to the recent trend. 20 and was not used as monotherapy agent.…”

Effect of Vildagliptin, Compared to Sitagliptin, on the Onset of Hyperglycemia-Induced Metabolic Memory in Human Umbilical Vein Endothelial Cells

“…Occurrence of this phenomenon has been reported in endothelial cells, in which it is driven by different mechanisms, such as oxidative stress and epigenetic changes [19]. DDP-4 inhibitors are anti-diabetic agents with vascular protective effects [32]. Yet, little is known about their impact on HG-induced stress and metabolic memory in endothelial cells.…”

Problems of hypoglycemic therapy in diabetic patients with acute coronary syndrome

“…Низкий риск гипогликемиче-ских состояний при терапии глимепиридом обусловлен деликатной стимуляцией секреции инсулина, а также способностью корригировать инсулинорезистентность. Считают, что кардиобезопасность СМ частично может быть разрешена после завершения РКИ по анализу ССС при лечении линаглиптином против глимепирида у пациентов с СД2 -CAROLINA [38].…”

“…Однако результаты SAVOR (саксаглиптин) не пред-ставили подтверждений кардиопротекции, продемон-стрировав в целом кардионейтральность; исследование TECOS (ситаглиптин) не показало повышение частоты каких-либо ССС, включая новые случаи сердечной недо-статочности [38].…”

“…Fisman и А. Tenenbaum (2015) «Антидиабетическая терапия глиптинами: фокус на кардиоваскулярные эффекты и исходы» отмечено, что алоглиптин не повышает ни сердечно-сосудистую забо-леваемость или смертность, не ухудшает уже существую-щую сердечную недостаточность, в т. ч. у больных с недав-ним ОКС при средней продолжительности лечения 18 месяцев. Кроме того, оценка концентрации мозгового натрий-уретического пептида в диапазоне до 6 месяцев не выявила каких-либо существенных изменений [38].…”