Translational research in cardiometabolic diseases: preclinical and clinical studies of the cardioprotective and antidiabetic mechanisms.

• Grant number: 24/09267-4
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: September 01, 2024
• End date: August 31, 2026
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Bruno Caramelli
• Grantee: Larissa Ferreira dos Santos
• Host Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated research grant: 20/02668-2 - Translational research in cardiometabolic diseases: preclinical and clinical studies of the cardioprotective and antidiabetic mechanisms, AP.TEM

Abstract

Diabetes mellitus (DM) is a complex disease that affects all organs of the body and whose prevalence is expanding in almostall countries of the world. The number of individuals with DM in Brazil increased from 2.7 to 11.7 million individuals from 1980 to 2014 (The Lancet 2016 387, 1513-1530). Regardless of the intrinsic mechanisms involved in the genesis of targetorgan involvement by diabetes, the common basis of all the consequences of DM is hyperglycemia, a condition associated 3with intense metabolic changes that will lead to increased morbidity and mortality in the long term. The introduction ofhypoglycemic treatment, mainly insulin and the first oral antidiabetic agents, in the first part of the 20th century, changedthis scenario, promoting an increase in the life expectancy of patients, with cardiovascular and renal diseases becoming themain causes of death. As a natural consequence, renal cardiovascular outcomes have become the most studied outcomes inclinical and preclinical trials involving patients with diabetes. Several different oral hypoglycemic drugs have been developedfor the treatment of hyperglycemia, with these substances acting at different sites of action. In 2009, a pathophysiologicalapproach was proposed as a new paradigm to achieve lasting and stable glycemic control in patients with DM. The paradigmis based on a creative scheme called the ominous octet that has hyperglycemia in the central nucleus (Ele Ferrannini, andRalph A. DeFronzo Eur Heart J 2015;eurheartj.ehv239). According to this model, at least a triple combination ofhypoglycemic drugs should be added to the lifestyle intervention, aiming to achieve glycated hemoglobin levels below 6.0%.For a certain period, in clinical practice, strict control of blood glucose was pursued, called the glucocentric axis of DMtreatment. This strategy, however, suffered an important setback when some clinical studies were not able to prove thereduction in mortality and cardiovascular complications and, in addition, they were associated with a higher incidence ofhypoglycemia with serious consequences, especially in the elderly population. This scenario has changed from the results ofrecent clinical trials, especially those involving drugs from the sodium-glucose cotransporter type 2 inhibitor (iSGLT2) class,which showed an impressive reduction in cardiovascular outcomes, which gave rise to the term cardiocentric to guide thetreatment of DM. A significant portion of the patients involved in these studies, however, were receiving, as proposed by theominous octet regimen, other classes of drugs such as metformin, insulin and sulfonylureas. It is possible to assume,therefore, that such results can be attributed to the set of drugs used, but, above all, it is imperative to understand whichmechanisms, in addition to the reduction in blood glucose, explain these results. Considering the growing number of patientswith diabetes worldwide, the proposal of this project is, through clinical and pre-clinical trials, to understand the complexmetabolic mechanism and sites of action that explain the benefits of antidiabetic drugs. This thematic project involvesresearchers with accumulated 4 experience in basic, translational and clinical research, creating a favorable and virtuousenvironment to answer the questions raised and to encourage the formation of new researchers. Based on this information,it will be possible to develop therapeutic proposals that combine the advantages of glucocentric and cardiocentric strategiesand avoid the occurrence of hypoglycemia. In addition, perspectives may arise for the development of new pharmacologicalinterventions that can act on these sites of action.