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

• Grant number: 20/02668-2
• Support Opportunities: Research Projects - Thematic Grants
• Duration: November 01, 2022 - October 31, 2027
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Bruno Caramelli
• Grantee: Bruno Caramelli
• 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 researchers: Adriana Castello Costa Girardi ; Andrey Jorge Serra ; Antonio Carlos Campos de Carvalho ; Erika Emy Nishi ; Richard Leonard Verrier

Abstract

Diabetes mellitus (DM) is a complex disease that affects all organs of the body and whose prevalence is expanding in almost all 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 target organ involvement by diabetes, the common basis of all the consequences of DM is hyperglycemia, a condition associated3with intense metabolic changes that will lead to increased morbidity and mortality in the long term. The introduction of hypoglycemic treatment, mainly insulin and the first oral antidiabetic agents, in the first part of the 20th century, changed this scenario, promoting an increase in the life expectancy of patients, with cardiovascular and renal diseases becoming the main causes of death. As a natural consequence, renal cardiovascular outcomes have become the most studied outcomes in clinical and preclinical trials involving patients with diabetes. Several different oral hypoglycemic drugs have been developed for the treatment of hyperglycemia, with these substances acting at different sites of action. In 2009, a pathophysiological approach was proposed as a new paradigm to achieve lasting and stable glycemic control in patients with DM. The paradigm is based on a creative scheme called the ominous octet that has hyperglycemia in the central nucleus (Ele Ferrannini, and Ralph A. DeFronzo Eur HeartJ 2015;eurheartj.ehv239). According to this model, at least a triple combination of hypoglycemic 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 DM treatment. This strategy, however, suffered an important setback when some clinical studies were not able to prove the reduction immortality and cardiovascular complications and, in addition, they were associated with higher incidence of hypoglycemia with serious consequences, especially in the elderly population. This scenario has changed from the results of recent 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 cardio centric to guide the treatment of DM. A significant portion of thepatients involved in these studies, however, were receiving, as proposed by the ominous 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 which mechanisms, in addition to the reduction in blood glucose, explain these results. Considering the growing number of patients with diabetes worldwide, the proposal of this project is, through clinical and pre-clinical trials, to understand the complex metabolic mechanism and sites of action that explain the benefits of antidiabetic drugs. This thematic project involves researchers with accumulated4experience in basic, translational and clinical research, creating a favorable and virtuous environment 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 cardio centric strategies and avoid the occurrence of hypoglycemia. In addition, perspectives may arise for the development of new pharmacological interventions that can act on these sites of action. (AU)