Why Should be the Strategy of Type 2 Diabetes Treatment Radically Changed

Abstract

Abstract Insulin resistance is a root cause of Type 2 Diabetes Mellitus (T2DM) appearing long time before the outbreak of hyperglycemia. On molecular level, a complex impairment of various biochemical processes occurs, the most important being the failure of phosphatidylinositol 3-kinase enzymatic chain responsible for activation of glucose transporters and endothelial nitric oxide (NO) synthesis. Therefore, in insulin resistant states the defect of glucose utilization is coupled with NO deficit and vasodilatory impairment, generating a huge body of residual cardiovascular risk. However, majority of drugs administered to treat T2DM (sulfonylureas, high doses of insulin) even amplify this malignant relationship, reflected by aggravated obesity, dyslipidemia and arterial hypertension. Early and tight glycemic control strategy is helpful to prevent cardiovascular complications in younger diabetics and harmful for long lasting diabetes in older patients, dying mostly from macrovascular complications (80%) for which hyperglycemia, responsible primarily for microvascular impairment, is a weak risk factor compared with hypercholesterolemia or high blood pressure. Glucocentric paradigm of T2DM treatment should be therefore revised in favor of pathophysiologic approaches with drugs selected to address multifactorial risk, affecting different components of diabetes pathophysiology, to achieve hypoglycemic goals without worsening obesity, insulin resistance, sympathetic overactivity and NO deficit, for example with dual or triple combinations (with dosage adjusted to glycemia) such as: metformin + SGLT2 inhibitor + GLP-1 agonist or metformin + SGLT2 inhibitor + pyoglitazone. Patients should be strongly advised to enhance physical activity, reduce body weight this being the most effective method to decrease insulin resistance, the key factor of extensive cardiovascular damage.