From Current Therapeutics to Multitarget Ligands: A Review of Diabetes Pharmacological Treatments

Diabetes is a chronic and complex pathological syndrome that includes a series of disorders and imbalances, whose first characterization is hyperglycemia, although, as it is a multifactorial phenomenon, it requires risk reduction strategies beyond glycemic control. Continuous education and support for diabetes self-management are essential to prevent acute complications and reduce the risk of long-term complications. Therefore, the guidelines for the treatment of diabetes emphasize the importance of lifestyle changes, including a reduced-calorie diet and increased physical activity. However, for many people, these changes can be difficult to maintain in the long term and eventually they must resort to pharmacological treatment that in most cases requires the combined use of two or more antidiabetic drugs with different mechanisms of action. This review explores the different pharmacological agents, authorized and used therapeutically, for the control of diabetes, especially type 2 diabetes, and analyzes the development strategies of multi-target agents whose effects, through distinct mechanisms and by acting on more than one receptor, could represent a promising alternative in the treatment of a multifactorial disease such as diabetes. As regards therapeutic uses, from metformin to glucose transporter inhibitors (SGLT2i), the potential mechanisms of action, pharmacological and clinical effects, safety, and use in therapeutics are described, presenting, as far as reasonably possible, diverse comparisons between them. In conclusion, although metformin remains the first-line agent for the treatment of type 2 diabetes, the choice of a second-line agent depends on several factors, in particular the cardiovascular risk profile, weight, and renal function of the patient; moreover, the ideal pharmacological treatment, although expected and desired, has in fact not been achieved so far, and physicians must consider not only the glycemic efficacy of the agent but also all the other potential benefits, balanced by the possible adverse effects. Compounds modulating multiple signaling pathways are a promising approach to manage this multifactorial disorder, with the primary objective of maintaining the therapeutic efficacy observed in several clinical studies, alongside reducing adverse effects, the main reason for the discontinuation of developments, to levels that enable a favorable risk-benefit balance.