Dipeptidyl Peptidase-4 Inhibitors: An Overview of Their Combination with Oral Hypoglycemic Agents

Type 2 diabetes mellitus (T2DM), the most prevalent form, is characterised by insulin insensitivity as a result of insulin resistance, declining insulin production, and eventual pancreatic beta-cell failure. Dipeptidyl peptidase 4 (DPP-4) inhibitors are a new class of Oral Hypoglycemic Drugs (OHD) that can control T2DM. This chapter aims to provide a critical and systematic update of the specialised literature on the therapeutic effects and safety profile of hypoglycemic drugs, used in combination with DPP-4 inhibitors, in the management of type 2 diabetes mellitus. Given the rapid advances in the field of medicine and the pharmaceutical industry, therapeutic strategies for this pathology have undergone significant changes, oriented not only towards effective glycemic control but also towards reducing cardiovascular risks and mortality associated with the disease. Numerous studies have investigated the impact of different therapeutic combinations on the evolution of patients with type 2 diabetes mellitus, paying particular attention to the associations between metformin and other classes of hypoglycemic drugs. An important part of the research has focused on comparing the classic metformin–sulfonylurea combination with more recent therapeutic regimens, such as metformin associated with DPP-4 inhibitors. The data suggest that the use of sulfonylureas combined with metformin is associated with a significantly increased risk of severe hypoglycemia compared with metformin–DPP-4 inhibitors. Another relevant observation is related to the use of insulin in combination with metformin. According to the analysed data, this therapeutic combination was associated with a higher risk of all-cause mortality, compared with treatment based on DPP-4 inhibitors combined with metformin. In conclusion, the current evidence supports the use of DPP-4 inhibitors in combination with metformin as a safer therapeutic alternative to sulfonylureas or insulin, especially in terms of reducing the risk of severe hypoglycemia, cardiovascular events and mortality. These results highlight the need to integrate recent clinical data into medical practice guidelines and to individualise the treatment for patients with type 2 diabetes.