Type 2 diabetes mellitus (T2DM) continues to be a major health problem worldwide. It is well known that T2DM is a metabolic disorder characterized by hyperglycemia, which arises from insufficient pancreatic insulin secretion, insulin resistance in peripheral tissues, and inadequate suppression of glucagon production. This suppression results in inadequate uptake, storage, and disposal of ingested glucose accompanied by elevated hepatic production of glucose and profound hyperglycemia. Notably, these pathophysiologic processes can progress to a clinically significant degree even in patients with impaired glucose tolerance. As researchers begin to unravel the genetic basis of T2DM, the gradual accumulation of genetic polymorphisms in multiple genes—rather than the mutation of a single “diabetes gene”—appears to be the driving force behind the increase in T2DM risk. Emergent therapies for the management of T2DM include incretin-based agents, which can effectively target two key processes in T2DM by augmenting insulin secretion and inhibiting glucagon production.
Treatment of patients with type 2 diabetes mellitus (T2DM) traditionally has involved a progression of phases, from conventional lifestyle interventions and monotherapy, to combination therapy involving oral agents, to insulin initiation and its use either alone or with oral pharmacotherapy. Currently, the need for antidiabetic therapies with fewer adverse effects (eg, weight gain, reduced rates of hypoglycemia) is unmet. In addition, most treatments fail to adequately control postprandial hyperglycemia. Traditional options have generally been directed at the “insulin demand” aspect and have targeted insulin secretion or insulin resistance in peripheral tissues. Only recently have agents been available to address the “glucose supply” aspect that leads to fasting hyperglycemia in patients with T2DM. Incretin-based therapies, however, address both aspects. Two classes of incretin-directed therapies are available and work by either increasing endogenous levels of glucagon-like peptide-1 (GLP-1) (ie, dipeptidyl peptidase-4 inhibitors) or by mimicking the activity of endogenous GLP-1 (ie, GLP-1 agonists). These therapies treat the key metabolic abnormalities associated with T2DM but do so with reduced rates of hypoglycemia and do not promote weight gain as compared with conventional therapies.
Management of type 2 diabetes mellitus (T2DM) can be challenging. Patients frequently present with poor glycemic control despite therapy. Other patients may be nonadherent or resistant to continuing their treatment when confronted with undesirable adverse effects, such as weight gain, that are associated with many conventional therapies. Incretin-based therapies developed to treat patients with T2DM, including oral dipeptidyl peptidase-4 inhibitor agents or glucagon-like peptide-1 agonists, offer the potential of sustained glycemic control for many patients without the adverse events associated with other classes of antihyperglycemic medications. Available safety data from clinical trials indicate that incretin-based therapies have weight-neutral or weight-reducing effects, with no apparent adverse impact on other important safety parameters, such as cardiovascular disease. The integration of these therapies into treatment algorithms, as highlighted in three case presentations, will increase treatment options for patients with T2DM.
