Type 2 diabetes exerts a huge toll on both morbidity and mortality, despite an expanding range of antiglycemic drugs and epidemiological evidence highlighting the benefits of effective glycemic control. Incretin-based agents offer important benefits, including a meal-dependent mode of action that may protect against hypoglycemia, and weight loss—in contrast to other antihyperglycemic drugs that cause weight gain. There are now two glucagon-like peptide-1 (GLP-1) receptor agonists and three dipeptidyl peptidase-4 (DPP-4) inhibitors approved for the management of type 2 diabetes in the US. Clinical trials have established the efficacy of incretin-based agents in controlling fasting and post-prandial blood glucose levels as well as glycosylated hemoglobin (HbA1c), both as monotherapy (including as first-line pharmacological treatment) and in combination with other antihyperglycemic treatments. GLP-1 receptor agonists and DPP-4 inhibitors have different mechanisms of action, which may explain their inconsistent efficacy results in direct comparator trials; for example, liraglutide has better efficacy than sitagliptin. However, GLP-1 receptor agonists can cause transient nausea in some patients. There is also evidence of different effects of individual agents within the same class; for example, liraglutide has shown superior efficacy to exenatide when added to metformin and/or sulfonylurea. Linagliptin is not cleared through renal mechanisms, unlike sitagliptin and saxagliptin. Isolated cases of pancreatitis led to concerns about a putative link with incretin-based therapies. However, the data currently available do not support a mechanistic or epidemiological link, although there does appear to be an increased risk of pancreatitis in people with diabetes that is independent of incretin-based treatment. Ongoing studies aim to extend our longer-term understanding of these agents, and hence, allow us to develop an optimal approach to patient management.
Combination therapy with once-weekly glucagon like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes: a case series
