Abstract
As knowledge of pathophysiologic mechanisms of diabetes mellitus has increased, clinical attention has shifted to the incretin system. Incretin hormones, including glucagon-like peptide-1, or GLP-1, and glucose-dependent insulinotropic polypeptide, are vital to the control of glucose homeostasis and pancreatic β-cell preservation. Novel strategies for the treatment of patients with type 2 diabetes mellitus (T2DM) engage the incretin system. Glucagon-like peptide-1 receptor agonists provide robust glycemic control as well as beneficial reductions in body weight. Dipeptidyl peptidase-4, or DPP-4, inhibitors exhibit beneficial glycemic effects and are weight-neutral. Incretin-based medications are becoming increasingly recognized in guidelines as early treatment options because of their efficacy and well-tolerated profiles. The author reviews the safety and efficacy of currently approved incretin-based agents, as well as the role of these medications in treatment paradigms for patients with T2DM. He also discusses investigational incretin-based agents.
The management of type 2 diabetes mellitus (T2DM) remains complex and challenging for patients and their physicians. Although the number of patients with T2DM who successfully achieve target levels of glycosylated hemoglobin (HbA
1c) is steadily increasing, a substantial number of patients continue to fall short of acceptable treatment goals, leaving them at high risk for development of diabetes mellitus-associated complications.
1,2
Traditional agents for the treatment of patients with T2DM include metformin, insulin secretagogues (ie, sulfonylureas and glinides), thiazolidinediones (TZDs), α-glucosidase inhibitors, and insulin. Unfortunately, these agents fail to adequately address the pathologic characteristics of T2DM, including insulin deficiency resulting from insufficient pancreatic insulin release, excess hepatic glucose output, and insulin resistance (which results in decreased glucose uptake in the liver and peripheral tissues [eg, muscle and fat]).
3 In addition, many traditional agents are associated with increased incidence of hypoglycemia (eg, glinides, insulin, sulfonylureas) or with unwanted increase in body weight (eg, glinides, glitazones, insulin, sulfonylureas).
4 Also, most traditional agents for managing T2DM have mechanisms that do not adequately control levels of postprandial glucose (PPG),
5 which is a dominant contributor to overall glycemia when HbA
1c levels are below 8.5%. Elevated PPG levels increase cardiovascular risk.
6
Two recent additions to the armamentarium of T2DM management are incretin-based therapies—glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors. These agents, which were developed to meet the need for antihyperglycemic agents that exhibit improved efficacy and safety relative to traditional therapies, represent a major paradigm shift in management because they address unique pathophysiologic pathways in T2DM.
Multiple guidelines exist for the treatment of patients with T2DM, including those put forth by the American Diabetes Association (ADA)
64 and the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE).
4 Figure 4 provides a schematic of the AACE/ACE treatment guideline recommendations.
4
Before selection of a particular drug regimen, it is important to establish an appropriate individualized HbA
1c goal for the patient. Several recent large-scale clinical trials have evaluated the effects of intensive lowering of glucose levels on macrovascular disease and major cardiovascular events.
65-67 Results from the Action to Control Cardiovascular Risk in Diabetes (ACCORD),
65 the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) trial,
66 and the Veterans Affairs Diabetes Trial (VADT)
67 suggested that intensive glycemic control to near normoglycemia had no effect on cardiovascular outcomes. In addition, the ACCORD trial
65 found increased mortality in patients undergoing tight glycemic control, though this finding was not replicated in the ADVANCE
66 and VADT trials.
67
In the ACCORD study,
65 randomization to the intensive treatment arm was associated with higher rates of severe hypoglycemia, which may be one possible explanation for the increased risk of cardiovascular death observed in the study.
68 In healthy individuals, acute hypoglycemia provokes sympathoadrenal activation and regulatory hormonal secretion that protects the brain from neuroglycopenia. Other metabolic changes also occur in healthy individuals to restore blood glucose to normal levels. However, in patients with T2DM who have endothelial dysfunction, acute hypoglycemia can lead to acute hemodynamic and hematologic changes, which can ultimately result, in turn, in increased tissue ischemia and major adverse vascular events, including myocardial infarction and stroke.
69
These adverse changes might be further confounded by hypoglycemia unawareness, particularly in patients with coexisting cardiovascular autonomic neuropathy (a strong risk factor for sudden death). Because no anatomic features of hypoglycemia can be detected postmortem, death resulting from a hypoglycemic event may be mistakenly ascribed to coronary artery disease, especially if blood glucose measurements of the individual are not available.
68
Other explanations proposed for the increased mortality observed in the ACCORD trial
65 include adverse effects from increased exposure to particular antidiabetic medications, from rapid correction of hyperglycemia, and from weight gain, as well as differences in baseline characteristics. None of these explanations have been validated in post hoc trial analyses. Thus, the ultimate cause of the increased mortality remains unknown.
68,70
The results of ACCORD and other trials
65-70 suggest that in patients with T2DM, glycemic targets should be individualized based on the particular characteristics of individual patients, including the following: projected benefits from glycemic control; presence of comorbidities and complications; risks and consequences of hypoglycemic events; and presence of hypoglycemic unawareness.
68,71,72 For most patients, thebest treatment strategy is one targeted to an HbA
1c level of less than 7%. Lower HbA
1c levels may be indicated in younger patients and in patients with no history of cardiovascular disease. Conversely, less stringent HbA
1c goals may be appropriate for patients with a history of severe hypoglycemia, advanced cardiovascular disease, or extensive comorbid conditions, or for individuals with advanced T2DM in whom an HbA
1c value of less than 7% has been difficult to achieve.
68
Consideration must also be given to the choice of antihyperglycemic agent. Agents should be considered not only on the basis of their ability to achieve a patient's HbA
1c goal, but also for their effects on weight, glycemic durability, and cardiovascular protection, as well as their adverse-effect profiles and methods of delivery.
72 Incretin-based medications are becoming increasingly recognized in guidelines as early treatment options because of their effects on glycemic and nonglycemic endpoints and their well-tolerated profiles.
The AACE/ACE guidelines
4 clearly state that incretin-based options should not be limited to third-line or fourth-line therapies.
35 In fact, one might argue that incretin-based agents could be used to replace the older insulin-secretory agents—sulfonylureas—in the treatment armamentarium for patients with T2DM. Although sulfonylureas have long been one of the most widespread treatment options for patients with T2DM, their use is associated with weight gain, risk of severe hypoglycemia, and a singular mechanism of action that often results in patients being treated with additional antihyperglycemic agents.
73 Recent studies have also shown that sulfonylureas may be associated with increased β-cell apoptosis, suggesting that sulfonylureas may actually accelerate the progressive decrease in β-cell mass, thereby promoting the need for insulin replacement.
73
Data from recent trials comparing sulfonylureas with DPP-4 inhibitors have demonstrated similar reductions in HbA
1c level with either medication, but changes in body weight consistently favored DPP-4 inhibitors. Furthermore, superior effects on lipid profiles were observed in patients treated with DPP-4 inhibitors relative to those treated with sulfonylureas.
74 Clinical trials also showed that severe hypoglycemia occurred at a rate of approximately 1.5% over 2 years with the use of sulfonylureas, but it was extremely rare with DPP-4 inhibitors.
74 Thus, any financial savings incurred by using sulfonylureas in the treatment of patients with T2DM could be quickly negated by the need for additional physician visits or even hospital admissions to manage hypoglycemic episodes.
Importantly, incretin-based agents potentiate glucose-stimulated insulin secretion and may restore reduced glucose-induced insulin secretion in patients with T2DM. The insulinotropic effects of GLP-1 receptor agonists and DPP-4 inhibitors are glucose dependent, reducing the risk of hypoglycemia.
When an incretin-based medication is indicated, the choice of the particular agent to use is a joint decision between physician and patient. The only available incretin-based agents at the time of publication of the AACE/ACE guidelines (November 2009)
4 were the GLP-1 receptor agonist exenatide and the DDP-4 inhibitors sitagliptin and saxagliptin. Since then, the GLP-1 receptor agonist liraglutide and the DPP-4 inhibitor linagliptin have been approved by the FDA, and these agents are now available for incorporation into the AACE/ACE algorithm (
Figure 4).
4
Patients at increased cardiovascular risk, including those who are overweight or have hypertension, may receive greater benefit from GLP-1 receptor agonists as a result of the effects of these drugs on body weight and blood pressure. Glucagon-like peptide-1 receptor agonists also offer more robust HbA
1c reductions compared to DPP-4 inhibitors.
35
Many patients may prefer to use DPP-4 inhibitors because these agents can be taken orally—in contrast to GLP-1 receptor agonists, which must be administered once or twice daily by subcutaneous injection with a prefilled pen. However, the reluctance that patients have at the prospect of self-administering injections can often be overcome by providing comprehensive instructions on how to use the pen devices. The physician should show the pen to the patient and demonstrate its use, with the patient then making a return demonstration. In many cases, the provider is able to make an injection without the patient realizing it, because the needles of modern pen devices have such fine gauges.
75
Finally, it is worth noting that both GLP-1 receptor agonists and DPP-4 inhibitors have low risks for hypoglycemia, and research to date has found no long-term toxicities with either of these incretin-based treatments.