Practical Strategies for the Clinical Use of Incretin Mimetics CME/CE Robert R. Henry, MD Authors and Disclosures CME/CE Released: 09/15/2009; Valid for credit through 09/15/2010 Introduction Type 2 diabetes mellitus (T2DM) occurs as the result of dysregulation in the complex balance of hormonal systems, including insulin secretion and utilization, glucagon secretion, and incretin hormonal effects. The incretin hormones are a relatively new target of both diabetes research and pharmaceutical interest; traditional therapies have often targeted abnormal insulin and glucagon levels and/or their metabolic consequences. However, frequent failure to achieve optimal glycemic control, a high prevalence of medication side effects, and excess cardiovascular (CV) events are prevalent because traditional antihyperglycemic agents only affect 1 or 2 underlying mechanisms of these processes. Data from the UK Prospective Diabetes Study (UKPDS) evaluated the long-term effects of insulin, sulfonylureas, and metformin therapy as monotherapy. Fifty percent of patients achieved an A1C of 7% after 3 years of monotherapy, and only 25% maintained this level of glycemic control after 9 years. [1] These findings illustrate the progressive nature of T2DM and the inability of traditional therapies to substantially impact this progression. Incretin mimetic agents offer a unique approach to the treatment of T2DM due to their ability to improve multiple aspects of hormonal dysregulation. Incretin hormones are secreted from the proximal small bowel, distal small bowel, and colon and stimulate insulin secretion from pancreatic β cells in response to an oral glucose load. [2] Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are the most widely studied incretin hormones. They increase the amount of insulin secreted up to 80% with an oral compared to an intravenous glucose load. [3] This enhanced insulin secretion after an oral glucose load is termed the "incretin effect" and has important therapeutic implications. While both hormones stimulate glucosedependent insulin secretion from pancreatic β cells, they vary in their pharmacokinetic and therapeutic potential. GLP-1 inhibits gastric emptying, decreases food intake, and inhibits glucagon secretion, while GIP has a minimal effect on gastric emptying and no effect on glucagon secretion or food intake. [4,5]
The incretin effect appears to be diminished, at least in some individuals with T2DM. [6] Nauck et al demonstrated this blunted insulin secretion in T2DM in response to an oral glucose load. While GIP concentrations are preserved in T2DM, the insulinotropic effect on the pancreatic receptor is reduced. GLP-1, however, exhibits a preserved insulinotropic effect, even when present in reduced amounts. [7] Nauck et al showed, in a proof-of-concept study, that an infusion of GLP-1 can result in normalization of plasma glucose in T2DM. [7] In addition, infusion of GLP-1 results in an increase in insulin secretion and a decrease in glucagon secretion compared with placebo. This retained insulinotropic effect in T2DM has made GLP-1 a target of pharmaceutical drug development via augmentation of circulating GLP-1 levels. [5] Native GLP-1 is rapidly degraded by the circulating enzyme dipeptidyl peptidase-4 (DPP-4), resulting in a halflife of approximately 2 minutes. [8] Thus, 2 approaches to increasing the circulating levels and effects of GLP-1 have been developed: injection of DPP-4 resistant GLP-1 receptor agonists (ie, incretin mimetics), and increasing the half-life of native GLP-1 through inhibition of DPP-4 (ie, DPP-4 inhibitors) (Figure 1). Figure 1.
Exenatide was the first incretin mimetic approved by the Food and Drug Administration (FDA) in 2005. It is a synthetic variant of GLP-1, derived from the saliva of the Gila monster (a venomous lizard), that is resistant to degradation by DPP-4, resulting in an extended plasma half-life. [8] Exenatide is approved for the treatment of T2DM that is inadequately controlled by oral antihyperglycemic medications and is administered by subcutaneous injection twice daily. [9] While exenatide is the only FDA-approved incretin mimetic at this time, several other promising therapies all with longer circulating half-lives are in development. Liraglutide is a once-daily, injectable human incretin mimetic awaiting FDA approval. [10] The Endocrinologic and Metabolic Drugs Advisory Committee of the United States FDA has evaluated liraglutide, and final FDA review is pending at this time. [11] Exenatide long-acting release (LAR) is a once-weekly formulation of exenatide, also under FDA review. Taspoglutide and albiglutide are new once-weekly incretin mimetics that are currently in phase 3 clinical testing. Properties of the incretin mimetics that are approved or are nearing market are summarized in Table 1. NOTE: Liraglutide, exenatide long-acting release (LAR), taspoglutide, and albiglutide are not currently FDA approved for this indication. Table 1.
GLP-1 retains its insulinotropic effects in T2DM In T2DM, GLP-1 retains its insulinotropic effects, even though it is present in diminished concentrations. GIP, however, is present in normal concentrations, while lacking insulinotropic effects. [6] Native GLP-1 is secreted by the proximal and distal small bowel and colon. [5] It is rapidly degraded by DPP-4, resulting in a half-life of approximately 2 minutes, whereas incretin mimetics exhibit a longer half-life due to DPP-4 resistance. [8,9] Enhanced insulin secretion after an oral glucose load is termed the incretin effect. The incretin effect is diminished in T2DM; therefore, the correct answer is GLP-1 retains its insulinotropic effects in T2DM. [3,6] The ADA recommends a general A1C goal of <7% for T2DM, and lower for selected individuals, if it can be safely achieved without significant hypoglycemia or adverse events. [12] Though previous data supported tight glycemic control to prevent or delay the onset of microvascular complications, [13] recent studies, such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and the Action in Diabetes and Vascular Disease (ADVANCE) trials, failed to show a CV benefit with A1C targets of <6.0% and <6.5%, respectively. [14] The ACCORD study showed increased mortality with intensive glucose control (mean A1C, 6.4%) compared to standard (mean A1C,
7.5%). [12,14] This patient has a short T2DM duration and no historical or active comorbidities. Thus, a goal of <7% may be appropriate. Both Enhanced postprandial insulin secretion and Weight loss Incretin mimetics stimulate post-meal insulin secretion and reduce increased glucagon secretion in T2DM, [9] contributing to improved PPG. [15-17] They also decrease mean body weight by up to 5 kg. [18-20] Recent exenatide data show a reduced mean body weight from baseline by up to 2.1 kg over 30 weeks and by up to 4.7 kg in a 2- year follow-up. [18] In another trial of exenatide vs insulin, a significantly greater proportion of exenatide patients (22% vs 2%, respectively) achieved a 5% weight loss. [21] A 2-year trial of liraglutide vs glimepiride showed significant and maintained liraglutide weight loss ( 2.7 kg vs +1.1 kg, respectively). [19] Likewise, weight reductions of up to 2.8 kg have been seen with the addition of liraglutide to metformin vs adding placebo or glimepiride. [22] Considerable insulin secretion occurs in healthy individuals in the first 10 minutes following a meal. Similarly, an early burst of insulin secretion following intravenous administration of glucose occurs in healthy individuals. This is called the "first-phase insulin response" and is impaired early in the progression of T2DM. [9] Incretin mimetics improve insulin secretion and restore this first-phase insulin response, contributing to improved PPG levels. [15,16] T2DM is associated with numerous pathophysiological defects. In addition to impaired insulin secretion, glucagon secretion is abnormal and excessive. While glucagon secretion is normally present in healthy individuals, excessive amounts lead to increases in glucose production by the liver and hyperglycemia. Glucagon is also inappropriately present in T2DM during times of hyperglycemia when it should be suppressed. [5] Incretin mimetics suppress inappropriate glucagon secretion in a glucose-dependent manner, thereby lowering plasma glucose levels. [9,17] GLP-1 and the incretin mimetics also have indirect effects on glycemic levels through decreased gastric emptying, decreased food intake, and weight loss. The observed weight loss of up to 5 kg with incretin mimetics provides a unique advantage over traditional T2DM therapies. In addition to the previously mentioned weight loss effects seen with exenatide and liraglutide, a 26-week study examining exenatide LAR versus sitagliptin or pioglitazone documented a significant reduction in A1C and weight loss in the exenatide LAR group. [20] Incretin mimetics reduce fasting plasma glucose and PPG levels in T2DM, with A1C reductions ranging from 0.9% to 1.7%. [23] In a 30-week study exenatide 10 mcg bid decreased A1C by 0.78%
±0.10% from a baseline of 8.2% when added to metformin [24] ; in a different study A1C reductions of 1.1% were maintained over 2 years with exenatide therapy. [18] Liraglutide resulted in a mean A1C decrease of 1.0% vs placebo ( 0.1%) when both were added to metformin. [22] In a recent study comparing liraglutide to exenatide, liraglutide resulted in greater A1C reductions ( 1.12% vs 0.79% respectively) when added to metformin or a sulfonylurea. [25] Exenatide LAR also showed significant A1C reductions in a 26-week trial: 66% of exenatide LAR patients achieved A1C target 7.0% vs 42% of sitagliptin patients and 56% of pioglitazone patients. [20] Pancreatic β-cell function in T2DM is impaired and associated with accelerated apoptosis. [26] The loss of β-cell function is progressive over time, with 50% or more of function already lost by the time of T2DM diagnosis. [26] This decrease in β-cell function may be altered, especially when targeted early in the disease process. GLP-1 and its analogs have demonstrated important effects on β cells in animal studies and show promise in maintaining long-term β-cell function and therefore glycemic control. [27] All of the above Agents should be selected based on glucose-lowering abilities, tolerability, safety, and effects on CV disease, BMI, insulin resistance, and insulin secretory capacity. [28,29] Incretin mimetics have positive effects on CV risk factors (blood pressure [BP], cholesterol, and liver enzymes). [30-32] The ADA guidelines emphasize using incretin mimetics in combination therapy when hypoglycemia or weight loss are concerns. [29] Incretin mimetics are not currently approved for monotherapy, so current metformin therapy makes this patient a candidate for addition of an incretin mimetic. [9] This patient's short T2DM duration also increases the likelihood for success with an incretin mimetic because it has recently been demonstrated that liraglutide is more effective than glimepiride at lowering A1C in patients with well-preserved β-cell function. [33] Data from the UKPDS show that 50% of patients will require combination therapy within 3 years of diagnosis. [1] This patient's elevated PPG and A1C require initiation of new and additional therapy, and effects on A1C, PPG, weight loss, hypoglycemia risk and CV risk factors make incretin mimetic therapy an appropriate selection for him when compared to other antihyperglycemic agents (Table 2). Table 2.
Several studies have examined the effects of incretin mimetics on CV risk factors. Fabunmi et al studied BP changes following 6 months of exenatide treatment. [30] In patients (n = 760) with a baseline systolic BP (SBP) 130 mm Hg, mean SBP decreased by 8.5 mm Hg. [30] A meta-analysis of 6 phase 3 clinical trials examined the effect of liraglutide on SBP. Liraglutide 1.8 mg reduced SBP by 2.59 mm Hg, whereas there was no change with placebo. The greatest reductions were seen in those with baseline SBP in the highest quartile. [31] Lastly, exenatide LAR reduced SBP, diastolic BP, cholesterol levels, and liver enzymes in a 52-week study. [3 If the patient experiences significant nausea within 1 week of initiating therapy, he should switch therapy Nausea is a common incretin mimetic side effect, occurring in up to 57% of exenatide-treated patients. [23] It is usually mild to moderate, peaks by 4 to 8 weeks, and improves with therapy duration. [25,34] Hypoglycemia risk is increased with combination sulfonylurea use but is generally low due to glucose-dependent insulin secretion. [5,34-35] Pancreatitis has been observed with incretin mimetics. [22,36,37] A recent study evaluating risks of acute pancreatitis found no increased risk with exenatide compared with other T2DM therapies. [38] The FDA cautions against incretin
mimetics if there is high risk for pancreatitis and recommends discontinuing therapy without restart if symptoms (abdominal pain and vomiting) occur. [36] The patient is concerned that he has gained some weight recently and cannot take his daily walks because of knee pain. Some of his friends who are taking other medications for their diabetes have put on weight since they started taking the medicine. His wife is worried he will not start a new medicine if it results in more weight gain. Both He may experience some weight loss with an incretin mimetic and Incretin mimetics may make him feel fuller and help him control his appetite Incretin mimetics, unlike most other T2DM agents, are usually associated with modest and sustained weight loss. [18-20] In a 24- week study, patients administered 5 or 10 mcg exenatide achieved greater A1C reductions ( 0.7% and 0.9%, respectively) compared with placebo ( 0.2%) and greater weight loss. [39] The Liraglutide Effect and Actions in Diabetes (LEAD) 6 study showed a similar degree of weight loss with liraglutide ( 3.24 kg) vs exenatide ( 2.87 kg) when added to traditional T2DM therapies. [25] Weight loss with incretin mimetics may be in part due to treatment-associated nausea but also occurs in the absence of nausea and is consistent with the ability of these agents to increase feelings of satiety and decrease food intake. [23] Both The patient should inject his medication before eating and The medication should be injected within a 60-minute period before a meal and is unlikely to cause hypoglycemia during this time. Exenatide and other incretin mimetics achieve glycemic control through several mechanisms, including delayed gastric emptying and weight loss. According to the prescribing information, exenatide should be injected "within a 60-minute period before the morning and evening meals." [9] Injecting before a meal allows the incretin mimetic to exert its effects on postprandial insulin secretion, delayed gastric emptying, and decreased food intake. Because this process is glucose dependent, hypoglycemia is not a typical side effect. [5]