Pharmacist to Pharmacist: Incretin-based Treatment of Type 2 Diabetes
Christina L. Aquilante, PharmD
Published Online: August 15, 2009 - 12:00:01 AM (CDT)
Dr. Aquilante is assistant professor, Department of Pharmaceutical Sciences, at the University of Colorado-Denver School of Pharmacy.
The incidence of type 2 diabetes is increasing at an alarming rate, affecting more than 225 million individuals worldwide.1 Type 2 diabetes is a progressive disease and is associated with adverse clinical sequelae, such as retinopathy, nephropathy, neuropathy, cardiovascular disease, peripheral artery disease, and stroke. In order to prevent these long-term complications, attainment of a hemoglobin A1C (HbA1C) <7% is the primary goal of treatment. 2 Although diet and exercise are effective modalities to achieve normo - glycemia, most patients with type 2 diabetes eventually require antihyperglycemic pharmacologic therapy to control their disease.3
The hallmarks of type 2 diabetes are diminished insulin secretion from pancreatic β cells and diminished tissue responsiveness to the normal action of insulin (ie, insulin resistance). Drugs such as the sulfonylureas (eg, glimepiride, glyburide) and short-acting insulin secretagogues (eg, repaglinide, nateglinide) address defects in insulin secretion by stimulating insulin release from the β cells. Drugs such as thiazolidinediones (eg, pioglitazone, rosiglitazone) and biguanides (eg, metformin) address defects in insulin action by improving insulin sensitivity and decreasing insulin resistance in the muscle, liver, and fat. Recently, our understanding of the type 2 diabetes disease process has moved beyond just defects in insulin secretion and action and now encompasses the role of incretin hormones in glucose homeostasis.
How Incretins Work
Incretins are endogenous peptide hormones that are secreted from cells in the small intestine in response to food intake.4 The recognition of the importance of gut hormones in glucose regulation came from the observation that insulin secretion is greater after oral versus intravenous administration of glucose. 5 The primary action of incretin hormones is to increase glucose-dependent insulin secretion from pancreatic β cells. Thus, incretins work to stimulate insulin secretion when glucose levels rise, but the effects of incretins on insulin secretion diminish when glucose levels start to decline.5 Deficient incretin secretion and/or incretin action are thought to contribute, in part, to the hyperglycemia observed in type 2 diabetes.
Two of the most well-studied incretin hormones are glucagon-like peptide- 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 is released from neuroendocrine L cells of the ileum and colon, and GLP-1 receptors are expressed on pancreatic β cells.4 Studies also suggest that GLP-1 receptors may be located on pancreatic α cells, endothelial cells, and in the brain, nervous system, heart, kidney, lungs, and gastrointestinal tract.6 In addition to promoting glucose-dependent insulin secretion, GLP-1 suppresses the release of glucagon after a meal, slows gastric emptying, promotes satiety, and reduces food intake. In patients with type 2 diabetes, the release of GLP-1 following food intake is decreased, and the action of GLP-1 is blunted.6
The incretin hormone GIP is released from K cells in the duodenum and jejunum. 4 Unlike GLP-1, GIP does not suppress postprandial glucagon release, nor does it slow the rate of gastric emptying. Although the amount of GIP is only slightly decreased in patients with type 2 diabetes, its glucose-dependent insulin secretory effects are almost completely abolished.6 Both GLP-1 and GIP have a short halflife in the body (approximately 1-2 minutes), because they are rapidly degraded and inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4).5 As such, exogenous administration of GLP-1 or GIP is not a likely treatment modality because of this rapid in vivo degradation. Instead, the focus of drug development has been on agents that mimic the naturally occurring actions of incretins, but which are resistant to DPP-4 degradation (eg, exenatide, liraglutide), or agents that inhibit DPP-4 and prolong the action of endogenous incretin hormones.
Incretin Mimetics
In the search for potential incretin mimetic drugs, researchers found that the Gila monster lizard produced a salivary protein called exendin-4. Exendin-4 has a similar amino acid sequence and glucose-regulating function as endogenous GLP-1 found in humans. Importantly, exendin-4 is resistant to degradation by DPP-4. Currently, the only available product in this class is exenatide (Byetta), which is a synthetically derived peptide of exendin-4, and is only 9 amino acids longer than human GLP-1.7 Exenatide binds to GLP-1 receptors and works to increase glucosedependent insulin secretion, decrease postprandial glucagon secretion, slow gastric emptying, and improve satiety.7 As a result of these pharmacodynamic effects, exenatide is associated with a 1% decrease in HbA1C, which is primarily due to its effects on postprandial glucose, and, to a lesser extent, fasting glucose.4
Exenatide is indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes who are taking metformin, a sulfonylurea, a thia zolidinedione, a combination of metformin and a sulfonylurea, or a combination of metformin and a thiazolidinedione but who have not achieved adequate glycemic control.7 The most common side effects are nausea and vomiting, particularly at the initiation of therapy.7 Less common side effects include pancreatitis and hypersensitivity reactions.7 Exenatide is administered as a subcutaneous injection twice daily, within 60 minutes of the morning and evening meals. A long-acting, once-weekly depot formulation of exenatide (exenatide LAR) is currently under development.
Other GLP-1 mimetics, such as liraglutide, are currently in the drug approval process. Liraglutide is a GLP-1 analog with a fatty acid attached to the molecule. The fatty acid molecule promotes binding to albumin, thus prolonging the drug’s duration of action. Liraglutide is a subcutaneous injection and has a longer half-life than exenatide. As such, liraglutide is administered once daily. Clinical studies have shown that, depending on dose, liraglutide lowers HbA1C 0.8% to 1.45%.8-10 Some concerns have been raised regarding thyroid tumors observed in animal models following administration of liraglutide. The clinical relevance of these findings in humans is currently undergoing evaluation by the FDA.
DPP-4 Inhibitors
Sitagliptin (Januvia) is a highly selective, reversible inhibitor of the DPP-4 enzyme and also the first available product representing this class. By inhibiting DPP- 4, sitagliptin slows the inactivation of endogenous incretin hormones such as GLP-1 and GIP.4 The 2- to 3-fold increase in circulating endogenous GLP-1 and GIP concentrations is associated with enhanced glucose-dependent insulin secretion and a decrease in postprandial glucagon excursions. These pharmacodynamic effects result in a 0.5% to 0.8% reduction in HbA1C levels.4
Sitagliptin is indicated as monotherapy, or in combination with metformin, sulfonylureas, or thiazolidinediones, in patients with type 2 diabetes.11 Unlike exenatide, sitagliptin is administered orally once daily. Sitagliptin appears to be well-tolerated with few side effects. Although causality has not been determined, postmarketing reports have indicated cases of anaphylaxis, angioedema, and rash.11
Other DPP-4 inhibitors are currently in the drug approval process in the United States. Published clinical data are currently limited for most of these agents. Preliminary data suggest, however, that these new agents have similar efficacy and safety profiles as sitagliptin.12
Additional Benefits of Incretin-Based Agents
Interest in the nonglycemic effects of incretin mimetic drugs and the DPP-4 inhibitors has recently heightened. In clinical studies of currently available agents, exenatide has been associated with a 1- to 5-kg weight loss in patients with type 2 diabetes.4 This is presumed to be due to exenatide’s ability to slow gastric emptying and increase satiety. Liraglutide also appears to be associated with weight loss in the 1- to 3-kg range.8,9 Sitagliptin appears to have a neutral effect on weight.8 Exenatide has beneficial effects on indirect measures of b cell function, and in animals, the drug has been shown to increase b cell mass.10 The effects of sitagliptin and liraglutide on b cell function and mass remain to be determined.
In terms of cardiovascular effects, clinical studies suggest that exenatide may cause modest reductions in systolic and diastolic blood pressure (-2.6 mm Hg and -1.9 mm Hg, respectively).13 Liraglutide also has been associated with modest reductions in systolic blood pressure (-2.1 to 3.6 mm Hg).9 Additionally, clinical data indicate a modest decrease in tri - glycerides (-38.6 mg/dL) and increase in high-density lipoprotein cholesterol (4.6 mg/dL) associated with exenatide therapy. 14 The clinical significance of these findings has yet to be determined.
The effects of exenatide and sitagliptin on cardiovascular end points are not known; however, data suggest that GLP-1 supplementation may have beneficial effects on the cardiovascular system. In one study of patients with low left ventricular ejection fraction following myocardial infarction, GLP-1 infusion significantly improved ejection fraction.15 Infusion of GLP-1 significantly improved markers of endothelial function in patients with type 2 diabetes.16 Data with liraglutide suggest that it may have a beneficial effect on the cardiovascular risk biomarkers, plasminogen activator inhibitor 1 and B-type natriuretic peptide in patients with type 2 diabetes. 17 Long-term studies are needed.
Conclusion
Incretin-based therapy represents a new strategy for treating type 2 diabetes by targeting defects in pathophysiology, beyond just insulin secretion and action. Currently, the American Diabetes Association recommends lifestyle therapy, metformin, insulin, and sulfonylureas as tier 1, “well-validated core” therapies for the treatment of type 2 diabetes.3 Agents such as exenatide and pioglitazone are recommended as tier 2, “less well-validated” options for treatment. DPP-4 inhibitors, such as sitagliptin, are classified as “other therapy” due to lack of long-term safety data and lower effectiveness, compared with tier 1 or tier 2 agents.
Nonetheless, DPP-4 inhibitors may be appropriate choices for certain patients, especially because they are weight-neutral. Although some of the incretin-based therapies have ancillary benefits, the clinical relevance of those findings is unclear at this time. Long-term trials that include cardiovascular safety and efficacy data are eagerly awaited.
The incidence of type 2 diabetes is increasing at an alarming rate, affecting more than 225 million individuals worldwide.1 Type 2 diabetes is a progressive disease and is associated with adverse clinical sequelae, such as retinopathy, nephropathy, neuropathy, cardiovascular disease, peripheral artery disease, and stroke. In order to prevent these long-term complications, attainment of a hemoglobin A1C (HbA1C) <7% is the primary goal of treatment. 2 Although diet and exercise are effective modalities to achieve normo - glycemia, most patients with type 2 diabetes eventually require antihyperglycemic pharmacologic therapy to control their disease.3
The hallmarks of type 2 diabetes are diminished insulin secretion from pancreatic β cells and diminished tissue responsiveness to the normal action of insulin (ie, insulin resistance). Drugs such as the sulfonylureas (eg, glimepiride, glyburide) and short-acting insulin secretagogues (eg, repaglinide, nateglinide) address defects in insulin secretion by stimulating insulin release from the β cells. Drugs such as thiazolidinediones (eg, pioglitazone, rosiglitazone) and biguanides (eg, metformin) address defects in insulin action by improving insulin sensitivity and decreasing insulin resistance in the muscle, liver, and fat. Recently, our understanding of the type 2 diabetes disease process has moved beyond just defects in insulin secretion and action and now encompasses the role of incretin hormones in glucose homeostasis.
How Incretins Work
Incretins are endogenous peptide hormones that are secreted from cells in the small intestine in response to food intake.4 The recognition of the importance of gut hormones in glucose regulation came from the observation that insulin secretion is greater after oral versus intravenous administration of glucose. 5 The primary action of incretin hormones is to increase glucose-dependent insulin secretion from pancreatic β cells. Thus, incretins work to stimulate insulin secretion when glucose levels rise, but the effects of incretins on insulin secretion diminish when glucose levels start to decline.5 Deficient incretin secretion and/or incretin action are thought to contribute, in part, to the hyperglycemia observed in type 2 diabetes.
Two of the most well-studied incretin hormones are glucagon-like peptide- 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 is released from neuroendocrine L cells of the ileum and colon, and GLP-1 receptors are expressed on pancreatic β cells.4 Studies also suggest that GLP-1 receptors may be located on pancreatic α cells, endothelial cells, and in the brain, nervous system, heart, kidney, lungs, and gastrointestinal tract.6 In addition to promoting glucose-dependent insulin secretion, GLP-1 suppresses the release of glucagon after a meal, slows gastric emptying, promotes satiety, and reduces food intake. In patients with type 2 diabetes, the release of GLP-1 following food intake is decreased, and the action of GLP-1 is blunted.6
The incretin hormone GIP is released from K cells in the duodenum and jejunum. 4 Unlike GLP-1, GIP does not suppress postprandial glucagon release, nor does it slow the rate of gastric emptying. Although the amount of GIP is only slightly decreased in patients with type 2 diabetes, its glucose-dependent insulin secretory effects are almost completely abolished.6 Both GLP-1 and GIP have a short halflife in the body (approximately 1-2 minutes), because they are rapidly degraded and inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4).5 As such, exogenous administration of GLP-1 or GIP is not a likely treatment modality because of this rapid in vivo degradation. Instead, the focus of drug development has been on agents that mimic the naturally occurring actions of incretins, but which are resistant to DPP-4 degradation (eg, exenatide, liraglutide), or agents that inhibit DPP-4 and prolong the action of endogenous incretin hormones.
Incretin Mimetics
In the search for potential incretin mimetic drugs, researchers found that the Gila monster lizard produced a salivary protein called exendin-4. Exendin-4 has a similar amino acid sequence and glucose-regulating function as endogenous GLP-1 found in humans. Importantly, exendin-4 is resistant to degradation by DPP-4. Currently, the only available product in this class is exenatide (Byetta), which is a synthetically derived peptide of exendin-4, and is only 9 amino acids longer than human GLP-1.7 Exenatide binds to GLP-1 receptors and works to increase glucosedependent insulin secretion, decrease postprandial glucagon secretion, slow gastric emptying, and improve satiety.7 As a result of these pharmacodynamic effects, exenatide is associated with a 1% decrease in HbA1C, which is primarily due to its effects on postprandial glucose, and, to a lesser extent, fasting glucose.4
Exenatide is indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes who are taking metformin, a sulfonylurea, a thia zolidinedione, a combination of metformin and a sulfonylurea, or a combination of metformin and a thiazolidinedione but who have not achieved adequate glycemic control.7 The most common side effects are nausea and vomiting, particularly at the initiation of therapy.7 Less common side effects include pancreatitis and hypersensitivity reactions.7 Exenatide is administered as a subcutaneous injection twice daily, within 60 minutes of the morning and evening meals. A long-acting, once-weekly depot formulation of exenatide (exenatide LAR) is currently under development.
Other GLP-1 mimetics, such as liraglutide, are currently in the drug approval process. Liraglutide is a GLP-1 analog with a fatty acid attached to the molecule. The fatty acid molecule promotes binding to albumin, thus prolonging the drug’s duration of action. Liraglutide is a subcutaneous injection and has a longer half-life than exenatide. As such, liraglutide is administered once daily. Clinical studies have shown that, depending on dose, liraglutide lowers HbA1C 0.8% to 1.45%.8-10 Some concerns have been raised regarding thyroid tumors observed in animal models following administration of liraglutide. The clinical relevance of these findings in humans is currently undergoing evaluation by the FDA.
DPP-4 Inhibitors
Sitagliptin (Januvia) is a highly selective, reversible inhibitor of the DPP-4 enzyme and also the first available product representing this class. By inhibiting DPP- 4, sitagliptin slows the inactivation of endogenous incretin hormones such as GLP-1 and GIP.4 The 2- to 3-fold increase in circulating endogenous GLP-1 and GIP concentrations is associated with enhanced glucose-dependent insulin secretion and a decrease in postprandial glucagon excursions. These pharmacodynamic effects result in a 0.5% to 0.8% reduction in HbA1C levels.4
Sitagliptin is indicated as monotherapy, or in combination with metformin, sulfonylureas, or thiazolidinediones, in patients with type 2 diabetes.11 Unlike exenatide, sitagliptin is administered orally once daily. Sitagliptin appears to be well-tolerated with few side effects. Although causality has not been determined, postmarketing reports have indicated cases of anaphylaxis, angioedema, and rash.11
Other DPP-4 inhibitors are currently in the drug approval process in the United States. Published clinical data are currently limited for most of these agents. Preliminary data suggest, however, that these new agents have similar efficacy and safety profiles as sitagliptin.12
Additional Benefits of Incretin-Based Agents
Interest in the nonglycemic effects of incretin mimetic drugs and the DPP-4 inhibitors has recently heightened. In clinical studies of currently available agents, exenatide has been associated with a 1- to 5-kg weight loss in patients with type 2 diabetes.4 This is presumed to be due to exenatide’s ability to slow gastric emptying and increase satiety. Liraglutide also appears to be associated with weight loss in the 1- to 3-kg range.8,9 Sitagliptin appears to have a neutral effect on weight.8 Exenatide has beneficial effects on indirect measures of b cell function, and in animals, the drug has been shown to increase b cell mass.10 The effects of sitagliptin and liraglutide on b cell function and mass remain to be determined.
In terms of cardiovascular effects, clinical studies suggest that exenatide may cause modest reductions in systolic and diastolic blood pressure (-2.6 mm Hg and -1.9 mm Hg, respectively).13 Liraglutide also has been associated with modest reductions in systolic blood pressure (-2.1 to 3.6 mm Hg).9 Additionally, clinical data indicate a modest decrease in tri - glycerides (-38.6 mg/dL) and increase in high-density lipoprotein cholesterol (4.6 mg/dL) associated with exenatide therapy. 14 The clinical significance of these findings has yet to be determined.
The effects of exenatide and sitagliptin on cardiovascular end points are not known; however, data suggest that GLP-1 supplementation may have beneficial effects on the cardiovascular system. In one study of patients with low left ventricular ejection fraction following myocardial infarction, GLP-1 infusion significantly improved ejection fraction.15 Infusion of GLP-1 significantly improved markers of endothelial function in patients with type 2 diabetes.16 Data with liraglutide suggest that it may have a beneficial effect on the cardiovascular risk biomarkers, plasminogen activator inhibitor 1 and B-type natriuretic peptide in patients with type 2 diabetes. 17 Long-term studies are needed.
Conclusion
Incretin-based therapy represents a new strategy for treating type 2 diabetes by targeting defects in pathophysiology, beyond just insulin secretion and action. Currently, the American Diabetes Association recommends lifestyle therapy, metformin, insulin, and sulfonylureas as tier 1, “well-validated core” therapies for the treatment of type 2 diabetes.3 Agents such as exenatide and pioglitazone are recommended as tier 2, “less well-validated” options for treatment. DPP-4 inhibitors, such as sitagliptin, are classified as “other therapy” due to lack of long-term safety data and lower effectiveness, compared with tier 1 or tier 2 agents.
Nonetheless, DPP-4 inhibitors may be appropriate choices for certain patients, especially because they are weight-neutral. Although some of the incretin-based therapies have ancillary benefits, the clinical relevance of those findings is unclear at this time. Long-term trials that include cardiovascular safety and efficacy data are eagerly awaited.
References
1. International Diabetes Federation Web site. www.idf.org.
2. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2008;31(suppl 1):S12-S54.
3. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32(1):193-203.
4. Inzucchi SE, McGuire DK. New drugs for the treatment of diabetes: part II: incretin-based therapy and beyond. Circulation. 2008;117(4):574-584.
5. Holst JJ, Vilsboll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus. Mol Cell Endocrinol. 2009;297(1-2):127-136.
6. Aaboe K, Krarup T, Madsbad S, Holst JJ. GLP-1: physiological effects and potential therapeutic applications. Diabetes Obes Metab. 2008;10(11):994-1003.
7. Byetta [prescribing information]. San Diego, CA: Amylin Pharmaceuticals, Inc; 2008.
8. Nauck M, Frid A, Hermansen K, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (Liraglutide Effect and Action in Diabetes)-2 study. Diabetes Care. 2009;32(1)84-90.
9. Garber A, Henry R, Ratner R, et al. Liraglutide vs glimepiride monotherapy for type 2 diabetes (LEAD-3 Monograph): a randomised 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2009;373(9662):473-481.
10. Chia CW, Egan JM. Incretin-based therapies in type 2 diabetes mellitus. J Clin Endocrinol Metab. 2008;93(10):3703-3716.
11. Januvia [prescribing information]. Rahway, NJ: Merck & Co, Inc; 2007.
12. DeFronzo RA, Fleck PR, Wilson CA, Mekki Q. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control: a randomized, double-blind, placebo-controlled study. Diabetes Care. 2008;31(12:2315-2317.
13. Buse JB, Klonoff DC, Nielsen LL, et al. Metabolic effects of two years of exenatide treatment on diabetes, obesity, and hepatic biomarkers in patients with type 2 diabetes: an interim analysis of data from the open-label, uncontrolled extension of three double-blind, placebo-controlled trials. Clin Ther. 2007;29(1):139-153.
14. Blonde L, Klein EJ, Han J, et al. Interim analysis of the effects of exenatide treatment on A1C, weight and cardiovascular risk factors over 82 weeks in 314 overweight patients with type 2 diabetes. Diabetes Obes Metab. 2006;8(4):436-447.
15. Nikolaidis LA, Mankad S, Sokos GG, et al. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation. 2004;109(8):962-965.
16. Nystrom T, Gutniak MK, Zhang Q, et al. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol Endocrinol Metab. 2004;287(6):E1209-E1215.
17. Courreges JP, Vilsboll T, Zdravkovic M, et al. Beneficial effects of once-daily liraglutide, a human glucagon-like peptide-1 analog, on cardiovascular risk biomarkers in patients with type 2 diabetes. Diabet Med. 2008;25(9):1129-1131.
18. Madsbad S. Treatment of type 2 diabetes with incretin-based therapies. Lancet. 2009;373(9662)438-439.
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