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Tapping incretin-based therapy for type 2 diabetes

Appel, Susan J. PhD, ACNP-BC, CCRN, FNP-BC, FAHA

doi: 10.1097/01.NURSE.0000394397.55390.75
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Incretin mimetics are exciting new drugs that offer two significant advantages over many other antidiabetic medications: They don't cause weight gain and they're unlikely to cause hypoglycemia. Learn more about them here.

Susan J. Appel is an associate professor and an acute care and family nurse practitioner at the School of Nursing at the University of Alabama at Birmingham.

TWO EXCITING CATEGORIES of incretin mimetics, dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, are now available to manage type 2 diabetes mellitus.1 They're called incretin mimetics because they mimic the effect of the incretin hormones. This article explains their mechanism of action and how your patient would use them. Begin by considering their major advantages over current therapy.

The information about these drugs applies to adults, not children. Consult a pharmacist or the package insert for information about each drug's safety during pregnancy and breastfeeding. Consult a pharmacist, the package insert, or a comprehensive drug reference for more details on precautions, drug interactions, and adverse reactions for these drugs.

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Weighty advantages

Unlike some antidiabetic drugs, these medications don't cause weight gain. DPP-4 inhibitors and GLP-1 receptor agonists are considered weight neutral because they cause neither weight gain nor loss. However, incretin mimetics frequently do cause weight loss.2 Weight loss is believed to be due to the slowing of gastric emptying, which leads to a feeling of early satiety.

Also, these agents lower blood glucose levels with minimal risk of hypoglycemia: they don't act if the circulating glucose level isn't at least 70 mg/dL.2 These are major advantages because weight gain and hypoglycemia have long been the limiting adverse reactions to some pharmacologic regimens used to manage patients with type 2 diabetes.

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Understanding the incretin effect

Incretin hormones are peptides secreted by the gastrointestinal tract (small intestine) in response to food. These hormones, which stimulate insulin secretion and inhibit glucagon secretion, include glucose-dependent insulinotropic polypeptide (GIP) and GLP-1. (See A closer look at the islet of Langerhans.)

The incretin effect describes the increase in insulin secretion by incretin hormones (GIP and GLP-1) in response to food intake. Incretin hormones act on the endocrine pancreas to stimulate postprandial insulin secretion from the beta cells and inhibit glucagon secretion from the alpha cells, helping to control serum glucose levels after a meal. Eating also stimulates the gastrointestinal tract to produce enzymes such as DPP-4 that degrade the endogenous incretin human hormones GIP and GLP-1. Both GIP and GLP-1 have extremely short half-lives and are rendered ineffective primarily due to circulating DPP-4.2

In type 2 diabetes, the incretin effect is much less effective because pancreatic islet cell function progressively declines, disrupting glucagon-insulin balance.2,3 As a result, incretin hormone release is blunted and postprandial blood glucose levels increase.

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Looking at DPP-4 inhibitors

The incretin effect can be boosted by drugs that act by inhibiting DPP-4. Currently, the only FDA-approved DPP-4 inhibitors available in the United States are sitagliptin (Januvia) and saxagliptin (Onglyza). Sitagliptin and saxagliptin are oral agents that increase and prolong the action of both GLP-1 and GIP in the gut by slowing their inactivation.4–8 As an adjunct to diet and exercise, sitagliptin or saxagliptin may be given as monotherapy or in combination with other oral agents, including thiazolidinediones, metformin, or sulfonylureas.9 However, lowered doses should be considered to avoid hypoglycemia. A combination of sitagliptin and metformin (Janumet) is also available.

Although hepatic function isn't a concern, baseline renal function should be evaluated before starting any DPP-4 inhibitor and monitored regularly during therapy. The FDA recommends that patients with a creatinine clearance of less than 50 mL/minute receive a reduced dosage.10

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GLP-1 receptor agonists

Exenatide (Byetta) and liraglutide (Victoza) are the only GLP-1 receptor agonists currently approved in the United States. Exenatide, the first to be approved, is derived from the saliva of the Gila monster, a poisonous lizard native to the American southwest.4

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Figure

Exenatide is administered subcutaneously twice a day within an hour before the two main meals of the day (approximately 6 hours or more apart).3,11 Recently, studies have demonstrated positive results associated with an investigational therapy of exenatide in a once-weekly formulation.8 When exenatide was administered to patients with type 2 diabetes once a week, its efficacy was found to be comparable to that of a twice-daily dose.12

Liraglutide was approved in early 2010. The starting dose is administered subcutaneously once a day for 1 week, and then the dose is increased to obtain glycemic control.

Exenatide promotes an estimated weight loss of 4 to 5 lb (1.8 to 2.3 kg) and liraglutide promotes a similar weight loss.2,13 GLP-1 receptor agonists may improve insulin sensitivity and delay the need for insulin therapy.2

Because they profoundly slow gastric emptying, GLP-1 receptor agonists can reduce the extent and rate of absorption of orally administered drugs.11,14 Carefully consider other medications your patient is using, especially those requiring rapid gastrointestinal absorption and those with a narrow therapeutic index, such as digoxin.11 Oral medications should be taken 1 hour before injecting a GLP-1 receptor agonist because this may help absorption and minimize nausea that may occur with this medication.

GLP-1 receptor agonists can be used in combination with thiazolidinediones, metformin, or sulfonylureas, but administration with insulin therapy isn't recommended.

GLP-1 receptor agonists have been associated with postmarketing reports of nonfatal and fatal hemorrhagic or necrotizing pancreatitis.11,14 Healthcare providers and researchers theorize that GLP-1 receptor agonists may overstimulate the pancreas. Also, patients with type 2 diabetes may be at increased risk for pancreatitis. It's generally agreed that GLP-1 receptor agonists should be avoided in patients with a history of pancreatitis and should be promptly stopped when any patient experiences symptoms of pancreatitis, such as persistent severe abdominal pain, sometimes radiating to the back.11,14

Liraglutide is contraindicated for patients with a personal or family history of medullary thyroid carcinoma and those with multiple endocrine neoplasia syndrome type 2.

Both categories of the incretin mimetics, DPP-4 inhibitors and GLP-1 receptor agonists, offer viable options in the management of patients with type 2 diabetes. These agents may delay the need to start insulin while preserving beta cell function.

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REFERENCES

1. Green BD, Flatt PR, Bailey CJ. Dipeptidyl peptidase IV (DPP IV) inhibitors: A newly emerging drug class for the treatment of type 2 diabetes. Diab Vasc Dis Res. 2006;3(3):159–165.
2. Stonehouse A, Okerson T, Kendall D, Maggs D. Emerging incretin based therapies for type 2 diabetes: incretin mimetics and DPP-4 inhibitors. Curr Diabetes Rev. 2008;4(2):101–109.
3. Deacon CF. Incretin-based treatment of type 2 diabetes: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes Obes Metab. 2007;9(suppl 1):23–31.
4. Ahrén B. GLP-1-based therapy of type 2 diabetes: GLP-1 mimetics and DPP-IV inhibitors. Curr Diab Rep. 2007;7(5):340–347.
5. McKennon SA, Campbell RK. The physiology of incretin hormones and the basis for DPP-4 inhibitors. Diabetes Educ. 2007;33(1):55–56, 60–62, 65–66.
6. Scheen AJ, Van Gaal LF. [Sitagliptine (Januvia): incretin enhancer potentiating insulin secretion for the treatment of type 2 diabetes]. Rev Med Liege. 2008;63(2):105–109.
7. Sitagliptin (Januvia) tablets prescribing information. Merck & Co; 2010.
8. Saxagliptin (Onglyza) tablets prescribing information. Bristol-Myers Squibb; 2009.
9. Raz I, Chen Y, Wu M, et al. Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes. Curr Med Res Opin. 2008;24(2):537–550.
10. Chan JC, Scott R, Arjona Ferreira JC, et al. Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency. Diabetes Obes Metab. 2008;10(7):545–555.
11. Exenatide (Byetta) injection prescribing information. Amylin Pharmaceuticals. 2010 .
12. Lilly. Exenatide once weekly provided superior glucose control compared to BYETTA(R) in DURATION-5 study .
13. Buse JB, Rosenstock J, Sesti G, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet. 2009;374(9683):39–47.
14. Liraglutide (rDNA origin) injection (Victoza) prescribing information. Novo Nordisk; 2010.
15. Green BD, Flatt PR. Incretin hormone mimetics and analogues in diabetes therapeutics. Best Pract Res Clin Endocrinol Metab. 2007;21(4):497–516.
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