HORMONES: GASTROINTESTINAL 
 

Exenatide is indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes mellitus who are taking metformin, a sulfonylurea, or a combination of metformin and a sulfonylurea but have not achieved adequate glycemic control.

Prescribing Information

Frequently Asked Questions: Gastrointestinal Hormones
What are incretin hormones?
What is the incretin effect?
What is GIP?
What are the physiologic effects/mechanisms of action of GIP?
What is GLP-1?
What are the physiologic effects/mechanisms of action of GLP-1?
Does GLP-1 have a direct effect on the pancreatic β cells?
What is DPP-IV?
Are GIP levels altered in people with type 2 diabetes?
Are GLP-1 levels altered in people with type 2 diabetes?
Why are therapies in development targeting GLP-1 pathways and not GIP pathways?
What are some of the GLP-1–based therapies currently in development?
Why is there so much excitement surrounding these therapies?
How do the GLP-1R agonists differ from DPP-IV inhibitors?
What are GLP-1 mimetics?
What are GLP-1 analogues?
Has GLP-1 administration been studied?
What is exendin-4?
Do exendin-1, -2, and -3 exist?
How does exendin-4 differ from GLP-1?
What is exenatide?
How do exendin-4 and exenatide differ?
What has been seen in clinical trials with exenatide?
What has been seen in terms of direct effects on the β cells with exendin-4?
What is liraglutide (NN2211)?
What has been seen in clinical trials with liraglutide (NN2211)?
What is vildagliptin (LAF237)?
What has been seen in clinical trials with vildagliptin (LAF237)?
How far into development are these agents?
Are there any other GLP-1–based compounds in development?
References

 
What are incretin hormones?
 
Incretin hormones are, by definition, gastrointestinal hormones that stimulate insulin secretion in
a glucose-dependent manner.1,2 Some incretin hormones also have other glucoregulatory-related actions. The existence of incretin hormones was first postulated when it was observed that orally administered glucose (absorbed through the gut) was associated with a greater degree of insulin release than intravenously administered glucose. Important incretin hormones include what was originally termed gastric inhibitory polypeptide (GIP)— however, it was subsequently determined
that GIP had no inhibitory effects on gastric functioning, and the name was changed to glucose-dependent insulinotropic polypeptide (but still GIP)—and glucagon-like peptide 1 (GLP-1).
 
Return to Top
 
What is the incretin effect?
 
The incretin effect is the difference between the level of insulin release seen with intravenously administered glucose and the greater insulin release seen with orally administered glucose.
 
Return to Top
 
What is GIP?
 
GIP was the first incretin hormone to be identified and is responsible for approximately
20% of the incretin effect.2,3 A single 42–amino acid peptide, GIP is derived from a 153–amino
acid precursor.2 GIP is released from the enteroendocrine cells in the duodenum and proximal
jejunum after nutrient intake.2
 
Return to Top
 
What are the physiologic effects/mechanisms of action of GIP?
 
GIP stimulates insulin secretion in a glucose-dependent manner and may contribute to
islet-cell proliferation.2
 
Return to Top
 
What is GLP-1?
 
GLP-1 is a naturally occurring peptide, responsible for approximately 80% of the incretin effect.2,3 There are 2 active forms: GLP-1(7-37) amide (which accounts for approximately 80% of all GLP-1)
and GLP-1(6-37). It is synthesized from the 160–amino acid proglucagon molecule, along with glucagon and GLP-2, within L cells primarily located in the ileum and colon. GLP-1 is secreted
in response to meals.2,3
 
Return to Top
 
What are the physiologic effects/mechanisms of action of GLP-1?
 
GLP-1 has a potent glucose-dependent effect on insulin secretion and insulin gene expression.1 It
also has a number of additional glucoregulatory actions that GIP does not, including glucose-dependent inhibition of glucagon secretion (and thus hepatic glucose output), a delaying of gastric emptying, and an effect on satiety.3
 
Return to Top
 
Does GLP-1 have a direct effect on the pancreatic β cells?
 
Yes. In animal models, GLP-1 has been shown to enhance β-cell replication, neogenesis, volume,
and mass,4-6 and ex vivo studies on human islet cells have shown that treatment with GLP-1 decreases β-cell apoptosis in human islet cells.7
 
Return to Top
 
What is DPP-IV?
 
Dipeptidyl peptidase IV (DPP-IV) is an enzyme naturally present in the body that rapidly inactivates native GIP and GLP-1.2 In the natural state, DPP-IV limits the half-life of GLP-1 to approximately
90 seconds. DPP-IV occurs in 2 forms: soluble (circulating) or membrane bound as CD26. It has numerous functions other than the degradation of GIP and GLP-1.
 
Return to Top
 
Are GIP levels altered in people with type 2 diabetes?
 
In people with type 2 diabetes, levels of circulating GIP are normal or slightly increased, both basally and postprandially, compared with levels in people without diabetes.2 In addition, GIP tends to lose its effectiveness (ie, it exhibits reduced insulinotropic action) in people with type 2 diabetes.2
 
Return to Top
 
Are GLP-1 levels altered in people with type 2 diabetes?
 
In contrast to GIP, modest but significant reductions in postprandial levels of circulating GLP-1 are seen in people with impaired glucose tolerance or type 2 diabetes compared with those without diabetes. Also in contrast to GIP, the response to GLP-1 does not appear to be compromised in people with type 2 diabetes.2
 
Return to Top
 
Why are therapies in development targeting GLP-1 pathways and not GIP pathways?
 
As mentioned, in people with type 2 diabetes, levels of circulating GIP are normal or slightly increased basally and postprandially. In contrast, modest but significant reductions in postprandial levels of circulating GLP-1 are seen in people with impaired glucose tolerance or type 2 diabetes. In addition, GIP tends to exhibit reduced insulinotropic action in people with type 2 diabetes, whereas the response to GLP-1 does not appear to be compromised.2 Because of these factors, GLP-1 is an attractive choice for development as an antihyperglycemic agent.
 
Return to Top
 
What are some of the GLP-1–based therapies currently in development?
 
In April 2005, the FDA approved the first of these therapies, exenatide, which is a GLP 1 mimetic
that stimulates the GLP-1 receptor (GLP-1R). A number of other GLP-1–based therapies are under investigation in an attempt to better control plasma glucose levels (especially those seen in the postprandial period) in patients with type 2 diabetes. These include liraglutide (formerly known as NN2211), a GLP-1 analogue and also a GLP-1R agonist, and vildagliptin (formerly known as LAF237), sitagliptin, and saxagliptin, DPP-IV inhibitors.
 
Return to Top
 
Why is there so much excitement surrounding these therapies?
 
In people with type 2 diabetes, it is difficult to maintain reductions in A1C that have been achieved with oral agents and insulin. Even in those patients who are treated aggressively, there continues to be a deterioration in glycemic control over time.8 GLP-1–based therapies have the potential to improve glycemic control by more naturally replicating normal fasting and—especially—postprandial hormonal responses. As with native GLP-1, use of these therapies may also directly affect the integrity of the pancreatic β cells (encouraging results have been seen in animal models): something no currently available therapeutic intervention does. In addition, traditional intensive glycemic control regimens are associated with weight gain and an increased incidence of hypoglycemia in patients with type 2 diabetes.8 In contrast, preliminary results with GLP-1R agonists (exenatide and liraglutide) show weight loss concurrent with improvements in glycemic control.9-11 Also, because of their glucose-dependent mechanisms of action (the insulinotropic action of GLP-1 ceases at a glycemic level of
60 mg/dL), an increased incidence of severe hypoglycemia has not been seen with these agents.9-11 
 
Return to Top
 
How do the GLP-1R agonists differ from DPP-IV inhibitors?
 
GLP-1R agonists are injectable, have a single known target (G protein–coupled receptor), are associated with higher levels of GLP-1 and more potent glucose-lowering effects than DPP-IV inhibitors, and have a well-described and tolerable side-effect profile (nausea and vomiting are among the side effects). GLP-1R agonists have been associated with weight loss in clinical trials and early clinical experience.2 DPP-IV inhibitors, on the other hand, are orally available, have multiple targets, are GLP-1 pharmacokinetic favorable, and are less potent than the receptor agonists.2 Drug overdose is nontoxic, and there are no central nervous system side effects, although the side-effect profile overall is less defined. DPP-IV inhibitors have not been associated with nausea, and, although there is no weight loss, there is no weight gain with their use.2 

Return to Top
 
What are GLP-1 mimetics?
 
GLP-1 mimetics are, as their name implies, substances that mimic the effects of incretin hormones but are not as vulnerable to the actions of DPP-IV as GLP-1. Incretin mimetics work as receptor agonists. The primary GLP-1 mimetic is exenatide (synthetic exendin-4), which is now approved in
the United States.
 
Return to Top
 
What are GLP-1 analogues?
 
An analogue is a molecule very similar to the native protein but with slight modification to achieve a specific goal. Liraglutide is very similar to native GLP-1, but it is slightly altered to add a fatty acid chain that binds with albumin after liraglutide has been injected. This increases its circulating half-life to the extent that liraglutide is suitable for once-daily dosing.
 
Return to Top
 
Has GLP-1 administration been studied?
 
Yes, although the short half-life of this hormone makes its widespread therapeutic use impractical.
The long-term effects of continuous GLP-1 administration in patients with type 2 diabetes have been reported in a 6-week pilot study employing a continuous subcutaneous infusion with an insulin pump.12 Twenty subjects were alternately assigned 6 weeks of continuous subcutaneous infusion of GLP-1 or placebo. In those receiving GLP-1, fasting and 8-hour mean plasma glucose levels decreased by
77 and 99 mg/dL, respectively (P<0.0001 vs placebo). A1C levels decreased by 1.3% (P=0.003). In addition, gastric emptying was delayed, body weight was decreased by 1.9 kg, and appetite was reduced. Both insulin sensitivity and β-cell function improved (P=0.003 for both measures), and no clinically significant side effects were observed.
 
Return to Top
 
What is exendin-4?
 
Exendin-4 is a 39–amino acid protein that occurs naturally in the salivary gland venom of the Gila monster (Heloderma suspectum).2 In the Gila monster, exendin-4 circulates in the bloodstream following ingestion of a meal and may have endocrine functions related to metabolic control. Exendin-4 is not the Gila monster's homologue of mammalian GLP-1. In the Gila monster, GLP-1 and exendin-4 are distinct peptides and are products of distinct genes. Also, as the peptide sequence of exendin-4 was not created by modification of the primary sequence of GLP-1, exendin-4 is not an analogue of GLP-1. Exendin-4 has approximately 53% amino acid sequence identity with mammalian or Gila monster GLP-1. To date, no exendin-4 gene has been found in mammals.
 
Return to Top
 
Do exendin-1, -2, and -3 exist?
 
Yes. Exendin-1 (helospectin), -2 (helodermin), and -3 are other bioactive peptides from reptilian sources. Note that not all exendins come from the Gila monster.
 
Return to Top
 
How does exendin-4 differ from GLP-1?
 
There are several differences between exendin-4 and GLP-1. For example, unlike GLP-1—half of which is degraded in the plasma after subcutaneous injection in 90 seconds by DPP-IV—subcutaneous exendin-4 is resistant to DPP-IV degradation and has a much longer plasma half-life (2 to 3 hours). Also, exendin-4 is transcribed from a distinct gene, not the Gila monster homologue of the mammalian proglucagon gene from which GLP-1 is expressed.
 
Return to Top
 
What is exenatide?
 
Exenatide (formerly referred to as AC2993) is the generic name for synthetic exendin-4. As the
peptide sequence of exendin-4 was not created by modification of the primary sequence of GLP-1,
it is not an analogue of GLP-1.
 
Return to Top
 
How do exendin-4 and exenatide differ?
 
Exendin-4 and exenatide have identical amino acid sequences. The only difference is that exendin-4 occurs naturally, and exenatide is synthesized by recombinant technology.
 
Return to Top
 
What has been seen in clinical trials with exenatide?
 
Results from the pivotal exenatide phase 3 trials—the AC2993 Diabetes Management for Improving Glucose Outcomes (AMIGO) trials—have recently been reported. In a randomized, triple-blind, placebo-controlled 30-week trial evaluating the effects of exenatide on glycemic control in patients inadequately controlled with maximally effective doses of metformin (N=336 [intent-to-treat population]), A1C changes from baseline at week 30 were –0.86%, –0.46%, and 0% for those receiving 10 mcg exenatide, 5 mcg exenatide, and placebo, respectively (P<0.01).8 Of evaluable subjects, 46% (10 mcg), 32% (5 mcg), and 13% (placebo) of those with a baseline A1C of >7% achieved an A1C of <7% by week 30 (P<0.01). Both fasting and postprandial plasma glucose levels decreased with exenatide versus placebo (P<0.05), and β-cell secretory function as assessed by HOMA-B increased with exenatide versus placebo (P<0.01). Exenatide was associated with dose-dependent and progressive weight loss and with significant end-of-study reductions versus baseline (P<0.05). The most frequently reported adverse events were generally mild to moderate and gastrointestinal in nature, and there was no incidence of severe hypoglycemia.

In a randomized, triple-blind, placebo-controlled, 30-week trial evaluating the effects of exenatide on glycemic control in patients inadequately controlled with maximally effective doses of a sulfonylurea (N=377 [intent-to-treat population]), A1C changes from baseline at week 30 were –0.86%, –0.46%, and +0.12% for those receiving 10 mcg exenatide, 5 mcg exenatide, and placebo, respectively (P<0.01).8 Among evaluable subjects with baseline A1C >9%, there was a 1.22% drop in A1C with exenatide 10 mcg; for those patients with baseline A1C <9%, the reduction was 0.65%. Both fasting and postprandial plasma glucose levels decreased with exenatide versus placebo (P<0.05). Exenatide was associated with dose-dependent and progressive weight loss and with significant end-of-study reductions versus baseline (P<0.05). The most frequently reported adverse events were generally mild to moderate and gastrointestinal in nature, and there was no incidence of severe hypoglycemia.

In another triple-blind, placebo-controlled study, 30 weeks of exenatide therapy was evaluated in patients with type 2 diabetes receiving maximal doses of metformin and a sulfonylurea (N=733
[intent-to-treat population]).9 End-of-study A1C changes from baseline were –0.77% (10 mcg exenatide), –0.55% (5 mcg exenatide), and +0.23% (placebo; P<0.001 vs placebo). Mean placebo-adjusted A1C reductions were –1.0% and –0.8% for those receiving 10 and 5 mcg exenatide, respectively. A1Cs of <7% were achieved by 30%, 24%, and 7% of those receiving 10 or 5 mcg exenatide or placebo, respectively (P<0.001). At week 30, both exenatide arms had significant weight loss from baseline (–1.6 kg in each exenatide arm vs –0.9 kg with placebo; P<0.01 vs placebo). Mild-to-moderate nausea was the most common adverse event. There was one episode of severe hypoglycemia in the 5-mcg exenatide group. Mild-to-moderate hypoglycemia was seen in 28%
(10 mcg), 19% (5 mcg), and 13% (placebo) of subjects, and appeared to be lower in those receiving
a minimum recommended versus maximally effective dose of sulfonylurea.

Return to Top
 
What has been seen in terms of direct effects on the β cells with exendin-4?
 
In a partial pancreatectomy rat model of type 2 diabetes, daily exendin-4 administration for 10 days postsurgery attenuated the development of diabetes by stimulating pancreatic regeneration and β-cell mass expansion via neogenesis (stimulation of β-cell differentiation from the ductal progenitor cells) and proliferation (enhanced replication of β cells).6 In this study, β-cell mass increased 40% with exendin-4 administration versus placebo (P<0.05). The authors concluded that GLP-1 and related compounds hold promise as novel therapies to enhance β-cell growth and differentiation when administered to patients with type 2 diabetes. This is important, as there are currently no therapeutic options that are known to benefit the structural integrity of the pancreatic β cells consistently. Farilla and associates7 isolated β cells from live human donors and observed that the percentage of apoptotic nuclei, and therefore the rate of programmed cell death, was reduced after processing with rHu +
GLP-1.7
 
Return to Top
 
What is liraglutide (NN2211)?
 
Liraglutide is an incretin analogue that is a fatty-acid–linked derivative of GLP-1. Its pharmacokinetic profile is compatible with once-daily injections.2 Liraglutide has not yet been approved for clinical use by the FDA.
 
Return to Top
 
What has been seen in clinical trials with liraglutide (NN2211)?
 
In one clinical study, a single 10-mcg/kg injection of liraglutide at 11:00 PM was shown to significantly reduce fasting glycemia and postprandial glycemia in patients with diabetes.13 Inhibition of gastric emptying and reductions in postprandial glucagon were also observed.

In another study designed to establish the dose-response relationship to glycemic control,
192 patients with type 2 diabetes received liraglutide for 12 weeks.11 Liraglutide administration
was associated with improved glycemic control versus placebo (at the 60- and 75-mg doses, the improvement was comparable to that seen with glimepiride), even in fairly well-controlled subjects. Weight was maintained, with a trend toward a decline. Gastrointestinal side effects (mainly mild
and transient) were seen. The risk of hypoglycemia was “very low.”
 
Return to Top
 
What is vildagliptin (LAF237)?
 
Vildagliptin is a DPP-IV inhibitor that prolongs the activity of endogenous GLP-1. It is suited to
once-daily oral administration. Vildagliptin has not yet been approved for clinical use by the FDA.
 
Return to Top
 
What has been seen in clinical trials with vildagliptin (LAF237)?
 
A recently reported study investigated the effects of 50 mg once-daily vildagliptin (n=42) or placebo (n=29) administered for 52 weeks in patients with type 2 diabetes maintaining a stable dose of metformin.14 The between-group difference in adjusted mean change in A1C at week 52 was –1.1% in favor of vildagliptin (P<0.0001). Treatment was generally well tolerated, with 76.2% and 89.7% of vildagliptin- and placebo-treated patients completing the study, respectively. Over the study period, body weight decreased by 0.2 kg in both groups.
 
Return to Top
 
How far into development are these agents?
 
Phase 2 trials have been completed for liraglutide and vildagliptin.
 
Return to Top
 
Are there any other GLP-1–based compounds in development?
 
Other GLP-1–related compounds in earlier stages of development include AVE0010 (formerly ZP10), AC2993 LAR (a long-acting form of exenatide), and the DPP-IV inhibitors saxagliptin and sitagliptin. None of these agents has been approved for clinical use by the FDA.
 
Return to Top
 

REFERENCES

1. Drucker DJ. Glucagon-like peptides. Diabetes. 1998;47(2):159-169.
2. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26(10):2929-2940.
3. Perfetti R, Merkel P. Glucagon-like peptide-1: a major regulator of pancreatic β-cell function. Eur J Endocrinol. 2000;143(6):717-725.
4. Gotfredsen CF, Larsen MO, Knudsen LB. Effects of NN2211, a long acting derivative of
   GLP-1, on β-cell proliferation and β-cell mass in db/db mice [abstract]. Diabetes. 2001;
   50(suppl 2):A31. Abstract 126-OR.
5. Sturis J, Jappe MB, Knudsen LB, et al. The long-acting GLP-1 derivative NN2211 markedly slows the development of diabetes in the male Zucker diabetic fatty rat [abstract]. Diabetes. 2000;49(suppl 1):A228. Abstract 943-P.
6. Xu G, Stoffers DA, Habener JF, Bonner-Weir S. Exendin-4 stimulates both β-cell replication and neogenesis, resulting in increased β-cell mass and improved glucose tolerance in diabetic rats. Diabetes. 1999;48(12):2270-2276.
7. Farilla L, Bulotta A, Hirshberg B, et al. Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology. 2003;
   144(12):5149-5158.
8. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131):837-853.
9. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28(5):1092-1100.
10. Kendall DM, Riddle MC, Rosenstock J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care. 2005;28(5):1083-1091.
11. Madsbad S, Schmitz O, Ranstam J, Jakobsen G, Matthews DR, for the NN2211-1310 International Study Group. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211): a 12-week, double-blind, randomized, controlled trial. Diabetes Care. 2004;27(6):1335-1342.
12. Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002;359(9309):824-830.
13. Juhl CB, Hollingdal M, Sturis J, et al. Bedtime administration of NN2211, a long-acting GLP-1 derivative, substantially reduces fasting and postprandial glycemia in type 2 diabetes. Diabetes. 2002;51(2):424-429.
14. Ahren B, Gomis R, Standl E, Mills D, Schweizer A. Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes. Diabetes Care. 2004;27(12):2874-2880.
    Return to Top