The most common side effect or adverse event associated with GLP-1 therapy is nausea, and occasionally vomiting. For the majority of subjects, the extent of nausea generally diminishes over time, and most subjects do not report ongoing nausea after several months of therapy with a GLP-1R agonist. Diarrhea has also been reported in subjects taking GLP-1R agonists. Other reported AEs may include hypoglycemia, particularly if GLP-1 is used together with an insulin secretagogue, such as a sulfonylurea. Injection site reactions, including itching and skin rashes have also been described. Less commonly, allergic reactions have been reported. On November 2 2009, the FDA issued a Press Release in conjunction with updated safety information regarding possible associations between use of exenatide and altered renal function in patients treated with Exenatide.

                                                     Thyroid C cells and calcitonin

Preclinical studies demonstrate that rodent, specifically mouse and rat thyroid calcitonin-producing C cells express a functional GLP-1 receptor. Indeed several studies employing rodent C cell lines demonstrate that GLP-1R activation in vitro leads to rapid stimulation of calcitonin secretion, actions that are attenuated by blocking the GLP-1 receptor with the antagonist exendin(9-39) Effects of glucagon and glucagon-like peptide-1-(7-36) amide on C cells from rat thyroid and medullary thyroid carcinoma CA-77 cell line Endocrinology. 1996 Sep;137(9):3674-80 Effects of glucagon and glucagon-like peptide-1-(7-36) amide on C cells from rat thyroid and medullary thyroid carcinoma CA-77 cell line.

and Expression of glucagon-like peptide 1 receptor in a murine C cell line: regulation of calcitonin gene by glucagon-like peptide 1 FEBS Lett. 1996 Sep 16;393(2-3):248-52. In contrast, functional GLP-1 receptors coupled to calcitonin secretion have not been detected in human C cell lines.

The role and importance of GLP-1 receptor activity in rodent C cells is likely related to the gut-bone axis and control of bone resorption. In rodents, and to some extent in humans many gastrointestinal peptides inhibit bone resorption in the postprandial state Potential role of pancreatic and enteric hormones in regulating bone turnover. J Bone Miner Res. 2005 Sep;20(9):1497-506. Indeed administration of the GLP-1R agonist exendin-4 increases calcitonin gene expression in WT mice, whereas Glp1r-/- mice exhibit increased bone resorption and reduced calcitonin expression in the thyroid The murine glucagon-like peptide-1 receptor is essential for control of bone resorption Endocrinology. 2008 Feb;149(2):574-9. Nevertheless, in contrast to the biology in rodents, GIP or GLP-1 do not inhibit bone resorption in human subjects whereas the related peptide GLP-2 is a potent inhibitor of bone resorption Role of gastrointestinal hormones in postprandial reduction of bone resorption J Bone Miner Res. 2003 Dec;18(12):2180-9.

Continuous activation of the GLP-1 receptor in rats and to a lesser extent in mice produces C-cell hyperplasia, periodically associated, after sustained administration, with the subsequent development of medullary thyroid cancer. Moreover, acute administration of any GLP-1R agonist produces a rapid increase in plasma calcitonin levels in rodents. In contrast, studies with monkeys demonstrate a) no increase in plasma calcitonin levels and b) no C-cell hyperplasia and c) no MTC despite continuous prolonged GLP-1R agonist administration. Similarly, administration of liraglutide once daily to thousands of human subjects with diabetes or obesity did not result in significant increases in plasma calcitonin over time. Taken together, the available data demonstrate a major species-specific difference in the biology of GLP-1 receptor activity in the rodent vs primate thyroid gland. See Glucagon-like peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation Endocrinology 2010 in press

          

                                                                    Pancreatitis

Adverse event reporting has also raised an association between use of Exenatide and pancreatititis, an inflammation of the pancreas that can, in rare cases be quite severe, and even fatal. There is very limited information about the true incidence of pancreatitis in patients with diabetes. A retrospective claims database analysis from Amylin Pharmaceuticals Inc suggested that patients with diabetes have a 2.8-fold greater risk of developing pancreatitis and a 1.9-fold greater risk of developing biliary tract disease; the relative risk for pancreatitis was highest in younger patients les than 45 years of age- See Increased Risk of Acute Pancreatitis and Biliary Disease Observed in Patients with Type 2 Diabetes: a Retrospective, Cohort Study Diabetes Care 2009 in press

Analysis of the biological activity of exendin-4 in guinea pig pancreatic exocrine slices revealed that exendin-4 stimulates cyclic AMP release through incompletely characterized mechanisms as outlined in Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem. 1992 Apr 15;267(11):7402-5. Subsequent experiments revealed that although exendin-4 alone did not stimulate amylase release, exendin-4 potentiated amylase release induced by CCK, carbamylcholine, bombesin or a calcium ionophore, A23187 Exendin-4, a new peptide from Heloderma suspectum venom, potentiates cholecystokinin-induced amylase release from rat pancreatic acini. Regul Pept. 1992 Sep 22;41(2):149-56. These interactions of exendin-4 with pancreatic acinar cells are also seen with native GLP-1, which increased cyclic AMP release in comparable studies, actions which were blocked by the GLP-1R antagonist exendin(9-39); similarly, binding sites for both exendin-4 and GLP-1 were detected in experiments using radiolabelled peptides and guinea pig pancreatic acinar cells Truncated glucagon-like peptide-1 interacts with exendin receptors on dispersed acini from guinea pig pancreas. Identification of a mammalian analogue of the reptilian peptide exendin-4. J Biol Chem. 1992 Oct 25;267(30):21432-7. and Use of 125I-[Y39]exendin-4 to characterize exendin receptors on dispersed pancreatic acini and gastric chief cells from guinea pig. Regul Pept. 1994 Aug 31;53(1):47-59

There is very little information available about the possible effects of GLP-1/exendin-4 on the gall bladder or biliary tract. Preclinical studies in rats demonstrate that GLP-1/exendin-4 stimulates cholangiocyte growth, and that proliferating cholangiocytes may be capable of actually synthesizing GLP-1 Glucagon-like peptide-1 and its receptor agonist exendin-4 modulate cholangiocyte adaptive response to cholestasis. Gastroenterology. 2007 Jul;133(1):244-55. Subsequent studies demonstrated that exendin-4 is also capable of exerting anti-apoptotic effects on rat cholangiocytes cultured in vitro, and in a bile duct ligation/toxin (Ccl4)-induced model of cholangiocyte apoptosis in vivo Exendin-4, a Glucagon-Like Peptide 1 receptor agonist, protects cholangiocytes from apoptosis. Gut. 2008 Oct 1. [Epub ahead of print]

Case reports of pancreatitis have been described, and the FDA has provided updates through correspondence in the literature and periodic safety alerts, as outlined in FDA NEJM Pancreatitis and Information for healthcare professionals about Exenatide and pancreatitis . To review the May 2007 AGA criteria for diagnosis and management of acute pancreatitis, see AGA Institute medical position statement on acute pancreatitis. Analysis of hospitalized patients diagnosed with pancreatitis in a large health insurance data base was carried out using data assessed from June 2005-2008. Patients were analyzed by the type of anti-diabetic therapy they were using, with a specific focus on patients taking exenatide vs sitagliptin. Acute pancreatitis ocurred in 0.13% and 0.12% of patients taking exenatide vs. sitagliptin, respectively, rates comparable to patients on metformin/glyburide as outlined in Use of a claims-based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide  Curr Med Res Opin. 2009 Apr;25(4):1019-27.

The prescribing information for Exenatide was revised on October 30 2009 to include new language and advice surrounding pancreatitis:

....Acute Pancreatitis: Based on postmarketing data BYETTA has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. After initiation of BYETTA, and after dose increases, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting). If pancreatitis is suspected, BYETTA should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, BYETTA should not be restarted. Consider antidiabetic therapies other than BYETTA in patients with a history of pancreatitis.

The putative mechanism through which GLP-1R agonists may act on the exocrine pancreas remains uncertain, and pancreatitis has not been commonly described in hundreds of preclinical studies of GLP-1R agonists or DPP-4 inhibitors. Infusion of GLP-1 inhibits pancreatic exocrine secretions in short term studies of normal human subjects Truncated GLP-1 (proglucagon 78-107-amide) inhibits gastric and pancreatic functions in man. Dig Dis Sci. 1993 Apr;38(4):665-73. These effects are likely indirect, due to the effects of GLP-1 on reduction of gastric emptying, and hence reduced transit of food into the small bowel.

Treatment of Sprague Dawley rats with exendin-4 once daily for 75 days produced no changes in amylase, but a 2-fold increase in serum lipase was noted, in associated with histological changes consistent with mild pancreatitis in some acini. Remarkably, the exendin-4-treated rats exhibit a profound reduction in body weight gain, with the control rats starting at ~250 grams and ending up at 600 grams after 9 weeks, whereas rats treated with exendin-4 started at ~240 grams and ended up at ~ 390 grams. No other anti-diabetic agents were included as controls, and no pair-fed controls were studied to assess the effects of marked weight loss alone, a know risk factor for pancreatitis, in the study. The authors stated that "the histological differences observed between controls and exendin-4-treated animals were not very striking". Some exendin-4-treated rats exhibited morphological changes consistent with acinar fibrosis, and focal acinar degeneration and inflammation, as outlined in Biochemical and histological effects of exendin-4 (exenatide) on the rat pancreas Diabetologia. 2009 Sep 13. [Epub ahead of print]. In an accompanying Editorial, Butler and colleagues summarized the available evidence, and based on their interpretation of the available animal data, recommended that therapy with GLP-1 mimetics only be used in conjunction with metformin Glucagon-like peptide-1 therapy and the exocrine pancreas: innocent bystander or friendly fire? Diabetologia. 2009 Nov 6. [Epub ahead of print]. Transgenic over-expression of exendin-4 has also been associated with the development of an immune response against the preproexendin-4 transgene but not exendin-4 alone in mice, in association with tissue infiltrates involving multiple organs, including the, heart, liver, kidney and pancreas Lymphocytic infiltration and immune activation in metallothionein promoter-exendin-4 (MT-Exendin) transgenic mice Diabetes. 2006 Jun; 55 (6): 1562-70

The putative relationship between GLP-1 receptor activation, exenatide, sitagliptin and the expression of genes and proteins that modules the risk of pancreatitis was examined in WT and Glp1r-/- mice. WT mice on a regular diet, a high fat diet, or following induction of diabetes with STZ, were treated, for both acute periods, and for several months with different GLP-1R agonists, metformin, or sitagliptin. Although GLP-1 receptor activation with exendin-4(exenatide) or liraglutide regulates gene and protein expression in the exocrine pancreas, GLP-1 receptor activation prior to or following the induction of experimental pancreatitis with the CCK analogue careulein had no effect on the development of experimental pancreatitis. Therapy with GLP-1R agonists actually induced a gene/protein expression program that would be predicted to be protective agaonst the development of pancreatitis. Moreover the molecular, biochemical and histological course and severity of pancreatitis was comparable in Glp1r-/- vs. Glp1r+/+ mice. See GLP-1 receptor activation modulates pancreatitis-associated gene expression but does not modify the susceptibility to experimental pancreatitis in mice Diabetes ; published ahead of print June 9, 2009, doi:10.2337/db09-0626

Matveyenko and colleagues demonstrated adverse effects of sitagliptin on pancreatic histology in HIP-transgenic rats with overexpression of human amylin in the beta cells of transgenic animals. Groups of rats were treated with either sitagliptin alone, metformin, or both drugs together. Significantly increased ductal turnover was observed in non-treated transgenic rats, and sitagliptin increased whereas metformin decreased ductal turnover. Sitagliptin was also associated with increased ductal metaplasia, and one sitagliptin-treated rat developed focal pancreatitis. See Beneficial endocrine but adverse exocrine effects of sitagliptin in the human islet amyloid polypeptide transgenic rat model of type 2 diabetes: interactions with metformin  Diabetes. 2009 Jul;58(7):1604-15.

In a subsequent study Pancreatic duct replication is increased with obesity and type 2 diabetes in humans Diabetologia. 2009 Oct 21. [Epub ahead of print], the same authors studied rates of ductal replication in pancreata from autopsy studies of 45 humans subdivided into 4 groups; lean, obese, non-diabetic, and subjects with type 2 diabetes. Obesity (BMI greater than 27) was associated with a 10-fold increase in the rate of ductal replication as assessed by staining with Ki67. Cytokeratin was used as a marker for ductal cells. Lean subjects with type 2 diabetes exhibited a 4-fold increase in ductal cell replication compared to lean non-diabetic controls. Obese individuals with diabetes did not exhibit a further increase in ductal cell replication. The autopsy series represents a subgroup selected from a previously published analysis of beta cell mass and replication Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes Diabetes. 2003 Jan;52(1):102-10. The authors suggest a note of caution in regard to therapeutic strategies based on incretin action that are used to treat human diabetics as these agents (GLP-1R agonists and DPP-4 inhibitors) have been shown to increase ductal replication in rodents. Intriguingly, a similar analysis of pancreatic ductal turnover in human subjects subjected to one or 2 pancreatic surgeries, who exhibited progressive increases in blood glucose to the frankly diabetic range, did not reveal any increases in pancreatic ductal replication Partial pancreatectomy in adult humans does not provoke beta-cell regeneration Diabetes. 2008 Jan;57(1):142-9. Although the Butler paper Pancreatic duct replication is increased with obesity and type 2 diabetes in humans Diabetologia. 2009 Oct 21. [Epub ahead of print] and Editorial Glucagon-like peptide-1 therapy and the exocrine pancreas: innocent bystander or friendly fire? Diabetologia. 2009 Nov 6. [Epub ahead of print] speculates that GLP-1 may induce chronic pancreatitis leading to enhanced ductal cell replication and an increased risk of pancreatitis, careful quantitative analysis of pancreatic tissue from 43 human subjects with chronic pancreatitis did not reveal any differences in ductal replication between subjects with pancreatitis vs. control subjects without pancreatitis. These authors speculate that the high rates of ductal turnover seen in many rodent studies may not be representative of ductal replication rates in humans. See Figure 6 in Reduced pancreatic volume and beta-cell area in patients with chronic pancreatitis Gastroenterology. 2009 Feb;136(2):513-22.

Koehler and colleagues have directly examined whether GLP-1receptor activation modifies the proliferation or survival of human pancreatic cancer cells that express the endogenous GLP-1 receptor. The effect of Exenatide on human pancreatic cancer cell growth and survival was examined in studies using three different human pancreatic cancer cell lines that express the endogenous GLP-1receptor. Although Exenatidewas able to activate several different signal transduction pathways in these cells, no significant effects of Exenatide were observed on stimulation of cell growth or cell survival in vitro. Furthermore, Exenatide had no effect on cell killing induced by multiple different cytotoxic agents in vitro. Tumor growth was also studied in vivo in mice treated with daily injections of Exenatide following implantation of human pancreatic tumors into nude mice. Exenatide did not stimulate cell proliferation or expansion of tumor mass in vivo. See Activation of Glucagon-Like Peptide-1 Receptor Signaling Does Not Modify the Growth or Apoptosis of Human Pancreatic Cancer Cells Diabetes 2006 55: 1369-1379

 

The following summary of patient safety and limitations of use information is taken from the Exenatide Prescribing information:

Important Limitations of Use

  • BYETTA is not a substitute for insulin. BYETTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
  • The concurrent use of BYETTA with insulin has not been studied and cannot be recommended.
  • BYETTA has not been studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis.

Important Safety Information for BYETTA® (exenatide) injection

Contraindications

  • BYETTA is contraindicated in patients with prior severe hypersensitivity reactions to exenatide or to any of the product components.

Warnings and Precautions

  • Based on postmarketing data BYETTA has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected, BYETTA should be discontinued promptly. BYETTA should not be restarted if pancreatitis is confirmed.
  • The risk of hypoglycemia is increased when BYETTA is used in combination with a sulfonylurea. Clinicians may consider reducing the sulfonylurea dose.
  • There have been postmarketing reports of renal impairment sometimes requiring hemodialysis and kidney transplantation. BYETTA should not be used in patients with severe renal impairment or end-stage renal disease and should be used with caution in patients with renal transplantation. Caution should be applied when initiating BYETTA or escalating the dose of BYETTA in patients with moderate renal failure.
  • Use of BYETTA is not recommended in patients with severe gastrointestinal disease (e.g., gastroparesis).
  • There have been postmarketing reports of hypersensitivity reactions (e.g., anaphylaxis and angioedema). If hypersensitivity reaction occurs, the patient should discontinue BYETTA and other suspect medications and promptly seek medical advice.

Adverse Reactions:

  • The most common (≥5%) adverse reactions occurring more frequently than placebo in clinical trials were nausea, hypoglycemia, vomiting, diarrhea, feeling jittery, dizziness, headache, and dyspepsia. Nausea usually decreases over time.

Drug Interactions

  • There have been postmarketing reports of increased international normalized ratio (INR) sometimes associated with bleeding with concomitant use of warfarin and BYETTA. Monitor INR frequently until stable upon initiation or alteration of BYETTA therapy.

Use in Specific Populations

  • Based on animal data, BYETTA may cause fetal harm. BYETTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
  • Caution should be exercised when BYETTA is administered to a nursing woman.

On Sept 25 2009, the FDA posted the following notice about case reports of pancreatitis in patients treated with sitagliptin.

Sitagliptin (marketed as Januvia and Janumet) - acute pancreatitis

FDA notified healthcare professionals and patients of revisions to the prescribing information for Januvia (sitagliptin) and Janumet (sitagliptin/metformin) to include information on reported cases of acute pancreatitis in patients using these products. Eighty-eight post-marketing cases of acute pancreatitis, including two cases of hemorrhagic or necrotizing pancreatitis in patients using sitagliptin, were reported to the Agency between October 2006 and February 2009. It is recommended that healthcare professionals monitor patients carefully for the development of pancreatitis after initiation or dose increases of sitagliptin or sitagliptin/metformin. Sitagliptin has not been studied in patients with a history of pancreatitis. Therefore, it is not known whether these patients are at an increased risk for developing pancreatitis and the medication should be used with caution and with appropriate monitoring in patients with a history of pancreatitis. Considerations for healthcare professionals, information for patients, and a Data Summary are provided.