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Diabetes Management Adverse Effects Gastrointestinal Adverse Reactions


Gastrointestinal adverse reactions to lixisenatide were frequently observed in clinical trials. Nausea was the most frequent event – the incidence ranged from 20 % to 40 % in the lixisenatide arm compared with 4–5 % in the placebo arm24, 26–29 and dose-dependent.


– but it was transient


Other reported gastrointestinal reactions included vomiting, diarrhoea, constipation, dyspepsia, abdominal distension and abdominal pain.11


(10.4 % and 13.3 %) and vomiting (10.1 % and 13.3 %) in the lixisenatide and exenatide groups, respectively, were also similar.29


Hypoglycaemia


Symptomatic hypoglycaemia has been reported with lixisenatide as monotherapy27 insulin.28


and in combination with other diabetes agents24 and/or


No case of severe hypoglycaemia has been reported.24,28,29 Symptomatic hypoglycaemia was reported in more patients on lixisenatide 20 µg once daily added to basal insulin and/or sulfonylurea (42.9 %) than in patients on placebo (23.6 %).28


The rate of symptomatic hypoglycaemia in the lixisenatide group was reduced if patients taking a sulfonylurea were excluded (lixisenatide 31.8 %; placebo 28.3 %).28


The risk of symptomatic hypoglycaemia


was not significantly increased with lixisenatide 20 µg once daily as an add-on to sulfonylurea with or without metformin compared to placebo at week 24.30


In the GetGoal-X study, patients taking


lixisenatide had six-fold fewer hypoglycaemic events and three-fold fewer instances of symptomatic hypoglycaemia (2.5 %) than patients taking exenatide (7.9 %) [p<0.05].29


Antibodies to Lixisenatide


It is postulated that antibody formation may decrease the effect of GLP-1 agonists on glucose control.11


however,


no differences were observed in the efficacy and safety profile of lixisenatide when given to patients with or without antibodies.24


Other Reported Adverse Effects


Reported rates of dizziness and headache with lixisenatide are similar to those reported in placebo groups.24


30 µg once daily experienced loss of consciousness of a few seconds’


1. Centers for Disease Control and Prevention, National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011; Atlanta, GA, Department of Health and Human Services.


2. Shaw J, Sicree R, Zimmet P, Global estimates of the prevalence of diabetes for 2010 and 2030, Diabetes Res Clin Pract, 2010;87:4–14.


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;32:193–203.


4. Rodbard HW, Blonde L, Braithwaite SS, et al., American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus, Endocr Pract, 2007;13(Suppl. 1):1–68.


5. Garber AJ, Long-acting glucagon-like peptide 1 receptor agonists: a review of their efficacy and tolerability,


One patient taking lixisenatide The rate of antibody formation in


patients treated with lixisenatide ranged from 43.1 % with lixisenatide 10 µg once daily to 71.2 % with lixisenatide 20 µg twice daily;24


Lixisenatide has not been compared with liraglutide, the other once-daily GLP-1 agonist. Because liraglutide has a substantially longer half-life, it may reduce fasting plasma glucose more effectively than lixisenatide; however, potential slowing of gastric emptying with lixisenatide may result in greater improvements in post-prandial glucose levels. Additional clinical trials are required to confirm this. Data from further clinical trials and post-approval clinical experience will help clinicians decide how well lixisenatide compares with the other GLP-1 agonists. n


Diabetes Care, 2011;34(Suppl. 2):S279–84.


6. Drucker DJ, Nauck MA, The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes, Lancet, 2006;368:1696–705.


7. Pratley RE, Overview of glucagon-like peptide-1 analogs and dipeptidyl peptidase-4 inhibitors for type 2 diabetes, Medscape J Med, 2008;10:171.


8. Zealand Pharma A/S, Lixisenatide (Lyxumia®). Available at: www.zealandpharma.com/Pipeline/Lixisenatide_(Lyxumia) (accessed 25 December 2011).


9. Werner U, Haschke G, Herling AW, Kramer W, Pharmacological profile of lixisenatide: a new GLP-1 receptor agonist for the treatment of type 2 diabetes, Regul Pept, 2010;164:58–64.


10. Christensen M, Knop FK, Vilsboll T, Holst JJ, Lixisenatide for type 2 diabetes mellitus, Expert Opin Investig Drugs, 2011; 20:549–57.


11. Christensen M, Knop FK, Holst JJ, Vilsboll T, Lixisenatide, a novel GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus, IDrugs, 2009;12:503–13.


12. Thorkildsen C, Neve S, Larsen BD, et al., Glucagon-like peptide 1 receptor agonist ZP10A increases insulin mRNA expression and prevents diabetic progression in db/db mice, J Pharmacol Exp Ther, 2003;307:490–6.


13. Werner U, Preclinical pharmacology of the new GLP-1 receptor agonist AVE0010, Ann Endocrinol (Paris), 2008;69:164–5.


14. Becker R, Ruus P, Liu Y, Kapitza C, Restoration of insulin release with lixisenatide in patients with type 2 diabetes [abstract], Diabetologia, 2010;53(Suppl. 1):S339.


15. Liu Y-H, Ruus P, Effect of the GLP-1 agonist AVE0010 on absorption of concomitant oral drugs, Diabetes, 2009; 58(Suppl. 1). Available at:


http://professional.diabetes.org/Abstracts_Display.aspx?TYP =1&CID=73257 (accessed 19 December 2011).


16. Tews D, Werner U, Eckel J, Enhanced protection against cytokine- and fatty acid-induced apoptosis in pancreatic beta cells by combined treatment with glucagon-like peptide-1 receptor agonists and insulin analogues, Horm Metab Res, 2008;40:172–80.


17. Haschke G, Haag-Diegarten S, Werner U, et al., The GLP-1 duration, which led to withdrawal from the study.24 One patient taking


lixisenatide 10 µg once daily discontinued the medication three weeks into the study following two separate allergic reactions 10 minutes after receiving the drug; on the first occasion, the patient developed pruritus, and three days later the patient had swollen lips and tongue and difficulty breathing. The events were resolved with an oral antihistamine.24


Two cases of urticaria occurred with lixisenatide (compared to three with placebo).24


In the GetGoal-X study, nausea was experienced less frequently with lixisenatide 20 µg once daily (24.5%) than with exenatide 10 µg twice daily (35.1 %) [p<0.05].29


Incidences of diarrhoea


Potential Role of Lixisenatide Among Glucagon-like Peptide-1 Receptor Agonist Medications


Exenatide, the first incretin-based therapy, was launched in 2005. The novel mechanisms of action of GLP-1 agonists and their multiple associated benefits make them desirable options for the treatment of type 2 diabetes. The second incretin-based therapy to be approved, liraglutide, overcame some of the disadvantages of exenatide, including the need for multiple daily injections timed with meals and a relatively high incidence of nausea. Once-weekly exenatide (Bydureon®; Amylin Pharmaceuticals, Inc., Lilly USA, LLC, and Alkermes, Inc.) has been approved for use in Europe and is currently under review by the US Food and Drug Administration. Once-weekly administration will appeal to many patients, although the delivery system may not be as simple or as comfortable as those of the shorter-acting medications in this class. Medical providers will be able to offer patients the choice between the convenience of the once-weekly injection and the simplicity of the once-daily devices.


Review of the available data suggests that lixisenatide will be effective as a once-daily GLP-1 receptor agonist. Although it has a short half-life, similar to that of exenatide, its biological effects appear prolonged, perhaps due its higher affinity to the GLP-1 receptor. Once-daily administration of lixisenatide and twice-daily


administration of exenatide achieved similar lowering of HbA1C levels in the GetGoal-X study.29


16


EUROPEAN ENDOCRINOLOGY


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