Hiroshi Yamamoto, Charlotte E. Lee, Jacob N. Marcus, Todd D. Williams, J. Michael Overton, Marisol E. Lopez, Anthony N. Hollenberg, Laurie Baggio, Clifford B. Saper, Daniel J. Drucker, Joel K. Elmquist
Submitter: Andrew A Young | firstname.lastname@example.org
Amylin Pharmaceuticals Inc., 9373 Towne Centre Drive, San Diego, CA 92121
Published July 4, 2002
Yamamoto et al. have elegantly shown an effect of exendin-4 to elevate blood pressure and heart rate in conscious rats investigated using telemetry. These results are consistent with previous work in anesthetized rats (2,3) and concur with telemetry data we reported in rats (14). Since it could be blocked with exendin[9-39], Yamamoto et al. interpret the effect as being mediated via GLP-1 receptors. The important clinical question raised here by Yamamoto et al., and previously by others (3) is whether chronic administration of long-lasting GLP-1 agonists (as currently being developed for humans with metabolic disease) will elevate blood pressure. The answer to this question, especially relevant in those with pre-existing hypertension, is vexing since cardiodynamic responses reported for exendin-4 and GLP-1 are highly species specific. While increases in blood pressure are observed in rats (2,3,14) and rabbits, no effects are observed in mice, dogs (10), conscious calves (5) or monkeys (13), diminishing the confidence with which animal studies, such as the present one, can be used to predict responses in man. Therefore, acute toxicological studies designed to elicit potential cardiodynamic effects of exendin-4 were performed in non-human primates, and were shown to not affect ECG, arterial pressure or heart rate at doses up to 10,000x those proposed for antidiabetic therapy (11). In humans, acute GLP-1 administration has been reported to elevate blood pressure in association with the stress of reactive hypoglycemia (6), but did not otherwise elevate blood pressure (12). When infused continuously for 6 weeks in type 2 diabetic subjects, antidiabetic doses of GLP-1 did not elevate blood pressure (15). Similarly, when synthetic exendin-4 (AC2993) was administered acutely to non-diabetic human subjects (9) or to type 2 diabetic subjects (1,8) over a 30-fold dose range, it did not change blood pressure. Neither did it change blood pressure during administration for 5 days (4) or 28 days (7) in patients with type 2 diabetes. It thus appears that a pressor effect of exendin-4 described by Yamamoto et al. in rats does not predict a hypertensive effect in man and several other species, but instead highlights the risk in inferring drug effects across species.
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6. Edwards CMB, Todd JF, Ghatei MA, Bloom SR. Subcutaneous glucagon-like peptide-I (7-36) amide is insulinotropic and can cause hypoglycaemia in fasted healthy subjects. Clin Sci 1998;95(6):719-24.
7. Fineman M, Bicsak T, Shen L, Gaines E, Varns A, Baron A. AC2993 (synthetic exendin-4) improved glycemic control in patients with type 2 diabetes during 28 days of treatment in a multicenter, randomized, triple- blind, placebo-controlled study. ADA, 61st Scientific Sessions, June 22- 26, 2001, Philadelphia, PA 2001; Late-breaking abstract 36.
8. Kolterman O, Fineman M, Gottlieb A, Petrella E, Prickett K, Young A. AC2993 (synthetic exendin-4) lowered postprandial plasma glucose concentrations in people with type 2 diabetes. Diabetologia 1999;42(Suppl 1):A41 (abstract).
9. Kolterman O, Young G, Parker J, Amin D, Prickett K. Stimulation of endogenous insulin secretion by subcutaneous AC2993 (synthetic exendin-4) in healthy overnight fasted volunteers. Diabetes 1999;48(Suppl 1):A199 (abstract).
10. Mistry M, Ehlers MR. Intravenous administration of recombinant glucagon like peptide-1 (rGLP-1) does not affect cardiovascular performance in anesthetized dogs. Program and Abstracts, 82nd Annual Endocrine Meeting 2000;94.
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12. Toft-Nielsen MB, Madsbad S, Holst JJ. Continuous subcutaneous infusion of glucagon-like peptide 1 lowers plasma glucose and reduces appetite in type 2 diabetic patients. Diabetes Care 1999;22(7):1137-43.
13. Young AA, Gedulin BR, Bhavsar S, Bodkin N, Jodka C, Hansen B, Denaro M. Glucose-lowering and insulin-sensitizing actions of exendin-4: studies in obese (ob/ob, db/db) diabetic mice, diabetic Fatty Zucker rats and diabetic rhesus monkeys (Macaca mulatta). Diabetes 1999;48(5):1026-34.
14. Young AA, Vine W, Beeley RA, Prickett K, inventors; Amylin Pharmaceuticals Inc, assignee. Inotropic and diuretic effects of exendin and GLP-1. US International Application 1999; WO 99/40788. 15. Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet 2002;359(9309):824-30.