Surgery for Obesity and Related Diseases ] (2013) 00–00
Case report
Treatment of severe postRYGB hyperinsulinemic hypoglycemia with pasireotide: a comparison with octreotide on insulin, glucagon, and GLP-1 Loek J.M. de Heide, M.D.a,*, Anke J. Laskewitz, Ph.D.b, Jan A. Apers, M.D.c a
Department of Internal Medicine, Medical Centre Leeuwarden, Leeuwarden, The Netherlands b Clinical Chemistry, Medical Centre Leeuwarden, Leeuwarden, The Netherlands c Metabolic and Bariatric Surgery, Medical Centre Leeuwarden, Leeuwarden, The Netherlands Received October 29, 2013; accepted November 12, 2013
Keywords:
Pasireotide; Octreotide; Roux-en-Y gastric bypass; Hyperinsulinemic hypoglycemia; GLP-1; Glucagon
Bariatric surgery, especially Roux-en-Y gastric bypass (RYGB), can induce remission of diabetes in 4 80% of morbidly obese type 2 diabetic patients [1]. This effect is not only attributed to the weight loss but also to an improvement of insulin release by the beta-cells of the pancreatic islets under the influence of increased levels of gut hormones, especially glucagon-like peptide-1 (GLP-1) [2]. It is postulated that chronic stimulation by GLP-1 of beta cells after RYGB can lead to hyperplasia of the islets, nesidioblastosis, resulting in postprandial hyperinsulinemic hypoglycemia (PHH) [3]. Of all patients undergoing RYGB, 1%–6% develop some degree of PHH, and .5% have severe neuroglycopenic symptoms [4]. Treatment of patients with severe neuroglycopenic episodes is difficult, often with poor response to frequent low carbohydrate meals and mixed results of the effect of medications such as acarbose, diazoxide, and octreotide. Pasireotide (SOM 230) is a new somatostatin analogue with a high affinity to the somatostatin subclass 1, 2, 3, and 5 receptor [5]. It is known to suppress insulin secretion, frequently leading to diabetes during treatment of patients with Cushing’s disease [6]. Whether pasireotide is able to suppress the exaggerated insulin response to meals in patients with postRYGB hypoglycemia is not yet known. Case report A 50-year-old woman developed frequent hypoglycemic episodes with loss of consciousness, usually 1 hour *
Correspondence: Loek J. M. de Heide, Medical Centre Leeuwarden, Department of Medicine, H. Dunantweg 2, Leeuwarden 8934AD, The Netherlands. E-mail: [email protected]
postprandially, 4 months after laparoscopic RYGB . Selfmeasured blood glucose values below 2.5 mmol/L (45 mg/dL) were documented. A standardized mixed meal tolerance test (MMTT, semi-liquid formula, 500 kcal, 21 gram protein, 17 gram fat, and 69 gram carbohydrates: Ensure Plus) was performed, confirming PHH. During this test. the patient developed blurred vision and slurring of speech after 75 minutes, which she recognized as symptoms resembling earlier periods of hypoglycemia. Glucose excursion showed initial hyperglycemia followed by a hyperinsulinemic response, leading to symptomatic hypoglycemia with a nadir of 2.9 mmol/L 75 minutes after ingestion of the meal. There were no changes in blood pressure, heart rate, or hematocrit, ruling out early dumping as the cause of the symptoms. 18 F-DOPA PET scintigraphy showed a diffuse and increased uptake in the whole pancreas compatible with nesidioblastosis [7] . Despite frequent meals low in carbohydrates and acarbose, the hypoglycemic episodes persisted. Diazoxide was not tolerated. After an overnight fast, the MMTT was repeated 2 hours after the administration of octreotide 100 μg sc. One day later, the next MMTT was performed 2 hours after pasireotide 300 μg sc. Immediately before the challenge, a venous blood sample was obtained (t ¼ 0) followed by consumption of the mixed meal. Venous blood samples were then taken at 10, 20, 30, 45, 60, 75, 90, 120, and 180 minutes after ingestion of the formula for measurement of hemoglobin, glucose, insulin, glucagon, and active GLP-1. Results At the given dose, octreotide caused higher glucose values (maximum 13.3 mmol/L) initially than pasireotide
1550-7289/13/$ – see front matter r 2013 American Society for Metabolic and Bariatric Surgery. All rights reserved. http://dx.doi.org/10.1016/j.soard.2013.11.006
2
Loek J.M. de Heide et al. / Surgery for Obesity and Related Diseases ] (2013) 00–00
Fig. 1. (A) Glucose (A), (B) insulin, (C) glucagon, and (D) active GLP-1 levels during a mixed meal tolerance test after 100 μg octreotide (octerotide) and after 300 μg pasireotide s.c., 2 hours before the test.
(maximum 11.3 mmol/L) (Fig. 1A). However, octreotide pretreatment resulted in less suppression of insulin secretion compared with pasireotide (peak insulin 270 versus 162 mU/L, Fig. 1B), leading to hypoglycemia at the end of the MMTT (nadir glucose 2.0 mmol/L at 180 minutes versus 3.5 mmol/L with pasireotide). Furthermore glucagon levels during the MMTT were much higher after pasireotide (12– 29 ng/L) compared with octreotide (8–15 ng/L) (Fig. 1C). Active GLP-1 levels were higher in the first 45 minutes after pasireotide compared with octreotide, but after 60 minutes, the opposite was true, with much lower active GLP-1 concentrations after pasireotide due to the absence of a second phase GLP-1 secretion (Fig. 1D). After starting pasireotide twice daily s.c., the patient remained free of hypoglycemic episodes and continued to have good glycemic control, with a recent glycated hemoglobin (HbA1c) of 34 mmol/mol. Discussion Pasireotide 300 μg s.c., given 2 hours before a test meal, inhibited insulin and GLP-1 release more efficiently than octreotide 100 μg, resulting in better control of PHH. This may in part be attributable to higher glucagon concentrations after pasireotide treatment. Medical treatment of PHH is often unsuccessful, and there is no definitive treatment
algorithm reported in the literature. Some authors claim success with acarbose, diazoxide, verapamil, or nifedipine. Octreotide has been used with success in a case of PHH for up to 4 years [8]. It is known from animal studies that somatostatin receptors are present on L-cells and that locally produced somatostatin acts as a paracrine inhibitor of GLP-1 release from L-cells in normal physiology [9]. Octreotide also suppresses insulin release from islet beta cells [10]. Pasireotide (SOM 230) is a new somatostatin analogue with high binding affinity to the somatostatin receptor subtypes (SSTR) 1,2,3, and 5 [5]. In a study in healthy volunteers, pasireotide suppressed both insulin release during oral glucose tolerance tests and response of the incretins GLP-1 and glucose-dependent insulinotropic polypeptide GIP [11]. No effect on insulin sensitivity was found. Inhibition of insulin secretion by islet beta cells is mediated by both SSTR2 and SSTR5, and glucagon inhibition from alpha cells is mediated almost entirely by SSTR2 [10]. Pasireotide has much stronger binding affinity to SSTR5 yet slightly weaker affinity to SSTR2 compared with octreotide [5]. Therefore, octreotide can be expected to inhibit both insulin and glucagon secretion from islets, and pasireotide suppresses predominantly only insulin. This was evident in the comparison of the 2 MMTT’s with octreotide and pasireotide (Fig. 1B, 1C).
Pasireotide for Severe PostRYGB Hypoglycemia / Surgery for Obesity and Related Diseases ] (2013) 00–00
Active GLP-1 levels were much lower in the first phase after the MMTT with octreotide compared with pasireotide. The reason for this finding is not known, but it can be speculated that the slowing of gastric emptying caused by octreotide delays the passage of the mixed meal into the ileum leading to a later response of the GLP-1 producing Lcells. Alternatively, second phase GLP-1 secretion is a result of direct stimulation of L-cells by food in the distal ileum and colon and may be more sensitive to suppression by pasireotide than the first phase response, which is presumed to be mediated by the vagal nerve. The suppression of GLP-1 by pasireotide after 45 minutes could very well play an additional role in the lower insulin response compared with octreotide, avoiding severe hypoglycemia. Whether the differences in the response of insulin, glucagon, and GLP-1 are caused by the difference in affinity of the somatostatin-receptor subtypes or because of difference in doses of octreotide and pasireotide used in the study is not known. Initially, a dose of pasireotide comparable with previous studies in Cushing’s disease was used. Lower doses also are possibly effective, but dose finding studies will have to be performed to confirm. Conclusion In conclusion, this case report shows a favorable response in glycemic control of pasireotide compared with octreotide in a MMTT in a patient with PHH. The difference in effect of these somatostatin-analogues can be explained by their effects on insulin, glucagon, and GLP-1 responses to meals. Dose finding studies, currently initiated, and long-term data are necessary before pasireotide can definitely be considered to be a treatment option for PHH. Disclosures The authors have no commercial associations that might be a conflict of interest in relation to this article. Acknowledgments Pasireotide was kindly provided by Novartis Oncology for study purpose and for compassionate use. We are
3
grateful to Mr. O. Anema for technical support in the performance of the MMTTs.
References [1] Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med 2012;366:1577–85. [2] Rabiee A, Magruder JT, Salas-Carrillo R, et al. Hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass: unraveling the roles of gut hormonal and pancreatic endocrine dysfunction. J Surg Res 2011;167:199–205. [3] Servic GJ, Thompson GB, Service FJ, Andrews JC, Collazo-Clavell ML, Lloyd RV. Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. N Engl J Med 2005;353:249–54. [4] Marsk R, Rasmussen JR, Näslund E. Nationwide cohort study of post-gastric bypass hypoglycaemia including 5,040 patients undergoing surgery for obesity in 1986–2006 in Sweden. Diabetologia 2010;53:2307–11. [5] Boerlin V, van der Hoek J, Beglinger Ch, et al. New insights on SOM230, a universal somatostatin receptor ligand. Endocrinol Invest 2003;26(Suppl):14–16. [6] Boscaro M, Ludlam WH, Atkinson B, et al. Treatment of pituitary– dependent Cushing’s disease with the multireceptor ligand somatostatin analog pasioreotide (Som230): a multicenter phase II trial. J Clin Endocrinol Metab 2009;94:115–22. [7] de Heide LJ, Glaudemans AW, Oomen PH, Apers JA, Totté ER, van Beek AP. Functional imaging in hyperinsulinemic hypoglycemia after gastric bypass surgery for morbid obesity. J Clin Endocrinol Metab 2012;97:e963–7. [8] Myint KS, Greenfield JR, Farooqi IS, Henning E, Holst JJ, Finer N. Prolonged successful therapy for hyperinsulinemic hypoglycemia after gastric bypass: the pathophysiological role of GLP1 and its response to a somatostatin analogue. Eur J Endocrinol 2012;166: 951–5. [9] Hansen L, Hartmann B, Bisgaard T, Mineo H, Jørgensen PN, Holst JJ. Somatostatin restrains the secretion of glucagon-like peptide-1 and -2 from isolated perfused porcine ileum. Am J Physiol Endocrinol Metab 2000;280:e1010–8. [10] Singh V, Brendel MD, Zacharias S, et al. Characterization of somatostatin subtype-specific regulation of insulin and glucagon secretion: an in vitro study on isolated human pancreatic islets. J Clin Endocrinol Metab 2007;92:673–80. [11] Henry RR, Mudaliar S, Hermosillo Resendiz K, Ligueros-Saylan M, Chenji S, Golor G. Mechanism and Management of hyperglycemia associated with pasireotide: results from studies in healthy volunteers. J Clin Endocrin Metabol 2013;98:3446–51.
Case report
Treatment of severe postRYGB hyperinsulinemic hypoglycemia with pasireotide: a comparison with octreotide on insulin, glucagon, and GLP-1 Loek J.M. de Heide, M.D.a,*, Anke J. Laskewitz, Ph.D.b, Jan A. Apers, M.D.c a
Department of Internal Medicine, Medical Centre Leeuwarden, Leeuwarden, The Netherlands b Clinical Chemistry, Medical Centre Leeuwarden, Leeuwarden, The Netherlands c Metabolic and Bariatric Surgery, Medical Centre Leeuwarden, Leeuwarden, The Netherlands Received October 29, 2013; accepted November 12, 2013
Keywords:
Pasireotide; Octreotide; Roux-en-Y gastric bypass; Hyperinsulinemic hypoglycemia; GLP-1; Glucagon
Bariatric surgery, especially Roux-en-Y gastric bypass (RYGB), can induce remission of diabetes in 4 80% of morbidly obese type 2 diabetic patients [1]. This effect is not only attributed to the weight loss but also to an improvement of insulin release by the beta-cells of the pancreatic islets under the influence of increased levels of gut hormones, especially glucagon-like peptide-1 (GLP-1) [2]. It is postulated that chronic stimulation by GLP-1 of beta cells after RYGB can lead to hyperplasia of the islets, nesidioblastosis, resulting in postprandial hyperinsulinemic hypoglycemia (PHH) [3]. Of all patients undergoing RYGB, 1%–6% develop some degree of PHH, and .5% have severe neuroglycopenic symptoms [4]. Treatment of patients with severe neuroglycopenic episodes is difficult, often with poor response to frequent low carbohydrate meals and mixed results of the effect of medications such as acarbose, diazoxide, and octreotide. Pasireotide (SOM 230) is a new somatostatin analogue with a high affinity to the somatostatin subclass 1, 2, 3, and 5 receptor [5]. It is known to suppress insulin secretion, frequently leading to diabetes during treatment of patients with Cushing’s disease [6]. Whether pasireotide is able to suppress the exaggerated insulin response to meals in patients with postRYGB hypoglycemia is not yet known. Case report A 50-year-old woman developed frequent hypoglycemic episodes with loss of consciousness, usually 1 hour *
Correspondence: Loek J. M. de Heide, Medical Centre Leeuwarden, Department of Medicine, H. Dunantweg 2, Leeuwarden 8934AD, The Netherlands. E-mail: [email protected]
postprandially, 4 months after laparoscopic RYGB . Selfmeasured blood glucose values below 2.5 mmol/L (45 mg/dL) were documented. A standardized mixed meal tolerance test (MMTT, semi-liquid formula, 500 kcal, 21 gram protein, 17 gram fat, and 69 gram carbohydrates: Ensure Plus) was performed, confirming PHH. During this test. the patient developed blurred vision and slurring of speech after 75 minutes, which she recognized as symptoms resembling earlier periods of hypoglycemia. Glucose excursion showed initial hyperglycemia followed by a hyperinsulinemic response, leading to symptomatic hypoglycemia with a nadir of 2.9 mmol/L 75 minutes after ingestion of the meal. There were no changes in blood pressure, heart rate, or hematocrit, ruling out early dumping as the cause of the symptoms. 18 F-DOPA PET scintigraphy showed a diffuse and increased uptake in the whole pancreas compatible with nesidioblastosis [7] . Despite frequent meals low in carbohydrates and acarbose, the hypoglycemic episodes persisted. Diazoxide was not tolerated. After an overnight fast, the MMTT was repeated 2 hours after the administration of octreotide 100 μg sc. One day later, the next MMTT was performed 2 hours after pasireotide 300 μg sc. Immediately before the challenge, a venous blood sample was obtained (t ¼ 0) followed by consumption of the mixed meal. Venous blood samples were then taken at 10, 20, 30, 45, 60, 75, 90, 120, and 180 minutes after ingestion of the formula for measurement of hemoglobin, glucose, insulin, glucagon, and active GLP-1. Results At the given dose, octreotide caused higher glucose values (maximum 13.3 mmol/L) initially than pasireotide
1550-7289/13/$ – see front matter r 2013 American Society for Metabolic and Bariatric Surgery. All rights reserved. http://dx.doi.org/10.1016/j.soard.2013.11.006
2
Loek J.M. de Heide et al. / Surgery for Obesity and Related Diseases ] (2013) 00–00
Fig. 1. (A) Glucose (A), (B) insulin, (C) glucagon, and (D) active GLP-1 levels during a mixed meal tolerance test after 100 μg octreotide (octerotide) and after 300 μg pasireotide s.c., 2 hours before the test.
(maximum 11.3 mmol/L) (Fig. 1A). However, octreotide pretreatment resulted in less suppression of insulin secretion compared with pasireotide (peak insulin 270 versus 162 mU/L, Fig. 1B), leading to hypoglycemia at the end of the MMTT (nadir glucose 2.0 mmol/L at 180 minutes versus 3.5 mmol/L with pasireotide). Furthermore glucagon levels during the MMTT were much higher after pasireotide (12– 29 ng/L) compared with octreotide (8–15 ng/L) (Fig. 1C). Active GLP-1 levels were higher in the first 45 minutes after pasireotide compared with octreotide, but after 60 minutes, the opposite was true, with much lower active GLP-1 concentrations after pasireotide due to the absence of a second phase GLP-1 secretion (Fig. 1D). After starting pasireotide twice daily s.c., the patient remained free of hypoglycemic episodes and continued to have good glycemic control, with a recent glycated hemoglobin (HbA1c) of 34 mmol/mol. Discussion Pasireotide 300 μg s.c., given 2 hours before a test meal, inhibited insulin and GLP-1 release more efficiently than octreotide 100 μg, resulting in better control of PHH. This may in part be attributable to higher glucagon concentrations after pasireotide treatment. Medical treatment of PHH is often unsuccessful, and there is no definitive treatment
algorithm reported in the literature. Some authors claim success with acarbose, diazoxide, verapamil, or nifedipine. Octreotide has been used with success in a case of PHH for up to 4 years [8]. It is known from animal studies that somatostatin receptors are present on L-cells and that locally produced somatostatin acts as a paracrine inhibitor of GLP-1 release from L-cells in normal physiology [9]. Octreotide also suppresses insulin release from islet beta cells [10]. Pasireotide (SOM 230) is a new somatostatin analogue with high binding affinity to the somatostatin receptor subtypes (SSTR) 1,2,3, and 5 [5]. In a study in healthy volunteers, pasireotide suppressed both insulin release during oral glucose tolerance tests and response of the incretins GLP-1 and glucose-dependent insulinotropic polypeptide GIP [11]. No effect on insulin sensitivity was found. Inhibition of insulin secretion by islet beta cells is mediated by both SSTR2 and SSTR5, and glucagon inhibition from alpha cells is mediated almost entirely by SSTR2 [10]. Pasireotide has much stronger binding affinity to SSTR5 yet slightly weaker affinity to SSTR2 compared with octreotide [5]. Therefore, octreotide can be expected to inhibit both insulin and glucagon secretion from islets, and pasireotide suppresses predominantly only insulin. This was evident in the comparison of the 2 MMTT’s with octreotide and pasireotide (Fig. 1B, 1C).
Pasireotide for Severe PostRYGB Hypoglycemia / Surgery for Obesity and Related Diseases ] (2013) 00–00
Active GLP-1 levels were much lower in the first phase after the MMTT with octreotide compared with pasireotide. The reason for this finding is not known, but it can be speculated that the slowing of gastric emptying caused by octreotide delays the passage of the mixed meal into the ileum leading to a later response of the GLP-1 producing Lcells. Alternatively, second phase GLP-1 secretion is a result of direct stimulation of L-cells by food in the distal ileum and colon and may be more sensitive to suppression by pasireotide than the first phase response, which is presumed to be mediated by the vagal nerve. The suppression of GLP-1 by pasireotide after 45 minutes could very well play an additional role in the lower insulin response compared with octreotide, avoiding severe hypoglycemia. Whether the differences in the response of insulin, glucagon, and GLP-1 are caused by the difference in affinity of the somatostatin-receptor subtypes or because of difference in doses of octreotide and pasireotide used in the study is not known. Initially, a dose of pasireotide comparable with previous studies in Cushing’s disease was used. Lower doses also are possibly effective, but dose finding studies will have to be performed to confirm. Conclusion In conclusion, this case report shows a favorable response in glycemic control of pasireotide compared with octreotide in a MMTT in a patient with PHH. The difference in effect of these somatostatin-analogues can be explained by their effects on insulin, glucagon, and GLP-1 responses to meals. Dose finding studies, currently initiated, and long-term data are necessary before pasireotide can definitely be considered to be a treatment option for PHH. Disclosures The authors have no commercial associations that might be a conflict of interest in relation to this article. Acknowledgments Pasireotide was kindly provided by Novartis Oncology for study purpose and for compassionate use. We are
3
grateful to Mr. O. Anema for technical support in the performance of the MMTTs.
References [1] Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med 2012;366:1577–85. [2] Rabiee A, Magruder JT, Salas-Carrillo R, et al. Hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass: unraveling the roles of gut hormonal and pancreatic endocrine dysfunction. J Surg Res 2011;167:199–205. [3] Servic GJ, Thompson GB, Service FJ, Andrews JC, Collazo-Clavell ML, Lloyd RV. Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. N Engl J Med 2005;353:249–54. [4] Marsk R, Rasmussen JR, Näslund E. Nationwide cohort study of post-gastric bypass hypoglycaemia including 5,040 patients undergoing surgery for obesity in 1986–2006 in Sweden. Diabetologia 2010;53:2307–11. [5] Boerlin V, van der Hoek J, Beglinger Ch, et al. New insights on SOM230, a universal somatostatin receptor ligand. Endocrinol Invest 2003;26(Suppl):14–16. [6] Boscaro M, Ludlam WH, Atkinson B, et al. Treatment of pituitary– dependent Cushing’s disease with the multireceptor ligand somatostatin analog pasioreotide (Som230): a multicenter phase II trial. J Clin Endocrinol Metab 2009;94:115–22. [7] de Heide LJ, Glaudemans AW, Oomen PH, Apers JA, Totté ER, van Beek AP. Functional imaging in hyperinsulinemic hypoglycemia after gastric bypass surgery for morbid obesity. J Clin Endocrinol Metab 2012;97:e963–7. [8] Myint KS, Greenfield JR, Farooqi IS, Henning E, Holst JJ, Finer N. Prolonged successful therapy for hyperinsulinemic hypoglycemia after gastric bypass: the pathophysiological role of GLP1 and its response to a somatostatin analogue. Eur J Endocrinol 2012;166: 951–5. [9] Hansen L, Hartmann B, Bisgaard T, Mineo H, Jørgensen PN, Holst JJ. Somatostatin restrains the secretion of glucagon-like peptide-1 and -2 from isolated perfused porcine ileum. Am J Physiol Endocrinol Metab 2000;280:e1010–8. [10] Singh V, Brendel MD, Zacharias S, et al. Characterization of somatostatin subtype-specific regulation of insulin and glucagon secretion: an in vitro study on isolated human pancreatic islets. J Clin Endocrinol Metab 2007;92:673–80. [11] Henry RR, Mudaliar S, Hermosillo Resendiz K, Ligueros-Saylan M, Chenji S, Golor G. Mechanism and Management of hyperglycemia associated with pasireotide: results from studies in healthy volunteers. J Clin Endocrin Metabol 2013;98:3446–51.
