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ADA/JDRF Type 1 Diabetes Sourcebook, Excerpt #2:Adjunctive Therapies, Part 1 of 3

Anne Peters, MD, and Lori Laffel, MD, MPH, editors
Jane Lee Chiang, MD, managing editor

ADA-JDRF-Type-1-Diabetes-Sourcebook-image

 

Introduction

Jeremy Hodson Pettus, MD, and Steven Edelman, MD

 

The discovery of insulin over 90 years ago remains one of the greatest success stories in the history of medicine.

Although insulin remains the mainstay of therapy for patients with type 1 diabetes (T1D), the greatest deterrents to the use of intensive insulin regimens are hypoglycemia, weight gain, and the need for frequent fine-tuning of insulin doses on a day-to-day basis. Furthermore, despite advances in diabetic technologies and new insulin formulations, the majority of T1D patients do not reach an A1C of less than 7%, putting them at higher risk for developing diabetic complications over time. There exists a very real need to explore other therapeutic agents that may assist T1D patients to reach therapeutic goals, reduce hypoglycemia, minimize glucose variability, and offset weight gain. While we have seen an explosion of therapeutic agents available for type 2 diabetes (T2D), only one other medication, pramlintide, has been approved by the FDA (Food and Drug Administration) for use in T1D. In this chapter we will review the use of pramlintide in T1D as well as discuss other medications that may have clinical benefits in T1D….
AMYLIN, THE HORMONE 

Amylin is a 37 amino acid β-cell hormone that is packaged together and cosecreted with insulin during times of nutrient intake. In healthy individuals, amylin is secreted in a similar manner to insulin, whereby low baseline plasma concentrations are followed by surges at mealtimes (see Figure 13.1).1–5 However, in T1D, there is an absolute deficiency in amylin. Experiments in rodents have demonstrated that amylin exerts its effects as a neuroendocrine hormone, activating specific amylin receptors in the area postrema and nucleus accumbens, components of the central nervous system.6 Via this central binding, amylin acts to slow the appearance of glucose in the circulation through three different mechanisms: glucagon suppression, slowing of gastric emptying, and promotion of early satiety.7–12 Together, these actions complement insulin’s effects on postprandial glucose regulation, help to reduce glycemic fluctuations, and maintain glucose homeostasis (see Figure 13.2).13

PRAMLINTIDE 

Pramlintide aggregates into amyloid when injected subcutaneously, making the physiological hormone itself unsuitable for therapeutic use. Pramlintide, an amylin analogue, was therefore developed as a pharmaceutical agent via manipulation of three of the amino acids, allowing the hormone to be injected subcutaneously and exert its physiological effects without aggregating. Peak concentrations of pramlintide are achieved 20 min after the injection, regardless of the dose. Pramlintide has a half-life of approximately 50 min, and is cleared by the kidneys.

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Figure 13.1 (a) Amylin is colocated and cosecreted with insulin and T1D patients have an absolute deficiency of amylin. Source: Original work: (a) Koda JE, Fineman MS, Kolterman OG, et al.: 24 hour plasma amylin profiles are elevated in IGT subjects vs. normal controls [abstract 876]. Diabetes 44 (Suppl. 1):A238, 1995. (b) Fineman MS, Giotta MP, Thompson RG, et al.: Amylin response following Sustacal ingestion is diminished in type II diabetic patients treated with insulin. Diabetologia 39 (Suppl.1):A149, 1996. Taken from: Kruger DF, Gatcomb PM, Owen SK: Clinical implications of amylin and amylin deficiency. Diabetes Educ 25:389–397; quiz 398, 1999. Reprinted with permission from the publisher.

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Slowing of Gastric Emptying 

In healthy individuals, pramlintide acts via the vagus nerve to modulate the rate of gastric emptying. Slowing of gastric emptying acts to modulate the inflow of nutrients to the small intestine, which in turn aids in reducing the postprandial rise in glucose. The rate of gastric emptying is accelerated in patients with T1D, with increases in postprandial glucose directly proportional to the rate of gastric emptying.14 When pramlintide is administered, the rate of gastric emptying is slowed or normalized and postprandial hyperglycemia is mitigated. Studies in patients with T1D have found that pramlintide prolonged the half-gastric emptying time of meals by 60 to 90 min without influencing emptying rates of subsequent meals.15,16

Postprandial Glucagon Suppression

Glucagon is produced by the α-cells in the islets of the pancreas and acts to increase glucose production in the liver. It has a central role in maintaining appropriate levels of glucose in the circulation during times of fasting and is normally suppressed during and after meals. Patients with T1D not only fail to suppress glucagon in the postprandial period but often have a paradoxical increase in glucagon release. Pramlintide administration inhibits this inappropriate increase in postprandial glucagon, thereby lowering postprandial blood glucose levels.17,18

It is important to note that in the setting of hypoglycemia, glucagon release is not inhibited by pramlintide.19,20

Regulation of Food Intake

Pramlintide has also been shown to promote early satiety via its action on the central nervous system, specifically the area postrema.21 A study specifically designed to assess this effect of pramlintide showed that pramlintide administered as a single preprandial injection increased levels of satiety, leading to reduced food intake.22 In addition, the satiety effect appears to be independent of the nausea that can accompany pramlintide treatment. The effect of early satiety leading to reduced nutrient intake appears to be the mechanism that leads to the weight loss seen in multiple clinical trials as described below.

Postprandial Glucose Control

The collective mechanisms of action of pramlintide described above complement insulin in the postprandial period by slowing the appearance of glucose in the circulation, thereby reducing postprandial hyperglycemia (Figure 13.2). The ability of pramlintide to control postprandial glucose has been evaluated in multiple randomized, placebo-controlled trials. Specifically, when administered prior to a standardized meal, pramlintide was shown to reduce postprandial glucose excursions compared to insulin therapy alone (see Figure 13.3).23

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This effect was seen with both regular and a rapid-acting insulin analog. In a separate study using continuous glucose monitoring, pramlintide therapy led to significantly less glucose variability during the 4 weeks of treatment compared to baseline readings.24 Finally, in both T1D and T2D patients, 6 months of open-label pramlintide reduced postprandial glucose values and resulted in smoother self-monitored glucose profiles when compared to baseline (see Figure 13.4).25–27

Long-Term Placebo-Controlled Trials 

The long-term effects of pramlintide treatment in patients with T2D and T1D were investigated in four separate randomized, placebo-controlled, 52-week trials.28–31 The studies consistently demonstrated that adding pramlintide to existing insulin therapy improved long-term glycemic and weight control. Specifically in T1D, two 52-week trials (n = 480 and n = 651) showed an A1C reduction of –0.39% and –0.34% with pramlintide at 30 or 60 mcg doses 4 times daily, respectively. In patients with T1D who completed 2 years of pramlintide treatment, these A1C reductions were sustained over the treatment period. Furthermore, a statistically significant increase in the number of patients reaching an A1C goal of <7% was reported in both studies. In the initial trial, a three-fold greater proportion of patients achieved this goal, and in the second trial, more than twice the proportion of patients in the pramlintide arm reached an A1C <7%. This improved glycemic profile was achieved while mitigating the usual increase in insulin dose seen over time. Over a 1-year period, insulin dose increased by 2.3% in the pramlintide group and 10.3% in the control arm during one study. Changes in insulin dose were typically in the mealtime insulin rather than basal rates (see Figure 13.5).26,28,31

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Next text: Part 2 – Adjunctive Therapies
  1. Koda JE, Fineman M, Rink TJ, Dailey GE, Muchmore DB, Linarelli LG: Amylin concentrations and glucose control. Lancet 339:1179–1180, 1992
  2. Weyer C, Maggs DG, Young AA, Kolterman OG: Amylin replacement with pramlintide as an adjunct to insulin therapy in type 1 and type 2 diabetes mellitus: a physiological approach toward improved metabolic control. Curr Pharm Des 7:1353–1373, 2001
  3. Kruger DF, Gatcomb PM, Owen SK: Clinical implications of amylin and amylin deficiency. Diabetes Educ 25:389–397; quiz 398, 1999
  4. Koda JE, Fineman MS, Kolterman OG, et al.: 24 hour plasma amylin pro-files are elevated in IGT subjects vs. normal controls [abstract 876]. Diabetes 44 (Suppl. 1):A238, 1995
  5. Fineman MS, Giotta MP, Thompson RG, et al.: Amylin response following Sustacal ingestion is diminished in type II diabetic patients treated with insulin. Diabetologia 39 (Suppl. 1):A149, 1996
  6. Beaumont K, Kenney MA, Young AA, Rink TJ: High affinity amylin binding sites in rat brain. Mol Pharmacol 44:493–497, 1993
  7. Gedulin BR, Rink TJ, Young AA: Dose-response for glucagonostatic effect of amylin in rats. Metabolism 46:67–70, 1997
  8. Silvestre RA, Rodríguez-Gallardo J, Jodka C, Parkes DG, Pittner RA, Young AA, Marco J: Selective amylin inhibition of the glucagon response to argi-nine is extrinsic to the pancreas. Am J Physiol Endocrinol Metab 280:E443– E449, 2001
  9. Young AA, Gedulin B, Vine W, Percy A, Rink TJ: Gastric emptying is accel-erated in diabetic BB rats and is slowed by subcutaneous injections of amy-lin. Diabetologia 38:642–648, 1995
  10. Young AA, Gedulin BR, Rink TJ: Dose-responses for the slowing of gastric emptying in a rodent model by glucagon-like peptide (7-36) NH2, amylin, cholecystokinin, and other possible regulators of nutrient uptake. Metabolism 45:1–3, 1996
  11. Rushing PA, Hagan MM, Seeley RJ, Lutz TA, Woods SC: Amylin: a novel action in the brain to reduce body weight. Endocrinology 141:850–853, 2000
  12. Rushing PA:,Central amylin signaling and the regulation of energy homeo-stasis. Curr Pharm Des 9:819–825, 2003
  13. Edelman SV, Weyer C: Unresolved challenges with insulin therapy in type 1 and type 2 diabetes: potential benefit of replacing amylin, a second beta-cell hormone. Diabetes Technol Ther 4:175–189, 2002
  14. Rayner CK, Samsom M, Jones KL, Horowitz M: Relationships of upper gastrointestinal motor and sensory function with glycemic control. Diabetes Care 24:371–381, 2001
  15. Kong MF, King P, Macdonald IA, Stubbs TA, Perkins AC, Blackshaw PE, Moyses C, Tattersall RB: Infusion of pramlintide, a human amylin analogue, delays gastric emptying in men with IDDM. Diabetologia 40:82–88, 1997
  16. Kong MF, Stubbs TA, King P, Macdonald IA, Lambourne JE, Blackshaw PE, Perkins AC, Tattersall RB: The effect of single doses of pramlintide on gastric emptying of two meals in men with IDDM. Diabetologia 41:577–583, 1998
  17. Fineman M, Weyer C, Maggs DG, Strobel S, Kolterman OG: The human amylin analog, pramlintide, reduces postprandial hyperglucagonemia in patients with type 2 diabetes mellitus. Horm Metab Res 34:504–508, 2002
  18. Fineman MS, Koda JE, Shen LZ, Strobel SA, Maggs DG, Weyer C, Kolt-erman OG: The human amylin analog, pramlintide, corrects postprandial hyperglucagonemia in patients with type 1 diabetes. Metabolism 51:636–641, 2002
  19. Amiel SA, Heller SR, Macdonald IA, Schwartz SL, Klaff LJ, Ruggles JA, Weyer C, Kolterman OG, Maggs DG: The effect of pramlintide on hor-monal, metabolic or symptomatic responses to insulin-induced hypogly-caemia in patients with type 1 diabetes. Diabetes Obes Metab 7:504–516, 2005
  20. Nyholm B, Møller N, Gravholt CH, Orskov L, Mengel A, Bryan G, Moyses C, Alberti KG, Schmitz O: Acute effects of the human amylin analog AC137 on basal and insulin-stimulated euglycemic and hypoglycemic fuel metabo-lism in patients with insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 81:1083–1089, 1996
  21. Potes CS, Turek VF, Cole RL, Vu C, Roland BL, Roth JD, Riediger T, Lutz TA: Noradrenergic neurons of the area postrema mediate amylin’s hypo-phagic action. Am J Physiol Regul Integr Comp Physiol 299:R623–R631, 2010
  22. Chapman I, Parker B, Doran S, Feinle-Bisset C, Wishart J, Strobel S, Wang Y, Burns C, Lush C, Weyer C, Horowitz M: Effect of pramlintide on satiety and food intake in obese subjects and subjects with type 2 diabetes. Diabeto-logia 48:838–848, 2005
  23. Weyer C, Gottlieb A, Kim DD, Lutz K, Schwartz S, Gutierrez M, Wang Y, Ruggles JA, Kolterman OG, Maggs DG: Pramlintide reduces postprandial glucose excursions when added to regular insulin or insulin lispro in subjects with type 1 diabetes: a dose-timing study. Diabetes Care 26:3074–3079, 2003
  24. Levetan C, Want LL, Weyer C, Strobel SA, Crean J, Wang Y, Maggs DG, Kolterman OG, Chandran M, Mudaliar SR, Henry RR: Impact of pram-lintide on glucose fluctuations and postprandial glucose, glucagon, and tri-glyceride excursions among patients with type 1 diabetes intensively treated with insulin pumps. Diabetes Care 26:1–8, 2003
  25. Karl D, Philis-Tsimikas A, Darsow T, Lorenzi G, Kellmeyer T, Lutz K, Wang Y, Frias JP: Pramlintide as an adjunct to insulin in patients with type 2 diabetes in a clinical practice setting reduced A1C, postprandial glucose excursions, and weight. Diabetes Technol Ther 9:191–199, 2007
  26. Edelman SV, Darsow T, Frias JP: Pramlintide in the treatment of diabetes. Int J Clin Pract 60:1647–1653, 2006
  27. Maggs DG, Fineman M, Kornstein J, Burrell T, Schwartz S, Wang Y, Rug-gles JA, Kolterman OG, Weyer C: Pramlintide reduces postprandial glucose excursions when added to insulin lispro in subjects with type 2 diabetes: a dose-timing study. Diabetes Metab Res Rev 20:55–60, 2004
  28. Whitehouse F, Kruger DF, Fineman M, Shen L, Ruggles JA, Maggs DG, Weyer C, Kolterman OG: A randomized study and open-label extension evaluating the long-term efficacy of pramlintide as an adjunct to insulin therapy in type 1 diabetes. Diabetes Care 25:724–730, 2002
  29. Ratner RE, Want LL, Fineman MS, Velte MJ, Ruggles JA, Gottlieb A, Weyer C, Kolterman OG: Adjunctive therapy with the amylin analogue pramlintide leads to a combined improvement in glycemic and weight con-trol in insulin-treated subjects with type 2 diabetes. Diabetes Technol Ther 4:51–61, 2002
  30. Hollander PA, Levy P, Fineman MS, Maggs DG, Shen LZ, Strobel SA, Weyer C, Kolterman OG: Pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in patients with type 2 diabetes: a 1-year randomized controlled trial. Diabetes Care 26:784–790, 2003
  31. Ratner RE, Dickey R, Fineman M, Maggs DG, Shen L, Strobel SA, Weyer C, Kolterman OG: Amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycaemic and weight control in type 1 diabetes mellitus: a 1-year, randomized controlled trial. Diabet Med 21:1204–1212, 2004

Used with permission by the American Diabetes Association. Copyright © 2013 American Diabetes Association.

Please note: We are proud to have Dr. Anne Peters as a member of our Advisory Board member for Diabetes In Control, Inc.

 

T1-diabetes-sourcebookIf you would like to purchase the full text of The Type 1 Diabetes Sourcebook, Anne Peters, MD, and Lori Laffel, MD, MPH, editors, and Jane Lee Chiang, MD, managing editor, just follow this link.