Tuesday , December 12 2017
Home / Resources / Clinical Gems / ADA/JDRF Type 1 Diabetes Sourcebook, Excerpt #3: Adjunctive Therapies, Part 2 of 3

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

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

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

Jeremy Hodson Pettus, MD, and Steven Edelman, MD

Weight Loss

Weight gain is associated with intensive insulin regimens. During the first year of the DCCT, subjects assigned to intensive insulin therapy gained twice as much weight as those given conventional therapy.12 This increased weight is concerning in diabetes as it can lead to and exacerbate factors such as hypertension and hyperlipidemia that place patients at even higher risk for cardiovascular complications. Fortunately, improved glycemic control in pramlintide-treated patients in long-term, placebo-controlled studies was not accompanied by weight gain, but instead was associated with a sustained and significant reduction in body weight. Following 6 months of pramlintide treatment, patients with T1D lost an average of approximately 1 kg compared with an average gain of 0.6 kg in placebo-treated patients (see Figure 13.5).28,31 Weight reductions were sustained up to 1 year, however, in an open-label extension trial, patients who continued on pramlintide tended to begin to regain weight. Stratification of patients based on baseline body mass index demonstrated that body weight reductions were greatest in patients who were over-weight or obese, and that pramlintide did not change weight in lean patients….

Dose Titration Study

Hypoglycemia was a concern highlighted by the early pivotal trials. This side effect was typically noticed in the initiation of the medication (first 4 weeks) without any proactive reduction in insulin dosing and no titration of the dose, both of which led to an FDA black box warning. To address initiation strategies, a 29-week, placebo-controlled dose titration study was conducted in which pramlintide was initiated at 15 mcg with a 30–50% proactive reduction in meal-time insulin dosing.

DCMS139CG1

Figure 13.5 Effects from combined placebo-controlled trials on A1C, insulin dose, and weight. Source: Taken from: Edelman SV, Darsow T, Frias JP: Pramlintide in the treatment of diabetes. Int J Clin Pract 60:1647–1653, 2006. Reprinted with permission from the publisher.

Pramlintide was then increased to a goal dose of 60 mcg before meals as tolerated with insulin doses adjusted to blood glucose values. Using this strategy, hypoglycemic events during initiation of pramlintide were reduced and not statistically different from placebo. Consistent with previous studies, significant reductions in postprandial glucose, insulin dose, and weight were observed.33

Side Effects

Hypoglycemia. Pramlintide does not cause hypoglycemia when administered alone. However, the addition of an antihyperglycemic agent to a patient’s insulin therapy has the potential to increase the risk of insulin-induced hypoglycemia, particularly at the start of therapy. As mentioned above, hypoglycemia was observed more frequently in the initial trials when insulin doses were not prophylactively reduced and pramlintide was initiated at the highest recommended dose of 60 mcg. It has since been demonstrated that this risk was short-term and manageable with adequate glucose monitoring, a 30–50% reduction of preprandial insulin doses at initiation of pramlintide, and gradual upward titration of the pramlintide dose during its initiation.33

Gastrointestinal. Beyond hypoglycemia, the most common side effects seen with pramlintide are nausea followed by anorexia and vomiting.28,31 Nausea is particularly an issue in the T1D population, with rates as high as 48% in the initiation period. Practitioners and patients need to be aware of this common phenomenon and address it specifically at the time of initiation. It seems as though, based on the authors extensive clinical experience, the longer the duration of T1D, the more susceptible the individual is to nausea. With diligent slow up-titration, the effect can be minimized. Furthermore, it should be emphasized to the patient that the gastrointestinal side effects are typically mild to moderate in intensity and transient. However, given that pramlintide slows the rate of gastric emptying, this can lead to more severe symptoms in patients with established gastroparesis.

Clinical Use

Pramlintide is an appropriate adjunct to mealtime insulin to consider for any patient with T1D that is not meeting their desired A1C goal. However, there are some basic concepts to keep in mind prior to initiation. Patients should begin with reasonable blood glucose control with an A1C <9% indicating a somewhat stable insulin regimen and compliance with their insulin therapy. Patients should monitor their blood glucose frequently (or use a continuous glucose monitor) and have frequent contact with a health care provider skilled in insulin use. Pramlintide should be avoided in patients with hypoglycemia unawareness or with episodes of severe hypoglycemia in the preceding 6 months. Patients with severe gastroparesis should not use pramlintide as its effect on slowing gastric emptying can exacerbate these symptoms. In patients with mild gastroparesis the effects of pramlintide can actually improve symptoms because it helps to prevent over eating, which makes the stomach wall atonic. The pramlintide dose should be gradually titrated upwards with an initial 50% decrease in mealtime insulin. In the clinical trials the final reduction in mealtime insulin was ~30% so a discussion should be held with the patient telling them that the 50% may be too much and to expect higher blood glucose values upon initiation. Doses of both pramlintide and insulin should be adjusted according to the patient based on symptoms and home or continuous glucose monitoring. Figure 13.6 details dose titration when initiating pramlintide.

The timing of the mealtime insulin bolus should also be taken into consideration. Pramlintide reduces the postprandial glucose concentrations via the mechanisms described above. Dosing a rapid-acting insulin analog before a meal in a typical fashion may result in an initial reduction in postprandial glucose, but can also result in a late, gradual increase in glucose concentrations after peak mealtime insulin action (see Figure 13.3). Experimenting with dosing the rapid- acting analog insulin after the meal or using an extended wave bolus via an insulin pump may help to further fine-tune the overall postprandial glucose profile in patients using pramlintide and provide a better matching of the pharmacokinetics of rapid-acting insulin.

Pramlintide in the Pediatric Population

Pramlintide is currently FDA-approved for adults but not in the pediatric population; however, several small trials have evaluated its use in children and

DCMS139CG2

Figure 13.6 Stepwise approach to initiating pramlintide therapy. Adapted from: Pramlintide Acetate Prescribing Information [package insert], 2005

adolescents.34–37 Overall, these trials have demonstrated similar effects as seen in the adult population in regard to decreasing postprandial hyperglycemia, reducing insulin dose, and improving body weight profiles — an overall proof of concept. The aim of these trials has largely been to establish a safe dose that can be administered without undue side effects. Pramlintide is frequently used in the adolescent population; however, this is an off-label indication. A 4-month trial comparing pramlintide with insulin vs. exenatide and insulin in 12–21 year olds is currently underway and may help answer some of these questions.

Future Roles of Pramlintide in Insulin Pumps and the Artificial Pancreas

With the improvement in continuous glucose monitors, insulin pumps, and insulin formulations, the artificial pancreas has become an increasingly possible technology. Studies have commenced testing prototype models for at home use in real-world situations.38 However, the lag time between insulin infusion in the subcutaneous tissue and its onset of metabolic action remains a significant barrier to perfecting the insulin delivery algorithms. This lag can result in unacceptable postprandial glucose spikes with potential late hypoglycemic reactions. To solve this problem, one could imagine multiple possible solutions. One solution would be to add pramlintide into the infusion device itself along with insulin to help mitigate postprandial hyperglycemia. This addition, however, would mean a separate chamber for pramlintide in the device with a separate infusion site since the two medications are currently believed to be incompatible. Furthermore, the larger clinical trials above only assessed pramlintide as an adjunct in a mealtime fashion. Therefore, it remains to be seen if infusion of the medication in a basal-bolus fashion would confer any additional benefits beyond mealtime delivery alone.

Several small trials have begun to address these issues. A 16-week open-label study of 11 patients with long-standing T1D used pramlintide in a basal-bolus fashion administered via an insulin pump. A continuous infusion was maintained at 9 mcg/hr with boluses at mealtime titrated up to 60 mcg. Over the study period, patients had lower A1C values, and lower fasting glucoses, and lost weight.39 However, there was no control group that used pramlintide in a bolus fashion only, making it impossible to determine the benefit of a continuous infusion. A similar study was done in adolescents where 13 patients were observed on insulin monotherapy and then crossed over to insulin along with pramlintide in a basal-bolus fashion.40 Improvement in glucose variability, reduction in insulin dose, and decreased glucagon response were all observed with the addition of pramlintide. Together these trials show that it is technically possible and safe to administer pramlintide in a continuous fashion along with insulin therapy. However, larger studies need to be done with an appropriate control group.

The need for separate infusions of pramlintide and insulin is cumbersome. To address this issue, one randomized, placebo-controlled study of 51 patients evaluated the effects of mixing various insulin formulations with pramlintide and ultimately found that this had no effect on the area under the concentration-vs.-time curve and the maximum concentration of serum-free insulin.41 However, it remains unknown if the two can be mixed in a pump.

Pramlintide has been shown to be a useful addition to insulin in the treatment of T1D. Not only has it been shown to reduce A1C in the adult population but it does so while reducing overall insulin dose and weight. Furthermore, with proper dose titration at initiation, side effects can be effectively reduced, making the medication safe and tolerable. Going forward, the medication will need to be evaluated in the pediatric population, and if deemed safe and effective, would add a long-awaited adjunct in this group. Finally, with the advent of the artificial pancreas looming in the near future, the role of pramlintide in a continuous infusion setting along with insulin needs to be evaluated. The beneficial postprandial glucose profile provided by pramlintide could potentially help to close the loop sooner.

Next text: Part 3 – 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
  32. Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986, 1993 33
  33. Edelman S, Garg S, Frias J, Maggs D, Wang Y, Zhang B, Strobel S, Lutz K, Kolterman O: A double-blind, placebo-controlled trial assessing pramlint-ide treatment in the setting of intensive insulin therapy in type 1 diabetes. Diabetes Care 29:2189–2195, 2006
  34. Kishiyama CM, Burdick PL, Cobry EC, Gage VL, Messer LH, McFann K, Chase HP: A pilot trial of pramlintide home usage in adolescents with type 1 diabetes. Pediatrics 124:1344–1347, 2009 35.
  35. Chase HP, Lutz K, Pencek R, Zhang B, Porter L: Pramlintide lowered glu-cose excursions and was well-tolerated in adolescents with type 1 diabetes: results from a randomized, single-blind, placebo-controlled, crossover study. J Pediatr 155:369–373, 2009.
  36. Hassan K, Heptulla RA: Reducing postprandial hyperglycemia with adju-vant premeal pramlintide and postmeal insulin in children with type 1 dia-betes mellitus. Pediatr Diabetes 10:264–268, 2009.
  37. Raman VS, Mason KJ, Rodriguez LM, Hassan K, Yu X, Bomgaars L, Hep-tulla RA: The role of adjunctive exenatide therapy in pediatric type 1 diabe-tes. Diabetes Care 33:1294–1296, 2010
  38. Hovorka R, Kumareswaran K, Harris J, Allen JM, Elleri D, Xing D, Kollman C, Nodale M, Murphy HR, Dunger DB, Amiel SA, Heller SR, Wilinska ME, Evans ML: Overnight closed loop insulin delivery (artificial pancreas) in adults with type 1 diabetes: crossover randomised controlled studies. BMJ 342:d1855, 2011
  39. Huffman DM, McLean GW, Seagrove MA: Continuous subcutaneous pramlintide infusion therapy in patients with type 1 diabetes: observations from a pilot study. Endocr Pract 15:689–695, 2009
  40. Heptulla RA, Rodriguez LM, Mason KJ, Haymond MW: Twenty-four-hour simultaneous subcutaneous Basal-bolus administration of insulin and amylin in adolescents with type 1 diabetes decreases postprandial hyperglycemia. J Clin Endocrinol Metab 94:1608–1611, 2009
  41. Weyer C, Fineman MS, Strobel S, Shen L, Data J, Kolterman OG, Sylvestri MF: Properties of pramlintide and insulin upon mixing. Am J Health Syst Pharm 62:816–822, 2005
  42. Nauck MA, Homberger E, Siegel EG, Allen RC, Eaton RP, Ebert R, Creutzfeldt W: Incretin effects of increasing glucose loads in man calcu-lated from venous insulin and C-peptide responses. J Clin Endocrinol Metab 63:492–498, 1986
  43. Hare KJ, Knop FK: Incretin-based therapy and type 2 diabetes. Vitam Horm 84:389–413, 2010
  44. Hare KJ, Vilsbøll T, Holst JJ, Knop FK: Inappropriate glucagon response after oral compared with isoglycemic intravenous glucose administration in patients with type 1 diabetes. Am J Physiol Endocrinol Metab 298:E832–E837, 2010
  45. Kielgast U, Krarup T, Holst JJ, Madsbad S: Four weeks of treatment with liraglutide reduces insulin dose without loss of glycemic control in type 1 diabetic patients with and without residual beta-cell function. Diabetes Care 34:1463–1468, 2011
  46. Varanasi A, Bellini N, Rawal D, Vora M, Makdissi A, Dhindsa S, Chaudhuri A, Dandona P: Liraglutide as additional treatment for type 1 diabetes. Eur J Endocrinol 165:77–84, 2011
  47. Nauck MA: Incretin-based therapies for type 2 diabetes mellitus: properties, functions, and clinical implications. Am J Med 124 (Suppl. 1):S3–S18, 2011
  48. Ellis SL, Moser EG, Snell-Bergeon JK, Rodionova AS, Hazenfield RM, Garg SK: Effect of sitagliptin on glucose control in adult patients with type 1 diabetes: a pilot, double-blind, randomized, crossover trial. Diabet Med 28:1176–1181, 2011
  49. Standards of medical care in diabetes: 2012. Diabetes Care 35 (Suppl. 1):S11– S63, 2012
  50. Abdelghaffar S, Attia AM: Metformin added to insulin therapy for type 1 diabetes mellitus in adolescents. Cochrane Database Syst Rev CD006691, 2009
  51. Vella S, Buetow L, Royle P, Livingstone S, Colhoun HM, Petrie JR: The use of metformin in type 1 diabetes: a systematic review of efficacy. Diabetologia 53:809–820, 2010
  52. Lund SS, Tarnow L, Astrup AS, Hovind P, Jacobsen PK, Alibegovic AC, Parving I, Pietraszek L, Frandsen M, Rossing P, Parving HH, Vaag AA: Effect of adjunct metformin treatment in patients with type-1 diabetes and persistent inadequate glycaemic control. A randomized study. PLoS One 3:e3363, 2008
  53. Oral EA, Chan JL: Rationale for leptin-replacement therapy for severe lipo-dystrophy. Endocr Pract 16:324–333, 2010
  54. Fujikawa T, Chuang JC, Sakata I, Ramadori G, Coppari R: Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice. Proc Natl Acad Sci U S A 107:17391–17396, 2010
  55. Wang MY, Chen L, Clark GO, Lee Y, Stevens RD, Ilkayeva OR, Wenner BR, Bain JR, Charron MJ, Newgard CB, Unger RH: Leptin therapy in insulin-deficient type I diabetes. Proc Natl Acad Sci U S A 107:4813–4819, 2010

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.