Adjunctive Therapy with Pramlintide Lowers HbA1c without Concomitant Weight Gain and Increased Risk of Severe Hypoglycemia in Patients with Type 1 Diabetes Approaching Glycemic Targets

Abstract

Aims: In long-term clinical trials in patients with type 1 diabetes spanning a wide range of HbA1c, addition of pramlintide to existing insulin regimens led to reductions in HbA1c that were accompanied by weight loss and no increase in overall severe hypoglycemia event rates. Given that weight gain and increased hypoglycemia risk contribute to the difficulty of attaining HbA1c targets (< 7 %), the question arose whether pramlintide could benefit patients approaching, but not reaching glycemic targets with insulin alone. To address this question, we conducted a pooled analysis from 3 long-term clinical trials, including all patients with an entry HbA1c between 7.0 % and 8.5 %. Methods: Within the subset of patients with an entry HbA1c between 7.0 % and 8.5 % (approximately 28 % of all patients enrolled in the 3 studies), 196 were treated with placebo + insulin (baseline HbA1c 7.9 ± 0.4 %, body weight 76.0 ± 14.3 kg [mean ± SD]) and 281 with pramlintide + insulin (baseline HbA1c 7.9 ± 0.4 %, body weight 75.4 ± 13.1 kg). Endpoints included placebo-corrected changes from baseline to week 26 in HbA1c, body weight, and the event rate of severe hypoglycemia. Results: Adjunctive therapy with pramlintide resulted in significant reductions in HbA1c and body weight from baseline to week 26 (0.3 % and 1.8 kg, placebo-corrected treatment differences, respectively, both p ≤ 0.0009). These changes occurred without an increase in the overall risk of severe hypoglycemia (1.40 pramlintide vs. 1.86 placebo, events/patient-year of exposure). Conclusions: Addition of pramlintide to insulin therapy may help patients with type 1 diabetes who are approaching, but not yet reaching, glycemic targets with insulin alone to achieve further reductions in HbA1c without concomitant weight gain and increased risk of severe hypoglycemia.

Key words

HbA1c - pramlintide - type 1 diabetes - glycemic targets

References

• 1 American Association of Clinical Endocrinologists . American College of Endocrinology consensus statement on guidelines for glycemic control.  Endocr Pract. 2002;  8 5-11
• 2 American Diabetes Association . Standards of medical care for patients with diabetes mellitus (Position Statement).  Diabetes Care. 2003;  26 (Suppl 1) S33-S50
• 3 Boland E, Monsod Delucia T M, Brandt C A, Fernando S, Tambolane W V. Limitations of conventional methods of self-monitoring of blood glucose: lessons learned from 3 days of continuous glucose sensing in pediatric patients with type 1 diabetes.  Diabetes Care. 2001;  24 1858-1862
• 4 Bolli G B, Di Marchi R D, Park G D, Pramming S, Koivisto V A. Insulin analogues and their potential in the management of diabetes mellitus.  Diabetologia. 1999;  42 1151-1167
• 5 Booth G L, Zinman B, Redelmeier D A. Diabetes care in the U. S. and Canada.  Diabetes Care. 2002;  25 1149-1153
• 6 Bryden K S, Neil A, Mayou R A, Peveler R C, Fairburn C G, Dunger D B. Eating habits, body weight and insulin misuse. A longitudinal study of teenagers and young adults with type 1 diabetes.  Diabetes Care. 1999;  22 1956-1960
• 7 Buse J B, Weyer, Maggs D G. Amylin replacement with pramlintide in type 1 and type 2 diabetes: a physiological approach to overcome barriers with insulin therapy.  Clinical Diabetes. 2002;  20 137-144
• 8 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.  Diabetologia. 2005;  48 in press
• 9 Cryer P E. Banting Lecture. Hypoglycemia: the limiting factor in the management of IDDM.  Diabetes. 1994;  43 1378-1389
• 10 DCCT Research Group . Epidemiology of severe hypoglycemia in the Diabetes Control and Complications Trial.  Am J Med. 1991;  90 450-459
• 11 DCCT Research Group . Hypoglycemia in the Diabetes Control and Complications Trial.  Diabetes. 1997;  46 271-286
• 12 DCCT Research Group . Influence of intensive diabetes treatment on body weight and composition of adults with type 1 diabetes in the diabetes control and complication trial.  Diabetes Care. 2001;  24 1711-1721
• 13 DCCT 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. 1993;  329 977-986
• 14 DCCT Research Group . Weight gain associated with intensive therapy in the diabetes control and complications trial.  Diabetes Care. 1988;  11 567-573
• 15 Edelman S V, Weyer C. Unresolved challenges with insulin therapy in type 1 and type 2 diabetes: potential benefit of replacing amylin, a second β-cell hormone.  Diabetes Technol Ther. 2002;  4 175-189
• 16 Felig P, Tamborlane W, Sherwin R S, Genel M. Insulin-infusion pump for diabetes.  New Engl J Med. 1979;  301 1004-1005
• 17 Fineman M, Gottlieb A, Bahner A, Parker J, Waite G, Kolterman O. Pramlintide therapy in addition to insulin in type 1 diabetes: effect on metabolic control after 6 months.  Diabetologia. 1999;  42 A232-(abstract 0872)
• 18 Fineman M S, Koda J E, Shen L Z, Strobel S A, Maggs D G, Weyer C, Kolterman O G. The human amylin analog, pramlintide, corrects postprandial hyperglucagonemia in patients with type 1 diabetes.  Metabolism. 2002;  51 636-641
• 19 Gedulin B R, Rink T J, Young A A. Dose-response for glucagonostatic effect of amylin in rats.  Metabolism. 1997;  46 67-70
• 20 Kaufman F R, Gibson L C, Halvorson M, Carpenter S, Fisher L K, Pitukcheewanont P. A pilot study of the continuous glucose monitoring system: clinical decisions and glycemic control after its use in pediatric type 1 diabetic subjects.  Diabetes Care. 2001;  24 2030-2034
• 21 Klein R, Klein B E, Moss S E, Cruickshanks K J. The medical management of hyperglycemia over a 10-year period in people with diabetes.  Diabetes Care. 1996;  19 744-750
• 22 Koda J E, Fineman M, Rink T J, Dailey G E, Muchmore D B, Linarelli L G. Amylin concentrations and glucose control.  Lancet. 1992;  339 1179-1180
• 23 Kolterman O G, Gottlieb A, Moyses C, Colburn W. Reduction of postprandial hyperglycemia in patients with IDDM by intravenous infusion of AC137, a human amylin analogue.  Diabetes Care. 1995;  18 1179-1182
• 24 Kong M F, King P, Macdonald I A, Stubbs T A, Perkins A C, Blackshaw P E, Moyses C, Tattersall R B. Infusion of pramlintide, a human amylin analogue, delays gastric emptying in men with IDDM.  Diabetologia. 1997;  40 82-88
• 25 Levetan C, Want L, Weyer C, Strobel S A, Crean J, Wang Y, Maggs D G, Kolterman O G, Chandran M, Mudaliar S R, Henry R R. Impact of pramlintide on glucose fluctuations and postprandial glucose, glucagon, and triglycerides excursions among patients with type 1 diabetes intensively treated with insulin pumps.  Diabetes Care. 2003;  26 1-8
• 26 Nathan D M, McKitrick C, Larkin M, Schaffran R, Singer D E. Glycemic control in diabetes mellitus: have changes in therapy made a difference?.  Am J Med. 1996;  100 157-163
• 27 Nyholm B, Orskov L, Hove K, Gravholt C, Moller N, Alberti K, Moyses C, Kolterman O, Schmitz O. The amylin analog pramlintide improves glycemic control and reduces postprandial glucagon concentrations in patients with type 1 diabetes mellitus.  Metabolism. 1999;  48 935-941
• 28 Purnell J, Weyer C. Weight effect of current and experimental diabetes drugs: from promotion to alleviation of obesity.  Treatments in Endocrinology. 2003;  2 23-37
• 29 Purnell J Q, Hokanson J E, Marcovina S M, Steffes M W, Cleary P A, Brunzell J D. Effect of excessive weight gain with intensive therapy of type 1 diabetes on lipid levels and blood pressure: results from the DCCT.  JAMA. 1998;  280 140-146
• 30 Ratner R E, Dickey R, Fineman M, Maggs D G, Shen L, Strobel S A, Weyer C, Kolterman O G. 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, randomised controlled trial.  Diabetic Medicine. 2004;  21 1204-1212
• 31 Rushing P A, Hagan M M, Seeley R J, Lutz T A, Woods S C. Amylin: a novel action in the brain to reduce body weight.  Endocrinology. 2000;  141 850-853
• 32 Rushing P A, Hagan M M, Seeley R J, Lutz T A, D'Alessio D A, Air E L, Woods S C. Inhibition of central amylin signaling increases food intake and body adiposity in rats.  Endocrinology. 2001;  142 5035-5038
• 40 SYMLIN® Prescribing Information and Patient Medication Guide. March/2005
• 33 Vella A, Lee J S, Camilleri M, Szarka L A, Burton D D, Zinsmeister A R, Rizza R A, Klein P D. Effects of pramlintide, and amylin analogue, on gastric emptying in type 1 and type 2 diabetes mellitus.  Neurogastroenterol Motil. 2002;  14 123-131
• 34 Weyer C, Maggs D G, Young A A, Kolterman O G. 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. 2001;  7 1353-1373
• 35 Weyer C, Gottlieb A, Kim D D, Lutz K, Schwartz S, Gutierrez M, Wang Y, Ruggles J A, Kolterman O G, Maggs D G. 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. 2003;  26 3074-3079
• 36 Whitehouse F, Kruger D F, Fineman M, Shen L, Ruggles J A, Maggs D G, Weyer C, Kolterman O G. A randomized study and open-label extension evaluating the long-term efficacy of pramlintide as an adjunct to insulin therapy tin type 1 diabetes.  Diabetes Care. 2002;  25 724-730
• 37 World Health Organization .Obesity: Preventing and Managing the Global Epidemic. Report of a WHO Consultation. No. 894. Geneva; WHO Tech Ref Series 2000
• 38 Young A A, Gedulin B, Vine W, Percy A, Rink T J. Gastric emptying is accelerated in diabetic BB rats and is slowed by subcutaneous injections of amylin.  Diabetologia. 1995;  38 642-648
• 39 Young A A. Amylin's physiology and its role in diabetes.  Curr Opin Endocrinol Diabetes. 1997;  4 282-290