Effect of Pramlintide on Weight in Overweight

and Obese Insulin-Treated Type 2
Diabetes Patients
Priscilla Hollander,* David G. Maggs,† James A. Ruggles,† Mark Fineman,† Larry Shen,†
Orville G. Kolterman,† and Christian Weyer†

Abstract
HOLLANDER, PRISCILLA, DAVID G. MAGGS, JAMES
A. RUGGLES, MARK FINEMAN, LARRY SHEN,
ORVILLE G. KOLTERMAN, AND CHRISTIAN
WEYER. Effect of pramlintide on weight in overweight and
obese insulin-treated type 2 diabetes patients. Obes Res.
2004;12:661-668.
Objective: Several randomized, placebo-controlled, doubleblind trials in insulin-treated patients with type 2 diabetes
have shown that adjunctive therapy with pramlintide reduces hemoglobin (Hb)A1c with concomitant weight loss.
This analysis further characterizes the weight-lowering effect of pramlintide in this patient population.
Research Methods and Procedures: This pooled post hoc
analysis of two long-term trials included all patients who
were overweight/obese at baseline (BMI ⬎ 25 kg/m2), and
who were treated with either 120 ␮g pramlintide BID (n ⫽
254; HbA1c 9.2%; weight, 96.1 kg) or placebo (n ⫽ 244;
HbA1c 9.4%; weight, 95.0 kg). Statistical endpoints included changes from baseline to week 26 in HbA1c, body
weight, and insulin use.
Results: Pramlintide treatment resulted in significant reductions from baseline to week 26, compared with placebo, in
HbA1c and body weight (both, p ⬍ 0.0001), for placebocorrected reductions of ⫺0.41% and ⫺1.8 kg, respectively.
Approximately three times the number of patients using
pramlintide experienced a ⱖ5% reduction of body weight

Received for review September 11, 2003.
Accepted in final form February 9, 2004.
The costs of publication of this article were defrayed, in part, by the payment of page
charges. This article must, therefore, be hereby marked “advertisement” in accordance with
18 U.S.C. Section 1734 solely to indicate this fact.
*Baylor College of Medicine, Dallas, Texas and †Amylin Pharmaceuticals, Inc., San Diego,
California.
Address correspondence to Christian Weyer, Amylin Pharmaceuticals, Inc., 9360 Towne
Centre Drive, San Diego, CA 92121.
E-mail: cweyer@amylin.com
Copyright © 2004 NAASO

than with placebo (9% vs. 3%, p ⫽ 0.0005). Patients using
pramlintide also experienced a proportionate decrease in
total daily insulin use (r ⫽ 0.39, p ⬍ 0.0001). The greatest
placebo-corrected reductions in weight at week 26 were
observed in pramlintide-treated patients with a BMI ⬎40
kg/m2 and in those concomitantly treated with metformin
(both, p ⬍ 0.001), for placebo-corrected reductions of ⫺3.2
kg and ⫺2.5 kg, respectively.
Discussion: These findings support further evaluation of the
weight-lowering potential of pramlintide in obese patients
with type 2 diabetes.
Key words: hemoglobin A1c, weight gain, weight loss,
amylin

Introduction
A major, unresolved problem in the pharmacological
management of type 2 diabetes is that improvement of
glycemic control with insulin, insulin secretagogues (sulfonylureas, meglitinides), and insulin sensitizers (thiazolidinediones) is often accompanied by considerable weight
gain (1–7). In the United Kingdom Prospective Diabetes
Study, patients assigned to insulin therapy gained ⬃4.0 kg
more than the conventionally treated control patients (2).
Even greater weight gain with insulin therapy seems to
occur when insulin is used in the context of more intensive
basal/bolus regimens (3,4) or when it is used in combination
with oral insulin secretagogues or sensitizers (8,9). In a
study by Henry et al. (4), patients with type 2 diabetes
treated with an intensive basal/bolus insulin regimen for 6
months had a mean weight gain of 8.7 kg. The amount of
weight gain increased proportionally with increasing total
daily insulin doses and the resulting degree of peripheral
hyperinsulinemia (4). These data confirm the common clinical experience that aggressive insulin treatment of obese
OBESITY RESEARCH Vol. 12 No. 4 April 2004

661

and the proportion of patients achieving a reduction in weight of 2. 35 to 40 kg/m2 (obesity class 2). randomized. double-blind studies included in this pooled post hoc analysis have previously been described in detail (27. Amylin is a glucoregulatory ␤-cell hormone that is normally cosecreted with insulin in response to meals and is deficient in insulin-treated patients with type 1 and type 2 diabetes (11.0 to 7. and SD) and parametrically (ANOVA. Pramlintide is a synthetic amylin analog currently in late-stage clinical development as a potential adjunctive therapy to insulin in patients with type 1 and type 2 diabetes (11. and insulin use.23–25). before breakfast and dinner) was added to preexisting insulin regimens. Preclinical studies have shown that amylin acts as a neuroendocrine hormone that binds with high affinity to specific amylin receptors in certain areas in the brain.. and ⬎40 kg/m2 (obesity class 3. amylin may act as a signal that is involved in the central regulation of food intake and body weight (17).12). the overall pooled cohort was stratified into those patients who had or had never reported nausea at any time during the 26-week treatment period.28). pramlintide or placebo (injected subcutaneously twice per day. with repeated assessment of HbA1c. NC). Univariate correlation analyses were performed to examine relationships between changes in HbA1c. Changes from baseline in HbA1c and weight between pramlintide and placebo groups were analyzed descriptively (n.14). and insulin use. 6. Hollander et al.15. weight gain. For this analysis. the overall pooled cohort was stratified into those patients who were or were not concomitantly treated with metformin (along with their pre-existing insulin therapy). weight. including the area postrema (13. pharmacologically induced weight gain is a highly undesirable outcome. Data from these analyses were not imputed if patients withdrew but were observed cases at each visit. .e. and total daily insulin doses (recorded in patient diaries). Changes from baseline in total daily insulin use were analyzed descriptively. Pearson correlation coefficients were calculated to quantify the relationship between changes in HbA1c. Because these secondary analyses were post hoc in nature. SAS Institute. This is supported by results from several rodent studies where amylin administration reduced food intake and body weight (18 –21). To further characterize the weight-lowering effect of pramlintide in this patient population. and increased insulin requirements (3).0%. mean. Finally. both studies employed an add-on design. One study was 26 weeks in duration. Of note. 12 No. body weight. Endpoints and Statistical Methods Endpoints for the overall pooled cohort at week 26 included the change from baseline in HbA1c. To examine the effect of pramlintide in patients with different degrees of obesity. Both studies used similar efficacy and safety endpoints (see below).12. the studies were not 1 Nonstandard abbreviation: Hb. and ⱖ10%. we pooled both studies and included data from all patients who were overweight or obese at study entry (BMI ⬎ 25 kg/m2) and had been randomized to twice a day injections of 120 ␮g pramlintide or placebo. results in the metformin/no-metformin. 5. the overall pooled cohort was stratified into four categories based on baseline BMI: 25 to 30 kg/m2 (overweight). body weight.1 can lead to a cycle of peripheral hyperinsulinemia. i. according to the World Health Organization (29) and the International Obesity Task Force (30) criteria.5 to 10%. Research Methods and Procedures Study Design The designs of the two long-term. we conducted a pooled post hoc analysis of the data from these long-term trials. whereas administration of a selective amylin antagonist increased food intake and body fat stores (22).16). morbid obesity). SAS v. whereas generally effective in lowering hemoglobin (Hb)A1c.Effect of Pramlintide on Body Weight. To examine the effect of pramlintide in conjunction with metformin.12. Additionally. 7. to examine whether the weight reduction with pramlintide was associated with the occurrence of nausea.5%.5 to 5. This is especially the case for patients with type 2 diabetes who are markedly obese and for those requiring large doses of insulin. placebocontrolled. Cary. hemoglobin. In brief. 4 April 2004 designed as weight loss trials. and nausea/no-nausea subgroups were not subjected to formal analytical comparisons but were summarized descriptively instead. 30 to 35 kg/m2 (obesity class 1). patients with type 2 diabetes. Given that 90% or more of patients with type 2 diabetes are overweight or obese at the time of diagnosis (10). whereas the other study was 52 weeks in duration. Several long-term clinical studies in insulintreated patients with type 2 diabetes have shown that adjunctive treatment with pramlintide resulted in a reduction in HbA1c that was consistently accompanied by a significant weight loss rather than weight gain (26 –28). using the SAS PROC MIXED procedure. Amylin complements the effects of insulin in postprandial glucose homeostasis by regulating the rate of glucose appearance into the circulation through a suppression of postprandial glucagon secretion and a slowing of gastric emptying (11. and the observed weight changes occurred despite the fact that patients were discouraged from changing their routine diet and/or exercise regimens. weight. 662 OBESITY RESEARCH Vol. total daily insulin use.

6 ⫾ 6.5 to 5.5%.3%.1 ⫾ 19.4 13 ⫾ 7 254 47/53 83/8/10 57 ⫾ 10 96.3 9.4 ⫾ 1. The pooled pramlintide and placebo treatment groups were well matched with respect to demographics. Table 1.3 4. At that time.and long-acting (%) Number of Daily Insulin Injections 1 Injection (%) 2 Injections (%) ⬎2 Injections (%) Oral anti-hyperglycemic agents Metformin only (%) Sulfonylureas only (%) Metformin and sulfonylureas (%) 244 49/51 83/8/9 56 ⫾ 10 95. * Mean ⫾ SD. 44.6%).and long-acting insulin. The mean reduction in body weight from baseline with pramlintide was significant from week 2 onward and increased over time. The vast majority of patients used multiple injections of short.7 88.7 Percent of subjects may not add up to 100 due to rounding. Hollander et al.3 8. and ⬃23% of patients used oral antihyperglycemic agents in addition to their insulin therapies (Table 1).0 7.2 85. a larger proportion of pramlintide. 5. 498 were overweight (BMI ⬎ 25 kg/m2) and had been randomized to treatment with either 120 ␮g pramlintide BID or placebo (Table 1).18%).0 61. and Body Weight in the Overall Study Population Pramlintide-treated patients achieved a significant (p ⬍ 0. The mean baseline HbA1c was ⬃9. The greater reduction in HbA1c in the pramlintide group occurred despite a relative mean reduction in total daily insulin use (Figure 1B) and was associated with a significant mean reduction in body weight compared with placebo (Figure 1C).7 33. 0. for a placebo-corrected treatment effect of 0. Conversely.9 11. Interrelationship between Changes in HbA1c.5 to 10%. averaging 1. and concomitant treatment.4 14.1 13 ⫾ 8 69 ⫾ 37 66 ⫾ 34 0.2% vs.0 ⫾ 18.0 to 7.0 9. the proportion of pramlintide-treated patients who gained weight during the 26-week treatment period was approximately one-half that of the placebotreated group (23. and the mean baseline BMI was ⬃34 kg/m2 (Table 1).59% vs.8 10.0%. 7.8 kg.4 29. and Body Weight Univariate correlation analysis showed that the change in body weight from baseline to week 26 was not significantly OBESITY RESEARCH Vol. 4 April 2004 663 .1 ⫾ 6. Baseline demographics and characteristics Parameter Placebo ⴙ insulin Pramlintide ⴙ insulin n Sex: male/female (%) Race.Effect of Pramlintide on Body Weight.6 7.5 31. Insulin Use.5 0. Changes in HbA1c. and ⱖ10% (Figure 1D). Insulin Use. 12 No.5 63.0001) mean reduction in HbA1c compared with placebotreated patients from baseline to week 26 (0.1 12. Results Subject Disposition and Baseline Demographics Of the 1155 patients randomized in the two long-term studies.41% (Figure 1A). White/African American/other (%) Age (years)* Weight (kg)* BMI (kg/m2)* HbA1c (%)* Duration of diabetes (years)* Concomitant Medications Total daily insulin dose (unit)* Types of insulin used Short-acting only (%) Long-acting only (%) Short.2 ⫾ 1. for a placebo-corrected treatment difference of ⫺1.8 6.2 34.6 2. baseline characteristics.5 kg at week 26.than placebo-treated patients had achieved mean weight reductions of 2.

⬃83% of . However. p ⫽ 0.05. BMI ⬎ 40 kg/m2.25. and body weight (C). Statistically significant differences between placebo and pramlintide groups at each time-point are indicated by **p ⬍ 0. was seen in patients with marked obesity (placebo-corrected treatment difference: BMI ⫽ 35 to 40 kg/m2. and the proportion of subjects achieving various weight loss targets at week 26 (D) in the overall study population. and filled circles with solid lines and solid bars represent pramlintide ⫹ insulin. Changes in Body Weight and Insulin Use by Baseline BMI The greater reductions in body weight with pramlintide compared with placebo treatment were evident across all four BMI categories (Figure 2). total daily insulin use (B).Effect of Pramlintide on Body Weight.8%).4 kg.1% vs.5904 and r ⫽ ⫺0. ⬃17% of the patients) compared with those who were not (n ⫽ 210. Figure 1: Mean changes (SE) from baseline in HbA1c (A). p ⫽ 0. ⫺2. respectively). p ⫽ 0.39.0004 for the pramlintide and placebo groups.0001 and *p ⬍ 0. both on an absolute and percentage basis. Figure 2. 12 No. Open circles with dotted lines and open bars represent placebo ⫹ insulin. related to the concomitant change in HbA1c (r ⫽ 0. respectively). whereas pramlintide treatment led to a moderate reduction in body weight in overweight and moderately obese patients (BMI of 25 to 30 and 30 664 OBESITY RESEARCH Vol.2 kg. Changes in Body Weight and Insulin Use by Concomitant Use of Metformin The weight reduction with pramlintide seemed to be somewhat greater in patients who were concomitantly treated with metformin (n ⫽ 44. However.0001 and r ⫽ 0.038.084. the most pronounced weight loss. ⫹5.2465 for the pramlintide and placebo groups. p ⬍ 0. Pramlintide-treated patients in the highest BMI category (⬎40 kg/m2) also experienced the greatest reduction in total daily insulin use compared with placebotreated patients (⫺3. ⫺3. there was a strong positive relationship between the change in body weight from baseline to week 26 and the concomitant change in total daily insulin use (r ⫽ 0. A and B). Hollander et al. 4 April 2004 to 35 kg/m2).

especially when considering that it was concomitant with a significant placebo-corrected mean HbA1c reduction of ⬃0. Open bars represent placebo ⫹ insulin.2 kg (⬃3%). Safety Pramlintide treatment was generally well tolerated. n ⫽ 72.3 kg for patients not reporting any nausea (Figure 3. Hollander et al.5% vs. n ⫽ 76. In these patients.4% and that insulin-treated obese patients with type 2 diabetes generally respond less well to nonpharmacological (31) and pharmacological (32. and ⬎40 kg/m2 BMI groups. 6. There was no evidence of cardiovascular. ⬎35 to 40.4% for weeks 0 to 26). It is important to point out that the studies included in this analysis were not designed as weight loss trials and the observed weight reduction occurred despite the fact that patients were discouraged from changing their routine diet and/or exercise regimens. placebo-controlled long-term trials in patients with type 2 diabetes have consistently shown that the addition of pramlintide to preexisting insulin regimens led to a further improvement in glycemic control that was associated with statistically significant weight loss rather than weight gain (26 –28).9 kg for patients reporting nausea and 1. lipid profile.1%). ⬃76% of patients) compared with those who did experience nausea at some point during the 26-week treatment period (n ⫽ 60. patients). weeks 4 to 26: 9. This pooled post hoc analysis revealed further insights into the weight-lowering effect of pramlintide in overweight and obese patients with type 2 diabetes.33) weight loss interventions compared with obese individuals without diabetes. For the placebo-treated group. A greater proportion of pramlintide-treated patients completing 26 weeks of treatment did not experience nausea (n ⫽ 194. with an incidence ⬎10% and a 2-fold greater incidence among pramlintide-treated compared with placebo-treated patients.4% vs.6 kg for patients not using metformin (Figure 3. The only treatment-emergent adverse event. 3. which may improve glycemic control as a secondary consequence of weight loss.4 kg (⬃2. 9.33). and 33. This weight loss is clinically meaningful. and filled bars represent pramlintide ⫹ insulin.Effect of Pramlintide on Body Weight. ⬃24% of patients). C and D). and 36 for the ⬎25 to 30. there was a weight reduction from baseline to week 26 of 1.5 kg for patients using metformin and ⫺1. Stratification of patients based on their baseline BMI showed that. Greater than 95% of nausea cases were of mild-to-moderate intensity. or renal toxicity. 12 No. 53. respectively. placebo-corrected weight reduction at week 26 was ⫺2. or electrocardiogram variables were observed. and no changes in laboratory safety parameters. Statistically significant differences between placebo and pramlintide groups at each time-point are indicated by *p ⱕ 0.5%) and ⫺3. the weightlowering effect was most pronounced in those patients who were markedly obese (BMI ⫽ 35 to 40 and ⬎40 kg/m2). and most were confined to the first 4 weeks of treatment (weeks 0 to 4: 16. signs. 61. 82. pramlintide treatment for 26 weeks led to mean placebo-corrected differences in body weight of ⫺2. Although fundamental differences in study design precluded direct comparison of the weight effect of pramlintide with that of antiobesity agents in obese patients with type 2 diabetes. hepatic. 85. was nausea (23. double-blind. ⬎30 to 35. Unlike these antiobesity agents.01. pramlintide has a primary antihyperglycemic mechanism of action (11. A and B). Discussion Figure 2: Mean absolute (A) and relative (B) changes (SE) from baseline to week 26 in body weight by baseline BMI category. respectively (patients completing 26 weeks of treatment). Changes in Body Weight by Occurrence of Nausea The weight reduction with pramlintide occurred regardless of whether patients experienced nausea. and for the pramlintide-treated group. it is noteworthy that the 2% to 3% placebocorrected weight reduction with pramlintide treatment is not dissimilar from placebo-corrected weight reduction reported with orlistat and sibutramine in obese (non–insulin-treated) patients with type 2 diabetes (32.25) in that it potently reduces postprandial glucose excursions through a correction of postprandial hyperglucagonemia (34) and a slowing of gastric emptying (35).7%. OBESITY RESEARCH Vol. 4 April 2004 665 .6% vs.24. whereas pramlintide treatment induced a moderate weight loss in overweight and moderately obese patients (BMI ⫽ 25 to 30 and 30 to 35 kg/m2). vital Several randomized.

and reduction in insulin dosage represents potentially clinically beneficial outcomes for obese patients with type 2 diabetes. ⫺1. Because of the relatively small sample size and the post hoc nature of the analysis. n ⫽ 194 pramlintide) who never reported nausea and (D) in subjects (n ⫽ 23 placebo. Open circles with dotted lines represent placebo ⫹ insulin. and filled circles with solid lines represent pramlintide ⫹ insulin. weight loss. . Mean changes (SE) from baseline in body weight (C) in subjects (n ⫽ 221 placebo. In this respect. However.0001 and *p ⬍ 0. the combined effect of improved glycemic control. 4 April 2004 subjects would allow examination of the weight effect of pramlintide without the potential confounding effect of changes in insulin use. 12 No. n ⫽ 60 pramlintide) who did report nausea during the course of the study. which showed that changes in HbA1c and body weight on pramlintide treatment were independent effects. Studies in non–insulin-treated 666 OBESITY RESEARCH Vol.Effect of Pramlintide on Body Weight. it was an interesting finding that pramlintide seemed to have a somewhat greater weight-lowering effect in patients concomitantly treated with metformin (placebo-corrected treatment difference: ⫺2.05. The notion that pramlintide independently improves glycemic and weight control was further supported by the results of the correlation analyses. Adjunctive therapy with metformin in insulin-treated patients with type 2 diabetes has been reported to improve glycemic control without the weight gain typically seen with other oral antihyperglycemic agents (8). Statistically significant differences between placebo and pramlintide groups at each time-point are indicated by **p ⬍ 0. Hollander et al. n ⫽ 44 pramlintide) who were concomitantly treated with metformin. Although it cannot be determined from this analysis whether the reduction in insulin use is a cause or a consequence of the weight loss with pramlintide treatment. these results should be interpreted with caution. Figure 3: Mean changes (SE) from baseline in body weight (A) in subjects (n ⫽ 205 placebo. the weight reduction with pramlintide treatment was accompanied by a proportionate decrease in total daily insulin use.5 vs.6 kg in subjects not concomitantly treated with metformin). n ⫽ 210 pramlintide) who were not concomitantly treated with metformin and (B) in subjects (n ⫽ 39 placebo.

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