HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) All Versions of this Article: dc07-0589v1 30/11/2794    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Riddle, M. Articles by Kolterman, O. Search for Related Content PubMed PubMed Citation Articles by Riddle, M. Articles by Kolterman, O. Social Bookmarking                What's this?

Pramlintide Improved Glycemic Control and Reduced Weight in Patients With Type 2 Diabetes Using Basal Insulin

¹ Division of Endocrinology, Diabetes and Clinical Nutrition, Department of Medicine, Oregon Health and Science University, Portland, Oregon
² Amylin Pharmaceuticals, San Diego, California

Address correspondence and reprint requests to Orville Kolterman, MD, Amylin Pharmaceuticals, 9360 Towne Centre Dr., San Diego, CA 92121. E-mail: orville.kolterman{at}amylin.com

	ABSTRACT

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS-- RESULTS CONCLUSIONS-- APPENDIX References

 
OBJECTIVE— To assess the efficacy and safety of pramlintide in patients with type 2 diabetes suboptimally controlled with basal insulin.

RESEARCH DESIGN AND METHODS— In a 16-week, double-blind, placebo-controlled study, 212 patients using insulin glargine with or without oral antidiabetes agents (OAs) were randomized to addition of pramlintide (60 or 120 µg b.i.d./t.i.d.) or placebo. Insulin glargine was adjusted to target a fasting plasma glucose concentration of 70–100 mg/dl. One coprimary end point was the change in A1C at week 16. The other coprimary end point was a composite measure of overall diabetes control comprising A1C 7.0% or reduction 0.5%, mean daily postprandial glucose (PPG) increments 40 mg/dl, no increase in body weight, and no severe hypoglycemia. Patients meeting all four conditions at week 16 achieved this end point.

RESULTS—More pramlintide- than placebo-treated patients achieved the composite end point (25 vs. 7%; P < 0.001). Reductions (means ± SE) in A1C (–0.70 ± 0.11% vs. –0.36 ± 0.08%; P < 0.05) and PPG increments (–24.4 ± 3.6 mg/dl vs. –0.4 ± 3.0 mg/dl; P < 0.0001) were greater in pramlintide- versus placebo-treated patients, respectively. Glycemic improvements were accompanied by progressive weight loss with pramlintide and weight gain with placebo (–1.6 ± 0.3 kg vs. +0.7 ± 0.3 kg; P < 0.0001). No treatment-related severe hypoglycemia occurred.

CONCLUSIONS— Pramlintide improved multiple glycemic parameters and reduced weight with no increase in hypoglycemia in patients with type 2 diabetes who were not achieving glycemic targets with basal insulin with or without OAs.

Abbreviations: FPG, fasting plasma glucose • OA, oral antidiabetes agent • PPG, postprandial glucose

	INTRODUCTION

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS-- RESULTS CONCLUSIONS-- APPENDIX References

 
Type 2 diabetes is characterized by insulin resistance and progressive β-cell dysfunction resulting in deficiencies of insulin and amylin. Due to the progressive nature of the disease, therapy for most patients starts with medical nutrition therapy and exercise and is followed by the addition of one or more oral antidiabetes agents (OAs). Insulin, usually a basal, long-acting preparation, is eventually required to achieve adequate glycemic control. While basal insulin therapy can result in adequate fasting glucose control, it does not address postprandial hyperglycemia (1,2). Even with rigorous basal insulin titration, 30–40% of patients do not reach acceptable A1C levels (7.0%) (3,4). For those not achieving glycemic targets, intensification of therapy with the addition of mealtime insulin increases the risk of hypoglycemia (5–7) and often results in undesirable weight gain (8–10).

Pramlintide is a synthetic analog of human amylin, a naturally occurring neuroendocrine hormone cosecreted with insulin by pancreatic β-cells (11). Amylin regulates gastric emptying (12), suppresses inappropriate postprandial glucagon secretion (13), and reduces food intake (14,15). Through mechanisms similar to those of amylin, pramlintide reduces postprandial glucose (PPG), improving overall glycemic control (16,17), and increases satiety, resulting in reduced food intake and weight loss (16–19).

Therapies that improve glycemic control without weight gain and its associated long-term complications and do not increase the risk of severe hypoglycemia will significantly enhance treatment of patients with type 2 diabetes. This study investigated the efficacy and safety of pramlintide therapy with basal insulin titration in patients with type 2 diabetes suboptimally controlled with basal insulin, with or without OAs.

	RESEARCH DESIGN AND METHODS—

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS-- RESULTS CONCLUSIONS-- APPENDIX References

 
Enrolled patients were aged 25–75 years with type 2 diabetes and not achieving adequate glycemic control with insulin glargine (no mealtime insulin), with or without OA therapy (metformin, sulfonylurea, and/or thiazolidinedione). Inclusion criteria at screening included A1C >7.0% and 10.5%, BMI 25–45 kg/m², insulin glargine treatment 3 months with a stable dose (±10%) for 1 month, and, if applicable, a stable dose of OAs for 2 months. Female patients were postmenopausal, surgically sterile, or used adequate contraception throughout the study. Patients were excluded if they had a history of hypoglycemia unawareness or recurrent severe hypoglycemia during the preceding 6 months, were participating in a weight loss program, were using antiobesity agents, or had a confirmed diagnosis of gastroparesis or any other significant medical condition.

The study protocol was approved by an institutional review board. All patients provided written informed consent before study initiation. The study was conducted in accordance with principles outlined in the Declaration of Helsinki (1964), including all amendments through the South Africa revision (1996).

This was a 16-week, randomized, double-blind, placebo-controlled, multicenter study conducted in the U.S. (41 sites) between October 2005 and June 2006. After a screening visit, eligible patients made six visits to the study site (baseline, 2, 4, 8, 12, and 16 weeks). At the baseline visit, patients were randomized to receive pramlintide (Amylin Pharmaceuticals, San Diego, CA) or placebo (Amylin Pharmaceuticals). Randomization was stratified according to screening visit A1C (8 or >8%), BMI (35 or >35 kg/m²), and sulfonylurea use (yes/no).

Study medication (pramlintide or placebo) was self-administered subcutaneously immediately before major meals depending on the patient's typical meal pattern (b.i.d. or t.i.d.). Patients initiated study medication at a volume equivalent to 60 µg pramlintide per dose and escalated to a volume equivalent to 120 µg per dose within 3–7 days if no clinically significant nausea occurred. Once the maintenance dose was achieved, investigators were asked to make weekly adjustments in the insulin glargine dose to target a fasting glucose concentration of 70 to <100 mg/dl using an algorithm previously described by Riddle et al. (3). Patients self-monitored fasting glucose concentrations daily and completed two self-monitored, seven-point glucose profiles during the week before each visit consisting of measurements taken 15 min before and 1.5–2 h after the start of each meal and at bedtime. Patients were required to eat three meals on profile days. Patients used study-provided Accu-Chek Aviva blood glucose monitors (Roche Diagnostics, Indianapolis, IN), reporting plasma-referenced glucose concentrations. At each visit, weight and vital signs were measured and self-monitored blood glucose values, insulin dose, and adverse events reviewed. A1C was measured at screening, baseline, and every 4 weeks thereafter. Laboratory measurement of fasting plasma glucose (FPG) was performed at baseline and week 16. Patients were instructed to maintain their usual diet and exercise regimens throughout the study.

Study end points
Two coprimary end points were evaluated in this study. The first coprimary end point was the change in A1C from baseline to week 16. The second coprimary end point was a dichotomous composite end point assessing the proportion of patients meeting all of the following prespecified criteria at week 16: 1) A1C 7.0% or an A1C reduction from baseline 0.5%, 2) mean daily PPG increments 40 mg/dl, 3) no weight gain, and 4) no severe hypoglycemia. Severe hypoglycemia was defined as a hypoglycemic event requiring assistance from another individual and/or administration of glucagon or intravenous glucose. Secondary end points included components of the composite end point, the proportion of patients achieving A1C 7.0 or 6.5% and changes from baseline to each time point in A1C, seven-point glucose profiles, PPG increments, FPG, weight, and insulin glargine dose. Similar ad hoc analyses for secondary end points were performed on patients divided into subgroups according to baseline A1C 8.5 or >8.5%.

Statistical analyses
A sample size of 90 patients per treatment arm was predicted to provide 90% power to detect a difference in the proportion of patients achieving the coprimary composite end point and 95% power to demonstrate noninferiority of pramlintide versus placebo for change in A1C from baseline. Noninferiority for change in A1C was concluded if the upper limit of the two-sided 95% CI for the difference between pramlintide and placebo was below the noninferiority margin of 0.4%. The overall power for reaching both coprimary end points was expected to be 85%. As both coprimary end points were required to be met, no adjustment to the significance level ( = 0.05) was required.

Analyses were performed on patients within the intent-to-treat population, all of whom received at least one dose of study medication. Missing individual data were imputed from the last scheduled visit using the last-observation-carried-forward approach for all efficacy analyses, with the exception of FPG, insulin dose, and the seven-point glucose profiles that were analyzed using the intent-to-treat observed population. Fisher's exact test was used to compare the proportion of patients achieving the coprimary composite and secondary binary end points. A general linear model including treatment, baseline A1C stratum (8.0 or >8.0%), BMI stratum (35 or >35 kg/m²), and sulfonylurea use (yes/no) as covariates was used to compare the change in A1C at week 16. Parametric analyses of secondary continuous end points were performed using general linear models including treatment and baseline value as covariates. Descriptive analyses and P values used the arithmetic and least squares means, respectively.

	RESULTS

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS-- RESULTS CONCLUSIONS-- APPENDIX References

 
Patient disposition and baseline demographics
Of 212 patients randomized, 91 (85%) placebo-treated and 87 (83%) pramlintide-treated patients completed the study (Table 1). One patient in the placebo-treated arm withdrew consent before injection of study medication, resulting in an intent-to-treat population of 211 patients. Baseline demographics were well matched between treatment arms (Table 1). Eighty-nine percent used at least one OA, and 50% used two or three OAs. Within the pramlintide-treated population, 98 (93%) patients escalated to the 120-µg dose.

View larger version (21K): [in this window] [in a new window]   Figure 1— A: Mean (±SE) change in A1C from baseline to each visit. *P < 0.05 for pramlintide vs. placebo. , placebo; , pramlintide. B: Percentage of patients achieving the composite end point at week 16. C: Percentage of patients achieving each component within the composite end point at week 16. , placebo; , pramlintide. D: Percentage of patients achieving at least two components, not including severe hypoglycemia, within the composite end point at week 16. , placebo; , pramlintide. B–D: *P < 0.005; **P < 0.0001 for pramlintide vs. placebo.

Secondary end points
Components of the composite end point.
The percentage of pramlintide-versus placebo-treated patients achieving an A1C 7.0% or an A1C reduction 0.5% was not significantly different (Fig. 1C). Significantly more pramlintide-treated patients achieved mean PPG increments 40 mg/dl (P < 0.0001) and did not gain weight (P < 0.0001). Compared with placebo, more pramlintide-treated patients achieved both A1C and PPG components (P < 0.005), more reached the A1C goal without weight gain (P < 0.0001), and more had well-controlled PPG without weight gain (P < 0.0001) (Fig. 1D). One episode of severe hypoglycemia occurred in a pramlintide-treated patient but was deemed unrelated to pramlintide treatment by the investigator.

Insulin.
Insulin glargine dosage increased steadily throughout the study (Fig. 2A). Mean (±SE) week 16 dosage was 61.4 ± 3.4 units (pramlintide) and 69.5 ± 5.3 units (placebo), reflecting increases of 11.7 ± 1.9 units and 13.1 ± 1.6 units, respectively.

View larger version (24K): [in this window] [in a new window]   Figure 2— A: Mean (±SE) daily insulin glargine doses. , placebo; , pramlintide. B: Mean (±SE) change in PPG increments from baseline during the study. , placebo; , pramlintide. *P < 0.0001 for pramlintide vs. placebo. C: Mean (±SE) change in body weight from baseline during the study. *P < 0.0001 for pramlintide vs. placebo. , placebo; , pramlintide. D and E: Individual weight changes from baseline for placebo-treated (D) and pramlintide-treated (E) patients. Percentages of patients that gained or lost weight are indicated.

PPG increments.
Mean (±SE) PPG increments at week 16 were 34.8 ± 2.7 mg/dl (pramlintide) and 56.6 ± 2.3 mg/dl (placebo), reflecting significant decreases in PPG increments from baseline to week 16 in pramlintide- versus placebo-treated patients (–24.4 ± 3.6 mg/dl [pramlintide] vs. –0.4 ± 3.0 mg/dl [placebo]) (P < 0.0001) (Fig. 2B).

Weight.
Pramlintide treatment resulted in progressive weight loss, while placebo-treated patients gained weight (week 16: –1.6 ± 0.3 kg vs. 0.7 ± 0.3 kg, P < 0.0001) (Fig. 2C). At week 16, approximately two-thirds (68%) of pramlintide-treated patients had lost weight compared with approximately one-third (35%) of placebo-treated patients (P < 0.0001) (Fig. 2D and E).

Patient stratification according to baseline A1C
To further explore the implications of these results in clinical practice, we divided the study population into two subgroups according to the mean baseline A1C (8.5 or >8.5%) (Table 1). These subgroups were similar in baseline characteristics, except for mean A1C (7.8 vs. 9.4%) and mean FPG (132 vs. 158 mg/dl). Insulin glargine dosage increased steadily from baseline to week 16 in both subgroups.

Baseline A1C 8.5%.
At week 16, pramlintide-treated patients exhibited reductions from baseline in mean (±SE) A1C (–0.36 ± 0.13%), FPG (–17.3 ± 7.1 mg/dl), PPG increments (–24.9 ± 4.4 mg/dl), and weight (–2.0 ± 0.4 kg). In contrast, placebo-treated patients exhibited a reduction from baseline in mean (±SE) FPG (–7.5 ± 6.8 mg/dl) but did not exhibit changes from baseline in A1C (–0.08 ± 0.09%), PPG increments (–3.6 ± 3.8 mg/dl), or weight (0.4 ± 0.4 kg).

Baseline A1C >8.5%.
At week 16, pramlintide-treated patients exhibited reductions from baseline in mean (±SE) A1C (–1.19 ± 0.14%), FPG (–44.4 ± 12.7 mg/dl), PPG increments (–23.7 ± 5.9 mg/dl), and weight (–1.0 ± 0.3 kg). Placebo-treated patients exhibited reductions from baseline in mean (±SE) FPG (–18.4 ± 9.4 mg/dl) and A1C (–0.69 ± 0.13%) but did not exhibit a change in PPG increments (3.2 ± 4.6 mg/dl), and they gained weight (1.1 ± 0.4 kg). The reduction in PPG increments in pramlintide- but not placebo-treated patients in both A1C subgroups is illustrated by seven-point glucose profiles performed at baseline and week 16 (Fig. 3).

View larger version (21K): [in this window] [in a new window]   Figure 3— Mean (±SE) seven-point glucose profiles in patients with baseline A1C 8.5% (A and B) or >8.5% (C and D).

	CONCLUSIONS—

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS-- RESULTS CONCLUSIONS-- APPENDIX References

 
Patients with suboptimal glycemic control on basal insulin therapy may further improve control by increasing the basal insulin dose and/or adding mealtime insulin, but at the expense of additional weight gain and an increased risk of hypoglycemia (1,10). In addition to their clinical significance, these side effects are disliked by patients and, thus, may deter intensification of insulin therapy.

This study demonstrated that the addition of pramlintide with continued basal insulin titration allowed such patients to achieve improved glycemic control and additional metabolic benefits not achieved with insulin titration alone. Pramlintide, as an adjunct to basal insulin, allowed patients to achieve an A1C lower than that achieved with basal insulin titration alone. This was accomplished through pramlintide-dependent reductions in PPG increments coupled with reductions in fasting glucose resulting from basal insulin titration. Moreover, as in prior studies of pramlintide used in combination with mealtime insulin (16,17,19), this treatment regimen resulted in weight loss, while insulin titration alone caused weight gain. The coprimary composite study end point, comprising A1C, PPG, weight, and severe hypoglycemia components, was designed to measure the proportion of patients achieving a highly desirable clinical outcome. Significantly more pramlintide-treated patients achieved this end point (25%) than patients receiving insulin alone (7%), confirming the clinical advantages of pramlintide plus basal insulin over basal insulin alone.

Therapies that reduce PPG and body weight may provide long-term benefits to patients with type 2 diabetes. Postprandial hyperglycemia has been implicated in the development of micro- and macrovascular complications through mechanisms including increased oxidative stress and inflammation (20–22). Moreover, obesity is very common in patients with type 2 diabetes and contributes to an already-increased risk of cardiovascular disease.

Whether the severity of A1C elevation at baseline affects the benefits of adding pramlintide is of clinical interest. Therefore, ad hoc analyses were performed on patient subgroups with baseline A1C >8.5 or 8.5%. In patients with higher baseline A1C, basal insulin titration alone reduced A1C at the price of weight gain, while pramlintide plus basal insulin titration resulted in greater reductions in A1C (via PPG reductions) and induced weight loss. In patients with lower baseline A1C, basal insulin titration alone did not provide much benefit, indicating the need for additional therapy. In contrast, pramlintide plus basal insulin titration reduced both A1C and weight. Thus, pramlintide provided benefits beyond those of basal insulin alone regardless of baseline A1C.

This study had several limitations. First, the relatively short 16-week duration was not long enough to allow insulin dosage, A1C, and weight to plateau. Second, many patients entering this study had high A1C values despite substantial basal insulin doses (54 units daily for those with baseline A1C >8.5%), suggesting that endogenous insulin secretion was low. Many of those patients will eventually need mealtime insulin to reach an A1C 7.0%. Studying the use of pramlintide with basal insulin earlier in the course of type 2 diabetes is therefore of interest. Third, the seven-point glucose profiles demonstrated improved but persistently high postbreakfast glucose increments in pramlintide-treated patients. Some pramlintide-treated patients might have benefited from mealtime insulin at breakfast to achieve adequate glycemic control.

Pramlintide added to basal insulin was generally well tolerated. Earlier studies of pramlintide indicated an increased risk of insulin-induced severe hypoglycemia, which occurred primarily in the more hypoglycemia-prone type 1 diabetic population (16,17). In contrast, no treatment-related severe hypoglycemia occurred in the present study. Also, the frequency of mild-to-moderate hypoglycemia was similar between the two treatment arms, despite the fact that pramlintide-treated patients achieved significantly better glycemic control.

In summary, adding pramlintide to basal insulin improved multiple aspects of diabetes control, thereby addressing important challenges associated with intensifying insulin therapy. These findings support pramlintide as a potential option for the next therapeutic step when patients with type 2 diabetes are not achieving glycemic targets with basal insulin therapy. Further studies examining pramlintide as an alternative to mealtime insulin are warranted.

	APPENDIX

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS-- RESULTS CONCLUSIONS-- APPENDIX References

 
Participating investigators: A. Ahmann, S. Aronoff, R. Bhushan, W. Cheatham, R. Cherlin, G. Collins, M. Feinglos, N. Fishman, G. Grunberger, R. Guthrie, P. Hollander, R. Kaplan, D. Karl, A. King, E. Klein, L. Levinson, P. Levy, M. May, M. Magee, A. McCall, W. Miers, T. Moretto, L. Olansky, W. Petit, A. Philis-Tsimikas, S. Plevin, J. Pullman, B. Ramlo-Halsted, M. Rendell, M. Riddle, D. Robertson, R. Rood, J. Rosenstock, J. Shapiro, T. Wahl, R. Weinstein, F. Whitehouse, K. Williams, A. Wynne, C. Wysham, and L. Zemel.

	Acknowledgments

 
Data from this study were presented at the 67th annual meeting of the American Diabetes Association, Chicago, Illinois, 22–26 June 2007, and at the 43rd annual meeting of the European Association for the Study of Diabetes, Amsterdam, the Netherlands, 17–21 September 2007.

	Footnotes

 
Published ahead of print at http://care.diabetesjournals.org on 13 August 2007. DOI: 10.2337/dc07-0589. Clinical trial reg. no. NCT00240253, clinicaltrials.gov.

M.R. has received grant/research support from Amylin Pharmaceuticals, Eli Lilly, and sanofi-aventis; has received consulting fees from Amylin Pharmaceuticals, ConjuChem, Emisphere, Eli Lilly, and sanofi-aventis; and has received honoraria from Amylin Pharmaceuticals, Eli Lilly, GlaxoSmithKline, Pfizer, and sanofi-aventis.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

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.

Received for publication March 25, 2007. Accepted for publication August 3, 2007.

	References

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS-- RESULTS CONCLUSIONS-- APPENDIX References

 

1. U.K. Prospective Diabetes Study Group: U.K. Prospective Diabetes Study 16. Overview of 6 years’ therapy of type II diabetes: a progressive disease. U.K. Prospective Diabetes Study Group. Diabetes 44: 1249–1258, 1995[Abstract]
   
2. DeFronzo RA: Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 131: 281–303, 1999[Abstract/Free Full Text]
   
3. Riddle MC, Rosenstock J, Gerich J: The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 26: 3080–3086, 2003[Abstract/Free Full Text]
   
4. Hermansen K, Davies M, Derezinski T, Martinez Ravn G, Clauson P, Home P: A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetes Care 29: 1269–1274, 2006[Abstract/Free Full Text]
   
5. Jaap AJ, Jones GC, McCrimmon RJ, Deary IJ, Frier BM: Perceived symptoms of hypoglycaemia in elderly type 2 diabetic patients treated with insulin. Diabet Med 15: 398–401, 1998[Medline]
   
6. Gurlek A, Erbas T, Gedik O: Frequency of severe hypoglycaemia in type 1 and type 2 diabetes during conventional insulin therapy. Exp Clin Endocrinol Diabetes 107: 220–224, 1999[Medline]
   
7. Hepburn DA, MacLeod KM, Pell AC, Scougal IJ, Frier BM: Frequency and symptoms of hypoglycaemia experienced by patients with type 2 diabetes treated with insulin. Diabet Med 10: 231–237, 1993[Medline]
   
8. U.K. Prospective Diabetes Study (UKPDS) Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352: 837–853, 1998[Medline]
   
9. Henry RR, Gumbiner B, Ditzler T, Wallace P, Lyon R, Glauber HS: Intensive conventional insulin therapy for type II diabetes: metabolic effects during a 6-mo outpatient trial. Diabetes Care 16: 21–31, 1993[Abstract]
   
10. Purnell J, Weyer C: Weight effect of current and experimental drugs for diabetes mellitus: from promotion to alleviation of obesity. Treat Endocrinol 2: 33–47, 2003[Medline]
    
11. Young AA: Amylin's physiology and its role in diabetes. Curr Opin Endocrinol Diab 4: 282–290, 1997
    
12. Young AA, Gedulin B, Vine W, Percy A, Rink TJ: Gastric emptying is accelerated in diabetic BB rats and is slowed by subcutaneous injections of amylin. Diabetologia 38: 642–648, 1995[Medline]
    
13. Gedulin BR, Rink TJ, Young AA: Dose-response for glucagonostatic effect of amylin in rats. Metabolism 46: 67–70, 1997[Medline]
    
14. Lutz TA, Mollet A, Rushing PA, Riediger T, Scharrer E: The anorectic effect of a chronic peripheral infusion of amylin is abolished in area postrema/nucleus of the solitary tract (AP/NTS) lesioned rats. Int J Obes Relat Metab Disord 25: 1005–1011, 2001[Medline]
    
15. Rushing PA, Lutz TA, Seeley RJ, Woods SC: Amylin and insulin interact to reduce food intake in rats. Horm Metab Res 32: 62–65, 2000[Medline]
    
16. 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[Abstract/Free Full Text]
    
17. 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[Medline]
    
18. 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 48: 838–848,2005
    
19. 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[Abstract/Free Full Text]
    
20. Ceriello A: Oxidative stress and diabetes-associated complications. Endocr Pract 12(Suppl. 1): 60–62, 2006
    
21. Brownlee M: Biochemistry and molecular cell biology of diabetic complications. Nature 414: 813–820, 2001[Medline]
    
22. Home P: Contributions of basal and post-prandial hyperglycaemia to micro- and macrovascular complications in people with type 2 diabetes. Curr Med Res Opin 21: 989–998, 2005[Medline]
    

CiteULike

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				S. V. Edelman Optimizing Diabetes Treatment Using an Amylin Analogue The Diabetes Educator, January 1, 2008; 34(1_suppl): 4S - 10S. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: dc07-0589v1 30/11/2794    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Riddle, M. Articles by Kolterman, O. Search for Related Content PubMed PubMed Citation Articles by Riddle, M. Articles by Kolterman, O. Social Bookmarking                What's this?