The British Journal of Diabetes & Vascular Disease

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Amylin analogue as an antidiabetic agent

Caroline Day
British Journal of Diabetes & Vascular Disease 2005; 5; 151
DOI: 10.1177/14746514050050030701

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Amylin analogue as an antidiabetic agent

CAROLINE DAY

Abstract

T
he amylin analogue pramlintide (SYMLIN®) is the first in a new class of injectable amylinomimetic agents to be
approved for the treatment of diabetes. This adjunct to insulin treatment of type 1 and type 2 diabetes has
recently been approved for use in the USA. Pramlintide, unlike native amylin is soluble. It acts mainly via

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central effects (area postrema) resulting in deceased glucagon secretion, slowing gastric emptying and a satiety
effect. It is injected subcutaneously separately from insulin, and usually before each of the main meals. It has been

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shown to improve glycaemic control without causing weight gain but the dose must be titrated slowly in

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association with appropriate insulin adjustments to guard against insulin-induced hypoglycaemia and nausea. Thus,

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pramlintide is an injected amylin replacement therapy that can be used with an insulin regimen to improve

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glycaemic control without weight gain.

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Br J Diabetes Vasc Dis 2005;5:151–4

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Key words: amylin, pramlintide, type 1 diabetes, type 2 diabetes, injections.
PR IA
Introduction
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Figure 1. Normal day profiles of plasma amylin and insulin

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Despite an extensive range of oral antidiabetic agents and

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insulins, these therapies do not reinstate normal glucose-insulin

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homeostasis in people with diabetes.1 The first non-insulin

Key:
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injectable antidiabetic agent to receive marketing approval 30

Meal Insulin
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(March 2005) is SYMLIN® (pramlintide acetate) injection, which is Amylin

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now available in the USA as an adjunct to insulin therapy in type 25 Meal Meal 600

Plasma insulin pmol/L

Plasma amylin pmol/L
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1 and type 2 diabetes.

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20
Amylin
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400
The islet polypeptide amylin – otherwise known as IAPP – was
15
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initially identified in the islet amyloid deposits of people with type

2 diabetes and therefore originally termed diabetes-associated 200
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peptide. Amylin is synthesised by the islet beta-cells: it is co- 10

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localised with insulin and is usually co-secreted with insulin,

although secretory granules can vary in their proportions of 0
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0
amylin and insulin. However, some amylin does not remain pack- 6am Noon 6pm Midnight 6am
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aged in secretory granules and these ‘itinerant’ amylin

monomers polymerise to form insoluble amyloid fibrils within the
islets.2 Although amyloid deposition is a normal feature of age-
ing, amylin has been reported to promote beta-cell maturation.3
In non-diabetic individuals amylin and insulin show similar
day profiles (figure 1) and in type 1 and type 2 diabetes concen-
trations of circulatory amylin are consistent with endogenous
Correspondence to: Dr Caroline Day
Diabetes Group, Life and Health Sciences, Aston University, Birmingham,
B4 7ET, UK.
Tel: +44 (0)121 204 3898; Fax: +44 (0)121 204 3892
E-mail: cday@mededuk.com
Based on Koda et al. 19954
insulin status (figure 2). Thus, in type 1 diabetes there is an
absence of amylin, and in more advanced states of type 2 dia-
betes there is very little circulating amylin.
Amylin appears to have a physiological role, acting centrally
to induce satiety, slow gastric emptying and suppress pancreatic
glucagon secretion.
Pramlintide
Pramlintide acetate (SYMLIN®) was approved by the US FDA as an
adjunct treatment in type 1 and type 2 diabetic patients who use

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Abbreviations
Figure 4. Sites of action of amylin to reduce hyperglycaemia and
weight gain
FDA Food and Drug Administration
HbA1C glycated haemoglobin A1C
HGO hepatic glucose output
IAPP Islet Amyloid PolyPeptide
sc subcutaneous Pramlintide

Beta-cells Brain
Pancreas
Amylin (IAPP)

Area
Figure 2. Plasma amylin response to a sustacal meal postrema

Alpha cells
Gastric
emptying
20 Glucagon

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Sustacal
Plasma amylin pmol/L

secretion
meal Normal
Rate of

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15 HGO digestion Satiety

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10 Type 2 DM

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Hyperglycaemia Food intake
5

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Type 1 DM

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0
0 60 120 180

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pramlintide decreases the rate of gastric emptying8 and reduces
Minutes
PR IA secretion of gastric acid and pancreatic juice, all of which col-
laborate to retard the rate of digestion, but not overall nutrient
Based on Weyer et al. 20015
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absorption, and thereby decrease circulatory appearance of
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glucose (figure 5). These effects are mediated through central

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pathways that may be activated by binding of pramlintide to

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the amylin receptors within the area postrema in the brainstem.

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Figure 3. Amino acid sequence of human amylin and its analogue Pramlintide may also act as a signal for the central regulation
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pramlintide of food intake and body weight.5,6 Indeed, administration of

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pramlintide to people with type 1 (30 µg sc) or type 2 (120 µg

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sc) diabetes one hour before an unlimited buffet meal

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Amylin YTNSGVNTSSLIAGFNNSSHVLFNALRQTACTATNCK decreased total calorie intake by at least 20% compared with
placebo, without decreasing meal duration.
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Using pramlintide
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Pramlintide YTNSGVNTPPLIPGFNNSSHVLFNALRQTACTATNCK
Pramlintide is a peptide hormone analogue and should be
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stored in a refrigerator at 2–8ºC (36–46ºF). It should be

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administered subcutaneously immediately prior to a major meal

mealtime insulin therapy and who have failed to achieve desired (> 250 kcal or > 30 g carbohydrate), and must be administered
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glucose control despite optimal insulin therapy (+ concurrent as a separate injection to insulin. This reflects differences of
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sulphonylurea and/or metformin therapy in type 2 diabetes).
Pramlintide is a soluble analogue of amylin in which the
amino acid sequence has been modified by the replacement of
alanine and serine with proline at positions 25 and 28, 29
respectively (figure 3). Since pramlintide is soluble it does not
aggregate or accumulate in islet tissue, and is not therefore
associated with the detrimental effects of insoluble native
amylin.
Pramlintide, like amylin, complements the effects of insulin
in postprandial glucose homeostasis by a range of actions that
regulate the rate of glucose appearance into the circulation5,6
(figure 4). These actions include suppression of pancreatic
glucagon secretion (not normalised by insulin alone) which in
turn reduces hepatic glucose output7 (figure 5). Additionally
pH that can alter the pharmacokinetic properties of both
agents.9
The effects of pramlintide last for about three hours after
administration. To reduce variability pramlintide should be inject-
ed into the thigh or abdominal area rather than the arm. The
bioavailability of a single sc injection of pramlintide is 30–40%:
approximately 60% is bound in the plasma and there are no indi-
cations of bioaccumulation with repeat dosing. Pramlintide is
metabolised mostly by the kidneys to form a primary metabolite
that is also active.
The main potential side effect of pramlintide administration
is insulin-induced hypoglycaemia, which is most likely to occur
within the first three hours after injection. Although pramlintide
alone does not cause hypoglycaemia, when it is administered

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Figure 5. Effects of pramlintide on glucagon7 and gastric emptying in Figure 6. Effects of pramlintide on HbA1C and weight in type 1 and
type 1 diabetes8 type 2 diabetes

20 Type 1 diabetes
Plasma glucagon, pg/mL

0
Liquid

HbA 1C (%)
Change in
meal -0.5

10
-1.0

-1.5
0 6 12
Months
0

ED
0 60 120 +1

Change in body
weight (kg)
Minutes

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0
Key:

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Insulin + placebo
-1
Insulin + pramlintide 30 μg qid

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4 -2

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0 6 12
Gastric empty t1/2(h)

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Months
Key:

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Insulin + placebo
2 PR IA Insulin + pramlintide 30/60 μg qid
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Type 2 diabetes
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0
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0
HbA 1C (%)
Change in
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Insulin 30 60 90 -0.5
only
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Pramlintide (μg) -1.0

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Based on Fineman et al. 19987 and Kong et al. 19988

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-1.5
R E

0 6 12
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Months
+1
Change in body

during insulin therapy the risk of insulin-induced hypoglycaemia,

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weight (kg)

especially in patients with type 1 diabetes, is increased. This risk 0

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has been recognised by inclusion of a black box warning in the

drug labelling. In order to reduce this risk of hypoglycaemia a -1
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50% reduction in the pre-meal dose of short-acting insulin is rec-

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-2
ommended in association with regular pre- and postprandial
0 6 12
glucose monitoring. Further insulin dose adjustment may be
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Months
necessary in patients also taking other drugs that affect glucose
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homeostasis. Modification of the insulin-pramlintide regimen is
explained in the medication guide.9
The most commonly observed side effects of amylin replace-
ment therapy were gastrointestinal in nature – mainly nausea –
which usually resolved within days to weeks of commencing
treatment. These effects can be minimised by gradual escalation
of the pramlintide dose.
Clinical trials
A plethora of clinical studies has been published in journals
indexed on the Medline database (http://www.ncbi.nlm.nih.gov/
entrez/query.fcgi – search for: ‘clinical trials, pramlintide’) and
data from these studies plus information on file with the manu-
facturer have been reviewed.5,6,10
Based on Whitehouse et al. 200211 and Ratner et al. 200212
Studies undertaken in people with type 1 and type 2 diabetes
have consistently shown that addition of pramlintide to existing
insulin treatment regimens improved glycaemic control. For
example treatment over a 12-month period significantly reduced
HbA1C by ~0.5–1% from baseline, and significant decreases ver-
sus placebo were evident within a few weeks of commencing
treatment (figure 6). These improvements were achieved without
increasing insulin dosage and the number of patients able to
achieve HbA1C < 7% was 2–3-fold greater than amongst
patients not taking pramlintide. In type 1 diabetic patients using

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insulin pumps administration of pramlintide (30–45 µg) was also

effective in controlling the post-meal glycaemic swings in type 1
diabetic patients on insulin pumps.13 Key messages
Of particular interest is that improvements in glycaemic
control on pramlintide therapy were accompanied by weight
loss. By the end of 1 year of treatment with pramlintide plus ● The soluble amylin analogue pramlintide:
insulin patients with type 1 and type 2 diabetes had lost a
- is an injectable adjunct to insulin therapy
mean of ~0.5 kg and 1.5 kg respectively whilst patients on
placebo plus insulin had gained a mean of ~1 kg in body - improves HbA1C in type 1 and type 2 diabetes
weight compared with baseline (figure 6). Acute administration - enhances satiety and aids weight loss
of pramlintide (120 µg sc) to overweight insulin-treated type 2 - should be administered as prandial injections separate
diabetic men (mean BMI 28.9 kg/m2) and obese non-diabetic from insulin
men (mean BMI 34.4 kg/m2) significantly reduced energy

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intake, with hormonal analyte profiles suggesting that pramlin- - requires dose adjustment, as does the insulin dose,
to guard against insulin-induced hypoglycaemia
tide exerts satiety effects independently of other anorexigenic

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gut peptides.14

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Of the 5,325 people who participated in the pramlintide clin-

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ical trials submitted to the FDA, 1,688 had type 2 diabetes and

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2,375 had type 1 diabetes. With regard to the activity of pram- References

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lintide no age-related differences were noted in patients > 65 1. Bailey CJ. New drugs for the treatment of diabetes mellitus in DeFronzo

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RA, Ferrannini E, Keen H, Zimmet P (eds). International textbook of dia-
years (n=539), and no consistent gender-related (n=2,799 males; betes mellitus, 3rd edn, John Wiley and Sons Ltd, Chichester, 2004,

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n=2,085 females) or race/ethnicity (n=4,257 whites; n=229 pp951-79.
blacks; n=337 Hispanics; n=61 other origins) differences were
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observed in these trials. However, these studies were not an aetiological factor in Type 2 diabetes? Diabetologia 2004;47:157-69.
3. In’t Veld PA, Zhang F, Madsen OD, Kloppel G. Islet amyloid polypeptide
N D
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O (

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C W

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due to the renal metabolism of the drug circulatory concentra-

control. Current Pharmaceutical Design 2001;7:1353-73.
R E

tions of pramlintide are not expected to be affected by hepatic

6. Buse JB, Weyer C, Maggs DG. Amylin replacement with pramlintide as
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dysfunction. Interestingly no pramlintide-treated patient was an adjunct to insulin therapy in type 1 and type 2 diabetes mellitus: A
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but some patients experienced local allergy at the injection site Diabetes 2002;20:137-44.
7. Fineman M, Koda J, Lolterman O. Subcutaneous administration of a
IG

which resolved within a few days or weeks. Antibodies to pram-

human amylin analogue suppresses postprandial plasma glucagon con-
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R

ation to clinical effect was noted. 8. Kong MF, Stubbs TA, King P et al. The effect of single doses of pramlin-
PY

The commonest adverse event was nausea which affected tide on gastric emptying of two meals in men with IDDM. Diabetologia
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9. Symlin prescriber information. www.symlin.com/docs/Symlin_PI_and_

pramlintide in addition to insulin therapy in long-term placebo
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controlled studies. Nausea was more evident at the commence-
ment of pramlintide treatment and generally resolved. Gradual
up-titration of the pramlintide dosage reduced the incidence and
severity of nausea.
Conclusion
Under normal physiological circumstances amylin is co-secreted
with insulin to maintain glucose homeostasis. Amylin replacement
therapy with pramlintide provides an opportunity to mimic the
non-diabetic state with a reduction in hyperglycaemia without
increasing the insulin dosage. A further advantage of this strategy
is that improvements in glycaemic control are achieved without an
associated gain in body weight – this is particularly attractive in the
treatment of overweight patients with type 2 diabetes.
Med_Guide.pdf
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litus. Ann Pharmacother 2003;37:1082-9.
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open-label extension evaluating the long-term efficacy of pramlintide as
an adjunct to insulin therapy in type 2 diabetes. Diabetes Care 2002;25:
724-30.
12. Ratner RE, Want LL, Fineman MS et al. Adjunctive therapy with the
amylin analogue pramlintide leads to a combined improvement in
glycemic and weight control in insulin-treated subjects with type 2 dia-
betes. Diabetes Technol Ther 2002;4:63-5.
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food intake in obese subjects and subjects with type 2 diabetes.
Diabetologia 2005;48:838-48.

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