Incretin Deficiency Non-Insulin Injectable Agents1 Non-Insulin Injectable Agents Longer-acting...

1

Non-Insulin Injectable Agents ●  Longer-acting analogs? (Incretin mimetics)

●  GLP-1 Analogs

Drucker DJ et al. Lancet. 2006;368:1696–1705.

●  Inhibition of inactivation? (Incretin enhancers) ●  DPP-4 Inhibitors

Approaches to Addressing Incretin Deficiency

DPP-4 = dipeptidyl-peptidase 4 1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913. 2. Ahrén B. Curr Diab Rep. 2003;2:365–72. 3. Drucker DJ. Diabetes Care. 2003;26:2929–40. 4. Holst JJ. Diabetes Metab Res Rev. 2002;18:430–41.

Ingestion of food

Beta cells Alpha cells

Release of gut hormones — Incretins1,2

Pancreas2,3

Glucose-dependent Insulin from beta cells

(GLP-1 and GIP) Glucose

uptake by muscles2,4

Glucose production

by liver

Blood glucose

Glucose dependent Glucagon from

alpha cells (GLP-1)

GI tract

Active GLP-1 & GIP

Inactive GIP

Inactive GLP-1 Concentrations of the active intact

hormones are increased by sitagliptin, thereby increasing and prolonging their action

Supra-physiologic

Incretin Concentrations

Incretin Mimetics GLP-1 Analogues

Incretin Enhancers DPP-4 Inhibitors

Approaches to Addressing Incretin Deficiency

GLP-1 vs DPP-4 Inhibitors: Understanding the Actions of Incretin-Based Therapies

Stomach: Delays gastric emptying

CNS Promotes satiety and reduces appetite

Liver: ↓ Glucagon reduces

hepatic glucose output Beta cells: Enhances glucose-dependent

insulin secretion

Alpha cells: ↓ Glucose-dependent

post-prandial glucagon secretion

GLP-1: Secreted upon the ingestion of food

Data from Flint A, et al. J Clin Invest 1998;101:515-520. Data from Larsson H, et al. Acta Physiol Scand 1997;160:413-422. Data from Nauck MA, et al. Diabetologia 1996;39:1546-1553. Data from Drucker DJ. Diabetes 1998;47:159-169.

Food Intake

GLP-1

β-Cell Function

GLP-1 & DPP-4 Inhibitors

Glucose Absorption

GLP-1

Glucose Production

GLP-1 & DPP-4 Inhibitors

Incretin Mimetics

Develop Drugs that Bind to the Incretin Receptor (mimetics that are resistant to DPP-4 inhibition)

Drucker DJ et al. Lancet. 2006;368:1696–1705.

Exenatide ●  GLP-1 agonist ●  53% homology to human GLP-1 ●  SC BID ●  Low risk of hypoglycemia ●  Mainly PPG effects ●  Side effects: nausea; rare reports of

hemorrhagic or necrotizing pancreatitis

Exenatide QW ●  Long-acting-release (LAR) formula of

exenatide ●  SC once per week ●  More effective than twice-daily form, similar

safety and weight loss, less nausea

Liraglutide ●  GLP-1 analog ●  Human GLP-1 derivative, 97%

homology to human GLP-1 ●  SC once-daily ●  Reduces FPG and PPG ●  Less nausea, greater BG

reductions than exenatide ●  Low risk of hypoglycemia ●  A1C reduced by 0.8% to 1.75%

and weight by 2.5 to 3 kg 0 3 6 9 12

0

100000

200000

300000

400000

Time After Meal (h)

Exendin-4 in the Gila Monster ●  Exendin-4 was originally

isolated from the salivary secretions of the Gila monster

●  The Gila monster eats large amounts of food, but does that quite seldom. These lizards eat as few as four times each year, storing large amounts of fat in their tails and living off that in longer periods of time. When the lizard eats, the exendin-4 in the spit of the animal "wakes" pancreatic islet activity, giving rise to beta-cell activity, insulin release and control of glucose and fat metabolism.

●  Exenatide is a synthetic version of Exendin-4

●  Exenatide was the first incretin mimetic

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Effect of Exenatide on Fasting Plasma Glucose and Insulin in Type 2 Diabetes

Data from: Kolterman OG, et al. J Clin Endocrinol Metab 2003; 88:3082-3089

Evaluable population (n=12) Mean ± SE

-1 0 1 2 3 4 5 6 7 8 -1 0 1 2 3 4 5 6 7 8 5

7.5

10

12.5

15

0

50

100

150

200

250

300

Time (h) Time (h)

Placebo 0.05 µg/kg exenatide 0.1 µg/kg exenatide 0.2 µg/kg exenatide

Placebo 0.05 µg/kg exenatide 0.1 µg/kg exenatide 0.2 µg/kg exenatide

Plas

ma

Glu

cose

(mm

ol/L

)

Seru

m In

sulin

(pm

ol/L

)

Effect of Exenatide on Post-prandial Glucose and Glucagon in Type 2 Diabetes

Plas

ma

Glu

cago

n (p

g/m

L)

Plas

ma

Glu

cose

(mm

ol/L

)

0

5

10

15

20 Exenatide or Placebo

Standardized Breakfast

0 60 120 180 240 300

Time (min) 0 120 180 30 90 60 150

Time (min)

50

100

150

200

250 Exenatide or Placebo

Standardized Breakfast

Placebo Exenatide 0.1 µg/kg

Placebo Exenatide 0.1 µg/kg

Data from Kolterman OG, et al. J Clin Endocrinol Metab 2003; 88:3082-3089

n=20 Mean ± SE

Exenatide: Effects on Glycemic Control in Combination With Current Oral Therapies

Exenatide: Clinical Pharmacology

●  Indication: ●  Indicated as an adjunct to diet and exercise to improve

glycemic control in adults with type 2 diabetes mellitus

●  Metabolism: ●  Predominantly eliminated by glomerular filtration

●  Drug Interactions: Use caution in patients taking … ●  Oral meds requiring rapid absorption ●  Meds dependent on threshold concentrations for efficacy

such as contraceptives and antibiotics – advise pt to take these meds at least 1hr before exenatide

●  If drugs are to be administered with food, pts should be advised to take them with a meal or snack when exenatide is not administered


●  Effectiveness: 5mcg BID 10mcg BID

●  A1C -0.4% -0.8%

●  FBG -8 mg/dL -10 mg/dL

●  PPG -63 mg/dL -71 mg/dL

●  Administration: ●  Available in pre-filled pens (5 µg, 10 µg) for SC injection ●  Each pen delivers 60 doses (30 day BID dosing) ●  Administered anytime within 60-minute period before the

morning and evening meal (DO NOT give after meals)


●  Precautions: ●  Acute Pancreatitis

●  Post-marketing data has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis.

●  After initiation and dose increases, observe patients carefully for signs and symptoms of pancreatitis.

●  Medications Known to Cause Hypoglycemia ●  Patients receiving a sulfonylurea may require a lower dose of the

sulfonylurea to reduce the risk of hypoglycemia.

●  Renal Impairment ●  Should not be used in patients with severe renal impairment (CrCl < 30

mL/min) or end-stage renal disease. ●  Used with caution in patients with renal transplantation. ●  Exenatide may induce nausea and vomiting with transient hypovolemia,

and therefore worsen renal function. Caution should be applied when initiating or escalating the dose from 5 mcg to 10 mcg in patients with moderate renal impairment (CrCl 30 to 50 mL/min).

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●  Precautions: ●  Gastrointestinal Disease

●  Is commonly associated with gastrointestinal adverse reactions, including nausea, vomiting, and diarrhea, the use of exenatide is not recommended in patients with severe gastrointestinal disease.

●  Immunogenicity •  Pts may develop antibodies to exenatide. Antibody formation was

associated with an attenuated glycemic response. If there is worsening glycemic control or failure to achieve targeted glycemic control, alternative antidiabetic therapy should be considered.

●  Hypersensitivity ●  Postmarketing reports of serious hypersensitivity reactions (e.g.

anaphylaxis and angioedema) have been documented


●  Adverse Effects: •  Nausea •  Jittery •  Dyspepsia

•  Vomiting •  Dizziness •  Hypoglycemia (with sulfyl use)

•  Diarrhea •  Headache •  Weight Loss

●  Dosage: ●  5 µg BID within a 60-minute period before the morning and evening

meals ●  Based on clinical response dosage may be increased to 10 µg BID after

1 month of therapy

●  Storage: ●  Exenatide pens should be refrigerated at 36º F to 46º F. After first

use, your BYETTA Pen can be kept at a room temperature not to exceed 77°F (25°C)

●  Pen should be discarded 30 days after first use, even if some drug remains in the pen

Nausea Is Dose-dependent and Decreases Over Time

Buse JB, et al. Diabetes Care. 2004;27:2628-2635.

0

5

10

15

20

25

30

0-4 >4-8 >8-12 >12-16 >16-20 >20-24 >24-28 >28

Treatment (wk)

Inci

denc

e of

Nau

sea

(%

ITT

Subj

ects

)

10 µg 5 µg Placebo

Effect of Exenatide on Body Weight

Buse JB, et al. Diabetes Care. 2004;27:2628-2635.

0 10 20 30 40 50 60 70 80 90

Mea

n Δ

Wei

ght (

kg)

Exenatide Continued to Reduce Weight

Time (wk)

Baseline Weight 98 kg

100 kg 100 kg

Placebo BID 5 µg Exenatide BID 10 µg Exenatide BID

-5

-4

-3

-2

-1

0

1

82-wk completers; N = 393; Mean ± SE; Weight was a secondary endpoint Data on file, Amylin Pharmaceuticals, Inc.

Open-Label Extension Placebo-Controlled

Exenatide Continued to Reduce A1C Weight at 2.5 Years

2.5-y completers; N = 241; Mean ± SE; Patients were not required to follow any specified diet or exercise plan

Data on file, Amylin Pharmaceuticals, Inc.

-6

-5

-4

-3

-2

-1

0 0.5 2.5

Time (y)

Mean Δ Weight (kg)

-2.5

-5.1

Open-Label Extension – Combined Exenatide 10 µg BID Mean Baseline Weight 100 kg

-1.2 -1.1

0.5 2.5

-2

-1

Mean Δ A1C (%)

0

Time (y)

Mean Baseline A1C 8.3%

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Long-Acting Release Technology

●  Exenatide QW: Bydureon ●  A long-acting formulation of exenatide ●  Once weekly injection ●  Biodegradable polymeric microspheres for extended release ●  Detectable plasma concentrations of exenatide for weeks to

months after a single dose Initial release (1st 24 hours)

Extended release

hydration diffusion degradation erosion

Bartus RT et al. Science. 1998;281:1161-1162

release of surface drug

Lag phase

Plasma Exenatide QW Levels

Plas

ma

Exen

atid

e (p

mol

/L)

Time (weeks)

Mean Css,ave = 71.7 pmol/L

Data are Geometric mean ± 25-75th percentile range Data on file, Amylin Pharmaceuticals, Inc. Drucker DJ, et al. Presented at ADA, 68th Scientific Sessions; 2008; San Francisco, CA

Time (weeks)

Δ A

1C (%

)

* * *

* * *

-1.5±0.1%

-1.9±0.1%

Exenatide QW Produced a Greater Change in A1C

Data are LS mean (SE); *p<0.01, QW vs. BID Data on file, Amylin Pharmaceuticals, Inc. Drucker DJ, et al. Presented at ADA, 68th Scientific Sessions; 2008; San Francisco, CA

Proportion of Patients Achieving A1C Targets

Prop

ortio

n (%

)

* 77%

49%

25%

61%

42%

18%

≤7% ≤6.5% ≤6% *p=0.0039, QW vs BID Data on file, Amylin Pharmaceuticals, Inc. Drucker DJ, et al. Presented at ADA, 68th Scientific Sessions; 2008; San Francisco, CA

52-wk Evaluable Population (N=241); LS Mean (SE); *p<0.05 between groups Data on file, Amylin Pharmaceuticals, Inc. Buse JB, et al. Presented at ADA, 68th Scientific Sessions; 2008; San Francisco, CA

Exenatide QW Produced a Greater Change in A1C

Time (weeks)

Δ F

PG (m

g/dL

)

* * *

* * * *

-42 mg/dL

-25 mg/dL

Data are LS mean (SE); *p<0.05 QW vs BID Data on file, Amylin Pharmaceuticals, Inc. Drucker DJ, et al. Presented at ADA, 68th Scientific Sessions; 2008; San Francisco, CA

Exenatide QW Produced a Greater Change in FBG

5

Time (weeks)

Δ G

luca

gon

(pg/

mL)

*

* *

*

-6 mg/dL

-18 mg/dL

Data are LS mean (SE); *p<0.05 QW vs BID Data on file, Amylin Pharmaceuticals, Inc. Drucker DJ, et al. Presented at ADA, 68th Scientific Sessions; 2008; San Francisco, CA

Exenatide QW Produced a Greater Change in Levels of Fasting Plasma Glucagon

Time (weeks)

Δ B

ody

Wei

ght (

kg)

-3.7 kg -3.6 kg

Change in Body Weight at 30 Weeks

Data are LS mean (SE) Data on file, Amylin Pharmaceuticals, Inc. Drucker DJ, et al. Presented at ADA, 68th Scientific Sessions; 2008; San Francisco, CA

52-wk Evaluable Population (N=241); LS Mean (SE) Data on file, Amylin Pharmaceuticals, Inc. Buse JB, et al. Presented at ADA, 68th Scientific Sessions; 2008; San Francisco, CA

Change in Body Weight at 52 Weeks

●  Indications and usage ●  BYDUREON is an extended-release formulation of exenatide,

administered as an injection once every seven days (weekly). ●  Indicated as an adjunct to diet and exercise to improve glycemic

control in adults with type 2 diabetes mellitus. ●  Not recommended as first-line therapy. ●  Should not be used in patients with type 1 diabetes. ●  Has not been studied with insulin and cannot be recommended. ●  Exenatide has been associated with acute pancreatitis. Other

antidiabetic therapies should be considered in patients with a history of pancreatitis.

●  Administration ●  2 mg per dose should be administered once every seven days

(weekly). ●  May be administered at any time of day, with or without meals.

Exenatide Extended-Release: Clinical Pharmacology

Bydureon Package Insert , Amylin Pharmaceuticals, Inc., San Diego, CA

●  Administration ●  Missed doses should be administered as soon as noticed, provided the

next regularly scheduled dose is due at least three days later. Thereafter, patients can resume their usual dosing schedule of once every seven days (weekly).

●  If a dose is missed and the next regularly scheduled dose is due one or two days later, the patient should not administer the missed dose and instead resume injections with the next regularly scheduled dose.

●  The day of weekly administration can be changed if necessary as long as the last dose was administered 3 or more days before.

●  Administered as a subcutaneous injection in the abdomen, thigh or upper arm region.

●  Prior treatment with exenatide is not required when initiating exenatide extended-release therapy. If the decision is made to start exenatide extended-release in an appropriate patient already taking exenatide, the exenatide should be discontinued. Patients making the change may experience transient (approximately two weeks) elevations in blood glucose concentrations.



●  Contraindications ●  Exenatide extended-release is contraindicated in patients with a personal

or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).

●  Warnings ●  Risk of Thyroid C-cell Tumors---In both genders of rats, exenatide

extended-release caused a dose-related and treatment-duration dependent increase in the incidence of thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures compared to controls. It is unknown whether exenatide extended-release will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of exenatide extended-release-induced rodent thyroid C-cell tumors could not be determined by clinical or nonclinical studies.

  Acute Pancreatitis--- Exenatide has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. Observe patients carefully for signs and symptoms of pancreatitis.



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●  Warnings ●  Hypoglycemia---Risk of hypoglycemia is increased when exenatide is

used in combination with a insulin secretagogues. Therefore, a lower doses of secretagogues may be required.

●  Renal Impairment--- ●  Should not be used in patients with severe renal impairment (CrCl < 30 mL/

min) or end-stage renal disease. ●  Should be used with caution in patients with renal transplantation. ●  Exenatide may induce nausea and vomiting with transient hypovolemia, and

therefore worsen renal function. Caution should be applied when using in patients with moderate renal impairment (CrCl 30 to 50 mL/min)

●  Gastrointestinal Disease---Not recommended in patients with severe gastrointestinal disease.

●  Immunogenicity ---Pts may develop antibodies to exenatide resulting in an attenuated glycemic response. If worsening glycemic control or failure to achieve targeted glycemic control should occur an alternative antidiabetic therapy should be



●  Warnings ●  Hypersensitivity ---There have been postmarketing reports of

serious hypersensitivity reactions (e.g. anaphylaxis and angioedema) in patients treated with exenatide.

●  Drug Interactions ●  Exenatide slows gastric emptying and thus has the potential to

reduce the rate of absorption of orally administered drugs.

●  Storage ●  Should be stored in the refrigerator up to the expiration date or

until preparing for use. Each single-dose tray can be kept at room temperature for no more than a total of 4 weeks, if needed.



QW (N=148) %

BID (N=145) %

Nausea 26 35 Vomiting 11 19 Injection site pruritus 18 1 Upper respiratory tract infection

8 17

Diarrhea 15 13 Constipation 11 6 Injection site bruising 5 10 Urinary tract infection 10 8

* 2 patients withdrawn during lead-in not included

Data on file, Amylin Pharmaceuticals, Inc. Drucker DJ, et al. Presented at ADA, 68th Scientific Sessions; 2008; San Francisco, CA

30-week Assessment Period


Adverse Events With Overall Incidence ≥10%

Exenatide Extended-Release

BYDUREON must be administered immediately after the exenatide powder is suspended in the diluent and transferred to the syringe.

BYDUREON is provided in a single-dose tray containing: one vial of 2 mg exenatide, one vial connector, one prefilled diluent syringe and two needles (one provided as a spare).


Liraglutide a Long-acting GLP-1 Analogue

Knudsen et al. J Med Chem 2000;43: 1664-1669.

Acylation of GLP-1 leads to •  Self-association •  Albumin binding

•  Slow absorption from subcutaneous •  Long plasma half-life (Approx. 14 hours) •  Once daily dosing •  Resistance to DPP-IV

Based on natural GLP-1

(97% homology)

His Ala Thr Thr Ser Phe Glu Gly Asp

Val

Ser

Ser Tyr Leu Glu Gly Ala Ala Gln Lys

Phe

Glu

Ile Ala Trp Leu Gly Val Gly Arg

Glu

Arg

C-16 fatty acid (palmitoyl)

7 9

37

Liraglutide

●  Mechanism of Action ●  Stimulates insulin secretion in the presence of

elevated glucose concentrations ●  Suppresses glucagon secretion in a glucose-

dependent manner ●  A single dose of liraglutide did not impair glucagon

response to a low glucose concentration

●  Delays gastric emptying ●  Reduces the rate at which PPG appears in the

circulation

Victoza [package insert]. Novo Nordisk; Princton, NJ; January 2010.

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Liraglutide Enhances Glucose-Dependent Insulin Secretion and Glucagon Suppression

n = 10 patients with type 2 diabetes; mean (SE); *p,0.05. Reproduced from Nauck MA we al. Diabetologia. 1993;36:741-744.

Liraglutide

●  Indications and Usage ●  GLP-1 receptor agonist indicated as an

adjunct to diet and exercise in adults with type 2 DM ●  Not recommended as first line therapy for patients

inadequately controlled on diet and exercise ●  Has not been studied sufficiently in patients with a

history of pancreatitis ●  Use caution in patients with history of pancreatitis

●  Not for treatment of type 1 DM ●  Has not been studied in combination with prandial

insulin


Liraglutide: Phase 3a Clinical Trial Program

Liraglutide: Effect on A1C Reduction

Liraglutide: Effect on FBG Reduction

●  Dosage and Administration ●  Administered subcutaneously once daily

●  Any time of the day, independently of meals ●  Injected in the abdomen, thigh or upper arm ●  Injection site and timing can be changed

without dose adjustment


Liraglutide

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●  Mechanism of Protraction ●  Self-association that delays absorption ●  Plasma protein binding (>98%) ●  Stability against metabolic degradation by

DPP-4 enzymes ●  Half-life of ~ 13 hours ●  Once daily administration


Liraglutide

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

Once-daily Injection of Liraglutide Covers 24-h BG Profile in T2DM

Adapted from: Degn et al. Diabetes 2004;53: 1187-1194.

24-h glucose AUC (mmol/l/h, mean ± SE)

232.3 ± 21.9 187.5 ± 14.0 (p = 0.01)

Plas

ma

glu

cose

(m

mol/

l)

Injection (08.00)

Time after injection (hours)

0 0 4 8 12 16 20 24

6

8

10

12

14 Placebo

Liraglutide (6 µg/kg OD)

n=13

●  Dosage and Administration ●  Should be initiated with a dose of 0.6 mg once

daily for 1 week ●  0.6 mg dose is a starting dose intended to reduce

GI symptoms, and is not effective for glycemic control

●  After 1 week at 0.6 mg once daily, the dose should be increased to 1.2 mg once daily

●  If the 1.2 mg does not result in acceptable glycemic control, the dose may be increased to 1.8 mg once daily

●  Available in a pre-filled, multi-dose pen that delivers doses of 0.6 mg, 1.2 mg or 1.8 mg


Liraglutide Boxed Warning


Liraglutide

●  Contraindications ●  Do not use in patients with a personal or

family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type.

●  Do not use in patients with a prior serious hypersensitivity reaction.


Liraglutide

●  Warnings and Precautions ●  Thyroid C-cell tumors in animals: Human relevance

unknown. Counsel patients regarding the risk of medullary thyroid carcinoma and the symptoms of thyroid tumors. ●  In clinical trials, there have been 6 reported cases of thyroid

C-cell hyperplasia among liraglutide treated patients and 2 cases in comparator-treated patients.

●  One comparator-treated patient with MTC had pre-treatment serum calcitonin concentrations >1000 ng/L suggesting pre-existing disease.

●  Five of the six liraglutide treated patients had elevated calcitonin concentrations at baseline and throughout the trial.

●  One liraglutide and one non-liraglutide treated patient developed elevated calcitonin concentrations while on treatment.


Liraglutide

9

●  Warnings and Precautions ●  Pancreatitis:

●  In clinical trials, there have been 13 cases of pancreatitis among liraglutide treated patients and 1 case in a comparator (glimepiride) treated patient.

●  9 cases of acute and 4 cases of chronic. ●  Some patients had other risk factors for pancreatitis,

such as a history of cholelithiasis or alcohol abuse. ●  After initiation, and after dose increases, observe

patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting).


Liraglutide ●  Warnings and Precautions

●  Serious hypoglycemia: ●  Can occur when liraglutide is used with an insulin

secretagogue (e.g. a sulfonylurea) or insulin. Consider lowering the dose of the insulin secretagogue to reduce the risk of hypoglycemia.

●  Renal failure: ●  Postmarketing reports of acute renal failure and worsening of

chronic renal failure in liraglutide treated patients. ●  A majority of the reported events occurred in patients who had

experienced nausea, vomiting, diarrhea or dehydration. ●  Some of the reported events occurred in patients receiving

medications known to affect renal function or hydration status.

●  Hypersensitivity Reactions: ●  Postmarketing reports of serious hypersensitivity reactions

(e.g., anaphylactic reactions and angioedema)


Liraglutide

●  Drug Interactions ●  Liraglutide delays gastric emptying. May impact

absorption of concomitantly administered oral medications.


Liraglutide Liraglutide: Adverse Events Occurring in > 5%

Liraglutide: Minor Hypoglycemic Events

Liraglutide: Effect on Weight

10

Which Patients Are Most Likely to Benefit From a GLP-1 Agonist? ●  Individuals who are relatively early in the disease

process, and need sufficient benefit from an agent with good efficacy

●  Persons who could benefit from monotherapy, but are not good candidates for metformin or a sulfonylurea

●  Patients with hazardous occupations, for whom hypoglycemia is especially dangerous

●  Overweight patients ●  Who want to lose weight, especially if they have suboptimal

glycemic control with oral therapy ●  Who are reluctant to transition to insulin because of

concerns about further weight gain and/or hypoglycemia

Nathan DM et al. Diabetes Care. 2009;32:193–203. Pratley RE et al. Rev Diabet Stud. 2008;5:73–94.

Educating Patients About GLP-1 Agonists   Main BG effect is post-prandial with modest benefit on fasting   The disposable administration pen should be stored and used

appropriately   Following instructions about the timing of medication

administration is important with exenatide (within 60 minutes prior to meal)

  Renal function should be assessed before initiating treatment and periodically thereafter

  Patients who will be taking a GLP-1 agonist with a sulfonylurea or insulin should be familiar with the symptoms and treatment of hypoglycemia

  If taken with certain other medications, changes to the timing of medication administration or the frequency of monitoring may be necessary

  The health care provider should be notified immediately if pancreatitis symptoms develop

GLP-1 Analogues Verses DPP-IV Inhibitors

Drug Characteristics

GLP Analogues DPP-IV Inhibitors

Administration Injection Oral Tablet

Effect on A1C 0.8-1.8% 0.5-1.1%

Weight Change 3-5 kg No effect (neutral)

Beta Cell Mass Effect (in animals)

Robust increase Not as robust

Type 2 DM Pathophysiology

●  Increased glucagon secretion ●  Increased hepatic glucose production ●  Increased gastric emptying rate ●  Neuroendocrine dysfunction ●  Impaired incretin effect

●  Decreased secretion of GLP1 ●  Impaired response to GIP

●  Decreased amylin secretion

Pramlintide acetate

●  Synthetic analog of human amylin

●  Amylin is a 37-amino acid neuroendocrine hormone

●  Amylin is synthesized by pancreatic beta cells and co-secreted with insulin in response to food intake

Pramlintide vs. Amylin

●  Human amylin is not soluble and has a tendency to aggregate

●  Pramlintide is a soluble non-aggregating equipotent amylin analogue

●  Indications: ●  Type 1 diabetes, as an adjunct treatment in

patients who use mealtime insulin therapy. ●  Type 2 diabetes, as an adjunct treatment in

patients who use mealtime insulin therapy, with or without a sulfonylurea and/or metformin.

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Mechanism of Action

●  Pramlintide acting as an amylinomimetic •  Decreases postprandial glucagon secretion thereby reducing glucose output by the liver and reducing postprandial plasma glucose

•  Slows gastric emptying

•  Increases satiety and reduces food intake

Pharmacokinetics

●  Formulation – Injection ●  SymlinPen 60: 1 carton containing 2 x 1.5-mL disposable,

multidose pen-injector devices for doses of 15 mcg, 30 mcg, 45 mcg, and 60 mcg

●  SymlinPen 120: 1 carton containing 2 x 2.7-mL disposable, multidose pen-injector devices for doses of 60 mcg and 120 mcg

●  Route – subcutaneous ●  Injection in the arm showed higher exposure with

greater variability, compared to abdomen or thigh ●  60% bound to serum albumin or blood cells ●  Half-life – about 48 minutes ●  Metabolism – renal; one active metabolite has been

identified (des-lys pramlintide) ●  Excretion - renal

Efficacy of Pramlintide Type 1 Diabetes

●  Prescribing information summarizes data from 3 studies of pramlintide (30 -60µg) in patients with type 1 diabetes (A1C ~ 9%)

Efficacy of Pramlintide Type 2 Diabetes ●  Prescribing

information summarizes data from two trials in type 2 patients.

●  Placebo vs. pramlintide 120 mcg (both with usual insulin regimen)

Patient Selection

●  Pramlintide should only be considered for insulin-using patients who: ●  Have failed to achieve adequate glycemic

control despite individualized insulin management.

●  Are receiving ongoing care under the guidance of a health care provider skilled in the use of insulin and supported by the services of a diabetes educator.

Patient Selection

●  Patients meeting any of the following criteria should not be considered for pramlintide therapy: ●  Poor compliance with current insulin regimen ●  Poor compliance with SMBG

●  Have an A1C > 9% ●  Have recurrent severe hypoglycemia requiring assistance

during the past 6 months

●  Presence of hypoglycemic unawareness

●  Confirmed diagnosis of gastroparesis ●  Require medications that stimulate gastrointestinal motility

●  Pediatric patients

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Warnings and Precautions

●  When initiating pramlintide therapy, reduce short- or rapid-acting insulin dose by 50% including fixed mix insulins such as 70/30 ●  Other glucose-lowering medications may

require dosage adjustment as well

●  Frequent glucose monitoring ●  Pre- and post-meal ●  Bedtime

Contraindications

●  Hypersensitivity to pramlintide or any of its components

●  Confirmed diagnosis of gastroparesis

●  Hypoglycemic unawareness

Adverse Effects

●  Nausea, vomiting, dyspepsia, anorexia, headache, fatigue ●  Nausea in about 1/3 to 1/2 patients

●  Tolerance develops to the nausea and anorexia as therapy continues

●  Lower incidence if pramlintide gradually titrated to recommended dosage

●  Does not cause hypoglycemia alone

Dosing and Administration

●  Reduce preprandial, rapid-acting or short-acting insulin doses, including fixed mix insulins by 50%

●  Starting dose 15 mcg ●  Increase dose by 15 mcg increments (30, 45, 60 mcg)

when no clinically significant nausea has occurred for at least 3 days

●  Maintenance dose 30 mcg or 60 mcg as tolerated ●  Persistent nausea at the 45 or 60 mcg dose level requires

a reduction to 30 mcg ●  If the 30 mcg dose is not tolerated d/c therapy ●  Administer dose immediately before major meals (250

calories or > 30g CHO)

●  Type 1 DM


●  Reduce preprandial, rapid-acting or short-acting insulin doses, including fixed mix insulins by 50%

●  Starting dose 60 mcg ●  Increase dose to 120 mcg when no clinically significant

nausea has occurred for 3-7 days ●  Maintenance dose 120 mcg as tolerated ●  Persistent nausea at the 120 mcg dose level requires a

reduction to 60 mcg ●  Administer dose immediately before major meals (250

calories or > 30g CHO)

●  Type 2 DM


●  Once target dose of pramlintide is achieved, both insulin using type 1 and type 2 patients should have their insulin dose adjusted to optimize glycemic control

●  Administer into abdomen or thigh with injection sites rotated

●  Do not use same site repeatedly ●  Injection site selected should be distinct from

insulin injection site (at least 2 inches away) ●  Do not mix with insulin

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Storage

●  Unopened vials and pen-injectors should be refrigerated

●  Opened (in-use) vials and pen-injectors may be kept either refrigerated or at room temperature for up to 28 days

Incretin Deficiency Non-Insulin Injectable Agents1 Non-Insulin Injectable Agents Longer-acting...

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