update 2007.insulin therapies

8/2/2019 Update 2007.Insulin Therapies

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ObjectivesObjectives

Review rationale for insulin therapyReview rationale for insulin therapy

DescribeDescribe cell functional declinecell functional decline

Understand the advantages andUnderstand the advantages anddisadvantages of insulin therapydisadvantages of insulin therapy

Review insulin preparations and activityReview insulin preparations and activity

profilesprofiles

Introduce newer therapies in the pipelineIntroduce newer therapies in the pipeline


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Rationale for InsulinRationale for Insulin

Therapy in Type 2 DMTherapy in Type 2 DM

Up to 1/3 of patients may require insulin toUp to 1/3 of patients may require insulin to

achieve adequate glycemic controlachieve adequate glycemic control

The UKPDS TrialThe UKPDS Trial Demonstrated progressive hyperglycemiaDemonstrated progressive hyperglycemia

Decrease inDecrease in -cell function-cell function

All treatment groupsAll treatment groups

Gerich JE. Am J Med 2002;113:308-316.


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Beta-cell declineBeta-cell decline

0

20

40

60

80

100

-10 -8 -6 -4 -2 0 2 4 6

Years

Beta-cellFunction(%)

Mudaliar S, et al. Endo and Metab Clin of NA 2001;03(4):935-982.


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Indications for InsulinIndications for Insulin

Therapy in Type 2 DMTherapy in Type 2 DM

Persistently elevated FPGPersistently elevated FPG >> 300 mg/dL and300 mg/dL and

ketonuria or ketonemiaketonuria or ketonemia

Persistent elevations of FPGPersistent elevations of FPG >> 300 mg/dL300 mg/dLand sx of polyuria, polydipsia, and weightand sx of polyuria, polydipsia, and weightlossloss

All women with gestational diabetes whoseAll women with gestational diabetes whosedisease is not controlled with diet alone anddisease is not controlled with diet alone and

women with Type 2 DM who becomewomen with Type 2 DM who becomepregnantpregnant


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Insulin PreparationsInsulin Preparations

Lispro/Aspart/GlulisineLispro/Aspart/Glulisine HumalogHumalog , NovoLog, NovoLog, Apidra, Apidra

Human RegularHuman Regular Humulin RHumulin R , Novolin R, Novolin R

Human NPH/LenteHuman NPH/Lente Humulin NHumulin N, Novolin N, Novolin N

Humulin LHumulin L , Novolin L, Novolin L

UltralenteUltralente Humulin UHumulin U

GlargineGlargine

LantusLantus


7/34Campbell RK, et al. J Am Pharm Assoc2002;42:602-11.

Activity ProfilesActivity ProfilesPreparation Onset Peak Duration

Rapid-acting

Insulin lipsroInsulin aspart

15 minutes15 minutes

30-60 minutes30-60 minutes

3 hours3 hours

Short-actingRegular insulin 30 minutes 2-5 hours 5-8 hours

Intermediate-acting

Isophane (NPH)

insulinInsulin zinc (Lente)

1-2 hours

1-2 hours

6-10 hours

6-12 hours

16-20 hours

18-24 hours

Long-acting

Insulin zinc(Ultralente)

Insulin glargine

4-6 hours

2 hours

10-18 hours

None

24-48 hours

> 24 hours

MixturesIsophane/regularinsulin 70/30, 50/50

NPL/lisproMix 75/25

45 minutes

5 minutes

7-12 hours

7-12 hours

16-24 hours

1-24 hours

NPH = neutral protamine Hagedorn; NPL = neutral protamine lispro


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Novel InsulinsNovel Insulins

Novel Bolus InsulinsNovel Bolus Insulins

Insulin lisproInsulin lispro

Insulin aspartInsulin aspart Inhaled insulinInhaled insulin

Novel Basal InsulinsNovel Basal Insulins

Insulin glargineInsulin glargine Fatty acid acylated insulinsFatty acid acylated insulins

Insulin detemirInsulin detemir

Gerich JE. Am J Med. 2002;113:308-316.


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5 10 151

Insulin Lispro

Lys Pro

5 10 15 201

5 10 15 20 251

Asp

Inversion

3025

Insulin Aspart

Substitution

5 10 15 201

51 3025201510

Insulin Glargine

Arg Arg

30

201 5 10 15

A-CHAIN

A-CHAIN

A-CHAIN

B-CHAIN

B-CHAIN

B-CHAIN

Extension

Gly


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Insulin Lispro (HumalogInsulin Lispro (Humalog))

AdvantagesAdvantages Improved glycemic control in patients with TypeImproved glycemic control in patients with Type

1 DM who inject insulin immediately before1 DM who inject insulin immediately before

mealsmeals Subcutaneous absorption characteristics andSubcutaneous absorption characteristics and

plasma profile more closely resembling meal-plasma profile more closely resembling meal-stimulated physiologic insulin releasestimulated physiologic insulin release

More flexible lifestyle from immediateMore flexible lifestyle from immediatepreprandial dosing schedulepreprandial dosing schedule

Rapid-acting insulinRapid-acting insulin

Ability to administer a few minutes before mealsAbility to administer a few minutes before meals


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Insulin Aspart (NovoLogInsulin Aspart (NovoLog))

AdvantagesAdvantages

Absorption more than twice as fast, peakAbsorption more than twice as fast, peak

levels more than twice as high, as withlevels more than twice as high, as withregular insulinregular insulin

Improved glycemic control in patients withImproved glycemic control in patients with

Type 1 DM injecting insulin immediatelyType 1 DM injecting insulin immediatelybefore meals (in conjunction with regularbefore meals (in conjunction with regular

basal insulin)basal insulin)


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Insulin Lispro/AspartInsulin Lispro/Aspart

DisadvantagesDisadvantages

More rapid onset of ketoacidosis in casesMore rapid onset of ketoacidosis in cases

of continuous subcutaneous insulinof continuous subcutaneous insulininfusion pump failureinfusion pump failure

Unknown teratogenicity and long-termUnknown teratogenicity and long-term

safety profilesafety profile

Higher costHigher cost

Need for one to two more daily insulinNeed for one to two more daily insulininjectionsinjections


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Insulin Glargine (LantusInsulin Glargine (Lantus))

Long-acting, peakless insulinLong-acting, peakless insulin Administered once dailyAdministered once daily

Lower risk of nocturnalLower risk of nocturnalhypoglycemiahypoglycemia Less weight gain compared withLess weight gain compared with

NPHNPH Often used in combination with otherOften used in combination with other

insulins, oral agents, or possiblyinsulins, oral agents, or possiblyinhaled insulininhaled insulin


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Newer TherapiesNewer Therapies

Insulin glulisine (ApidraInsulin glulisine (Apidra))

Insulin detemir (LevemirInsulin detemir (Levemir))

Inhaled insulin (ExuberaInhaled insulin (Exubera))

Pramilintide acetate (SymlinPramilintide acetate (Symlin))

Exenatide (ByettaExenatide (Byetta

)) Sitagliptin (JanuviaSitagliptin (Januvia))


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Insulin glulisine (ApidraInsulin glulisine (Apidra))

Class: Rapid-acting insulinClass: Rapid-acting insulin IndicationIndication

Bolus insulin designed for meal-time coverage ofBolus insulin designed for meal-time coverage ofblood sugars in Type 1 or 2 DMblood sugars in Type 1 or 2 DM

AdministrationAdministration Injected subcutaneously 15 minutes before or afterInjected subcutaneously 15 minutes before or after

a meala meal

Adverse effectsAdverse effects Hypoglycemia, injection site reactions,Hypoglycemia, injection site reactions,

lipodystrophy, pruritis, rashlipodystrophy, pruritis, rash


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5 10 151

Insulin Glulisine

Lys Pro

5 10 15 201

5 10 15 20 251

Asp

Inversion

3025

Insulin Aspart

Substitution

5 10 15 201

51 3025201510

Insulin Glargine

Arg Arg

30

201 5 10 15

A-CHAIN

A-CHAIN

A-CHAIN

B-CHAIN

B-CHAIN

B-CHAIN

Extension

Gly


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Class: Long-acting insulinClass: Long-acting insulin

IndicationIndication

Basal insulin designed for meal-timeBasal insulin designed for meal-timecoverage of blood sugars in Type 1 or 2 DMcoverage of blood sugars in Type 1 or 2 DM

AdministrationAdministration

Injected SQ once or twice daily everyInjected SQ once or twice daily everyevening or hsevening or hs

Should not be mixed with other insulinsShould not be mixed with other insulins


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DoseDose Start with a 1:1 ratio from a basal insulinStart with a 1:1 ratio from a basal insulin

Can be given q12 hoursCan be given q12 hours

Some pts may need higher doses of Levemir thanSome pts may need higher doses of Levemir thanNPHNPH

Insulin nave pts with poor control on PO drugs:Insulin nave pts with poor control on PO drugs:0.1-0.2 units/kg once daily in evening or 10 units0.1-0.2 units/kg once daily in evening or 10 units

once/twice dailyonce/twice daily Adverse effectsAdverse effects

Hypoglycemia, injection site reactions,Hypoglycemia, injection site reactions,lipodystrophy, pruritis, rashlipodystrophy, pruritis, rash


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AdvantageAdvantage

Less burning on injectionLess burning on injection

Cheaper than LantusCheaper than Lantus


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Inhaled Insulin (ExuberaInhaled Insulin (ExuberaTMTM))

Insulin human [rDNA origin] inhalation powderInsulin human [rDNA origin] inhalation powder Rapid-acting, dry-powder insulinRapid-acting, dry-powder insulin

Should be given within 10 minutes before aShould be given within 10 minutes before amealmeal Side Effects: hypoglycemia, cough, drySide Effects: hypoglycemia, cough, dry

mouth, chest discomfortmouth, chest discomfort

Not recommended for those with a chronicNot recommended for those with a chroniclung disease (asthma, COPD)lung disease (asthma, COPD)
http://images.google.com/imgres?imgurl=http://diabeticnews.com/images/insulin-spray-exubera.jpg&imgrefurl=http://diabeticnews.com/2006/02/03/exubera-first-inhaled-insulin-for-the-treatment-of-diabetes/&h=244&w=192&sz=8&tbnid=J8QSV6lVFYKIVM:&tbnh=105&tbnw=82&hl=en&start=63&prev=/images%3Fq%3Dinhaled%2Binsulin%26start%3D60%26svnum%3D10%26hl%3Den%26lr%3D%26sa%3DN


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AdvantagesAdvantages Reaches peak level more than twice as fast asReaches peak level more than twice as fast as

insulin delivered via subcutaneous injectionsinsulin delivered via subcutaneous injections

Offers more flexible lifestyle through immediateOffers more flexible lifestyle through immediatepre-meal administrationpre-meal administration

Resembles meal-stimulated physiologic insulinResembles meal-stimulated physiologic insulin

release more closelyrelease more closely

Reduces duration of postprandial increases inReduces duration of postprandial increases inblood glucose levelsblood glucose levels

May be linked to less weight gainMay be linked to less weight gain

Eliminates need for preprandial injectionsEliminates need for preprandial injections


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DisadvantagesDisadvantages Requires much higher insulin dosesRequires much higher insulin doses

because of limited penetration to thebecause of limited penetration to the

alveolialveoli Higher costHigher cost

Permits less precise dose calibrationPermits less precise dose calibrationbecause of 1-mg and 3-mg minimumbecause of 1-mg and 3-mg minimumdose incrementsdose increments


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PrPramlinamlintide (Symlintide (Symlin))

Class: Amylin agonistsClass: Amylin agonists Indication: Patients with Type 1 or 2 DMIndication: Patients with Type 1 or 2 DM

uncontrolled on QID insulin therapyuncontrolled on QID insulin therapy MOAMOA

Synthetic analog of human amylinSynthetic analog of human amylin Naturally occurring hormone made in pancreaticNaturally occurring hormone made in pancreatic

beta cellsbeta cells

Reduction of postprandial glucagon secretionReduction of postprandial glucagon secretion Regulation of gastric emptying, and therefore theRegulation of gastric emptying, and therefore the

rate of nutrient delivery (exogenous glucose) to therate of nutrient delivery (exogenous glucose) to thesmall intestinesmall intestine


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PrPramlinamlintide (Symlintide (Symlin))

AdministrationAdministration Given SQ 15 minutes prior to mealsGiven SQ 15 minutes prior to meals Do not mix with other insulinsDo not mix with other insulins

Patient must give multiple injections at separatePatient must give multiple injections at separatetimestimes

Caution: Initially decrease insulin doses byCaution: Initially decrease insulin doses by50% to avoid hypoglycemia50% to avoid hypoglycemia

Medication Error Risk!!Medication Error Risk!! Doses available in 15, 30, 60, and 90Doses available in 15, 30, 60, and 90mcgmcg dosesdoses Patient must draw up dose inPatient must draw up dose in unitunit syringessyringes


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Cost ComparisonCost Comparison

Drug Vial Cost

Apidra 10ml $45.39

Humalog 10ml $46.33

Novolog 10ml $25.19

Humulin R 10ml $11.33

Humulin N 10ml $11.33

ExuberaTM Kit Starter kit $109.17

ExuberaTM Pack - #270 $101.86

ByettaTM 250mcg/ml Pen $108.78

Symlin 0.6mg/5ml $57.85


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The Incretin SystemThe Incretin System

Incretin hormonesIncretin hormones Glucose-dependent insulinotropic polypeptide (GIP)Glucose-dependent insulinotropic polypeptide (GIP)

Glucagon-like peptide-1 (GLP-1)Glucagon-like peptide-1 (GLP-1)

Eating causes secretion of hormones fromEating causes secretion of hormones from

the GI tractthe GI tract

EnzymeEnzyme

Dipeptidyl peptidase-4 (DPP-4) inactivates GLP-1Dipeptidyl peptidase-4 (DPP-4) inactivates GLP-1 G-protein-coupled receptors (GPCRs)G-protein-coupled receptors (GPCRs)

Lancet2006;368:1696-705.


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The Incretin SystemThe Incretin System

Actions of GLP-1Actions of GLP-1

Inhibits glucagon secretionInhibits glucagon secretion

Inhibits gastric emptyingInhibits gastric emptying Inhibits food ingestionInhibits food ingestion

Promotes glucose disposalPromotes glucose disposal

GLP-1 receptors (GLP-1R) are expressedGLP-1 receptors (GLP-1R) are expressedin isletin islet andand cells and in peripheralcells and in peripheral

tissuestissues

Lancet2006;368:1696-705.


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Exenatide (ByettaExenatide (ByettaTMTM))

ClassClass

Incretin mimeticsIncretin mimetics

GLP-1R agonistsGLP-1R agonists IndicationIndication

Adjunctive therapy in patients with TypeAdjunctive therapy in patients with Type2 diabetes uncontrolled on metformin, a2 diabetes uncontrolled on metformin, a

sulfonylurea, or their combinationsulfonylurea, or their combination Do not need to be on insulin therapyDo not need to be on insulin therapy
http://www.byetta.com/index.jsp


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Exenatide (ByettaExenatide (ByettaTMTM))

MOAMOA Mimics the effects of the incretin glucagon-likeMimics the effects of the incretin glucagon-like

peptide 1 (GLP-1)peptide 1 (GLP-1)

Enhances glucose-dependent insulin secretion byEnhances glucose-dependent insulin secretion bypancreatic beta-cellspancreatic beta-cells

Suppresses inappropriately elevated glucagonSuppresses inappropriately elevated glucagonsecretionsecretion

Slows gastric emptyingSlows gastric emptying

AdministrationAdministration SQ injections in pre-filled pensSQ injections in pre-filled pens

Major adverse effect: nauseaMajor adverse effect: nausea


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Sitagliptin (JanuviaSitagliptin (Januvia))

ClassClass Dipeptidyl peptidase-4 inhibitor (DPP-4)Dipeptidyl peptidase-4 inhibitor (DPP-4)

IndicationIndication Treatment of DM2Treatment of DM2

Monotherapy and as add-on therapy toMonotherapy and as add-on therapy tometformin or thiazolidinediones (TZDs)metformin or thiazolidinediones (TZDs)

NOT approved with insulin orNOT approved with insulin orsulfonylureassulfonylureas

Dose: 100 mg once dailyDose: 100 mg once daily


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Sitagliptin (JanuviaSitagliptin (Januvia))

MOAMOA

Enhances the incretin system by inhibitingEnhances the incretin system by inhibiting

DPP-4, which breaks down GLP-1DPP-4, which breaks down GLP-1 Helps to regulate glucose by affecting betaHelps to regulate glucose by affecting beta

cells and alpha cellscells and alpha cells

Adverse effectsAdverse effects (( 5%) stuffy or runny nose, sore throat,5%) stuffy or runny nose, sore throat,

URI, and headacheURI, and headache


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AdvantagesAdvantages Does not cause weight gainDoes not cause weight gain

Less GI side effectsLess GI side effects

Safety concernsSafety concerns May effect other endogenous hormonesMay effect other endogenous hormones

No long-term studies publishedNo long-term studies published

52 week ongoing study of patients inadequately52 week ongoing study of patients inadequatelycontrolled on metformin monotherapycontrolled on metformin monotherapy

Pts randomized to either sitagliptin 100mg qd plusPts randomized to either sitagliptin 100mg qd plusmetformin or glipizide plus metforminmetformin or glipizide plus metformin

Abstract suggested only HbA1c %0.67 decreaseAbstract suggested only HbA1c %0.67 decrease

Sitagliptin (Januvia)Sitagliptin (Januvia)

Diabetes Care 2006. 29(12):2632-2637.


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On the HorizonOn the Horizon

GLP-1R AgonistsGLP-1R Agonists

Liraglutide Novo NordiskLiraglutide Novo Nordisk

DPP-4 inhibitorsDPP-4 inhibitors Vildagliptin (GalvusVildagliptin (Galvus) Novartis) Novartis

SaxagliptinSaxagliptin

DenagliptinDenagliptin

Lancet2006;368:1696-705.


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SummarySummary

Diabetes affects a major percentage ofDiabetes affects a major percentage of

the US populationthe US population

Screening of at-risk patients early on isScreening of at-risk patients early on isessential to delay or prevent DM fromessential to delay or prevent DM from

developingdeveloping

Treat the whole patient, not just their DMTreat the whole patient, not just their DM More options on the horizon forMore options on the horizon for

controlling blood sugars, but be warycontrolling blood sugars, but be wary

update 2007.insulin therapies

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