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AN INTRODUCTION TO
INSULIN ANALOGS AND
PREMIXED INSULIN ANALOGS
A Continuing Education Monograph forPharmacists, Nurses, and Dietitians
This continuing education activity can also be completed online at www.MedEdToday.com.
This activity is supported by an educational grant from Novo Nordisk Inc.It has been accredited by the American Association of Diabetes Educators (AADE) for pharmacists, nurses, and dietitians.
i
Program GoalThe goal of this activity is to enhance the knowledge
and understanding of healthcare professionals about therole of insulin analogs and premixed insulin analogs for the treatment of diabetes.
Target AudienceThis continuing education (CE) program is intended
for pharmacists, nurses, and dietitians who work with or anticipate working with patients with diabetes requiring insulin.
Educational ObjectivesAfter reading this monograph, the participant should
be able to:• Describe the impact of diabetes on patient health and
the healthcare system• List currently available insulin analogs and premixed
insulin analogs• Describe the molecular alterations of insulin analogs
compared with human insulin• State the major pharmacokinetic differences between
human insulin and insulin analogs• Explain how insulin regimens are selected and what
factors should be considered when starting and adjusting insulin therapy
• Describe two different insulin regimens that coverboth fasting and postprandial glucose excursions
• Describe the practical aspects of storing and injectinginsulin
• Discuss the prevention and treatment of hypoglycemia
FeeThere is no fee to receive credits for this CE program.
Commercial SupporterThis activity is supported by an educational grant from
Novo Nordisk Inc.
Editorial Review BoardLinda Haas, PhC, RN, CDE
Endocrinology Clinical Nurse SpecialistVA Puget Sound Health Care SystemClinical Assistant Professor of NursingUniversity of Washington School of NursingSeattle, Washington
Karmeen Kulkarni, MS, RD, BC-ADM, CDECoordinator, Diabetes CenterSt. Mark’s Diabetes CenterSalt Lake City, Utah
Jerry Meece, RPh, FACA, CDEOwner and Director of Clinical ServicesPlaza Pharmacy and Wellness CenterGainesville, Texas
Faculty DisclosureStatements
It is the policy of the American Association of DiabetesEducators (AADE) and Scherer Clinical Communicationsto ensure independence, balance, objectivity, scientificrigor, and integrity in all of their continuing education (CE)activities. The faculty must disclose to the participants anysignificant relationships with the commercial companieswhose products or devices may be mentioned in the activity or with the supporter of this CE activity.The information is for participant information; it is notassumed that these relationships will have a negativeimpact on the content of the activity. Following are the disclosure statements made by the Editorial Review Board.
Linda Haas, PhC, RN, CDE, has disclosed that sheserves on the Diabetes Education Advisory Council forNovo Nordisk Inc., the Diabetes Advisory Board ofSanofi-Aventis, and that she holds stock in AmylinPharmaceuticals.
Karmeen Kulkarni, MS, RD, BC-ADM, CDE, has disclosed that she is a consultant for Eli Lilly and Companyand LifeScan Inc., a Johnson and Johnson company.
Jerry Meece, RPh, FACA, CDE, has disclosed that he is aconsultant for Eli Lilly and Company and LifeScan Inc., aJohnson and Johnson company. He is also on the speaker’sbureau for Eli Lilly and Company, LifeScan Inc., and NovoNordisk Inc.
ii
Accreditation
PharmacistsThe American Association of Diabetes Educators is
accredited by the Accreditation Council for PharmacyEducation (ACPE) as a provider of continuing pharmacyeducation. This program provides 1.50 contact hours(0.150 CEUs) of continuing education credit.
ACPE Universal Program Number 069-999-05-229-H01.
Release date: December 3, 2005Expiration date: December 3, 2007
Registered NursesThis continuing nursing education activity was
approved by the American Association of DiabetesEducators, an accredited approver by the American NursesCredentialing Center’s Commission on Accreditation. Thisprogram, 0506-022, is approved for 1.8 contact hours.
Expiration date: December 3, 2007
DietitiansAmerican Association of Diabetes Educators (AM001)
is a Continuing Professional Education (CPE) AccreditedProvider with the Commission on Dietetic Registration(CDR) from June 1, 2003 to May 31, 2006. Registered dietitians (RD) and dietetic technicians, registered (DTR)will receive 2 Continuing Professional Education Units(CPEUs) for completion of this program. ContinuingProfessional Education Provider Accreditation does notconstitute endorsement by CDR of a provider, program,or materials.
Expiration date: December 3, 2007
Disclaimers:Approval of credit for this continuing education (CE)
program does not imply endorsement by the AmericanAssociation of Diabetes Educators (AADE) of any productor manufacturer identified.• The treatment methods presented in the case studies
of this monograph are based on the clinical experience of the Editorial Review Board members and do not represent the opinions of the AADE or Scherer ClinicalCommunications.
• Any medications or treatment methods suggested in this CE activity should not be used by the practitionerwithout evaluation of their patient’s condition(s) andpossible contraindication(s) or danger(s) of use of any specific medication.
• This activity may include discussions of products ordevices that are not currently approved for use by the US Food and Drug Administration (FDA).
• The AADE, Scherer Clinical Communications, the commercial supporter, and the activity’s faculty do notendorse the use of any product in a manner that is notapproved by the FDA.
The author, sponsor, and publisher of this CE programhave made all reasonable efforts to ensure that the information contained herein is accurate in accordancewith the latest available scientific knowledge at the time ofaccreditation of this CE program. Information regardingdrugs (eg, their administration, dosages, contraindications,adverse reactions, interactions, special warnings, precautions)and drug delivery systems is subject to change, and thereader is advised to check the manufacturer’s packageinsert for information concerning recommended dosageand potential problems or cautions prior to dispensing oradministering the drug or using the drug delivery systems.
TrademarksNovoLog, NovoPen, PenFill, FlexPen, Levemir, and
Innovo are registered trademarks of Novo Nordisk A/S.Humalog is a registered trademark of Eli Lilly andCompany; Mix75/25 is a trademark of Eli Lilly andCompany. Lantus and Apidra are registered trademarks ofSanofi-Aventis. OptiClik is a trademark of Sanofi-Aventis.
Copyright © 2005 Scherer Clinical Communications. All rights reserved.
Published by Scherer Clinical Communications
117 West Prospect Street, Hopewell, NJ 08525.
Printed in USA.
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TABLE OF CONTENTS
Introduction.............................................................................................................................................................. 1
Impact of Diabetes.................................................................................................................................................... 1
Classification of Diabetes ........................................................................................................................................ 1
Type 1 Diabetes .................................................................................................................................... 1
Type 2 Diabetes .................................................................................................................................... 2
Gestational Diabetes ............................................................................................................................ 2
Prediabetes ............................................................................................................................................ 2
Criteria for Diagnosis and Monitoring of Diabetes .............................................................................................. 2
Diagnosis .............................................................................................................................................. 2
Capillary Blood Glucose Monitoring .................................................................................................. 3
Nature of Insulin and Insulin Analogs .................................................................................................................... 3
Insulin Structure .................................................................................................................................. 3
Insulin Analogs ........................................................................................................................................................ 3
Rapid-Acting Insulin Analogs.............................................................................................................. 4
Premixed Insulin Analogs .................................................................................................................... 5
Long-Acting Insulin Analogs .............................................................................................................. 5
Diabetes Therapy ...................................................................................................................................................... 6
Treatment Options for Patients with Type 2 Diabetes ...................................................................... 7
How to Initiate Insulin Therapy .............................................................................................................................. 7
Principles of Initiating Insulin Therapy.............................................................................................. 7
Insulin Pumps ...................................................................................................................................... 8
Addressing Concerns About Insulin Therapy ........................................................................................................ 8
Psychological Insulin Resistance (PIR) .............................................................................................. 8
Storing Insulin Analogs and Premixed Insulin Analogs .................................................................... 9
How to Administer Insulin Analogs and Premixed Insulin Analogs ................................................ 9
Use of Insulin Delivery Systems..........................................................................................................10
Hypoglycemia ..........................................................................................................................................................10
Prevention and Treatment of Hypoglycemia ....................................................................................12
The Role of Healthcare Professionals ....................................................................................................................12
Summary ..............................................................................................................................................................13
References ..............................................................................................................................................................14
Post-Test ..............................................................................................................................................................15
Program Evaluation ................................................................................................................................................16
1
IntroductionOver the past decade, the results of several landmark
clinical studies demonstrated that keeping blood glucoselevels as close to normal as possible can delay the onset and slow the progression of the microvascular andmacrovascular complications that may develop in patientswith diabetes.1–3
Despite the growing evidence of the benefits of optimalglycemic control, many individuals with diabetes do notachieve or maintain the levels of glycemic control recommended by key professional societies (Table 1).4 In an effort to improve this situation, a number of strategies can be utilized to manage diabetes more effectively. Effectivemanagement includes better and more convenient therapies.
Medications are only part of a multifaceted approach to treating diabetes; medical nutrition therapy, regularphysical activity, self-management education, and supportare also key elements of diabetes management. Physicians,nurses, pharmacists, dietitians, and other healthcare professionals are in a unique position to enhance a patient’sdiabetes knowledge. Diabetes therapy is most effective ifthe patient and caregiver understand and agree on thechoice of treatment regimen, recognize the value of treatment,and master the skills to perform required tasks correctly.
This monograph discusses the types of insulin analogsand premixed insulin analogs that are available for thetreatment of diabetes.
Impact of DiabetesDiabetes has a significant impact on many aspects of
health in the United States, as indicated by the followingstatistics5:
• An estimated 20.8 million people in the United States(7% of the population) have diabetes; nearly one
third (30%) of these people are unaware that they have the disease.
• The number of new diagnoses of diabetes is ~1.5 million per year for those over 20 years of age.
• The incidence of type 2 diabetes in children and adolescents is increasing rapidly.
• Diabetes was the sixth leading cause of death listed on US death certificates in 2002. However, diabetes isbelieved to be underreported as a cause of death.
• Combined direct and indirect (disability, work loss,premature mortality) medical costs of diabetes were~$132 billion in 2002.– Direct medical expenditures accounted for
$92 billion of this total; more than half of theseexpenses are incurred by people over 65 years of age.
• The annual healthcare cost for an individual with diabetes is more than $13,000; for a person withoutdiabetes, the cost is about $2,500.– Even when adjusted for factors that affect these costs
(eg, age, ethnicity), the yearly medical expenditurefor a person with diabetes is 2.4 times higher thanthat of someone without diabetes.6
Classification of DiabetesInsulin is secreted by the b-cells of the pancreas in
response to increasing blood glucose levels. Normal insulinsecretion is characterized by continuous (basal) release,with superimposed bursts (boluses) of additional insulinmatched to the increase in blood glucose level after theintake of food. Insulin is the primary hormone that suppresses hepatic glucose production, lipolysis, and proteolysis. It increases the transport of glucose into various insulin-sensitive tissues (primarily skeletal muscletissue and fat) and stimulates glycogen synthesis. Diabetesresults from a disruption in this process and is a chronicdisorder characterized by hyperglycemia associated withabnormalities in the metabolism of carbohydrate, protein,and fat. Over time, uncontrolled high blood glucose levelscan cause microvascular and macrovascular complications.Classic signs and symptoms of hyperglycemia includeexcessive thirst and hunger, frequent urination, fatigue,and slow wound healing.7
Type 1 DiabetesApproximately 5% to 10% of all patients with diabetes
have type 1 diabetes, which is characterized by an autoimmunedestruction of the b-cell resulting in virtually absolute
Table 1. American Diabetes Association (ADA) and American Association of Clinical Endocrinologists (AACE) Glycemic Goals.
Test ADA AACEAverage preprandial PG, mg/dL 90–130 110
Average postprandial PG, mg/dL <180 <140
A1C%* <7 ≤6.5
PG = plasma glucose.Standards of Medical Care for Patients with Diabetes Mellitus. Adapted with permission. Diabetes Care. 2005;28(Suppl 1):S4–36 and American Association ofClinical Endocrinologists (AACE) Medical Guidelines for the Management ofDiabetes Mellitus: The AACE System of Intensive Diabetes Self-Management-2002 update. Endocrine Practice . 2002;8(Suppl 1):40–82.
2
insulin deficiency. Type 1 diabetes can affect patients of anyage; however, patients are typically not obese and oftenhave an abrupt onset of overt signs and symptoms thatmay progress to diabetic ketoacidosis if untreated.7 The rateof autoimmune b-cell destruction is quite variable, generallyrapid in infants and children, and slower in adults when itoccurs.8 Treatment with insulin is required to sustain life.Patients are usually not resistant to insulin unless theybecome overweight or obese.
Type 2 DiabetesType 2 diabetes accounts for ~90% to 95% of individuals
with diabetes in the United States. It is a heterogeneousmetabolic disorder characterized by diminished tissue sensitivity to insulin (resistance) and inadequate b-cellfunction. The continuum ranges from extreme insulinresistance with minimal b-cell impairment to extreme b-cell impairment with limited insulin resistance.Incidence and prevalence of type 2 diabetes increases with age, degree of obesity, and lack of physical activity.
Though more common in adults, type 2 diabetes canoccur at any age. Pediatric and adolescent type 2 diabetes is increasingly more common. The percentage of childrenwith newly diagnosed diabetes who are classified as havingtype 2 diabetes has risen from <5% before 1994 to 30% to 50% in recent years, depending on the populationsinvolved.9,10 Most patients have a family history, and many present with few, if any, symptoms. Sometimes thediagnosis is made only when one of the symptoms associatedwith the long-term complications of diabetes prompts aclinic visit. Recent data suggest that one third of thepatients with type 2 diabetes have not yet been diagnosed.For those who are aware of their diagnosis and requiretreatment, nutrition therapy, oral agents, and insulin arecommonly used. Regardless of initial therapy, however,more than half will eventually require insulin.8
Gestational DiabetesThe term gestational diabetes mellitus (GDM) is used
to describe glucose intolerance that is first detected duringpregnancy. GDM occurs in ~7% of pregnancies. If the condition is not well controlled, GDM is associated withincreased maternal and fetal complications, including miscarriage and fetal anomalies. Insulin is the treatment of choice for the management of gestational diabetes unre-sponsive to diet therapy. Oral antidiabetic drugs (OADs)are generally not recommended, as most cross the placentaand can stimulate fetal islet cell production and insulin
release. After delivery, many women with GDM return to a state of normal glucose tolerance; however, 40% to 60%will develop diabetes within 5 to 15 years. There are~200,000 cases of GDM each year in the United States.11
PrediabetesBoth impaired glucose tolerance (IGT) and impaired
fasting glucose (IFG) are risk factors for type 2 diabetes.IGT is defined as a 2-hr plasma glucose level (postprandialor postchallenge) between 140 and 199 mg/dL. IFG isdefined as a fasting plasma glucose (FPG) level between100 and 125 mg/dL. The American Diabetes Association(ADA) refers to these states as prediabetes.7 It is estimatedthat 41 million individuals have prediabetes in the United States.12
IGT is more prevalent than IFG in patients diagnosedwith prediabetes. IGT and IFG are two distinct pathologicalstates. IGT is associated with insulin resistance in skeletalmuscle whereas control of fasting glucose is primarilydependent on adequate basal insulin secretion and liversensitivity to insulin. Thus, IGT is associated with inadequatebasal insulin secretion and liver insensitivity to insulin.Although the majority of individuals with IGT do not haveIFG and vice versa, the incidence of overt diabetes is higherin those who have both IGT and IFG.13 The DiabetesPrevention Trial showed that progression to diabetes, inindividuals with prediabetes, can be reduced by 58% withdietary intervention and physical activity, and by 31% with metformin.14
Criteria for Diagnosisand Monitoring ofDiabetesDiagnosis
Both the ADA and the American Association of ClinicalEndocrinologists (AACE) have developed guidelines for thediagnosis and monitoring of diabetes.7,15 The guidelinesrecommend the following three criteria for the diagnosis of diabetes:
1. Symptoms of diabetes (eg, polyuria, polydipsia,unexplained weight loss) with a casual plasma glucose level of ≥200 mg/dL obtained any time ofthe day without regard to time of the last meal
2. FPG level of ≥126 mg/dL3. 2-Hour plasma glucose level of ≥200 mg/dL during
a 75-gram oral glucose tolerance test Any one of these findings is to be confirmed on a
separate day, using any of the three methods.
3
The diagnostic criteria are based on epidemiological evidence that identifies individuals at increased risk foradverse outcomes caused by diabetes (eg, macro- andmicrovascular complications).
The glycemic goals for patients with diabetes are basedon blood glucose values and on values for A1C (Table 1).A1C values are considered an important indicator of thesuccess of therapies for glycemic control; however, A1C values are not used for diagnosis. Increased A1C values are associated not only with the development of diabetic complications, but also with their progression.1,2 NormalA1C values are established by the laboratory performingthe analysis and are sometimes listed as <6.0%.7
These goals are general guidelines; they may not beappropriate for all individuals or populations (eg, elderly,children, pregnant/lactating women, or those individualswith hypoglycemic unawareness). Each patient shoulddetermine his or her individual target goals in conjunctionwith his or her healthcare provider.
Capillary Blood Glucose MonitoringMaintenance of glucose levels within the normal range
(or as close as possible) should be a realistic goal for allpatients. Capillary blood glucose monitoring (CBGM) is anessential part of any diabetes treatment regimen. Frequentchecking not only provides crucial data to guide dosageadjustments, but also reduces the risk of hypoglycemia.
Blood glucose levels are typically measured two to eighttimes a day, depending on treatment goals and regimens.Testing should be advised routinely before meals and atbedtime. Postprandial or after meal testing may also beindicated. When medicine changes are necessary, glycemictargets are not met, or hypoglycemia occurs, more frequenttesting is recommended.
Nature of Insulin andInsulin AnalogsInsulin Structure
The b-cells, which make up 60% to 80% of the islet’s of Langerhans in the pancreas, are the site of synthesis,storage, and secretion of insulin. The process is orderly,but complicated. It begins with a precursor chain of 110amino acids called preproinsulin. Through enzymatic cleavage in specific regions preproinsulin is transformedinto proinsulin. Insulin, with its independent A and B chains, is produced when other enzymes excise the “c”-shaped amino acid fragment (so-called C peptide)shown in Figure 1. Note that for every molecule of insulinproduced, one molecule of C peptide is liberated.
Insulin AnalogsAn analog is defined as a chemical compound that
is structurally similar to another compound, but differsslightly in composition. It has long been considered desirable to alter the pharmacokinetics of exogenousinsulin preparations to more closely mimic the activity of endogenous insulin in individuals without diabetes.Researchers have manipulated the amino acids on the Aand B chains of the human insulin molecule to create clinically useful insulin analogs with altered pharmacokinetics.The changes made to the insulin molecule can result ineither shorter- or longer-acting products.
Insulin analogs were developed because of the limitingpharmacokinetic and pharmacodynamic properties ofrecombinant human insulin formulations.16 Variable absorption of insulin has been the largest confounder ofattempts to mimic physiological absorption.17 Because regular human insulin reaches a peak 2 to 4 hours afteradministration, it is injected 30 to 60 minutes before ameal.18 The problem that occurs with many patients whouse regular insulin is that they inject too close to mealtimeand the effect is early postprandial blood glucose excursions caused by the insulin reaching its peak effectiveness too late to match up with the carbohydratesingested. The slow decline in insulin level after the peak isreached extends the duration of action and can lead tobetween-meal hypoglycemia.19 Intermediate-acting insulinneutral protamine Hagedorn (NPH) also has a delayedonset of action as well as variable peak time and durationof action.18 This variable peak and trough effect can causewide glucose excursions with frequent highs and lows.19
Insulin analogs have more predictable and physiologic
Figure 1. Structure of the proinsulin molecule. Open circles represent amino acidsremoved in the final process of insulin synthesis; dark circles with the connectingdisulfide bonds represent human insulin: (1) the A chain, which is made up of21 amino acids; and (2) the B chain, which has 30 amino acids, connected by disulfide bonds.
A chain
B chain
C peptide
S S
SS
S
S
4
time-action profiles. Because of the more physiologicaltime-action profiles, use of insulin analogs can lower therisk of hypoglycemia, particularly at night. Due to the fast onset of action, rapid-acting insulin analogs can be administered within 15 minutes of mealtime, therebyincreasing flexibility for dosing.16,19
Rapid-Acting Insulin AnalogsInsulin typically exists as a six-molecule aggregate
(hexamer). Once injected into subcutaneous tissue, thehexamers must first dissociate into dimers (two insulinmolecules held loosely together by mutual attraction) andthen to single molecules (monomers) before significantabsorption of insulin can occur. Rapid-acting insulinanalogs that have less tendency for self-association havebeen developed to provide faster absorption. With theseproducts, peak serum insulin levels are achieved rapidly,approximating more closely the physiological release ofendogenous insulin (Figure 2).
Commercially available rapid-acting insulin analogs are Humalog (insulin lispro [recombinant DNA (rDNA)origin] injection), NovoLog (insulin aspart [rDNA origin]injection), and Apidra (insulin glulisine [rDNA origin]injection). With a rapid-acting insulin analog, peak levelsof insulin are twice as high and reached in half the timecompared with regular human insulin; intra- and intersubjectvariability in absorption is also lower with a rapid-actinginsulin analog.16
Humalog—The lispro molecule was created by transposing the amino acids at the 28 (proline) and 29(lysine) positions on the insulin B chain (placing a lysine
at B28 and a proline at B29) (Figure 3A).20 In the humaninsulin molecule, the proline at B28 is involved in the formation of dimers from insulin monomers. The aminoacid transposition results in an inhibition of dimer formation from insulin lispro monomers.
NovoLog—Insulin aspart was created by replacing the proline at the B28 position with another amino acid,aspartic acid (Figure 3B).21 The presence of the negativelycharged aspartic acid creates intermolecular repulsionbetween insulin molecules, thus reducing the tendency ofthe insulin molecule to form hexamers.
Apidra—In insulin glulisine, the amino acid asparagineat position B3 is replaced by lysine and the lysine in position B29 is replaced by glutamic acid (Figure 3C).These modifications to the insulin B chain allow the analogto associate less and be more rapidly absorbed after subcutaneous injection than regular human insulin.22
Because rapid-acting insulin analogs have a faster onsetof action, they can be administered within 15 minutes of ameal compared with 30 to 60 minutes before the meal for
Normal Insulin Secretionat Mealtime
Regular Human Insulin
NovoLog®
NPH insulin
NovoLog® Mix 70/30
BaselineLevel
Subcutaneous InjectionTime
Ser
um In
sulin
Figure 2. Theoretical representation of insulin analogs versus NPH and Regularhuman insulin time-action patterns.
Thr
ThrLys
ProThr
ThrPro
LysThr
LysPro
ThrTyr Phe Phe Gly
Gly
IIe
Val
Glu
Gln
CysCys Thr Ser IIe Cys Ser
LeuTyr
Gln
Leu
Glu
Asn
TyrCysAsn
ArgGlu
GlyCys
Val
Leu
Tyr
Leu
Ala
Glu
Val
Leu
HisSer
GlyCysLeuHisGlnAsnValPheB1
A1A21
B28B30
B20
B28B28
HumanInsulin
InsulinLispro
SS
SS
SS
Figure 3A. Modifications of the insulin sequence in insulin lispro.
Thr
ThrLys
ProThr
ThrLys
AspThr
LysPro
ThrTyr Phe Phe Gly
Gly
IIe
Val
Glu
Gln
CysCys Thr Ser IIe Cys Ser
LeuTyr
Gln
Leu
Glu
Asn
TyrCysAsn
ArgGlu
GlyCys
Val
Leu
Tyr
Leu
Ala
Glu
Val
Leu
HisSer
GlyCysLeuHisGlnAsnValPheB1
A1A21
B28B30
B20
B28B28
HumanInsulin
InsulinAspart
SS
SS
SS
Figure 3B. Modifications of the insulin sequence in insulin aspart.
5
regular human insulin.19 All three rapid-acting insulinanalogs have a higher peak serum concentration and ashorter duration of action compared with regular humaninsulin (Table 2). Rapid-acting analogs are commonly usedas the bolus (mealtime) part of a combination (basal/bolus) regimen with a longer-acting product used as thebasal component. NovoLog is available in vials, in cartridges for durable insulin pens, and in disposable pens(NovoLog FlexPen). Humalog is available in vials, in 3.0-mL cartridges, and in a disposable pen (Humalog Pen).Apidra is currently available in vials only (Table 3).
Thr
ThrLys
ProThr
ThrGlu
Val Asn Glu Val Lys Gln
ProThr
LysPro
ThrTyr Phe Phe Gly
Gly
IIe
Val
Glu
Gln
CysCys Thr Ser IIe Cys Ser
LeuTyr
Gln
Leu
Glu
Asn
TyrCysAsn
ArgGlu
GlyCys
Val
Leu
Tyr
Leu
Ala
Glu
Val
Leu
HisSer
GlyCysLeuHisGlnAsnValPheB1
A1B29
B29B29
B3
B3 B3
HumanInsulin
HumanInsulin
InsulinGlulisine
InsulinGlulisine
SS
SS
SS
Figure 3C. Modifications of the insulin sequence in insulin glulisine.
Table 2. Pharmacodynamics of Insulin Analogs and Premixed Analogs.
Formulation Time to Onset of Action (hr) Time of Peak Action (hr) Duration of Action (hr)Rapid-acting analogs
Insulin lispro (Humalog®) 0.25–0.5 0.8–4.323 4–623
Insulin aspart (NovoLog®) 0.16 –0.3221 1–3 3–524
Insulin glulisine (Apidra®) NA NA NA
Long-acting analogsInsulin glargine (Lantus®) 125 None 10.8 –2426
Insulin detemir (Levemir®) 0.8 –2.027 3.2–9.327 5.7–23.228
Premixed insulin analogsHumalog® Mix75/25TM <0.523 1–6.5 ~22
NovoLog® Mix 70/30 0.16 –0.3229 2.4 ≤24
NA = not available; data presented graphically in Figure 3 of the package insert.
Premixed Insulin AnalogsPremixed insulin analogs are dual-release mixtures of
free and protamine-bound analog.
NovoLog Mix 70/30 (70% insulin aspart protamine suspension and 30% insulin aspart injection [rDNA origin]) is a mixture of the soluble form of insulin aspart(30%) and the protaminated form of insulin aspart(70%).29 NovoLog Mix 70/30 is available in vials, in cartridges for durable pens and dosers, and in a disposable(prefilled) insulin pen (NovoLog Mix 70/30 FlexPen)(Table 3).
Humalog Mix75/25 (75% insulin lispro protamine suspension and 25% insulin lispro injection [rDNA origin]) contains 75% insulin lispro protamine suspensionand 25% insulin lispro injection.23 Humalog Mix75/25 isavailable in vials and in a disposable pen (HumalogMix75/25 Pen) (Table 3).
Long-Acting Insulin AnalogsResearchers have been using insulin analog technology
to develop longer-acting products that closely approximatephysiologic basal insulin levels.
Lantus (insulin glargine [rDNA origin]) is a long-actinginsulin analog, which has modifications at position 21 ofthe insulin A chain (glycine replaces asparagine) and theaddition of arginine at positions 31 and 32 of the B chain(Figure 4A).25
These sequence modifications make the analog less solubleat the neutral pH of the injection site. The associationproperties of insulin glargine also show increased stabilityof the hexamer structure. These characteristics slow itsabsorption and prolong the action. Lantus has a pH of ~4and is a clear solution. After injection into subcutaneoustissue, the acidic solution is neutralized, resulting in theformation of microprecipitates. Slow dissolution of insulin
glargine from the microprecipitates into the circulationresults in constant delivery with no distinct peak.25
Levemir (insulin detemir [rDNA origin]) is the onlybasal insulin analog modified through acylation. In thismolecule, threonine (B30) has been removed and a C14 fatty acid moiety has been added to lysine (B29)(Figure 4B). The fatty acid modification allows insulindetemir to reversibly bind to the long-chain fatty acidbinding sites of tissue and plasma albumin, which increaseshexamer stability, and provides a prolonged action profile.Levemir remains completely soluble after injection,allowing more predictable processing.30
Diabetes TherapyDiabetes therapy is customized based on the needs,
capabilities, and preferences of the individual patient.Patients with type 1 diabetes require insulin to sustain life and are prescribed treatment plans ranging from twice-daily premixed or self-mixed injections to multipledaily injections (MDIs, basal/bolus therapy) to an insulinpump. Appropriate meal plan and physical activity programs are also recommended.
Thr
ThrLys
Arg Asn Cys Gly CysArg
ThrLys
LysPro
ThrTyr Phe Phe Gly
Gly
IIe
Val
Glu
Gln
CysCys Thr Ser IIe Cys Ser
LeuTyr
Gln
Leu
Glu
Asn
TyrCysAsn
ArgGlu
GlyCys
Val
Leu
Tyr
Leu
Ala
Glu
Val
Leu
HisSer
GlyCysLeuHisGlnAsnValPheB1
A1A21
A21 A21
B28B30
B20
B30
B30
HumanInsulin Human
InsulinInsulinGlargine
InsulinGlargine
SS
SS
SS
Figure 4A. Modifications of the insulin sequence in insulin glargine.
Thr
LysPro
Thr
ThrLys
ProThr
LysPro
ThrTyr Phe Phe Gly
Gly
IIe
Val
Glu
Gln
CysCys Thr Ser IIe Cys Ser
LeuTyr
Gln
Leu
Glu
Asn
TyrCysAsn
ArgGlu
GlyCys
Val
Leu
Tyr
Leu
Ala
Glu
Val
Leu
HisSer
GlyCysLeuHisGlnAsnValPheB1
A1A21B29
B29B29
InsulinDetemir
C14 fatty acid chain(myristic acid)
HumanInsulin
SS
SS
SS
Figure 4B. Modifications of the insulin molecule in insulin detemir.
6
Table 3. Availability of Insulin Analog Products in the United States.
Product AvailabilityRapid-acting insulin analogs (rDNA origin)Humalog® (insulin lispro injection)* 3.0-mL cartridge for Owen Mumford pen; Humalog® Pen
(disposable); vials
NovoLog® (insulin aspart injection USP)† 3.0-mL cartridge for NovoPen®3, NovoPen® Junior, Innovo® (dosers);
NovoLog® FlexPen® (disposable); vials
Apidra® (insulin glulisine)‡ Vials
Long-acting insulin analogs (rDNA origin)Lantus® (insulin glargine injection)‡ OptiClikTM disposable pen; vials
Levemir® (insulin detemir)† 3.0-mL cartridge for FlexPen® and vials
Premixed insulin analogs (rDNA origin)Humalog® Mix75/25TM (75% insulin lispro protamine Humalog® Mix75/25 Pen (disposable); vials
suspension and 25% insulin lispro injection)*
NovoLog® Mix 70/30 (70% insulin aspart protamine 3.0-mL cartridge for NovoPen® 3, NovoPen® Junior, Innovo® (dosers);
suspension and 30% insulin aspart injection)† NovoLog® Mix 70/30 FlexPen® (disposable); vials
* Eli Lilly and Company. † Novo Nordisk A/S. ‡ Sanofi-Aventis.
7
Treatment Options for Patients with Type 2 Diabetes
For patients with type 2 diabetes, clinicians may beginwith a program of medical nutrition therapy and regularphysical activity. However, given the progressive nature oftype 2 diabetes,2 lifestyle modification alone is seldom sufficient and pharmacotherapy is required.31 In many cases,pharmacologic therapy for patients with type 2 diabetesbegins with a single oral agent (either an insulin secretagogue, biguanide, α-glucosidase inhibitor, or thiazolidinedione) depending on the pathophysiologicdefect (eg, insulin resistance, hepatic glucose production,decreased peripheral glucose uptake). If target blood glucose levels are not met, another OAD, with a differentmechanism of action, is often added (eg, a sensitizer isadded to a secretagogue). In some cases, a combination ofseveral OADs is used; however, many clinicians begininsulin therapy as soon as it is clear that glycemic goals arenot being achieved.31 Insulin therapy should be consideredas initial therapy in patients with severe hyperglycemia(FPG >350 mg/dL), ketonuria, or intolerance or con-traindications to OADs.32 At present, many patients mayhave had type 2 diabetes for 10 to 15 years (with complications)before insulin therapy is initiated.33 Patients with inadequatediabetes control have high morbidity and mortality rates,low quality of life, and incur higher healthcare costs.34
Because of the progressive decline in endogenousinsulin secretion, insulin is eventually required by themajority of patients with type 2 diabetes. Patients shouldbe informed of this when the disease is diagnosed. Asnoted, some authorities advocate the aggressive treatmentof type 2 diabetes by introducing insulin early in the progression of the disease. Availability of insulin analogsand premixed insulin analogs, as well as development ofmore convenient insulin delivery systems, have alleviatedsome barriers and fears associated with insulin initiation.35
How to Initiate InsulinTherapy
The aim of insulin therapy is to achieve optimalglycemic control without causing hypoglycemia or excessive weight gain. Individualized blood glucose targetsshould be established with each patient. The contributionsof fasting and postprandial glucose excursions to overallhyperglycemia should be considered. Many patients withtype 2 diabetes remain on OADs initially, but over time thedoses may be reduced; some may totally discontinue OADs
when started on insulin therapy. Metformin may be left inplace because of its ability to minimize weight gain. Theinsulin dose can be titrated slowly over several weeks asnecessary to achieve optimal glucose levels. The initial regimen should be simple and tailored to match thepatient’s needs and lifestyle.
Other considerations include the type(s) of insulin formulation, the number of injections, and the insulindelivery system that is appropriate for a particular patient.In choosing an insulin formulation, the following pointsshould be considered: how rapidly it works (onset); when it works at maximum capacity (peak); how long it works(duration); and impact on lifestyle. The predictability of these properties and the stability of the different formulations in various insulin delivery systems shouldalso be considered. Compared with the analogs, variabilityin absorption rate has limited the utility of human insulinformulations.
Healthcare providers should explain that insulinrequirements may increase over time. They should alsopoint out that some degree of disease progression isexpected, and is not related to patient adherence to anoptimal diabetes regimen.
Principles of Initiating Insulin Therapy• Determine degree of hyperglycemia by using fasting
and postprandial CBGM and A1C value.• Determine body weight.• Ascertain capabilities and lifestyle needs of the patient.• Decide on insulin delivery system.• Calculate appropriate starting insulin dose based on
weight, blood glucose, and A1C; for patients with type 2diabetes, degree of insulin resistance must be identified.A commonly used approach is to start low (0.1–0.2 unit/kg per day) and titrate up, using self-monitored bloodglucose (SMBG) as directed. Patients with insulin resistance may require higher doses.
• Determine the most appropriate insulin formulation andnumber of injections.
• Patient willingness, capability, and target blood glucoselevels should be taken into account.
The goals are to avoid hypoglycemia, achieve glycemiccontrol, and minimize impact on lifestyle.
Although there is no set formula to initiate insulin therapy, some basic recommendations are:• if glycemic goal is to improve FPG, long-acting analogs
(basal) may be used;
• if goal is to improve postprandial plasma glucose (PPG),rapid-acting analogs (bolus) are usually prescribed;
• if goal is to improve FPG plus PPG, OAD + long-actinganalog, premixed insulin analogs, MDI therapy, or insulinpump therapy are appropriate.
To achieve optimal glycemic control, both FPG andPPG should be targeted.
Insulin PumpsInsulin pump therapy, also called continuous
subcutaneous insulin infusion (CSII), provides advanceddelivery technology to more closely mimic insulin secretionby the pancreas. With CSII, a constant flow of insulin isprovided through a catheter to a subcutaneously insertedneedle, most commonly in the abdomen. All three rapid-acting insulin analogs are currently approved by theUS Food and Drug Administration for use in pumps.
Intermediate- and long-acting insulin formulations are notused in insulin pumps. A rapid-acting insulin analog isusually used to maintain basal insulin levels, providingmore predictable effects on blood glucose levels than areattainable through injections of longer-acting insulinpreparations (Figure 5). Before a meal, the patient canprogram the pump to deliver an appropriate bolus dose,which is typically calculated based on the premeal bloodglucose level and carbohydrate content of the meal. If ameal is missed, the bolus dose can be omitted.
The safe and effective use of these external pumpsrequires appropriate patient training and frequent self-monitoring of blood glucose levels so that properdosage decisions can be made. Insulin pumps are, therefore,most appropriate for use in carefully selected, highly motivated patients who have access to a healthcare teamtrained in pump use. The devices must be carefully monitored for insulin supply, cleanliness, battery chargelevel, and mechanical function. The infusion site must becarefully watched for signs of infection. Catheter “kinking”is a potential problem as well as dislodging of the infusionset due to excessive activity or excess perspiration. Anymalfunction associated with the pump should be quicklycorrected, especially in patients with type 1 diabetes, beforecomplications due to insulin deficiency occur, which in thecase of onset of ketoacidosis, can be within 4 to 10 hours.
Addressing ConcernsAbout Insulin Therapy
The healthcare provider can assist patients in adjustingto insulin therapy by understanding their concerns andproviding the information they require.36 Patients shouldbe referred to a certified diabetes educator (CDE) toincrease their knowledge and learn the various skillsrequired to manage diabetes. They should also be referredto a registered dietitian/CDE for individualized nutritioninformation.
Psychological Insulin Resistance (PIR)Patients with type 2 diabetes may resist treatment with
insulin injections for various reasons, including:• Fears about hypoglycemia • Needle phobia or fear of injection pain• Embarrassment of injecting in public• Concern about having to change their lifestyle• Fear that insulin therapy means the “end of the road”
Several countermeasures to PIR are:• Acknowledgment of disease progression early in treatment
(preferably at diagnosis) so patients will not perceive
8
CSII with Rapid-Acting Insulin AnalogMorning
Bolus Bolus Bolus
Basal Infusion
Afternoon
Insu
lin E
ffect
Evening Night
B L D HS B
Meals
CSII with Regular InsulinMorning
Bolus Bolus Bolus
Basal Infusion
Afternoon
Insu
lin E
ffect
Evening Night
B L D HS B
Meals
Arrow = time of bolus injection; B = breakfast; L = lunch; D = evening meal;HS = bedtime snack.
Figure 5. Schematic representation of idealized effect provided by insulin analog (top) and regular human insulin (bottom) in continuous subcutaneousinsulin infusion (CSII) regimens.
Copyright © 1998 American Diabetes Association. From: Medical Managementof Type 1 Diabetes. Adapted with permission from The American DiabetesAssociation.To order this book, please call 1-800-232-6733 or order online athttp://store.diabetes.org
9
Table 4. Recommendations for Storage of InsulinAnalogs After First Use.
Product/Formulation Days at Room TemperatureNovoLog (vials) 28 also refrigerated
NovoLog (PenFill®
cartridges, FlexPen) 28
Humalog (vials) 28 also refrigerated
Humalog (cartridges, pen) 28
Humalog Mix75/25 (vials) 28 also refrigerated
Humalog Mix75/25 (pen) 10
NovoLog Mix 70/30 (FlexPen
and PenFill cartridges) 14
NovoLog Mix 70/30 (vials) 28
Apidra (vials) 28 also refrigerated
Lantus (vials, cartridge) 28 also refrigerated
Levemir (vials, cartridge, 42
FlexPen)
insulin therapy as a personal failure (insulin should notbe used as a threat to achieve compliance with currenttherapy).
• Before insulin therapy is necessary, patients can learn toinject in case insulin would be necessary during illness.This may help them overcome the fear of injections.
• Education about hypoglycemia—learning cues that indicate onset (low blood glucose awareness) and appropriate treatment; starting with a single injectionmay avoid an immediate episode.
• Education about the early symptoms of hypoglycemiasuch as hunger, palpitations, tachycardia, perspiring,blurred vision, and other cues (hypoglycemia awarenesstraining), and the appropriate treatment to have available.
• Education about hyperglycemia and the risk of complications,including discussion of maintaining glucose targets.
• An explanation of the damage that may have already been done by the effects of long-term hyperglycemia mayhelp alleviate the fear that insulin will be the cause of adownward spiral.
• Discussion of how, in the past, insulin use was delayed,and persons with diabetes in those times were hyperglycemic too long and thus developed long-term complications.
• Availability of new insulin delivery systems– small needles– avoidance of syringe stigma: many patients report
that the use of insulin pens or dosers makes them more comfortable injecting in public
Storing Insulin Analogs and Premixed Insulin Analogs
Each vial, cartridge, and insulin-containing componentof an insulin delivery system (prefilled disposable) has anexpiration date and should not be used after that date.Once the expiration date has passed, the insulin may beginto lose potency and, if used, may not provide reliable control of blood glucose levels.
Unopened insulin containers should be stored in therefrigerator at 36oF to 46oF until the expiration date. Ifunopened containers are stored at room temperature,expiration time is the same as an opened container (Table 4). Patients should NOT store insulin in the freezer,as freezing may alter the consistency of the formulation.The insulin that is currently in use (eg, open insulin vials,cartridges, or prefilled pens) should be kept at room temperature away from heat and sunlight; the ADA recommends avoiding extreme temperatures. Storage
recommendations for vials, insulin cartridges, and prefilledpens, after puncture or first use, are shown in Table 4.If frosting (little white flecks that adhere to the inside of the container above the surface of the solution),clumping (aggregates of insulin remain after mixing), ordiscoloration appears, the container should be discarded.
Although premixed insulin analog preparations arecloudy, rapid- and long-acting insulin analog preparationsshould always appear clear. Any rapid- or long-actinginsulin analog product containing cloudy or discoloredcontents should be discarded. If there is any question about potency, the safest step is to discard such insulin.Unexplained hyperglycemia after using insulin that has been exposed to extremes is probably the result ofdiminished potency. In such cases, the product should be discarded.
How to Administer Insulin Analogs andPremixed Insulin Analogs
Before each injection, patients should wash their handsand make sure the work area is as clean as possible. The useof alcohol swabs to prepare the injection site is no longerrecommended. To inject, adult patients should be advisedto lightly grasp a fold of skin between the thumb and forefinger of one hand, and holding the dosing device perpendicular to the skin, quickly push the needle through.Make sure the needle has been completely introduced suchthat the hub of the injection device is flush with the skinsurface. No part of the needle should be visible when properly placed (see Figure 6).
10
Figure 6. Selecting insulin injection sites.
Skin
SubcutaneousTissue
Muscle
All insulins, except insulin glargine, are absorbed differently from different injection sites. Insulin is absorbedmost rapidly from the abdomen and least rapidly from thethigh. Absorption from the arm is intermediate. Thus,diabetes educators recommend that persons with diabetesselect one site to inject their insulin (preferably theabdomen). Within the selected anatomic area, injectionsites should be rotated. Changing where injections aregiven will reduce the risk of subcutaneous scarring, whichcould reduce insulin absorption. Effort should be made toselect a target area removed by at least an inch from theprevious injection. The incidence of lipohypertrophy,which presents as unsightly bulbous growths, is also significantly reduced or eliminated by rotating within a site.
If injecting into the abdomen, injections should alwaysbe kept at least two inches away from the umbilicus.Patients should also be warned about injecting into areaswhere the muscles will be used intensively within the nexthour. This may lead to hypoglycemia caused by rapid
absorption. For example, a jogger should not inject into the thigh just before running or a baseball pitcher into thepitching arm just before a ballgame.
Use of Insulin Delivery Systems Many patients with type 2 diabetes who are using
insulin therapy have difficulty with complex regimens.New patients are sometimes reluctant to inject themselvesand have difficulty accepting the changes in lifestylebrought about by daily administration of insulin with traditional vials and syringes. For these patients, and formany patients with type 1 diabetes, mixing and measuringinsulin and injecting multiple daily doses may be difficultand overwhelming and alternatives should be considered.
Table 5 lists the types of insulin pens and dosers available in the United States. These insulin delivery systems provide convenience and flexibility, as reported bythose who use them, as well as improved dosing accuracy.37
Patients in a recent study reported improved quality of lifeand better glycemic control with the use of a disposableinsulin pen.38 Patients have also reported less pain associatedwith insulin pen injections, partly attributed to the factthat the needle on an insulin pen never enters the rubberstopper present in insulin vials. Patients using insulin penand doser devices should be reminded that they do need to perform an “air shot” (dialing the pen to 2–4 units,depending on the manufacturer’s requirements, holdingthe pen with the needle pointed upward, and pressing theinjection knob to make sure that insulin is coming out the end of the needle and that any air accumulated in thebarrel has been removed) before each injection.
As discussed previously, insulin infusion pumps offeryet another option for highly motivated patients requiringintensive insulin therapy.
Hypoglycemia Hypoglycemia is the most common and potentially
dangerous acute complication associated with insulin therapy. Patients on intensive treatment programs are atincreased risk for hypoglycemic events and they should be told that tighter control of blood glucose levels is associated with this risk. Although minor hypoglycemiacan be self-treated, major episodes of hypoglycemia requirethe assistance of another person. Errors in insulin dose,confusion between insulin formulations and ratios, changesin timing of insulin administration and meals, missedmeals or decreased caloric intake, unusual physical activity(eg, raking leaves, shoveling snow, or climbing several sets
11
Table 5. Types of Pens and Dosers Available in the United States.
Manufacturer Name CharacteristicsDisetronic Disetronic® Pen • Delivers 1–80 U insulin
• 1-U increments; visual and audible dialing of dose
• 3.15-mL single-use, refillable cartridges
• Can custom mix insulin
Eli Lilly and Company Lilly Prefilled Pen • Delivers 1–60 U insulin
• 1-U increments
• Disposable; contains 3 mL of Humalog, Humalog
Mix75/25*
Novo Nordisk A/S NovoPen® 3 • Delivers 2–70 U insulin
• 1-U increments
• Use PenFill 3-mL for Levemir, NovoLog, and NovoLog
Mix 70/30†
NovoPen® Junior • Delivers 1–35 U insulin
• 0.5-U increments
• Use PenFill 3-mL for Levemir, NovoLog, and NovoLog
Mix 70/30†
FlexPen® • Delivers 1–60 U insulin
• 1-U increments
• Disposable; contains 3 mL of Levemir, NovoLog Mix
70/30,† NovoLog
• Compact, prefilled pen
Innovo® • Delivers 1–70 U insulin
• 1-U increments
• Use PenFill 3-mL for NovoLog and NovoLog Mix 70/30†
• Memory function displays previous dose and time since
administered
Owen Mumford Autopen® - • Delivers 1–16 or 1–21 U insulin in 1-U increments
4 models • Delivers 2–32 or 2–42 U insulin in 2-U increments
• Visual and audible measuring of dose
• Use with 1.5- or 3-mL insulin cartridges‡
Sanofi-Aventis OptiClikTM • 3-mL cartridges of Lantus
* Humalog Mix75/25 comprises 75% insulin lispro protamine/25% insulin lispro (rDNA origin).† NovoLog Mix 70/30 comprises 70% insulin aspart (rDNA origin) protamine suspension/30% insulin aspart (rDNA origin) injection.‡ The 3-mL Novo Nordisk PenFill cartridges are incompatible.
of stairs), illness, and consumption of alcohol are commoncauses of hypoglycemia. Unplanned physical activity orfailure to account for delayed effect of exercising can causeunexpected hypoglycemia. Alcohol interferes with mechanisms(largely in the liver) that produce glucose in response tolow blood glucose, increasing the risk of hypoglycemia.39
According to data from the Diabetes Control andComplications Trial (DCCT), major hypoglycemia is relatively rare, occurring once per year in 10% to 30% ofpatients with type 1 diabetes.1,40 Major hypoglycemia in
patients with type 2 diabetes has been estimated to occurone tenth as frequently as in type 1 patients, even in thosewho are treated aggressively with insulin.1,40
Severe, untreated hypoglycemic episodes may result in loss of consciousness, and may progress to coma anddeath. For many patients, clinical symptoms of hypoglycemiado not occur until blood glucose is <50 or 60 mg/dL. It isimportant that patients learn to recognize the symptoms of hypoglycemia, which include sweating, shaking,palpitations, hunger, confusion, unusual behavior patterns,
12
visual disturbances, and seizures.39 Symptoms may change with duration of diabetes or alterations in overall glycemic control.
Prevention and Treatment of HypoglycemiaAccording to the American Association of Diabetes
Educators (AADE), the best “treatment” of hypoglycemia is prevention. Once a situation leading to hypoglycemia isidentified, adjustments can be made to prevent futureepisodes. For example, if a patient is taking a premixedproduct twice a day, and lunch is often delayed or missed,a change in regimen from premixed to a rapid-actinginsulin analog before breakfast might be appropriate. Iflunch is missed or postponed, an insulin analog injectioncan be taken whenever it is eaten. Rapid-acting insulinanalogs have several potential advantages in the preventionof hypoglycemia: improved predictability, mealtime administration, and more physiologic time-action profile.If hypoglycemia occurs, it should be treated promptly dueto the risk for progression to a more severe reaction. Forthis reason, patients at risk for hypoglycemia should alwaysbe instructed to have a source of glucose with them.According to the AADE, a hypoglycemic episode should beinitially treated with 15 grams of oral carbohydrate such as:• 4 ounces of unsweetened fruit juice or carbohydrate-
containing drink• 6 crackers• 1 tablespoon of honey or corn syrup• 4 teaspoons/packets or six 1/2-inch cubes of sugar• 3 5-gram glucose tablets• Glucose gels or other glucose preparations
According to the AADE, foods high in fat, includingchocolate and ice cream, are not advisable for treating ahypoglycemic episode because fat slows the absorption ofcarbohydrates. Patients taking insulin should keep aglucagon emergency kit on hand and loved ones/significantothers should be taught how to inject subcutaneousglucagon in case of a severe hypoglycemic emergency,when the patient is unable to safely consume oral carbohydrate or is nonresponsive. If possible, it is advisableto teach patients’ loved ones/significant others how to give an intramuscular injection with normal saline, prior tohaving them give an injection for the first time during an emergency.
Glucagon emergency kits (GlucaGen HypoKit fromNovo Nordisk or Glucagon Emergency Kit from Eli Lilly)can be used with only a small amount of training whenmedical assistance is not available. Glucagon kits contain a
syringe, prefilled with sterile diluent, along with a vial ofdried recombinant glucagon, and instructions for mixingand administration. Use of a glucagon kit is recommendedwhen severe hypoglycemia prevents intake of oral glucose,frequently as a result of altered level or loss of consciousness,and trained medical professionals are not available orequipped to deliver intravenous glucose infusion. Glucagonadministration is also effective for restoring consciousnessif given soon after the onset of a hypoglycemic coma.41
When hypoglycemia is more severe and manifests neuroglycopenic symptoms that prevent consumption of carbohydrate, parenteral administration of glucose may be required. This is also recommended for patientswith type 2 diabetes who experience hypoglycemia withsulfonylureas. In both cases, intravenous glucose (25 grams)is infused. Since the response to an infused load of glucoseonly lasts 1 to 2 hours, in cases of severe, prolonged hypoglycemia, repeated glucose infusions and/or feedingsmay be required to completely correct the condition.
The availability of SMBG has made detection and treatment of hypoglycemia more precise and practical.Changes in insulin injection, eating or exercise schedules,or situations involving travel, illness, and other activitiesthat lead to hypoglycemic episodes usually call forincreased frequency of blood glucose monitoring.
The Role of HealthcareProfessionals
Diabetes self-management education is a critical component of the care and management of patients with diabetes. The physician, nurse, pharmacist, dietitian,mental health professional, and other members of the diabetes-care team can serve as teachers, each contributinghis or her own unique skills and focus. Every contact withthe patient should serve as an opportunity for counselingand evaluation of understanding. Information from members of the healthcare team must be consistent.Working in conjunction with each other, team memberscan provide patients and caregiver(s) with educationalmaterials, important product or research information,and overall advice on managing diabetes. They can alsolook for warning signs of hyperglycemia or hypoglycemia;emphasize the importance of frequent blood glucose monitoring; develop individualized meal and regular exercise plans; help select the most appropriate diabetes-related products; assist with financial issues related to treatment; help troubleshoot and solve problems; simplify treatment, if necessary; and advocate for the patient.
13
SummaryAdvances in technology have resulted in dramatic
advances in insulin formulations since 1922, when patientsreceived animal-derived soluble insulin, to the highly purified products of today. rDNA technology has providedthe expertise to improve upon fundamental properties ofinsulin by modifications on a molecular level. Rapid-actinginsulin analogs are quickly absorbed and provide consistentreproducibility of action from injection to injection.Long-acting insulin analogs and premixed insulin analogsafford patients and their providers the ability to furtherindividualize regimens, which may lead to greater successin their intensive pursuit of targeted blood glucose levels.
14
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long-term complications in insulin-dependent diabetes mellitus. N Engl J
Med. 1993;329(14):977–986.
2. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose
control with sulphonylureas or insulin compared with conventional treat-
ment and risk of complications in patients with type 2 diabetes (UKPDS 33).
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8. Marre M. Before oral agents fail: The case for starting insulin early. Int J Obes
Relat Metab Disord. 2002;26(Suppl 3):S25–S30.
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epidemic. J Pediatr Endocrinol Metab. 2002;15(Suppl 2):737–744.
10. Fagot-Campagna A, Pettitt DJ, Engelgau MM, et al. Type 2 diabetes among
North American children and adolescents: An epidemiologic review and a
public health perspective. J Pediatr. 2000;136:664–672.
11. Gestational diabetes mellitus. Diabetes Care. 2004;27(Suppl 1):S88–S90.
12. American Diabetes Association. National Diabetes Fact Sheet. Available at:
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13. Unwin N, Shaw J, Zimmet P, Alberti KG. Impaired glucose tolerance and
impaired fasting glycaemia: The current status on definition and intervention.
Diabet Med. 2002;19(9):708–723.
14. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence
of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med.
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15. American Association of Clinical Endocrinologists. Medical guidelines for
the management of diabetes mellitus: The AACE system of intensive diabetes
self-management-2002 update. Endocr Pract. 2002;8(Suppl 1):40–82.
16. Hirsch IB. Insulin analogues. N Engl J Med. 2005;352(2):174–183.
17. DeWitt DE, Hirsch IB. Outpatient insulin therapy in type 1 and type 2
diabetes mellitus: Scientific review. JAMA. 2003;289(17):2254–2264.
18. White JR, Jr., Campbell RK, Hirsch IB. Novel insulins and strict glycemic
control. Analogues approximate normal insulin secretory response.
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19. Oiknine R, Bernbaum M, Mooradian AD. A critical appraisal of the role
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Eli Lilly and Company; June 2004.
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Nordisk Inc.; January 2003.
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Kansas City, MO: Aventis Pharmaceuticals Inc.; April 2004.
23. Humalog Mix75/25 (75% insulin lispro protamine suspension and 25%
insulin lispro [rDNA origin] injection). Prescribing information.
Indianapolis, IN: Eli Lilly and Company; May 2002.
24. Mudaliar SR, Lindberg FA, Joyce M, et al. Insulin aspart (B28 asp-insulin):
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compared with regular human insulin in healthy nondiabetic subjects.
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Nordisk Inc.; June 2005.
29. NovoLog Mix 70/30 (70% insulin aspart protamine suspension and 30%
insulin aspart [rDNA origin] injection). Prescribing information. Princeton,
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management of type 1 and 2 diabetes mellitus. Drugs.2004;64(22):
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32. Chan JL, Abrahamson MJ. Pharmacological management of type 2 diabetes
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36. American Diabetes Association. Insulin administration. Diabetes Care.
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37. Graff MR, McClanahan MA. Assessment by patients with diabetes mellitus
of two insulin pen delivery systems versus a vial and syringe. Clin Ther.
1998;20(3):486–496.
38. Rubin RR, Peyrot M. Quality of life, treatment satisfaction, and treatment
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15
POST-TEST1. The ADA goal for glycemic control (measured as A1C) is
______________.(a) >7%(b) <7%(c) ≤6.5%(d) None of the above
2. Tight glycemic control reduces the rate of progression ofcomplications caused by diabetes.(a) True(b) False
3. Approximately 5% to 10% of patients with diabetes havetype 1 diabetes. All of these patients require insulin for survival.(a) True(b) False
4. Current guidelines for the diagnosis of diabetes include_____________.(a) two fasting plasma glucose levels ≥126 mg/dL,
obtained on two different days(b) two casual plasma glucose concentrations of
≥200 mg/dL on two different days(c) one casual plasma glucose value >200 mg/dL on
one day and a 2-hour postprandial plasma glucose level ≥200 mg/dL during an oral glucose tolerance test (75-g glucose) on a different day
(d) all of the above
5. What is an analog?(a) A six-molecule aggregate that dissociates to complexes
of two molecules.(b) A 24-amino acid N-terminal signal peptide that is cleaved
off during the formation of insulin.(c) A chemical compound that is structurally similar to
another compound, but differs slightly in composition.(d) A cartridge compatible with most disposable insulin pens.
6. Rapid-acting insulin analogs dissociate quickly tomonomer form after subcutaneous injection and aretherefore absorbed faster than Regular human insulin.(a) True(b) False
7. All of the following statements about insulin lispro andinsulin aspart are true except:(a) they are developed by manipulating the amino acids on
the B chain of the human insulin molecule(b) they are administered immediately before a meal (within
15 minutes)(c) their onset of action is slower and their duration of action
is longer than that of regular human insulin(d) they are most often used as the mealtime insulin in a
basal/bolus regimen with a longer-acting insulin
8. What is the basic composition of the premixed insulinanalog products such as Humalog Mix75/25 and NovoLog 70/30 Mix?(a) There is a portion that is rapid-acting insulin analog,
with the rest being insulin glargine.(b) There is a portion that is rapid-acting insulin analog,
and the rest consists of regular human insulin.(c) There is a portion that is rapid-acting insulin analog,
and the rest is the neutral protamine Hagedorn form of regular human insulin.
(d) There is a portion that is rapid-acting insulin analog, andthe rest of the formulation consists of a sustained-action,protaminated form of the rapid-acting insulin analog.
9. Which insulin analog is acylated with a 14-carbon myristic fatty acid chain?(a) Insulin detemir (Levemir)(b) Insulin glargine (Lantus)(c) Insulin lispro (Humalog)(d) Insulin aspart (NovoLog)
10. Common concerns for patients starting insulin therapyinclude all the following except:(a) fear of hypoglycemia(b) needle anxiety(c) weight loss(d) personal failure
11. Which of the following is not necessary for initiatinginsulin therapy?(a) Determine degree of hyperglycemia by using fasting and
postprandial blood glucose monitoring and the A1C value.(b) Determine body weight.(c) Determine the degree of insulin resistance in patients
with type 1 diabetes(d) Determine the capabilities and lifestyle needs of
the patient.
12. Vials of in-use insulin can be stored at room temperature or in the refrigerator for up to 30 days without a significant loss of potency.(a) True(b) False
13. Patient resistance to the use of insulin therapy may becircumvented by the use of:(a) short, fine needles(b) easy-to-use insulin administration systems(c) increased understanding of benefits and risks associated
with insulin therapy(d) all of the above
14. Major hypoglycemia can be treated by the patients themselves.(a) True(b) False
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EFFECTIVENESS OF TEACHING/LEARNING METHOD (Please circle one response per line.)
How well did this program achieve the following objectives? Poor Excellent
• Describe the impact of diabetes on patient health and the healthcare system 1 2 3 4 5
• List the currently available insulin analogs and premixed insulin analogs 1 2 3 4 5
• Describe the molecular alterations of insulin analogs compared with human insulin 1 2 3 4 5
• State the major pharmacokinetic differences between human insulin and insulin analogs 1 2 3 4 5
• Explain how insulin regimens are selected and what factors should be considered
when starting and adjusting insulin therapy 1 2 3 4 5
• Describe two different insulin regimens that cover both fasting and postprandial
glucose excursions 1 2 3 4 5
• Describe the practical aspects of storing and injecting insulin 1 2 3 4 5
• Discuss the prevention and treatment of hypoglycemia 1 2 3 4 5
The relationship of the learning objectives to the overall purpose/goal of this
independent study was effective. 1 2 3 4 5
The teaching/learning resources were effective. 1 2 3 4 5
This home study has contributed to my professional effectiveness and
improved my ability to: Strongly Disagree Strongly Agree
• Optimize patient care 1 2 3 4 5
• Communicate with patients 1 2 3 4 5
• Manage my practice 1 2 3 4 5
• Improve my clinical skills 1 2 3 4 5
Other
Poor Excellent
The overall program was: 1 2 3 4 5
Did you feel this program adequately covered the topic? Yes _____ No _____
Do you feel that the program was balanced, objective, and free of commercial bias? Yes ____ No ____
Will you change your clinical practice based on this activity? Yes _____ No _____
Suggested topics for future programs:
General comments/suggestions:
An Introduction to Insulin Analogs and Premixed Insulin Analogs
PROGRAM EVALUATION (069-999-05-229-H01)How many hours ____ and minutes ____ did it take you to complete this CE program? Please indicate date of completion. ________
DIRECTIONS: Please rate the following on a scale of 1–5 (1 = Poor, 5 = Excellent)
17
Post-Test Answer Grid
1 2 3 4 5 6 7
8 9 10 11 12 13 14
To obtain a statement of credit, you must complete the post-test with a score of at least 75%, complete the program evaluation,
and mail or fax both the evaluation form and the answer key to Program Management Services. Your statement of credit will be
mailed in 4 to 6 weeks.
Mail/fax pages to:Program Management Services, Inc.P.O. Box 490East Islip, NY 11730-9848
Fax: (631) 563-1907
Please print clearly
Name
Type of credit desired RPh RN RD
Professional License RD# RN, LD, or RPh# State
Street Address
City State Zip
Phone Number Fax Number
Signature
© 2005 Scherer Clinical Communications December 2005 Printed in USA.
