2/19/22, 10:34 AM
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`Insulin Lispro: A Fast-Acting Insulin Analog - American Family Physician
`
`Insulin Lispro: A Fast-Acting Insulin Analog
`
`SARA L. NOBLE, PHARM.D., ELIZABETH JOHNSTON, M.S.ED., and BILL WALTON, D.O., University of Mississippi Medical Center, Jackson, Mississippi
`
`Am Fam Physician. 1998 Jan 15;57(2):279-286.
`
`Researchhasestablished the importance of maintaining blood glucose levels near normalin patients with type 1 (insulin-dependent) diabetes
`mellitus. Short-acting insulin analogs are designed to overcomethelimitations of regular short-acting insulins. Compared with regular human
`insulin, the analog insulin lispro offers faster subcutaneous absorption, an earlier and greater insulin peak and a morerapid post-peak decrease.
`Insulin lispro begins to exert its effects within 15 minutes of subcutaneous administration, and peak levels occur 30 to 90 minutes after
`administration. Duration of activity is less than five hours. Ratesofinsulin allergy,lipodystrophy, hypoglycemia and abnormal laboratorytest
`results are essentially the samein patients using insulin lispro and in those using regular humaninsulin.
`
`The Diabetes Control and Complications Trial (DCCT)4 established the importance of maintaining near-normal blood glucoselevels in patients with
`type 1 (insulin-dependent) diabetes mellitus. In these patients, intensive therapeutic regimens have been found to delay the onset and reduce the
`progression of microvascular complications by 50 to 75 percent as compared with conventional regimens. Although no large-scale investigations have
`been completed, smaller studies have reported similar benefits for intensive therapeutic regimens in patients with type 2 (non—insulin-dependent)
`diabetes.2
`
`Primary care physicians provide medical care for 75 percent of children and 90 to 95 percentof adults with diabetes.2 Regardless of the type of
`diabetes, improved glycemic control often can be achieved with individualized tools for patient self-management, carefully formulated nutrition plans
`and the useofalternative insulin regimens.4
`
`Overview ofInsulin
`
`Insulin is necessary for the normal metabolism of carbohydrates, protein and fat. Normal insulin secretion has both basal and meal-stimulated
`components. Basal insulin secretion, which is usually in the range of 0.5 to 1.0 unit per hour, retards hepatic glucose production in the postabsorptive
`state. The fasting blood glucoselevel is the base on which prandial glycemia is added during the next 24 hours.£ The meal-stimulated phaseofinsulin
`secretion (1 unit of insulin per 10 g of carbohydrate) promotesthe dispersal of ingested nutrients, primarily glucose, into the peripheryInsulin is also
`released whenblood glucose concentrations exceed 100 mg perdL (5.6 mmol per L).5
`
`In persons who do not have diabetes, insulin is very sensitive to the rise in blood glucose concentration that occurs in response to meals. Endogenous
`insulin secretion generally peaks within one hour after a meal. Once the meal-stimulated glycemia has subsided,insulin and glucoselevels return to
`premeal levels within two hours. This does not occur in patients with diabetes. Therefore, commonly prescribed regimens consisting of combined
`short-acting (regular) and intermediate-acting insulins are used to mimic endogenous insulin response. However, these regimens have been incapable
`of adequately simulating the basal or meal-stimulated components of normal insulin secretion. The physiologic profile of insulin requires rapid changes
`in concentration as a result of food ingestion or other factors, such as exercise. Furthermore, insulin is a hormone witha half-life of only five to seven
`minutes.Z
`
`Regular human insulin (e.g., Humulin R, Novolin R, Velosulin BR) seldom achieves glycemic control becauseit contains hexamersof insulin crystallized
`around a zinc molecule. Although this hexameric insulin is injected subcutaneously,it cannot be absorbedinto the bloodstream in this form. Instead, it
`mustfirst dissociate into dimers and monomers. Dissociation occurs bydilution as the insulin diffuses from the injection site. Diffusion is slow,
`requiring 50 to 90 minutes, and thereforelimits insulin absorption.2 Factors that affect the action of insulin arelisted in Table 1.7
`
`
`View/Print Table
`
`TABLE 1
`
`Insulin: Factors Affecting Onset, Degree and Duration of Action
`
`Insulin source* and type
`
`Insulin antibodies
`
`Insulin dose
`
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`2/19/22, 10:34 AM
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`Insulin Lispro: A Fast-Acting Insulin Analog - American Family Physician
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`Injection site
`
`Injection technique
`
`Exercise
`
`Temperature
`
`*—I/nsulin source: beef, pork, recombinant DNA technology.
`Infaennatinn Fenn Tinnan ND
`Inniilin caninnann and atentanian fac INDRA Ninkatan Dancer TANT E(OVnm AL ONONA OO
`
`
`
`
`
`The administration of regular human insulin with each meal, a componentofintensive diabetes management, is intended to maintain postprandial
`blood glucoselevels as close to normal as possible.42 Thelimitations of regular human insulin therapyarelisted in Table 2Manydiabetic patients do
`not consider the importanceof timing in administering their insulin injections; instead, they elect to inject insulin at more convenient but inappropriate
`times. Inappropriate timing of insulin administration results in a mismatching of postprandial carbohydrate absorption and postinjection insulin peak.
`Regular human insulin is still present in the blood when peripheral glucose disposal occurs. This mismatch predisposespatients to development of
`acute complications of diabetes such as hypoglycemia.12 Suboptimal glucosecontrol also places patients at risk for long-term microvascular
`complications, nephropathy, neuropathy and retinopathy.+
`
`View/Print Table’
`
`TABLE 2
`
`Limitations of Regular HumanInsulin
`
`Sloweronset ofactivity that requires injections to be given 30 to 45 minutes before meals
`
`Patient inconvenience
`
`Safety concerns if the meal is not eaten when scheduled
`
`A prolonged duration of action (up to 12 hours ofactivity)
`
`Late postprandial hypoglycemia (4 to 6 hours after a meal)
`
`Risk of hyperinsulinemia
`
`Adapted with permission from Campbell RK, Campbell LK, White JR. Insulin lispro:its role in the treatmentof diabetes mellitus. Ann Pharmacother
`1996,;30:1263-77.
`
`
`
`Insulin Lispro
`Short-acting insulin analogs are designed to overcomethe limitations of conventional regular human insulin. Insulin lispro (Humalog), formerly called
`LYSPRO from the chemical nomenclature [LYS(B28), PRO(B29)], is the first commercially available insulin analog. Compared with regular human insulin,
`this insulin analog offers the advantagesof faster subcutaneous absorption, an earlier and greater insulin peak, and a shorter duration of action 1442
`
`The benefits achieved by insulin lispro are related to a sequence switch of two beta-chain amino acids. Human insulin, a protein hormone composed of
`two polypeptide chains,hasalinked A chain and B chain. In insulin lispro, reversal of the proline at B-28 and the lysine at B-29 results in more rapid
`
`dissolution of this insulin to a dimer and then to a monomerthat is absorbed morerapidly after subcutaneousinjection® (Figure 1) 13
`
`View/Print Figure’
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`2/19/22, 10:34 AM
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`Insulin Lispro: A Fast-Acting Insulin Analog - American Family Physician
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`ime-action profiles of insulin lispro (Humalog) and regular human insulin (Humulin R), both administered subcutaneously in a dose of0.2 units per
`kg.
`
`PHARMACOLOGY
`
`The pharmacologyoflispro insulin is similar to that of all insulins. Insulin lispro is equipotent to regular human insulin on a molar basis. One unit of this
`insulin has the same glucose-lowering effect as one unit of regular humaninsulin14
`
`PHARMACOKINETICS AND PHARMACODYNAMICS
`
`
`Insulin lispro and regular humaninsulin havedifferent pharmacokinetics (Table 3).14 Becauseinsulin lispro beginsto exertits effects within 15 minutes
`of administration, patients must eat within this time period. Compared with insulin lispro, regular human insulin has a slower onset of action. Thus,it
`should be injected 30 to 45 minutes before meals (personal communication from Eli Lilly and Company, based on data on file, September 1997). This
`time frameallows regular human insulin to reach peak activity at the time of the peak absorption of nutrients from a meal.18 Surveys indicate, however,
`that patientsfind it difficult to coordinate the insulin injection time of 30 to 60 minutes before a meal with the actual time that the meal is consumed.18
`
`
`
`TABLE 3
`
`Rapid- and Short-Acting Insulins: Pharmacokinetic Differences
`TYPE OFINSULIN
`
`ONSET
`
`PEAK EFFECT
`
`DURATION
`
`View/Print Table
`
`Rapid acting: insulin lispro (Humalog)
`
`0 to 15 minutes
`
`30 to 90 minutes
`
`Less than 5 hours
`
`Short acting: regular human insulin (Humulin R, Novolin R)
`
`30 to 45 minutes
`
`2 to 4 hours
`
`6 to 8 hours
`
`Information from Physicians’ desk reference. Montvale, N.J.: Medical Economics, 1997:1488—90, 1846-7, and from data on file with Eli Lilly and Company
`(personal communication, September 1997).
`
`
`
`Greater reductions in postprandial blood glucose excursions have been achieved with insulin lispro administered immediately before meals than with
`regular insulin given 30 minutes before meals.1Z-12 Wheninsulin lispro is used, postprandial self blood glucose monitoring should be addedto the
`monitoring schedule.
`
`Peak serum concentrations ofinsulin lispro occur 30 to 90 minutes after subcutaneous administration. With subcutaneously administered regular
`human insulin, peak serum concentrations occur within two to four hours. Therefore, regular human insulin therapy may lead to hypoglycemia between
`meals (i.e., after food has been absorbed but while insulin is still active).
`
`The duration of activity for insulin lispro is less than five hours, compared with six to 10 hours for regular human insulin (personal communication from
`Eli Lilly and Company, based on data on file, September 1997). With injection in the abdomen, the peak concentration ofinsulin lispro is slightly higher
`and the duration of action slightly shorter than when the analog is administered in the arm or thigh. However,insulin lispro is consistently absorbed
`faster than regular human insulin, regardless ofthe site of administration.18 As with anyinsulin preparation,differences in absorption may occur
`between patients or even in the same patient.
`
`INDICATIONS, DOSING AND ADMINISTRATION
`
`Insulin lispro is available only by prescription and is indicated for the managementof hyperglycemia in patients with diabetes mellitus. Guidelines for
`
`glycemic controlarelisted in Table 4.2921 Becauseofits more rapid onset and shorter duration ofaction,insulin lispro should always bepart of a
`regimen that includes a longer-acting human insulin2 except when continuous subcutaneousinsulin infusion therapy is used.22
`
`
`TABLE 4
`
`Glycemic Control for Persons with Diabetes*
`BIOCHEMICAL
`NORMS FOR NONDIABETIC
`ACTION SUGGESTEDft
`GLYCEMIC GOAL
`INDEX
`PERSONS
`
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`Insulin Lispro: A Fast-Acting Insulin Analog - American Family Physician
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`BIOCHEMICAL
`INDEX
`
`NORMS FOR NONDIABETIC
`PERSONS
`
`GLYCEMIC GOAL
`
`Preprandial
`glucoselevel
`
`Less than 115 mg per dL
`(6.4 mmol perL)
`
`80 to 120 mg perdL (4.4 to
`6.7 mmolperL)
`
`Bedtime
`glucoselevel
`
`Less than 120 mg per dL
`(6.7 mmol per L)
`
`100 to 140 mg per dL (5.6 to
`7.8 mmol perL)
`
`Hemoglobin
`AIC valuet
`
`Less than 6 percent
`
`Less than 7 percent
`
` *—Thesevalues given in this table are for patients who are not pregnant.
`
`ACTION SUGGESTED}
`
`Less than 80 mg perdL (4.4 mmol per L) or greater than
`140 mg per dL (7.8 mmol perL)
`
`Less than 100 mg perdL (5.6 mmol per L) or greater than
`160 mg per dL (8.9 mmol perL)
`
`Greater than 8 percent
`
`t+—The‘action suggested” dependsontheindividual patient. The action mayinclude increased patient education, more frequent self-monitoring of blood
`glucoselevels or referral to an endocrinologist.
`
`t—Hemoalobin Air is referenced to a nondiabetic rangeof 4.0 to 6.0 percent (mean: 5.0 percent; standard deviation: 0.5 percent).
`
`Based on product information from Eli Lilly and Company, the dosage ofinsulin lispro should be individualized, with therapyinitiated as outlined in
`
`Table 5, Patients who useinsulin lispro should monitor their blood glucoselevels frequently, especially their postprandial levels. The U.S. Food and
`Drug Administration has not approved insulin lispro for continuous subcutaneous infusion therapy, although this method has beenusedin clinical
`studies. Insulin lispro also is not approved for intravenous or intramuscular administration.
`
`
`TABLE 5
`
`DosingofInsulin Lispro* and Intermediate-or Long-Acting HumanInsulint
`
`View/Print Table’
`
`1. Calculate the TDD.
`
`2. Select the daily injection regimen:
`
`a. Twice-daily injection regimen
`
`Before breakfast
`
`Before dinner
`
`b. Multiple daily injection regimens
`
`Before breakfast
`
`Before lunch
`
`20 percent of TDD as Humalog and 50 percent of TDD as Humulin N
`
`10 percent of TDD as Humalog and 20 percent of TDD as Humulin N
`
`
`
`
`
`20 to 30 percent of TDD as Humalog
`
`20 percent of TDD as Humalog
`
`
`
`
`
`
`Before dinner
`20 percent of TDD as Humalog and 30 to 40 percent of TDD as Humulin U
`
`Insulin lispro is physically compatible with Eli Lilly's intermediate-acting human insulins (Humulin N, Humulin L) and longer-acting human insulin
`(Humulin U). Insulin lispro may be mixed in the samesyringe with theseinsulins, provided thatthe injection is administered immediately14 However,
`the insulin lispro should be drawninto the syringefirst so that the vial of short-acting insulin is not contaminated with a longer-acting insulin.24
`Predrawn syringes of mixed insulin should not be stored. Not enough information is available to determine whether insulin lispro can be mixed with
`other insulin types in pre-drawn syringes. Animal insulins or human insulins produced by companiesother than Eli Lilly should not be mixed with insulin
`lispro, because compatibilities have not yet been confirmed.244
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`2/19/22, 10:34 AM
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`Insulin Lispro: A Fast-Acting Insulin Analog - American Family Physician
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`Insulin lispro is packaged as 100 units per mL, in 10-mL vials, at an average wholesale price of $24.98pervial, or as five 1.5-mL cartridges at an
`average wholesale price of $29.99 forfive cartridges.18 In contrast, regular human insulin costs $19.84 for 100 units per mL,in 10-mL vials, or $24.11
`for five 1.5-mL cartridges.23 Insulin lispro should be kept refrigerated but not frozen. However, it can beleft unrefrigerated for up to 28 days, at which
`time it must be discarded.14
`
`Insufficient information exists concerning the effect of impaired renal or hepatic function on insulin lispro levels. Dose adjustments may be necessary
`becauseofthe possibility of higher insulin concentrations in patients with renal or hepatic disease.
`
`ADVERSE REACTIONS
`
`Hypoglycemia can occur if patients do not eat within 15 minutes after receiving insulin lispro. Furthermore, patients may experience postprandial
`hypoglycemia if the carbohydrate content of a mealis too low. Thus, the dosage of insulin lispro may need to be adjusted for meal composition and
`size. Late postprandial hyperglycemia can occur if the insulin lispro dosage is decreased and the patient subsequently consumesa low-carbohydrate
`meal.24
`
`The overall rate of hypoglycemia has notdiffered for diabetic patients receiving insulin lispro or regular human insulin. However, patients with type 1
`diabetes who aretreated with insulin lispro have been found to have fewer hypoglycemic episodes between midnight and 6 a.m. than patients treated
`with regular human insulin.22 The lower rate of hypoglycemia with insulin lispro may be related to higher nocturnalblood glucoselevels (due to the
`insulin's shorter duration of action), as reflected by an increase in morning blood glucoselevels.
`
`The DCCT28 established thatthe incidenceof severe treatment-induced hypoglycemia increasessignificantly with intensive therapy. Severe
`hypoglycemia is defined as any episode of hypoglycemia that impairs the patient's neurologic function so that the assistance of another person is
`required.22 Manifestations of severe hypoglycemia can include disoriented behavior, loss of consciousness,inability to be aroused from sleep and/or
`the occurrenceof seizures. Some patients with type 1 diabetes fear severe hypoglycemia as muchasthe long-term complications of the disease.28 In
`fact, this fear of hypoglycemia can be a major barrier to achieving glycemic control.28
`
`The magnitude of exercise-induced hypoglycemia with insulin lispro depends on the interval between insulin administration and exercise. Compared
`with regular human insulin, insulin lispro is morelikely to prevent exercise-induced hypoglycemia in patients with type 1 diabetes who choose to
`exercise two to three hours after a meal.22 If exerciseis to be performed soon after food ingestion andinsulin administration, the doseofinsulin lispro
`
`should be decreased. Practical considerations for patients experiencing hypoglycemic reactions arelisted in Table 6.
`
`TABLE 6
`
`Hypoglycemia: Practical Considerations in Changing Insulin Therapy
`CONSIDERATION
`COMMENTS
`
`View/Print Table’
`
`Is the correct amountof
`insulin being measured and
`given?
`
`Is the patient rotating
`injection sites?
`
`Is the patient performing
`regular blood glucose
`monitoring?
`
`Eyesight deteriorates as a consequenceof diabetic and nondiabetic eye disease.
`
`Consider having the patient use a pen device* or a magnifying glass thatfits around the insulin vial while he or
`she is drawing up the insulin dose, or have a caregiver or some other person provide assistancein drawing up the
`dose.
`
`Examine the injection sites; if necessary, remind the patient to rotate thesesites.
`
`Patients with longstanding diabetes often use single injection sites because they seem relatively pain-free; insulin
`absorption from thesesites is notoriously variable.
`
`Instruct the patient to monitor blood glucoselevels frequently at the time of a change in insulin therapy.
`
`Check the patient's monitoring technique for common mistakes,including not having sufficient blood on the
`stick, incorrect wiping of the sample and incorrect timing before the stick is read.
`
`The newer calfmoanitarina devices have eliminated mact errare af timina and winina and same even tell the
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`2/19/22, 10:34 AM
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`Insulin Lispro: A Fast-Acting Insulin Analog - American Family Physician
`
`Ratesofinsulin allergy,lipodystrophy, hypoglycemia and abnormal laboratory test results have not differed in patients using insulin lispro or regular
`human insulin.22
`
`DRUG INTERACTIONS
`
`No studies have specifically evaluated drug interactions in diabetic patients who are receiving lispro insulin. Close monitoring of blood glucoselevels is
`important when a drug regimen is changedin any patient with diabetes.
`
`THERAPEUTIC ROLE
`
`Insulin lispro has been found to be a safe and effective treatment for diabetes mellitus. Improvementin glycemic control is demonstrated by a
`decreased postprandial blood glucose concentration, although the clinical significance of this improvementis as yet unknown.
`
`Multinational clinical trials have shown no statistically significant difference between hemoglobin Aj, levels in patients treated with insulin lispro and
`patients treated with regular human insulin.242 However, the useofinsulin lispro in external insulin infusion pumps has been shownto produce a small,
`yet clinically significant (0.34 percent) reduction in hemoglobin Aj, levels compared with the reduction achieved using regular human insulin. Based on
`risk analysis of the DCCTdata, this improvement in hemoglobin Aj, represents an approximately 20 percent reduction in the risk of retinopathy in
`patients with diabetes.22
`
`Near-normal glycemic control is necessary to prevent or delay the onset of complications in patients with type 1 or type 2 diabetes. Patients with type 2
`diabetes who have not respondedto oral glucose-lowering agents often require insulin therapy to achieve the glycemic goals set forth by the American
`Diabetes Association. One study24 in both type 1 and type 2 diabetics concludedthat insulin lispro improves postprandial glycemic control without
`increasing the risk of hypoglycemia.22 Short- or long-term insulin therapy has been shownto beusefulin type 2 diabetics in whom therapid
`componentof endogenousinsulin secretion is missing.22 In these patients,insulin lispro is a physiologic therapy. Special dosing considerations for
`insulin lispro are listed in Table 733
`
`
`TABLE 7
`
`Special Considerationsin Using Insulin Lispro
`POTENTIAL PROBLEM
`
`COMMENTS ANDPOSSIBLE SOLUTIONS
`
`View/Print Tabl
`
`Patient eats dinner late
`
`Becauseofinsulin lispro's shorter duration of action, hyperglycemia may occur
`becausethe time from lunch to dinner may be too long.
`
`Consider adding a small dose of intermediate-acting (NPH) insulin at lunch to meet
`basal insulin requirements between meals.
`
`Patient has snacks containing more than 5 g of
`carbohydrate
`
`Consider adding an additional doseof insulin lispro;if the patient also eats dinner late
`in the evening, this additional dose of insulin lispro can replace lunchtime basal NPH
`insulin supplementation.
`
`Patient is a slow eateror a grazer (i.e., eats small
`amounts of carbohydrates throughout the day rather
`than at three meals)
`
`Becauseof the rapid onset ofinsulin lispro, this type of patient may not respond as
`well to insulin lispro as to regular human insulin.
`
`Patient has unpredictable eating habits
`
`Insulin lispro offers the patient flexibility, in that the administration of this insulin can
`be timed with meals.
`
`
`
`Primary care physicians should consider including mealtime insulin lispro in insulin regimens. The disadvantagesofinsulin lispro therapy are the
`increasedrisk of hypoglycemia if meal ingestion or absorption (gastroparesis) is delayed and the increased overall cost of therapy. In addition, insulin
`lispro is available by prescription only. Nonetheless, a short-acting insulin analog such as insulin lispro should provide increased convenience and
`flexibility to patients who are currently receiving regular human insulin. Furthermore, the characteristics of insulin lispro may help patients achieve
`improved long-term glycemic control and may reducethe incidence of hypoglycemic episodes. Insulin analogs may be an importanttoolfor helping
`patients with diabetes mellitus achieve their target glucose goals.
`
`https://www.aafp.org/afp/1998/0115/p279.html
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`2/19/22, 10:34 AM
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`Insulin Lispro: A Fast-Acting Insulin Analog - American Family Physician
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`The Authors_§showall authorinfo
`
`SARA L. NOBLE,PHarM.o., is assistant professor in the Department of Family Medicine at the University of Mississippi Medical Center, Jackson. She
`earned a doctorate in pharmacyfrom the University of Mississippi...
`
`Figure 1 adapted with permission from Johnson MD, White JR, Campbell RK. Insulin therapy in the era of insulin analogs. U.S. Pharmacist 1996;21:HS35-HS44.,
`
`REFERENCES_
`
`showall references
`
`1. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-
`term complications in insulin-dependent diabetes mellitus. N Eng! J Med. 1993;329:977—86....
`
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