2/19/22, 10:34 AM
`
`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 Earn Physician. 1998 Jan 15;57(2):279-286.
`
`See related patient information handout on insulin lispro (https:iiwww.aafp.orsiat/1sssro11s✓p2ss.htmq.
`
`Research has established the importance of maintaining blood glucose levels near normal in patients with type 1 (insulin-dependent) diabetes
`mellitus. Short-acting insulin analogs are designed to overcome the limitations 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 more rapid 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. Rates of insulin allergy, lipodystrophy, hypoglycemia and abnormal laboratory test
`results are essentially the same in patients using insulin lispro and in those using regular human insulin.
`
`The Diabetes Control and Complications Trial (DCCT)1 established the importance of maintaining near-normal blood glucose levels 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.?
`
`Primary care physicians provide medical care for 75 percent of children and 90 to 95 percent of adults with diabetes.5 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 use of alternative insulin regimens.4
`
`Overview of Insulin
`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.E The fasting blood glucose level is the base on which prandial glycemia is added during the next 24 hours.5 The meal-stimulated phase of insulin
`secretion (1 unit of insulin per 10 g of carbohydrate) promotes the dispersal of ingested nutrients, primarily glucose, into the periphery.5 Insulin is also
`released when blood glucose concentrations exceed 100 mg per dL (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 glucose levels 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 with a half-life of only five to seven
`minutes.?
`
`Regular human insulin (e.g., Humulin R, Novolin R, Velosulin BR) seldom achieves glycemic control because it contains hexamers of insulin crystallized
`around a zinc molecule. Although this hexameric insulin is injected subcutaneously, it cannot be absorbed into the bloodstream in this form. Instead, it
`must first dissociate into dimers and monomers. Dissociation occurs by dilution as the insulin diffuses from the injection site. Diffusion is slow,
`requiring 50 to 90 minutes, and therefore limits insulin absorption.5 Factors that affect the action of insulin are listed in Table 1.Z
`
`View/Print Table
`
`TABLE 1
`Insulin: Factors Affecting Onset, Degree and Duration of Action
`
`Insulin source* and type
`
`Insulin antibodies
`
`Insulin dose
`
`https://www.aafp.org/afp/1998/0115/p279.html
`
`2/19/22, 10:34 AM
`
`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.
`
`
`
`See related patient information handout on insulin lispro (https://www.aafp.org/afp/1998/0115/p289. html).
`
`Research has established the importance of maintaining blood glucose levels near normal in patients with type 1 (insulin-dependent) diabetes
`
`mellitus. Short-acting insulin analogs are designed to overcome the limitations 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 more rapid 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. Rates of insulin allergy, lipodystrophy, hypoglycemia and abnormal laboratory test
`
`results are essentially the same in patients using insulin lispro and in those using regular human insulin.
`
`The Diabetes Control and Complications Trial (DCCT)! established the importance of maintaining near-normal blood glucose levels 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 percent of 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 use of alternative insulin regimens 4
`
`Overview of Insulin
`
`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 glucose level is the base on which prandial glycemia is added during the next 24 hours 8 The meal-stimulated phase of insulin
`
`secretion (1 unit of insulin per 10 g of carbohydrate) promotes the dispersal of ingested nutrients, primarily glucose, into the periphery Insulin is also
`
`released when blood glucose concentrations exceed 100 mg per dL (5.6 mmol per L) 8
`
`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 glucose levels 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 with a half-life of only five to seven
`minutes Z
`
`Regular human insulin (e.g., Humulin R, Novolin R, Velosulin BR) seldom achieves glycemic control because it contains hexamers of insulin crystallized
`
`around a zinc molecule. Although this hexameric insulin is injected subcutaneously, it cannot be absorbed into the bloodstream in this form. Instead, it
`must first dissociate into dimers and monomers. Dissociation occurs by dilution as the insulin diffuses from the injection site. Diffusion is slow,
`requiring 50 to 90 minutes, and therefore limits insulin absorption.2 Factors that affect the action of insulin are listed in Table 1.2
`
`
`
`View/Print Table
`
`TABLE 1
`
`Insulin: Factors Affecting Onset, Degree and Duration of Action
`
`Insulin source* and type
`
`Insulin antibodies
`
`Insulin dose
`
`
`
`https://lwww.aafp.org/afp/1998/0115/p279.html
`
`
`
`1
`
`MYLAN EXHIBIT - 1028
`Mylan Pharmaceuticals, Inc. v. Bausch Health Ireland, Ltd. - IPR2022-00722
`
`

`

`2/19/22, 10:34 AM
`
`Insulin Lispro: A Fast-Acting Insulin Analog - American Family Physician
`
`Injection site
`
`Injection technique
`
`Exercise
`
`Temperature
`
`*—Insulin source: beef, pork, recombinant DNA technology.
`
`---:----
`
`------
`
`inn•
`
`•
`
`n-.—
`
`Innn.,
`
`n_ in. .--I nl.nn
`
`•
`
`nn
`
`The administration of regular human insulin with each meal, a component of intensive diabetes management, is intended to maintain postprandial
`blood glucose levels as close to normal as possible.42 The limitations of regular human insulin therapy are listed in Table 2.5 Many diabetic patients do
`not consider the importance of 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 predisposes patients to development of
`acute complications of diabetes such as hypoglycemia.'n Suboptimal glucose control also places patients at risk for long-term microvascular
`complications, nephropathy, neuropathy and retinopathy.1
`
`View/Print Table
`
`TABLE 2
`Limitations of Regular Human Insulin
`
`Slower onset of activity 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 of activity)
`
`Late postprandial hypoglycemia (4 to 6 hours after a meal)
`
`Risk of hyperinsulinemia
`
`Adapted with permission from Campbell RK, Campbell LI( White JR. Insulin lispro: its role in the treatment of diabetes mellitus. Ann Pharmacother
`1996;30:1263-77.
`
`Insulin Lispro
`Short-acting insulin analogs are designed to overcome the 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 advantages of faster subcutaneous absorption, an earlier and greater insulin peak, and a shorter duration of action.11 12
`
`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, has a linked 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 monomer that is absorbed more rapidly after subcutaneous injections (Figure 1).13
`
`View/Print Figure
`
`FIGURE 1.
`
`https://www.aafp.org/afp/1998/0115/p279.html
`
`2/19/22, 10:34 AM
`
`Insulin Lispro: A Fast-Acting Insulin Analog - American Family Physician
`
`Injection site
`
`Injection technique
`
`Exercise
`
`Temperature
`
`*—Insulin source: beef, pork, recombinant DNA technology.
`
`
`
`Iabmvimnmtinia Loma Tinmnnn PD danidin camiaaana An A mtvntanmina Fav INOAAE
`NiAbh adam Nava TNANNTL/O an] NN.ON A OO
`
`
`
`
`The administration of regular human insulin with each meal, a component of intensive diabetes management, is intended to maintain postprandial
`
`blood glucose levels as close to normal as possible.22 The limitations of regular human insulin therapy are listed in Table 2.5 Many diabetic patients do
`
`not consider the importance of 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 predisposes patients to development of
`
`acute complications of diabetes such as hypoglycemia. 22 Suboptimal glucose control also places patients at risk for long-term microvascular
`
`complications, nephropathy, neuropathy and retinopathy.
`
`
`
`View/Print Table
`
`TABLE 2
`
`Limitations of Regular Human Insulin
`
`Slower onset of activity 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 of activity)
`
`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 treatment of diabetes mellitus. Ann Pharmacother
`
`1996,30:71263-71.
`
`Insulin Lispro
`
`Short-acting insulin analogs are designed to overcome the 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 advantages of faster subcutaneous absorption, an earlier and greater insulin peak, and a shorter duration of action. 1112
`
`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, has a linked 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 monomer that is absorbed more rapidly after subcutaneous injection® (Figure 1)12
`
`
`
`
`
`View/Print Figure
`
`FIGURE 1.
`
`https://lwww.aafp.org/afp/1998/0115/p279.html
`
`2
`
`

`

`2/19/22, 10:34 AM
`
`Insulin Lispro: A Fast-Acting Insulin Analog - American Family Physician
`
`Time-action profiles of insulin lispro (Humalog) and regular human insulin (Humulin R), both administered subcutaneously in a dose of 0.2 units per
`kg.
`
`PHARMACOLOGY
`
`The pharmacology of lispro 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 human insulin.
`
`PHARMACOKINETICS AND PHARMACODYNAMICS
`
`Insulin lispro and regular human insulin have different pharmacokinetics (Table 3).41 Because insulin lispro begins to exert its 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 frame allows regular human insulin to reach peak activity at the time of the peak absorption of nutrients from a meal.15 Surveys indicate, however,
`that patients find 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.61
`
`TABLE 3
`Rapid- and Short-Acting Insulins: Pharmacokinetic Differences
`
`TYPE OF INSULIN
`
`ONSET
`
`PEAK EFFECT
`
`DURATION
`
`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
`
`View/Print Table
`
`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
`When insulin lispro is used, postprandial self blood glucose monitoring should be added to the
`monitoring schedule.
`
`Peak serum concentrations of insulin 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 of insulin 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 of the site of administration.'n As with any insulin 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 management of hyperglycemia in patients with diabetes mellitus. Guidelines for
`glycemic control are listed in Table 42921 Because of its more rapid onset and shorter duration of action, insulin lispro should always be part of a
`regimen that includes a longer-acting human insulin ,5 except when continuous subcutaneous insulin infusion therapy is used.22
`
`View/Print Table
`
`TABLE 4
`Glycemic Control for Persons with Diabetes*
`
`BIOCHEMICAL
`INDEX
`
`NORMS FOR NONDIABETIC
`PERSONS
`
`https://www.aafp.org/afp/1998/0115/p279.html
`
`GLYCEMIC GOAL
`
`ACTION SUGGESTED?
`
`2/19/22, 10:34 AM
`
`Insulin Lispro: A Fast-Acting Insulin Analog - American Family Physician
`
`Time-action profiles of insulin lispro (Humalog) and regular human insulin (Humulin R), both administered subcutaneously in a dose of 0.2 units per
`
`kg.
`
`
`
`PHARMACOLOGY
`
`The pharmacology of lispro 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 human insulin. 14
`
`PHARMACOKINETICS AND PHARMACODYNAMICS
`
`Insulin lispro and regular human insulin have different pharmacokinetics (Table 3) 1 Because insulin lispro begins to exert its 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 frame allows regular human insulin to reach peak activity at the time of the peak absorption of nutrients from a meal 12 Surveys indicate, however,
`
`that patients find 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
`
`
`
`View/Print Table
`
`TABLE 3
`
`Rapid- and Short-Acting Insulins: Pharmacokinetic Differences
`
`TYPE OF INSULIN
`
`ONSET
`
`PEAK EFFECT
`
`DURATION
`
`
`
`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. 22718 When insulin lispro is used, postprandial self blood glucose monitoring should be added to the
`
`monitoring schedule.
`
`Peak serum concentrations of insulin 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 of insulin 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 of the site of administration. 13 As with any insulin 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 management of hyperglycemia in patients with diabetes mellitus. Guidelines for
`
`glycemic control are listed in Table 4.2921 Because of its more rapid onset and shorter duration of action, insulin lispro should always be part of a
`
`
`regimen that includes a longer-acting human insulin,2 except when continuous subcutaneous insulin infusion therapy is used.22
`
`
`
`TABLE 4
`
`Glycemic Control for Persons with Diabetes*
`
`BIOCHEMICAL
`INDEX
`
`NORMS FOR NONDIABETIC
`PERSONS
`
`GLYCEMIC GOAL
`
`ACTION SUGGESTED}
`
`
`
`
`https://lwww.aafp.org/afp/1998/0115/p279.html
`
`3
`
`

`

`2/19/22, 10:34 AM
`
`Insulin Lispro: A Fast-Acting Insulin Analog - American Family Physician
`
`BIOCHEMICAL
`INDEX
`
`NORMS FOR NONDIABETIC
`PERSONS
`
`GLYCEMIC GOAL
`
`ACTION SUGGESTED?
`
`Preprandial
`glucose level
`
`Less than 115 mg per dL
`(6.4 mmol per L)
`
`80 to 120 mg per dL (4.4 to
`6.7 mmol per L)
`
`Less than 80 mg per dL (4.4 mmol per L) or greater than
`140 mg per dL (7.8 mmol per L)
`
`Bedtime
`glucose level
`
`Less than 120 mg per dL
`(6.7 mmol per L)
`
`100 to 140 mg per dL (5.6 to
`7.8 mmol per L)
`
`Less than 100 mg per dL (5.6 mmol per L) or greater than
`160 mg per dL (8.9 mmol per L)
`
`Hemoglobin
`Al C valuet
`
`Less than 6 percent
`
`Less than 7 percent
`
`Greater than 8 percent
`
`*—These values given in this table are for patients who are not pregnant.
`
`t —The "action suggested" depends on the individual patient. The action may include increased patient education, more frequent self-monitoring of blood
`glucose levels or referral to an endocrinologist.
`
`t —Hemoplobin Air is referenced to a nondiabetic range of 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 of insulin lispro should be individualized, with therapy initiated as outlined in
`Table 5. Patients who use insulin lispro should monitor their blood glucose levels 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 been used in clinical
`studies. Insulin lispro also is not approved for intravenous or intramuscular administration.
`
`View/Print Table
`
`TABLE 5
`Dosing of Insulin Lispro* and Intermediate-or Long-Acting Human Insulint
`
`1. Calculate the TDD.
`
`2. Select the daily injection regimen:
`
`a. Twice-daily injection regimen
`
`Before breakfast
`
`20 percent of TDD as Humalog and 50 percent of TDD as Humulin N
`
`Before dinner
`
`10 percent of TDD as Humalog and 20 percent of TDD as Humulin N
`
`b. Multiple daily injection regimens
`
`Before breakfast
`
`20 to 30 percent of TDD as Humalog
`
`Before lunch
`
`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 same syringe with these insulins, provided that the injection is administered immediately.41 However,
`the insulin lispro should be drawn into the syringe first so that the vial of short-acting insulin is not contaminated with a longer-acting insulin.a
`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 companies other than Eli Lilly should not be mixed with insulin
`lispro, because compatibilities have not yet been confirmed 5,1a
`
`https://www.aafp.org/afp/1998/0115/p279.html
`
`2/19/22, 10:34 AM
`
`Insulin Lispro: A Fast-Acting Insulin Analog - American Family Physician
`
`BIOCHEMICAL
`INDEX
`
`NORMS FOR NONDIABETIC
`PERSONS
`
`GLYCEMIC GOAL
`
`ACTION SUGGESTED}
`
`
`
`Preprandial
`
`Less than 115 mg per dL
`
`80 to 120 mg per dL (4.4 to
`
`Less than 80 mg per dL (4.4 mmol per L) or greater than
`
`glucose level
`
`(6.4 mmol per L)
`
`6.7 mmol per L)
`
`140 mg per dL (7.8 mmol per L)
`
`Bedtime
`
`Less than 120 mg per dL
`
`100 to 140 mg per dL (5.6 to
`
`Less than 100 mg per dL (5.6 mmol per L) or greater than
`
`glucose level
`
`(6.7 mmol per L)
`
`7.8 mmol per L)
`
`160 mg per dL (8.9 mmol per L)
`
`Hemoglobin
`
`A1C valuet
`
`Less than 6 percent
`
`Less than 7 percent
`
`Greater than 8 percent
`
`*—These values given in this table are for patients who are not pregnant.
`
`T—The “action suggested” depends on the individual patient. The action may include increased patient education, more frequent self-monitoring of blood
`
`glucose levels or referral to an endocrinologist.
`
`t—Hemoalobin Air is referenced to a nondiabetic range of 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 of insulin lispro should be individualized, with therapy initiated as outlined in
`
`Table 5. Patients who use insulin lispro should monitor their blood glucose levels 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 been used in clinical
`
`studies. Insulin lispro also is not approved for intravenous or intramuscular administration.
`
`
`
`View/Print Table
`
`TABLE 5
`
`Dosing of Insulin Lispro* and Intermediate-or Long-Acting Human Insulint
`
`1. Calculate the TDD.
`
`2. Select the daily injection regimen:
`
`a. Twice-daily injection regimen
`
`Before breakfast
`
`20 percent of TDD as Humalog and 50 percent of TDD as Humulin N
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`Before dinner
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`10 percent of TDD as Humalog and 20 percent of TDD as Humulin N
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`b. Multiple daily injection regimens
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`Before breakfast
`
`20 to 30 percent of TDD as Humalog
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`Before lunch
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`20 percent of TDD as Humalog
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`Before dinner
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`20 percent of TDD as Humalog and 30 to 40 percent of TDD as Humulin U
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`
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`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 same syringe with these insulins, provided that the injection is administered immediately.14 However,
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`the insulin lispro should be drawn into the syringe first so that the vial of short-acting insulin is not contaminated with a longer-acting insulin.2
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`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 companies other than Eli Lilly should not be mixed with insulin
`
`lispro, because compatibilities have not yet been confirmed 214
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`https://lwww.aafp.org/afp/1998/0115/p279.html
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`4
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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 $24.98 per vial, or as five 1.5-mL cartridges at an
`average wholesale price of $29.99 for five cartridges.
`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 2s Insulin lispro should be kept refrigerated but not frozen. However, it can be left unrefrigerated for up to 28 days, at which
`time it must be discarded.41
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`Insufficient information exists concerning the effect of impaired renal or hepatic function on insulin lispro levels. Dose adjustments may be necessary
`because of the possibility of higher insulin concentrations in patients with renal or hepatic disease.
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`ADVERSE REACTIONS
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`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 meal is 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 consumes a low-carbohydrate
`meal 24
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`The overall rate of hypoglycemia has not differed for diabetic patients receiving insulin lispro or regular human insulin. However, patients with type 1
`diabetes who are treated with insulin lispro have been found to have fewer hypoglycemic episodes between midnight and 6 a.m. than patients treated
`with regular human insulima The lower rate of hypoglycemia with insulin lispro may be related to higher nocturnal blood glucose levels (due to the
`insulin's shorter duration of action), as reflected by an increase in morning blood glucose levels.
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`The DCCT2 established that the incidence of severe treatment-induced hypoglycemia increases significantly 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.E Manifestations of severe hypoglycemia can include disoriented behavior, loss of consciousness, inability to be aroused from sleep and/or
`the occurrence of seizures. Some patients with type 1 diabetes fear severe hypoglycemia as much as the long-term complications of the diseaseA In
`fact, this fear of hypoglycemia can be a major barrier to achieving glycemic control.M
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`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 more likely to prevent exercise-induced hypoglycemia in patients with type 1 diabetes who choose to
`exercise two to three hours after a mealA If exercise is to be performed soon after food ingestion and insulin administration, the dose of insulin lispro
`should be decreased. Practical considerations for patients experiencing hypoglycemic reactions are listed in Table 6.
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`View/Print Table
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`TABLE 6
`Hypoglycemia: Practical Considerations in Changing Insulin Therapy
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`CONSIDERATION
`
`COMMENTS
`
`Is the correct amount of
`insulin being measured and
`given?
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`Is the patient rotating
`injection sites?
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`Is the patient performing
`regular blood glucose
`monitoring?
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`Eyesight deteriorates as a consequence of diabetic and nondiabetic eye disease.
`
`Consider having the patient us