Insulin Lispro (Monograph)

Brand name: HumaLOG
Drug class: Rapid-acting Insulins
ATC class: A10AB04
VA class: HS501
Chemical name: 28B-l-Lysine-29B-l-prolineinsulin (human)
Molecular formula: C₂₅₇H₃₈₃N₆₅O₇₇S ₆
CAS number: 133107-64-9

Medically reviewed by Drugs.com on Jan 22, 2024. Written by ASHP.

Introduction

Antidiabetic agent; a rapid-acting biosynthetic human insulin analog.¹ ² ⁸ ¹³ ⁵¹ ¹⁴⁵

Uses for Insulin Lispro

Diabetes Mellitus

Used to control hyperglycemia in the management of diabetes mellitus.¹ ² ³ ⁶ ¹² ⁴⁷ ⁷⁵ ⁷⁷ ⁷⁸

In patients with type 1 diabetes mellitus, generally used in conjunction with an intermediate-acting or long-acting insulin preparation (i.e., isophane [NPH] insulin human, insulin lispro protamine [as the fixed combination Humalog Mix 75/25], insulin zinc [Lente], extended insulin human zinc [Ultralente]), to provide prandial glycemic control.¹ ⁷³ ⁷⁴ ⁷⁶ ⁷⁷ ⁷⁸ ⁷⁹ ⁸¹ ⁹⁶ ¹⁴⁴ ¹⁴⁵ ¹⁵⁹ ¹⁶⁰ ¹⁶¹ ¹⁶⁵ In patients with type 2 diabetes mellitus, may be used without a longer-acting insulin when given with a sulfonylurea agent.¹ ¹⁵⁸ ¹⁵⁹ ¹⁶⁰ ¹⁶¹ ¹⁶⁵

Patients likely to benefit from insulin lispro therapy include type 1 diabetics who desire a more flexible injection schedule, those with low glycosylated hemoglobin values, and patients with recent-onset type 1 diabetes mellitus who have some residual β-cell function to provide basal insulin levels between meals.⁶ ¹² ⁵⁶ ⁵⁹ ⁷⁴ ⁷⁷ ⁷⁸ ⁷⁹ ⁸¹ ¹⁴⁴ ¹⁴⁵

The effects of age, obesity, gender, and type of diabetes mellitus on glycemic response do not appear to differ in patients receiving insulin lispro versus insulin human.¹ ⁵¹

Some clinicians suggest that patients who are well-controlled on conventional short-acting insulin preparations without frequent hypoglycemia should not be routinely switched to insulin lispro.⁷⁴ ¹⁴⁴

Insulin Lispro Dosage and Administration

General

Insulin lispro and insulin human are equipotent on a unit-for-unit basis with regard to glucose-lowering activity.¹ ² ³ ⁷ ⁹ ¹² ¹⁹ ⁴⁷ ⁵¹ ⁵⁹
Any change in insulin should be made cautiously and only under medical supervision.¹ Changes in insulin strength, manufacturer, type (e.g., regular, NPH), species (animal, human), or method of manufacture (rDNA versus animal-source insulin) may necessitate a change in dosage.¹
Monitor patients through regular laboratory evaluations, including fasting blood (or plasma) glucose determinations, to assess therapeutic response and obtain the minimum effective dosage of insulin lispro.¹ ²⁰ ²⁴ Whenever possible, patients should self-monitor blood glucose concentrations.¹ ⁵ ¹⁹ ²² ⁵¹ ⁶⁰ Following initiation of insulin lispro therapy and dosage titration, determine glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) concentrations at intervals of approximately 3 months.²² ²⁴ ¹⁴⁴ ¹⁴⁵

Transferring from Therapy with Other Insulins

Make any change in insulin preparation or dosage regimen with caution and only under medical supervision.¹ ¹⁹ ⁵¹
Not possible to clearly identify which patients will require a change in dosage when therapy with a different preparation is initiated.⁶ ⁹ ¹² ¹⁹ ⁵¹
When switching from insulin human (regular) in regimens consisting of multiple insulin doses, use the previous insulin (regular) dosage as the initial dosage of insulin lispro.¹ ⁷² ⁷⁴ ¹⁴⁷ Subsequent dosage adjustments may be required due to changes in insulin purity, strength, brand, type, species source, or method of manufacture.¹ ² ³ ⁷ ⁹ ¹² ¹⁹ ⁴⁷ ⁵¹ ⁵⁹ Adjustments may be needed with the first dose or over a period of several weeks.¹
When switching from insulin human (regular) in combination with a longer-acting insulin, dosage adjustment of the longer-acting insulin may be required.¹ ¹² ⁵¹ ⁵⁸ ⁷⁵ ⁷⁷ ⁷⁸ ¹⁴⁷ ¹⁵⁴
Patients receiving intensive insulin therapy (≥3 insulin injections daily with dosage adjusted according to results of at least 4 daily blood glucose determinations, dietary intake, and anticipated exercise) will achieve greater postprandial glycemic control than those receiving conventional therapy because of the increased use of rapid- or short-acting insulin.⁶ ⁹ ²² ⁵⁹
Patients who previously were inadequately controlled on conventional insulin therapy generally will require a smaller total daily insulin dosage when switched to an intensive insulin regimen.⁶ ⁹ ²² ⁵⁹

Administration

Administer by sub-Q injection or continuous sub-Q infusion.¹

Do not administer insulin lispro in fixed combination with insulin lispro protamine IV.^a

To improve accuracy of dosing in pediatric patients, may be diluted to a ratio of 1:10 or 1:2 with the sterile diluent supplied by the manufacturer.¹

Sub-Q Injection

For solution and drug compatibility information, see Compatibility under Stability.

Administer by sub-Q injection immediately (i.e., within 15 minutes before or after a meal) using a conventional insulin syringe or an injection pen (e.g., Becton-Dickinson [B-D] Pen, Humalog Pen, Novo Nordisk’s NovoPen).¹ ¹⁹ ¹⁵⁵ ¹⁵⁶ ¹⁵⁷

Generally administered in multiple daily doses in regimens that also include an intermediate- or long-acting insulin (e.g., NPH, Lente, Ultralente) given in the morning and/or evening to provide basal insulin needs.¹ ⁷² ⁷⁴

Administer insulin lispro in fixed combination with insulin lispro protamine (Humalog Mix 75/25) twice daily within 15 minutes prior to the morning and evening meal.¹⁵⁹ ¹⁶¹

Administer into abdominal wall, thigh, or upper arm.^g To avoid tissue damage, give the next injection at least 1/2 inch from the previous injection site.^g

Sub-Q Infusion

Administer by continuous sub-Q infusion using an external controlled-infusion device.¹ Recommended for use in Disetronic H-TRONplus V100 (with Disetronic 3.15 mL insulin reservoir), Disetronic D-TRON, or Disetronic D-TRONplus external infusion pumps with Disetronic Rapid infusion sets and in MiniMed model 506, 507, or 508 pumps with MiniMed Polyfin infusion sets.¹ Delivers rapid- or short-acting insulin at a basal rate continuously throughout the day, with patient-initiated delivery of insulin prior to meals.²⁷ ²⁸

Dosage

Dosage of insulin lispro is always expressed in USP units.¹ ¹⁹ ²⁰ ²² ²³ ²⁴ ³⁸ ⁶² ⁶³

Pediatric Patients

Diabetes Mellitus

Sub-Q Injection

Individualize dosage; adjust dosage regularly based on blood glucose determinations.¹ ⁿ Usually, the total daily insulin requirement in children with type 1 diabetes mellitus ranges from 0.2–1 units/kg (generally 0.5–0.8 units/kg daily).²² ²⁸ ⁴⁷ ^z Adolescents in a growth phase may require an initial insulin dosage of 1–1.5 units/kg daily.²⁸ No specific dosage recommendations by manufacturer.¹ When used as a preprandial treatment regimen in clinical trials, 26–64% of total insulin requirements have been provided by insulin lispro, with the remainder provided by an intermediate-acting or long-acting insulin.ⁿ ^o ^q ^t ^u

Sub-Q Infusion

Individualize dosage; adjust dosage regularly based on blood glucose determinations.¹ Glucose monitoring is particularly important for patients receiving insulin via an external infusion pump.¹

No specific dosage recommendations by manufacturer.¹ In a clinical trial, preprandial administration of insulin lispro injection comprised approximately 66% of the total daily insulin dosage, with the remainder given as a basal infusion.^q

Adults

Diabetes Mellitus

Sub-Q Injection

Individualize dosage; adjust dosage regularly based on blood glucose determinations.¹ Usually, the total daily insulin requirements in patients with type 1 diabetes mellitus is 0.5–1 unit/kg.^h No specific dosage recommendations by manufacturer.¹ When used in a preprandial treatment regimen in clinical trials, 39–66% of total insulin requirements have been provided by insulin lispro, with the remainder provided by an intermediate-acting or long-acting insulin.¹⁴⁷ ⁱ ^j ^k ^l ^r

In patients with type 2 diabetes mellitus who are not controlled on intermediate-acting or long-acting insulin, some clinicians suggest initiating preprandial therapy with a short-acting or rapid-acting insulin, with the preprandial injection comprising 40–50% of the total insulin dosage.^p

Sub-Q Infusion

Individualize dosage; adjust dosage regularly based on blood glucose determinations.¹ Glucose monitoring is particularly important for patients receiving insulin via an external infusion pump.¹

No specific dosage recommendations by the manufacturer.¹ In patients with type 1 diabetes mellitus, preprandial administration of insulin lispro injection has been used in clinical trials, comprising approximately 21–46% of the total daily insulin dosage, with the remainder given as a basal infusion.¹⁶⁸ ^m ^r ^s

Therapy with Fixed-Combination Insulin Lispro and Insulin Lispro Protamine

Sub-Q Injection

Individualize dosage; adjust dosage regularly based on blood glucose determinations.^a

No specific dosage recommendations by the manufacturer.^a Initially, 0.3–0.5 units/kg daily given in 2 divided doses (before morning and evening meal) has been used in patients with type 2 diabetes mellitus.^v ^y Subsequent dosage has been titrated in increments of 2–4 units per injection per day every 2–3 days to achieve the targeted fasting blood glucose concentration.^v ^y Mean daily maintenance insulin dosage achieved was 0.46–0.66 units/kg.¹⁵⁹ ^v ^w ^x ^y

In patients with type 1 diabetes mellitus in a clinical trial, mean daily maintenance insulin dosage achieved was 0.64 units/kg.^x

Special Populations

Renal and Hepatic Impairment

Careful monitoring of blood glucose and dosage adjustment may be necessary.¹

Cautions for Insulin Lispro

Contraindications

Use of insulin lispro during episodes of hypoglycemia.¹
Known hypersensitivity to insulin lispro or any of its excipients.¹

Warnings/Precautions

Warnings

Formulation Considerations

Insulin lispro has a more rapid onset and shorter duration of action than insulin human (regular).¹ Patients with type 1 diabetes require a longer-acting insulin to maintain adequate nighttime and preprandial blood glucose control.¹ ⁷⁴ ⁷⁶ ⁷⁷ ⁷⁸ ⁷⁹ ⁸¹ ¹⁴⁴

Hypoglycemia

Care should be taken in patients who are most at risk for the development of these effects, including patients who are fasting or those with defective counterregulatory responses (e.g., patients with autonomic neuropathy, adrenal or pituitary insufficiency, those receiving β-adrenergic blocking agents).^cc ^dd ^gg ^hh ^pp ^qq ^uu

Rapid changes in serum glucose concentrations may precipitate manifestations of hypoglycemia, regardless of glucose concentrations.¹ Homeostatic responses become defective, and early warning signs of hypoglycemia may be diminished or absent in patients with long-standing type 1 diabetes mellitus, diabetic neuropathy,¹ ^cc ^ee ^gg ^hh ⁱⁱ ^ll ⁿⁿ ^pp ^qq ^r ^ss and/or those receiving drugs such as β-adrenergic blocking agents that mask catecholamine-induced manifestations of hypoglycemia (e.g., tremors, palpitations).¹ ^cc ^ee ^gg ^hh ⁱⁱ ^ll ⁿⁿ ^pp ^qq ^r ^ss

Use intensive insulin therapy with caution in patients with a history of hypoglycemic unawareness or recurrent, severe hypoglycemic episodes.^cc ^ff ^gg ⁱⁱ ^ss Higher target blood glucose concentrations (e.g., fasting blood glucose concentrations of 140 mg/dL and 2-hour postprandial concentrations of 200–250 mg/dL) are advisable in these patients.^cc ^gg ^hh

Sensitivity Reactions

Local reactions (e.g., erythema, pruritus, swelling) reported.¹ Generalized hypersensitivity reactions (e.g., rash, shortness of breath, wheezing, hypotension, tachycardia, and diaphoresis) reported less frequently; may be life-threatening.¹

Localized reactions and generalized myalgias reported with the use of m-cresol, an excipient in the formulation.¹

Insulin lispro is no more immunogenic than insulin human.¹² ¹⁴ ¹⁵ ¹⁷ ¹⁸ ⁵¹ ⁵²

Weigh benefits versus risks in patients with a history of hypersensitivity to other insulins.⁵¹

General Precautions

Lipodystrophy

Atrophy or hypertrophy of subcutaneous fat tissue may occur at sites of frequent insulin injections.¹ Changing injection technique may reduce or prevent these effects.^g

Hypokalemia

Care should be taken in patients who are most at risk for the development of hypokalemia, such as those who are receiving potassium-lowering drugs.^a

Specific Populations

Pregnancy

Category B.¹

Lactation

Not known whether insulin lispro is distributed into milk, however, other insulins (e.g., insulin human) are distributed into milk.¹ ¹ Caution if used in nursing women.¹ Adjustments in insulin lispro dosage and/or meal plans may be required.¹

Pediatric Use

Safety and efficacy of insulin lispro in fixed combination with insulin lispro protamine not established in children <18 years of age.¹⁶⁵

Insulin lispro has been used in children aged 3–18 years of age with type 1 diabetes mellitus,¹ ⁵¹ ⁷⁴ and preliminary data suggest no unusual effects of insulin lispro therapy in adolescents receiving the drug.⁷⁴ ¹¹⁸ ¹⁴⁴ ¹⁴⁵ ¹⁴⁹ ¹⁵⁰ ¹⁵¹ Adjustment of basal insulin dosages may be required.¹

Geriatric Use

Safety of intensive insulin regimens in geriatric patients has been questioned.^hh ⁱⁱ ^jj ^mm ^vv ^ww Increased incidence of hypoglycemia associated with intensive insulin therapy may increase the probability of strokes and heart attacks in such patients.^hh ⁱⁱ ^jj ^mm ^vv ^ww

Hypoglycemic reactions may mimic a cerebrovascular accident.^d Patients with type 2 diabetes mellitus may be more vulnerable to serious consequences of hypoglycemia (e.g., fainting, seizures, falls, stroke, silent ischemia, MI, or sudden death) due to an increased incidence of macrovascular disease.ⁱⁱ

Response in patients ≥65 years of age does not appear to differ from that in younger adults.¹

Common Adverse Effects

Hypoglycemia.^aa ^bb ^hh ⁿⁿ ¹

Specific Drugs

Drugs That May Potentiate Hypoglycemic Effects

ACE inhibitors

Disopyramide

Fibrate derivatives

Fluoxetine

MAO inhibitors

Oral antidiabetic agents

Propoxyphene

Salicylates

Somatostatin derivatives (e.g., octreotide)

Sulfonamide anti-infectives

Drugs That May Antagonize Hypoglycemic Effects

Corticosteroids

Danazol

Diuretics

Estrogens and progestins (e.g., oral contraceptives)

Isoniazid

Phenothiazines

Somatropin

Sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline)

Thyroid hormones

Drugs That May Have a Variable Effect on Glycemic Control

Alcohol

β-Adrenergic blocking agents

Clonidine

Lithium salts

Pentamidine

Drugs That May Reduce or Eliminate Signs of Hypoglycemia (Sympatholytic Agents)

β-Adrenergic blocking agents

Clonidine

Guanethidine

Reserpine

Insulin Lispro Pharmacokinetics

Absorption

Bioavailability

Following sub-Q administration, more rapidly absorbed than soluble preparations of insulin human or insulins of animal origin.¹ ² ³ ⁶ ⁹ ¹⁰ ⁵¹ ⁷³ ¹⁴⁴ ¹⁴⁵ ¹⁶⁵

Peak plasma insulin concentrations are higher and occur earlier with insulin lispro (at 30–90 minutes) than with insulin human (at 50–120 minutes).¹ ² ⁶ ⁹ ¹⁰ ¹¹ ⁷³ ¹⁶⁵

Following sub-Q administration of the fixed combination of insulin lispro and insulin lispro protamine (Humalog Mix 75/25), peak serum insulin concentrations were observed at 30–240 minutes (median: 60 minutes).¹⁶⁵ More rapidly absorbed than the fixed combination of insulin human (regular) and isophane insulin human (Humulin 70/30).¹⁶⁵

Onset

Many factors can affect the onset, degree, and duration of insulin activity (e.g., injection technique, presence of insulin antibodies, site of injection, tissue blood supply, temperature, excipients in insulin formulations, and interindividual and intraindividual differences in response).¹ ¹⁹ ⁴⁷ ⁷⁴ ⁸³

Following sub-Q injection of insulin lispro, onset generally ranges from 0.25–0.5 hours versus 0.5–1 hours for insulin human, respectively.¹ ³ ⁹ ⁵¹ ⁷³ ⁷⁴ ⁸³ Peak glycemic response for insulin lispro or insulin human occurs at 0.5–2.5 or 1–5 hours, respectively.¹ ³ ⁹ ⁵¹ ⁷³ ⁷⁴ ⁸³

Duration

Following sub-Q administration, the duration of hypoglycemic action of insulin lispro is 3–6.5 hours compared with 6–10 hours for insulin human.⁴⁷ ⁵¹ ⁷³ ⁷⁴ ⁸³

The duration of action of Humalog Mix 75/25 is similar to that of Humulin 70/30.¹⁶⁵

Food

Administer 15 minutes before or immediately after meals.¹ ⁷²

Special Populations

The presence of hepatic impairment does not affect the absorption in patients with type 2 diabetes mellitus.¹

Distribution

Not known whether insulin lispro is distributed into human milk; however, other insulins (e.g., insulin human) are distributed into milk.¹ Does not appear to cross the placenta in pregnant women with gestational diabetes.¹⁶⁴

Extent

The volume of distribution of insulin lispro reportedly is identical to that of insulin human and ranges from 0.26–0.36 L/kg.¹

Special Populations

Hepatic impairment does not affect the distribution in patients with type 2 diabetes mellitus.¹

Elimination

Metabolic fate has not been determined in humans.¹ ¹⁶⁵ In animals, metabolism of insulin lispro is identical to that of insulin human.¹ ¹⁶⁵

Metabolism

Insulin is rapidly metabolized mainly in the liver and to a lesser extent in the kidneys and muscle tissue.^d

Half-life

1 or 1.5 hours for insulin lispro or insulin human, respectively.² ⁵¹

Special Populations

Circulating insulin concentrations may be increased in patients with renal or hepatic failure.¹

Stability

Storage

Parenteral

Injection, for Sub-Q Use

With unopened vials, disposable injection pens, or cartridges of the drug that have not been placed in a delivery device, 2–8°C.¹ ¹⁹ ¹⁵⁶ ¹⁶⁵ Do not freeze; discard vial or cartridge if frozen.¹ ¹⁹ ¹⁵⁶ ¹⁶⁵

With vials, pens, or cartridges of insulin lispro that cannot be refrigerated or vials, cartridges, and disposable injection pens that are in use, <30°C for up to 28 days.¹ ¹⁹ ⁵¹ ⁸¹ ¹⁵⁵ Protect from heat and light.¹ ¹⁵⁵

With disposable injection pens of insulin lispro in fixed combination with insulin lispro protamine (Humalog Mix 75/25 Pen) that are in use, room temperature for up to 10 days.¹⁶⁰ ¹⁶⁵ Protect from light and excessive heat.¹⁶⁰ ¹⁶⁵

When insulin lispro is diluted with the sterile diluent for pediatric use, discard the diluted solution after 28 days when stored at 5°C or after 14 days when stored at 30°C.¹⁶⁵

Should not expose insulin lispro in the external infusion device to temperatures >37°C during administration.¹ Replace infusion sets (reservoir syringe, tubing, and catheter), the DisetronicD-TRON or DisetronicD-TRONplus cartridge adapter, and insulin lispro in the pump reservoir and select a new infusion site at least every 48 hours.¹ Should discard the 3-mL cartridges used in the DisetronicD-TRON or DisetronicD-TRONplus insulin pumps after 7 days, even if some drug still remains in the reservoir.¹

Simulated administration of insulin lispro by continuous sub-Q infusion in several external infusion pump systems (i.e., Disetronic H-TRON, Minimed Model 504 pumps) revealed no changes in the potency, purity, or physical stability of the drug when stored within each of these devices for 48 hours.⁵¹ ⁸¹ ¹⁴⁶ ¹⁶³ However, precipitation of insulin lispro on infusion catheters (i.e., Silhouette, Soft-Set catheters) has been noted in several patients who were receiving insulin lispro via one of several external pump systems (i.e., Disetronic H-TRON V-100, Minimed 507C pumps).¹⁶⁷

Compatibility

Parenteral

When insulin lispro is mixed with a longer-acting insulin preparation, insulin lispro should be drawn into the syringe first in order to prevent precipitation or turbidity of the insulin lispro solution by the longer-acting insulin.¹ Insulin mixtures should not be administered IV.¹

Should not dilute or mix insulin lispro with any other insulin when administered via an external sub-Q controlled-infusion device (pump).¹

Drug Compatibility

Admixture Compatibility 1
Compatible
Extended human insulin zinc
Insulin, isophane human (recombinant DNA origin)

Actions

Facilitates cellular uptake of glucose in muscle and other tissues, except the brain.^c ^d Stimulates protein synthesis and inhibits protein catabolism.¹ ^d
Inhibits output of glucose from the liver.⁹ ^c ^d In the liver, insulin facilitates phosphorylation of glucose to glucose-6-phosphate which is converted to glycogen or further metabolized.^d Promotes the conversion of excess glucose into fat.¹
Stimulates lipogenesis and inhibits lipolysis and release of free fatty acids from adipose cells.^d
Promotes an intracellular shift of potassium^oo ^tt and thereby appears to temporarily decrease elevated blood concentrations of this ion.^d

Advice to Patients

Importance of providing the patient with a copy of the manufacturer’s patient information.¹ ² ²³ ²⁶
Importance of providing instructions regarding insulin storage, dosage, and proper injection technique.¹ ^e
Importance of strict adherence to manufacturer’s instructions regarding assembly, administration, and care of specialized delivery systems, such as insulin pens.⁷² ¹⁴⁴ ¹⁴⁵ ^e
Importance of changing insulin preparation or dosage with caution and only under medical supervision.¹ ¹⁹ ⁵¹ Discuss potential for alterations in insulin requirements and need for additional monitoring of blood glucose concentrations in special situations (e.g., illness, concomitant agents that alter glycemic control, travel, emotional disturbances, or other stresses).^bb ^cc ^oo ^ww
Advise patients of the risks and advantages of conventional and intensive insulin therapy.^cc ^ff ^gg ^hh
Importance of administering insulin lispro sub-Q within 15 minutes before or immediately after a meal.¹
Advise patient not to smoke within 30 minutes after insulin injection, due to potential for decreased absorption of insulin.^e
Importance of carefully advising patients of the differences in action profiles between insulin lispro and insulin human (regular) during transfer from insulin human to insulin lispro.¹ ⁷⁴ May be necessary to adjust the consumption and/or timing of snacks or exercise to avoid hypoglycemic episodes and/or prevent preprandial hyperglycemia.¹ ⁷⁴
Importance of regular self monitoring of blood glucose concentrations.¹ ^e Particular importance of frequent self monitoring of blood glucose concentrations in patients with a history of hypoglycemic unawareness or recurrent, severe hypoglycemic episodes.^cc ^gg
Provide instructions regarding adherence to meal planning, regular physical exercise, periodic HbA_1c monitoring, and management of hypoglycemia or hyperglycemia.¹ ^e
Importance of wearing a medical identification bracelet or pendant, carrying ample insulin supply and syringes on trips, and having carbohydrates (sugar or candy) on hand for emergency.^e
Importance of not changing the order of mixing insulins or the model or brand of syringe or needle without medical supervision.¹ ^e When mixing with long-acting insulin preparations, importance of drawing insulin lispro into the syringe first.^e
Importance of informing clinicians of the development of generalized hypersensitivity reactions (shortness of breath, hypotension, wheezing, whole body rash, tachycardia, diaphoresis).¹
Importance of patients being aware of symptoms of diabetic ketoacidosis and the need to monitor blood ketones if preprandial blood glucose concentrations repeatedly exceed 250–300 mg/dL^cc ^kk ^ww ^xx or if they have an acute illness.^kk ^ww Importance of contacting a physician if results of self-monitored blood glucose concentrations are consistently abnormal.^cc
Inform patient that use of marijuana may increase insulin requirements.^e
Instruct patient on the appropriate measures for safe disposal of needles.^e
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.¹
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹
Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Insulin Lispro (Recombinant DNA Origin)
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection	100 units/mL	HumaLOG (with cresol, glycerin and zinc oxide; available as 1.5-mL cartridge, 3-mL disposable delivery device, and 10-mL vial)	Lilly

Insulin Lispro Combinations (Recombinant DNA Origin)
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Suspension, Sterile	Insulin Lispro 25 units/mL with Insulin Lispro Protamine 75 units/mL	HumaLOG Mix 75/25 (with m-cresol, glycerin, and zinc oxide; available as 3-mL delivery device)	Lilly

References

1. Eli Lilly and Company. Humalog (insulin lispro, [rDNA origin]) injection prescribing information. Indianapolis, IN; 2004 Jun 2.

2. Howey DC, Bowsher RR, Brunelle RL et al. [Lys (B28), Pro (B29)]-human insulin: a rapidly absorbed analogue of human insulin. Diabetes. 1994; 43:396-402. http://www.ncbi.nlm.nih.gov/pubmed/8314011?dopt=AbstractPlus

3. Howey DC, Bowsher RR, Brunelle RL et al. [Lys (B28), Pro (B29)]–human insulin: effect of injection time on postprandial glycemia. Clin Pharmacol Ther. 1995; 58:459-69. http://www.ncbi.nlm.nih.gov/pubmed/7586939?dopt=AbstractPlus

4. Chance RE, Dimarchi RD, Frank BH et al; Eli Lilly and Company, assignee. Preparation of insulin with modified association and biological properties. European Patent Application patent 383472. 1990 Aug 22.

5. Burge MR, Castillo KR, Schade DS. Meal composition is a determinant of lispro-induced hypoglycemia in IDDM. Diabetes Care. 1997; 20:152-5. http://www.ncbi.nlm.nih.gov/pubmed/9118763?dopt=AbstractPlus

6. Pampanelli S, Torlone E, Lalli C et al. Improved postprandial metabolic control after subcutaneous injection of a short-acting insulin analog in IDDM of short duration with residual pancreatic β-cell function. Diabetes Care. 1995; 18:1452-9. http://www.ncbi.nlm.nih.gov/pubmed/8722069?dopt=AbstractPlus

7. Buelke-Sam J, Byrd RA, Hoyt JA et al. A reproductive and developmental toxicity study in CD rats of LY275585, [Lys(B28),Pro(B29)]-human insulin. J Am Coll Toxicol. 1994; 13:247-60.

8. Ciszak E, Beals JM, Frank BH et al. Role of C-terminal B-chain residues in insulin assembly: the structure of hexameric Lys^B28Pro^B29-human insulin. Structure. 1995; 3:615-22. http://www.ncbi.nlm.nih.gov/pubmed/8590022?dopt=AbstractPlus

9. Torlone E, Fanelli C, Rambotti AM et al. Pharmacokinetics, pharmacodynamics and glucose counterregulation following subcutaneous injection of the monomeric insulin analogue [Lys(B28),Pro(B29)] in IDDM. Diabetologia. 1994; 37:713-20. http://www.ncbi.nlm.nih.gov/pubmed/7958544?dopt=AbstractPlus

10. Betz JL. Fast-acting human insulin analogs: a promising innovation in diabetes care. Diabetes Educ. 1995; 21:195, 197-8, 200. http://www.ncbi.nlm.nih.gov/pubmed/7758386?dopt=AbstractPlus

11. Trautmann ME. Effect of the insulin analogue [LYS (B28),PRO(B29)] on blood glucose control. Horm Metab Res. 1994; 26:588-90. http://www.ncbi.nlm.nih.gov/pubmed/7705764?dopt=AbstractPlus

12. Pfützner A, Küstner E, Forst T et al for the German Insulin Lispro/IDDM Study Group. Intensive insulin therapy with insulin lispro in patients with type 1 diabetes reduces the frequency of hypoglycemic episodes. Exp Clin Endocrinol Diabetes. 1996; 104:25-30.

13. Brems DN, Alter LA, Beckage MJ et al. Altering the association properties of insulin by amino acid replacement. Protein Eng. 1992; 5:527-33. http://www.ncbi.nlm.nih.gov/pubmed/1438163?dopt=AbstractPlus

14. DiMarchi RD, Chance RE, Long HB et al. Preparation of an insulin with improved pharmacokinetics relative to human insulin through consideration of structural homology with insulin-like growth factor I. Horm Res. 1994; 41(Suppl 2):93-6. http://www.ncbi.nlm.nih.gov/pubmed/8088710?dopt=AbstractPlus

15. Jacobs MAJM, Salobir B, Popp-Snijders C et al. Counterregulatory hormone responses and symptoms during hypoglycaemia induced by porcine, human regular insulin, and Lys(B28), Pro(B29) human insulin analogue (insulin lispro) in healthy male volunteers. Diabetic Med. 1997; 14:248-57. http://www.ncbi.nlm.nih.gov/pubmed/9088775?dopt=AbstractPlus

16. Zimmermann J. A 12-month chronic toxicity study of LY275585 (human insulin analog) administered subcutaneously to Fischer 344 rats. Diabetes. 1994; 43(Suppl 1):166A.

17. Zwickl CM, Smith HW, Zimmermann JL et al. Immunogenicity of biosynthetic human LysPro insulin compared to native-sequence human and purified porcine insulins in Rhesus monkeys immunized over a 6-week period. Arzneimittelforschung. 1995; 45:524-8. http://www.ncbi.nlm.nih.gov/pubmed/7779155?dopt=AbstractPlus

18. Slieker LJ, Brooke GS, Chance RE et al. Insulin and IGF-I analogs: novel approaches to improved insulin pharmacokinetics. In: LeRoith D, Raizada MK eds. Current directions in insulin-like growth factor research. New York: Plenum Press; 1994:25-32.

19. American Diabetes Association. Insulin administration. Diabetes Care. 1997; 20(Suppl 1):S46-9.

20. European IDDM Policy Group 1993. Consensus guidelines for the management of insulin-dependent (type 1) diabetes. Diabetic Med. 1993; 10:990-1005. http://www.ncbi.nlm.nih.gov/pubmed/8306599?dopt=AbstractPlus

21. The 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 Engl J Med. 1993; 329:977-86. http://www.ncbi.nlm.nih.gov/pubmed/8366922?dopt=AbstractPlus

22. Campbell PJ, May ME. A practical guide to intensive insulin therapy. Am J Med Sci. 1995; 310:24-30. http://www.ncbi.nlm.nih.gov/pubmed/7604835?dopt=AbstractPlus

23. Ziegler O, Kolopp M, Louis J et al. Self-monitoring of blood glucose and insulin dose alteration in type 1 diabetes mellitus. Diabetes Res Clin Pract. 1993; 21:51-9. http://www.ncbi.nlm.nih.gov/pubmed/8253023?dopt=AbstractPlus

24. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care. 1997; 2000:23(Suppl 1):S32-42.

25. Olefsky JM. Diabetes mellitus. In: Wyngaarden JB, Smith LH Jr, Bennett JC, eds. Cecil textbook of medicine. 19th ed. Philadelphia: WB Saunders Company; 1992:1291-1310.

26. Mazze RS, Etzwiler DD, Strock E et al. Staged diabetes management. Diabetes Care. 1994; 17(Suppl 1):56-66. http://www.ncbi.nlm.nih.gov/pubmed/8088226?dopt=AbstractPlus

27. Foster DW. Diabetes mellitus. In: Fauci AS, Braunwald E, Isselbacher KJ et al, eds. Harrison’s principles of internal medicine. l4th ed. New York: McGraw-Hill, Inc; 1998:2060-81.

28. Koda-Kimble MA, Carlisle BA. Diabetes mellitus. In: Young LY, Koda-Kimble MA, eds. Applied therapeutics: the clinical use of drugs. 6th ed. Vancouver, WA: Applied Therapeutics, Inc; 1995:48-1–48-62.

29. Turner R, Cull C, Holman R et al. United Kingdom Prospective Diabetes Study 17: a 9-year update of a randomized, controlled trial on the effect of improved metabolic control on complications in non–insulin-dependent diabetes mellitus. Ann Intern Med. 1996; 124:136-45. http://www.ncbi.nlm.nih.gov/pubmed/8554206?dopt=AbstractPlus

30. Colwell JA. The feasibility of intensive insulin management in non–insulin-dependent diabetes mellitus: implications of the Veterans Affairs Cooperative Study on glycemic control and complications in NIDDM. Ann Intern Med. 1996; 124:131-5. http://www.ncbi.nlm.nih.gov/pubmed/8554205?dopt=AbstractPlus

31. Landstedt-Hallin L, Bolinder J, Adamson U et al. Comparison of bedtime NPH or preprandial regular insulin combined with glibenclamide in secondary sulfonylurea failure. Diabetes Care. 1995; 18:1183-6. http://www.ncbi.nlm.nih.gov/pubmed/7587856?dopt=AbstractPlus

32. Yki-Järvinen H, Kauppila M, Kujansuu E et al. Comparison of insulin regimens in patients with non–insulin-dependent diabetes mellitus. N Engl J Med. 1992; 327:1426-33. http://www.ncbi.nlm.nih.gov/pubmed/1406860?dopt=AbstractPlus

33. Chow CC, Sorensen JP, Tsang LWW et al. Comparison of insulin with or without continuation of oral hypoglycemic agents in the treatment of secondary failure in NIDDM patients. Diabetes Care. 1995; 18:307-14. http://www.ncbi.nlm.nih.gov/pubmed/7555472?dopt=AbstractPlus

34. Klein R, Klein BEK, Moss SE et al. Glycosylated hemoglobin predicts the incidence and progression of diabetic retinopathy. JAMA. 1988; 260:2864-71. http://www.ncbi.nlm.nih.gov/pubmed/3184351?dopt=AbstractPlus

35. American Society of Health-System Pharmacists. ASHP therapeutic position statement on strict glycemic control in selected patients with insulin-dependent diabetes mellitus. Am J Health-Syst Pharm. 1995; 52:2709-11. http://www.ncbi.nlm.nih.gov/pubmed/8601269?dopt=AbstractPlus

36. Reichard P, Nilsson BY, Rosenqvist U. The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med. 1993; 329:304-9. http://www.ncbi.nlm.nih.gov/pubmed/8147960?dopt=AbstractPlus

37. American Diabetes Association. Implications of the diabetes control and complications trial. Diabetes Care. 1997; 20(Suppl 1):S620-4.

38. Henry RR, Genuth S. Forum one: current recommendations about intensification of metabolic control in non–insulin-dependent diabetes mellitus. Ann Intern Med. 1996; 124:175-7. http://www.ncbi.nlm.nih.gov/pubmed/8554214?dopt=AbstractPlus

39. Ohkubo Y, Kishikawa H, Araki E et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract. 1995; 28:103-17. http://www.ncbi.nlm.nih.gov/pubmed/7587918?dopt=AbstractPlus

40. Klein R, Klein BEK, Moss SE. Relation of glycemic control to diabetic microvascular complications in diabetes mellitus. Ann Intern Med. 1996; 124:90-6. http://www.ncbi.nlm.nih.gov/pubmed/8554220?dopt=AbstractPlus

41. Henry RR. Glucose control and insulin resistance in non-insulin-dependent diabetes mellitus. Ann Intern Med. 1996; 124:97-103. http://www.ncbi.nlm.nih.gov/pubmed/8554221?dopt=AbstractPlus

42. Howanitz PJ, Howanitz JH. Carbohydrates. In: Henry JB, ed. Todd-Sanford-Davidsohn clinical diagnosis and management by laboratory methods. 17th ed. Philadelphia: WB Saunders Company; 1984:165-179.

43. Genuth S. Exogenous insulin administration and cardiovascular risk in non-insulin-dependent and insulin-dependent diabetes mellitus. Ann Intern Med. 1996;124:104-9.

44. Laakso M. Glycemic control and the risk for coronary heart disease in patients with non-insulin-dependent diabetes mellitus: the Finnish studies. Ann Intern Med. 1996; 124:127-30. http://www.ncbi.nlm.nih.gov/pubmed/8554204?dopt=AbstractPlus

45. Coniff RF, Shapiro JA, Seaton TB. Long-term efficacy and safety of acarbose in the treatment of obese subjects with non-insulin-dependent diabetes mellitus. Arch Intern Med. 1994; 154:2442-8. http://www.ncbi.nlm.nih.gov/pubmed/7979840?dopt=AbstractPlus

46. Zimmerman BR. Preventing long term complications: implications for combination therapy with acarbose. Drugs. 1992; 44(Suppl 3):54-60. http://www.ncbi.nlm.nih.gov/pubmed/1280578?dopt=AbstractPlus

47. Davis SN, Granner DK. Insulin, oral hypoglycemic agents, and the pharmacology of the endocrine pancreas. In: Hardman JG, Limbird LE, Molinoff PB et al, eds. Goodman and Gilman’s the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill; 1996:1487-517.

48. Reverter JL, Tural C, Rosell A et al. Self-induced insulin hypoglycemia in a bodybuilder. Arch Intern Med. 1994; 154:225-6. http://www.ncbi.nlm.nih.gov/pubmed/8285818?dopt=AbstractPlus

49. Cryer PE, Gerich JE. Glucose counterregulation, hypoglycemia, and intensive insulin therapy in diabetes mellitus. N Engl J Med. 1985; 313:232-41. http://www.ncbi.nlm.nih.gov/pubmed/2861565?dopt=AbstractPlus

50. Santiago JV. Intensive management of insulin dependent diabetes: risks, benefits, and unanswered questions. J Clin Endocrinol Metab. 1992; 75:977-82. http://www.ncbi.nlm.nih.gov/pubmed/1400891?dopt=AbstractPlus

51. Eli Lilly and Company, Indianapolis, IN: Personal communication.

52. Fineberg NS, Fineberg SE, Anderson JH et al. Immunologic effects of insulin lispro [Lys (B28), Pro (B29) human insulin] in IDDM and NIDDM patients previously treated with insulin. Diabetes. 1996; 45:1750-4. http://www.ncbi.nlm.nih.gov/pubmed/8922361?dopt=AbstractPlus

53. Henrichs HR, Unger H, Trautmann ME et al. Severe insulin resistance treated with insulin lispro. Lancet. 1996; 348:1248. http://www.ncbi.nlm.nih.gov/pubmed/8898065?dopt=AbstractPlus

54. Pérez A, Caixàs A, Payés A et al. Insulin lispro and regular insulin have a similar effect on lipolytic activities and VLDL composition in NIDDM. Diabetologia. 1994; 37(Suppl 1):A168.

55. Anderson JH, Vignati L, Brunelle RL. Therapy of type II diabetes with insulin lispro, a rapidly absorbed insulin analog. Diabetologia. 1994; 37(Suppl 1):A169.

56. Letiexhe MR, Rutters A, Schmitt H. [Lys(B28),Pro(B29)] human insulin: patients treated with LysPro vs human regular insulin: quality of life assessment. Diabetologia. 1994; 37(Suppl 1):A168.

57. Bohannon NJV, Jack DB. Type II diabetes: tips for managing your older patients. Geriatrics. 1996; 51:28-30,33-35. http://www.ncbi.nlm.nih.gov/pubmed/8641590?dopt=AbstractPlus

58. Bergenstal R, Spencer M, Castle G et al. Intensive insulin management of type I and type II diabetes: a comparison of [Lys(B28), Pro(B29) human insulin] (LP) and regular human insulin (REG). Diabetes. 1994; 43(Suppl 1):157A.

59. Garg SK, Carmain JA, Braddy KC et al. Pre-meal insulin analogue insulin lispro vs Humulin R insulin treatment in young subjects with type 1 diabetes. Diabetic Med. 1996; 13:47-52. http://www.ncbi.nlm.nih.gov/pubmed/8741812?dopt=AbstractPlus

60. Tuominen JA, Karonen SL, Melamies L et al. Exercise-induced hypoglycaemia in IDDM patients treated with a short-acting insulin analogue. Diabetologia. 1995; 38:106-11. http://www.ncbi.nlm.nih.gov/pubmed/7744214?dopt=AbstractPlus

61. Lebovitz HE. Stepwise and combination drug therapy for the treatment of NIDDM. Diabetes Care. 1994; 17:1542-4. http://www.ncbi.nlm.nih.gov/pubmed/7882832?dopt=AbstractPlus

62. The pharmacological treatment of hyperglycemia in NIDDM. Diabetes Care. 1996; 19:1510-18. (IDIS 355480).

63. Expert Committee of the Canadian Diabetes Advisory Board. Clinical practice guidelines for treatment of diabetes mellitus. CMAJ. 1992; 147:697-712. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1336391&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/1521215?dopt=AbstractPlus

64. Reviewers’ comments (personal observations) on metformin.

65. Holman RR, Steemson J, Turner RC. Sulphonylurea failure in type 2 diabetes: treatment with a basal insulin supplement. Diabetic Med. 1987; 4:457-62. http://www.ncbi.nlm.nih.gov/pubmed/2959438?dopt=AbstractPlus

66. MacCuish AC, Munro JF, Duncan LJP. Treatment of hypoglycaemic coma with glucagon, intravenous dextrose, and mannitol infusion in a hundred diabetics. Lancet. 1970; 2:946-9. http://www.ncbi.nlm.nih.gov/pubmed/4097595?dopt=AbstractPlus

67. Arem R, Zoghbi W. Insulin overdose in eight patients: insulin pharmacokinetics and review of the literature. Medicine (Baltimore). 1985; 64:323-32. http://www.ncbi.nlm.nih.gov/pubmed/3897766?dopt=AbstractPlus

68. Astra USA Inc. 50% Dextrose injection, USP prescribing information. Westborough, MA; 1994 Oct.

69. Chan JCN, Cockram CS. Drug-induced disturbances of carbohydrate metabolism. Adverse Drug React Toxicol Rev. 1991; 10:1-29. http://www.ncbi.nlm.nih.gov/pubmed/1878441?dopt=AbstractPlus

70. Pandit MK, Burke J, Gustafson AB et al. Drug-induced disorders of glucose tolerance. Ann Intern Med. 1993; 118:529-39. http://www.ncbi.nlm.nih.gov/pubmed/8442624?dopt=AbstractPlus

71. Sacher RA, McPherson RA, Campos JM. Glucose measurement. In: Sacher RA, McPherson RA, Campos JM, eds. Widman’s clinical interpretation of laboratory tests. 10th ed. Philadelphia: FA Davis Company; 1991:323.

72. Eli Lilly and Company. Humalog (insulin lispro, rDNA origin) injection (vial) patient information. Indianapolis, IN; 2004 Aug 20.

73. Barnett AH, Owens DR. Insulin analogues. Lancet. 1997; 349:47-51. http://www.ncbi.nlm.nih.gov/pubmed/8988131?dopt=AbstractPlus

74. Holleman F, Hoekstra JBL. Insulin lispro. N Engl J Med. 1997; 337:176-83. http://www.ncbi.nlm.nih.gov/pubmed/9219705?dopt=AbstractPlus

75. Anderson JH Jr, Brunelle RL, Koivisto VA et al et al. Improved mealtime treatment of diabetes mellitus using an insulin analogue. Clin Ther. 1997; 19:62-72. http://www.ncbi.nlm.nih.gov/pubmed/9083709?dopt=AbstractPlus

76. Zinman B, Tildesley H, Chiasson JL et al. Insulin lispro in CSII: results of a double-blind crossover study. Diabetes. 1997; 46:440-3. http://www.ncbi.nlm.nih.gov/pubmed/9032100?dopt=AbstractPlus

77. Anderson JH Jr, Brunelle RL, Keohane P et al. Mealtime treatment with insulin analog improves postprandial hyperglycemia and hypoglycemia in patients with non-insulin-dependent diabetes mellitus. Arch Intern Med. 1997; 157:1249-55. http://www.ncbi.nlm.nih.gov/pubmed/9183237?dopt=AbstractPlus

78. Anderson JH Jr, Brunelle RL, Koivisto VA et al et al. Reduction of postprandial hyperglycemia and frequency of hypoglycemia in IDDM patients on insulin-analog treatment. Diabetes. 1997; 46:265-70. http://www.ncbi.nlm.nih.gov/pubmed/9000704?dopt=AbstractPlus

79. Anon. Lispro, a rapid-onset insulin. Med Lett Drugs Ther. 1996; 38:97-8. http://www.ncbi.nlm.nih.gov/pubmed/8906134?dopt=AbstractPlus

80. Jehle PM, Fussgaenger RD, Kunze U et al. The human insulin analog insulin lispro improves insulin binding on circulating monocytes of intensively treated insulin-dependent diabetes mellitus patients. J Clin Endocrinol Metab. 1996; 81:2319-27. http://www.ncbi.nlm.nih.gov/pubmed/8964871?dopt=AbstractPlus

81. Campbell RK, Campbell LK, White JR. Insulin lispro: its role in the treatment of diabetes mellitus. Ann Pharmacother. 1996; 30:1263-71. http://www.ncbi.nlm.nih.gov/pubmed/8913409?dopt=AbstractPlus

82. Lahtela JT, Knip M, Paul R et al. Severe antibody-mediated human insulin resistance: successful treatment with the insulin analog lispro. Diabetes Care. 1997; 20:71-3. http://www.ncbi.nlm.nih.gov/pubmed/9028697?dopt=AbstractPlus

83. ter Braak EW, Woodworth JR, Bianchi R et al. Injection site effects on the pharmacokinetics and glucodynamics of insulin lispro and regular insulin. Diabetes Care. 1996; 19:1437-40. http://www.ncbi.nlm.nih.gov/pubmed/8941480?dopt=AbstractPlus

84. Stella VJ. Chemical and physical bases determining the instability and incompatibility of formulated injectable drugs. J Parenter Sci Tech. 1986; 40:142-63.

85. Trissel LA. Handbook on injectable drugs. 9th ed. Bethesda, MD: American Society of Health-System Pharmacists, Inc., Inc; 1996:605-610.

86. National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes. 1979; 28:1039-57. http://www.ncbi.nlm.nih.gov/pubmed/510803?dopt=AbstractPlus

87. American Diabetes Association. Office guide to diagnosis and classification of diabetes mellitus and other categories of glucose intolerance. Diabetes Care. 1995; 18(Suppl 1):4.

88. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 1997; 20:1183-97. http://www.ncbi.nlm.nih.gov/pubmed/9203460?dopt=AbstractPlus

89. Diabetes Control and Complications Trial Research Group. Hypoglycemia in the diabetes control and complications trial. Diabetes. 1997; 46:271-86. http://www.ncbi.nlm.nih.gov/pubmed/9000705?dopt=AbstractPlus

90. Cohen P, Barzilai N, Lerman A et al. Insulin effects on glucose and potassium metabolism in vivo: evidence for selective insulin resistance in humans. J Clin Endocrinol Metab. 1991; 73:564-8. http://www.ncbi.nlm.nih.gov/pubmed/1874934?dopt=AbstractPlus

91. Karsidag K, Satman I, Dinccag N et al. Comparison of metabolic control in IDDM with two different intensive regimens of [LYS(B28), PRO(B29)]-human insulin (lispro) plus NPH insulin. Diabetologia. 1996; 39(Suppl 1):A222.

92. Gibb DM, Foot ABM, May B et al. Human isophane or lente insulin? A double blind crossover trial in insulin dependent diabetes mellitus. Arch Dis Child. 1990; 65:1334-7. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1793083&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/2270941?dopt=AbstractPlus

93. Coretzee EJ, Jackson WPU. Pregnancy in established non-insulin-dependent diabetics. S Afr Med J. 1980; 58:795-802. http://www.ncbi.nlm.nih.gov/pubmed/6777880?dopt=AbstractPlus

94. American Diabetes Association. Preconception care of women with diabetes. Diabetes Care. 1997; 20(Suppl 1):S40-3.

95. American Diabetes Association. Gestational diabetes mellitus. Diabetes Care. 1997; 20(Suppl 1):S44-5.

96. Burge MR, Waters DL, Holcombe JH et al. Prolonged efficacy of short acting insulin lispro in combination with human ultralente in insulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1997; 82:920-4. http://www.ncbi.nlm.nih.gov/pubmed/9062507?dopt=AbstractPlus

97. Berger W, Honegger B, Keller U et al. Warning symptoms of hypoglycaemia during treatment with human and porcine insulin in diabetes mellitus. Lancet. 1989; 1:1041-4. http://www.ncbi.nlm.nih.gov/pubmed/2565999?dopt=AbstractPlus

98. Colagiuri S, Miller JJ, Petocz P. Double-blind crossover comparison of human and porcine insulins in patients reporting lack of hypoglycaemia awareness. Lancet. 1992; 339:1432-5. http://www.ncbi.nlm.nih.gov/pubmed/1351127?dopt=AbstractPlus

99. Anon. Hypoglycaemia and human insulin. Drug Ther Bull. 1993; 31:7-8. http://www.ncbi.nlm.nih.gov/pubmed/8344145?dopt=AbstractPlus

100. Deckert T. The immunogenicity of new insulins. Diabetes. 1985; 34(Suppl 2):94-6. http://www.ncbi.nlm.nih.gov/pubmed/3888748?dopt=AbstractPlus

101. Paterson KR, Paice BJ, Lawson DH. Undesired effects of insulin therapy. Adverse Drug React Acute Poisoning Rev. 1983; 2:219-34.

102. Anon. Hypoglycemia: a pitfall of insulin therapy. West J Med. 1983; 139:688-95. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1010967&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/6362204?dopt=AbstractPlus

103. Wilson DE. Excessive insulin therapy: biochemical effects and clinical repercussions: current concepts of counterregulation in type I diabetes. Ann Intern Med. 1983; 98:219-27. http://www.ncbi.nlm.nih.gov/pubmed/6337541?dopt=AbstractPlus

104. Knight G, Worth RC, Ward JD. Macrosomy despite a well-controlled diabetic pregnancy. Lancet. 1983; II:1431.

105. The MJ. Human insulin: DNA technology’s first drug. Am J Hosp Pharm. 1989; 46(Suppl 2):S9-11. http://www.ncbi.nlm.nih.gov/pubmed/2690608?dopt=AbstractPlus

106. Grant JA, Cooper JR, Arens JF et al. Anaphylactic reactions to protamine in insulin-dependent diabetics during cardiovascular surgery. Anesthesiology. 1983; 59(Suppl). Abstract No. A74. (IDIS 175001)

107. Polonsky KS, Herold KG, Gilden JL et al. Glucose counterregulation in patients after pancreatectomy: comparison with other clinical forms of diabetes. Diabetes. 1984; 33:1112-9. http://www.ncbi.nlm.nih.gov/pubmed/6389228?dopt=AbstractPlus

108. Horie H, Matsuyama T, Namba M et al. Responses of catecholamines and other counterregulatory hormones to insulin-induced hypoglycemia in totally pancreatectomized patients. J Clin Endocrinol Metab. 1984; 59:1193-6. http://www.ncbi.nlm.nih.gov/pubmed/6386840?dopt=AbstractPlus

109. Vigili de Kreutzenberg S, Maifreni L, Lisato G et al. Glucose turnover and recycling in diabetes secondary to total pancreatectomy: effect of glucagon infusion. J Clin Endocrinol Metab. 1990; 70:1023-9. http://www.ncbi.nlm.nih.gov/pubmed/2180971?dopt=AbstractPlus

110. Williams G, Gill GV, Pickup JC. “Brittle” diabetes. BMJ. 1991; 303:714. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1670919&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/1912923?dopt=AbstractPlus

111. Alvarez-Thull L, Rosenwasser LJ, Brodie TD et al. Systemic allergy to endogenous insulin during therapy with recombinant DNA (rDNA) insulin. Ann Allergy Asthma Immunol. 1996; 76:253-6. http://www.ncbi.nlm.nih.gov/pubmed/8634879?dopt=AbstractPlus

112. Armstrong L, Bell PM. Addison’s disease presenting as reduced insulin requirement in insulin dependent diabetes. BMJ. 1996; 312:1601-2. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2351308&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/8664674?dopt=AbstractPlus

113. Yoo J, Peter S, Kleinfeld M. Transient hypoglycemic hemiparesis in an elderly patient. J Am Geriatr Soc. 1986; 34:479-81. http://www.ncbi.nlm.nih.gov/pubmed/3517115?dopt=AbstractPlus

114. Bolli GB, Gottesman IS, Campbell PJ et al. Glucose counterregulation and waning of insulin in the somogyi phenomenon (posthypoglycemic hyperglycemia). N Engl J Med. 1984; 311:1214-9. http://www.ncbi.nlm.nih.gov/pubmed/6387483?dopt=AbstractPlus

115. Solley GO. Testing for drug allergy. Aust Prescriber. 1994; 17:62-5.

116. Clarke WL, Gonder-Frederick LA, Richards FE et al. Multifactorial origin of hypoglycemic symptom unawareness in IDDM: association with defective glucose counterregulation and better glycemic control. Diabetes. 1991; 40:680-5. http://www.ncbi.nlm.nih.gov/pubmed/2040384?dopt=AbstractPlus

117. Henrichs HR, Unger H, Fittkau T et al. Treatment of a case of severe subcutaneous insulin resistance using the insulin analogue Lys(B28), Pro(B29) for facilitated subcutaneous absorption. Diabetologia. 1994; 37(suppl 1):A168.

118. Pfutzner A, Gudat U, Trautmann ME et al. Use of insulin lispro in pediatric patients with IDDM. Diabetologia. 1996; 39(Suppl 1):A222.

119. Diamond T, Kormas N. Possible adverse fetal effect of insulin lispro. N Engl J Med. 1997; 337:1009. http://www.ncbi.nlm.nih.gov/pubmed/9312672?dopt=AbstractPlus

120. Anderson JH Jr, Bastyr EJ III, Wishner KL. Possible adverse fetal effect of insulin lispro. N Engl J Med. 1997; 337:1010. http://www.ncbi.nlm.nih.gov/pubmed/9312673?dopt=AbstractPlus

121. Torlone E, Pampanelli S, Lalli C et al. Effects of the short-acting insulin analog [Lys(B28),Pro(B29)] on postprandial blood glucose control in IDDM. Diabetes Care. 1996; 19:945-52. http://www.ncbi.nlm.nih.gov/pubmed/8875087?dopt=AbstractPlus

122. Bolli GB, Torlone E. Mixing insulin lispro and ultralente insulin. Diabetes Care. 1997; 20:1048.

123. Bastyr EJ III, Holcombe JH, Anderson JH et al. Mixing insulin lispro and ultralente insulin. Diabetes Care. 1997; 20:1047-8. http://www.ncbi.nlm.nih.gov/pubmed/9167130?dopt=AbstractPlus

124. Steel JM, Johnstone FD. Guidelines for the management of insulin-dependent diabetes mellitus in pregnancy. Drugs. 1996; 52:60-70. http://www.ncbi.nlm.nih.gov/pubmed/8799685?dopt=AbstractPlus

125. Unger RH, Foster DW. Diabetes mellitus. In: Wilson JD, Foster DW, eds. Williams textbook of endocrinology. 8th ed. Philadelphia: WB Saunders Company; 1992:1310-1.

126. Gale EA, Kurtz AB, Tattersall RB. In search of the Somogyi effect. Lancet. 1980; 2:279-82. http://www.ncbi.nlm.nih.gov/pubmed/6105438?dopt=AbstractPlus

127. Raskin P. The Somogyi phenomenon. Sacred cow or bull? Arch Intern Med. 1984; 144:781-7.

128. Havlin CE, Cryer PE. Nocturnal hypoglycemia does not commonly result in major morning hyperglycemia in patients with diabetes mellitus. Diabetes Care. 1987; 10:141-7. http://www.ncbi.nlm.nih.gov/pubmed/3582075?dopt=AbstractPlus

129. Failure of nocturnal hypoglycemia to cause fasting hyperglycemia in patients with insulin-dependent diabetes mellitus. N Engl J Med. 1987; 317:1552-9.

130. Cryer PE, Binder C, Bolli GB et al. Hypoglycemia in IDDM. Diabetes. 1989; 38:1193-9. http://www.ncbi.nlm.nih.gov/pubmed/2767340?dopt=AbstractPlus

131. Hirsch IB, Smith LJ, Havlin CE et al. Failure of nocturnal hypoglycemia to cause daytime hyperglycemia in patients with IDDM. Diabetes Care. 1990; 13:133-42. http://www.ncbi.nlm.nih.gov/pubmed/2190769?dopt=AbstractPlus

132. Kidson W. The Somogyi effect: has it ever existed and what harm has it caused? Med J Aust. 1993; 159:480-2. Editorial.

133. Silink M. The pediatric view. Med J Aust. 1993; 159:483-5. http://www.ncbi.nlm.nih.gov/pubmed/8412924?dopt=AbstractPlus

134. Campbell LV, Chisholm DJ. The problem of hypoglycaemia—Somogyi or not. Med J Aust. 1993; 159:485-6. http://www.ncbi.nlm.nih.gov/pubmed/8412925?dopt=AbstractPlus

135. Bolli GB, Perriello G, Fanelli CG et al. Nocturnal blood glucose control in type I diabetes mellitus. Diabetes Care. 1993; 16 Suppl 3:71-89. http://www.ncbi.nlm.nih.gov/pubmed/8299480?dopt=AbstractPlus

136. Kollind M, Adamson U, Lins PE et al. Diabetogenic action of GH and cortisol in insulin-dependent diabetes mellitus. Aspects of the mechanisms behind the Somogyi phenomenon. Horm Metab Res. 1987; 19:156-9. http://www.ncbi.nlm.nih.gov/pubmed/2884179?dopt=AbstractPlus

137. Winter RJ. Profiles of metabolic control in diabetic children-frequency of asymptomatic nocturnal hypoglycemia. Metabolism. 1981 30:666-72.

138. Duell PB. Nocturnal hypoglycemia as a cause of fasting hyperglycemia (Somogyi phenomenon). N Engl J Med. 1988; 318:1537. http://www.ncbi.nlm.nih.gov/pubmed/3285217?dopt=AbstractPlus

139. Rotenstein D. Nocturnal hypoglycemia as a cause of fasting hyperglycemia (Somogyi phenomenon). N Engl J Med. 1988; 318:1537. http://www.ncbi.nlm.nih.gov/pubmed/3285217?dopt=AbstractPlus

140. Perriello G, De Feo P, Torlone E et al. The effect of asymptomatic nocturnal hypoglycemia on glycemic control in diabetes mellitus. N Engl J Med. 1988; 319:1233-9. http://www.ncbi.nlm.nih.gov/pubmed/3054544?dopt=AbstractPlus

141. Gerich JE. Lilly lecture 1988. Glucose counterregulation and its impact on diabetes mellitus. Diabetes. 1988; 37:1608-17. http://www.ncbi.nlm.nih.gov/pubmed/3056759?dopt=AbstractPlus

142. Tordjman KM, Havlin CE, Levandoski LA et al. Nocturnal hypoglycemia as a cause of fasting hyperglycemia (Somogyi phenomenon). N Engl J Med. 1988; 318:1538. http://www.ncbi.nlm.nih.gov/pubmed/3130575?dopt=AbstractPlus

143. Vignati L, Anderson JH, Szwast S et al. Twice daily lispro results in less glucose variability compared to human regular insulin. Diabetologia. 1995; 38(Suppl 1):A191.

144. Reviewers’ comments (personal observations).

145. Eli Lily, Indianapolis, IN: Personal communication.

146. Lougheed WD, Weymouth AB, Zinman B et al. Stability of insulin lispro in insulin infusion systems. Diabetes Care. 1997; 20: 1061-5.

147. Ebeling P, Lalli C, Jansson PA et al. Strategies toward improved control during inulin lispro therapy in IDDM. Diabetes Care. 1997; 20:1287-9. http://www.ncbi.nlm.nih.gov/pubmed/9250455?dopt=AbstractPlus

148. Del Sindaco P, Ciofetta M, Lalli C et al. Importance of basal insulin to improve control without increasing hypoglycemia in intensively treated IDDM using a short-acting insulin analog at meals Diabetologica. 1997; 40 (suppl. 1):A352. Abstract.

149. Holcombe J, Zalani S, Arora V. Comparative study of insulin lispro and regular insulin in 481 adolescents with type I diabetes. Diabetologica. 1997; 40(suppl. 1):A344.

150. Holcombe J, Zalani S, Arora V et al. Comparative study of insulin lispro and regular insulin in 481 adolescents with type I diabetes. Diabetes. 1997; 46(suppl. 1):nr1253.

151. Holcombe J, Zalani S, Arora V et al. Insulin lispro (LP) results in less nocturnal hypoglycemia compared with regular human insulin in adolescents with type I diabetes. Diabetes. 1997; 46(suppl. 1):103A.

152. Kitzmiller JL, Buchanan TA, Kjos S et al. Preconception care of diabetes, congenital malformations, and spontaneous abortions. Diabetes. 1996; 19:514-41.

153. Becerra JE, Khoury MJ, Cordero JF et al. Diabetes mellitus during pregnancy and the risks for specific birth defects: a population-based case-control study. Pediatrics. 1990; 85:1-9. http://www.ncbi.nlm.nih.gov/pubmed/2404255?dopt=AbstractPlus

154. Jansson PA, Ebeling P, Smith P et al. Gycemic control in IDDM is improved by optimized combination of insulin lispro and basal insulin. Diabetologica. 1997; 40:A352.

155. Eli Lilly and Company. Humalog (insulin lispro) 3.0 mL disposable insulin delivery device patient information. Indianapolis, IN; 1999 Mar 26.

156. Eli Lilly and Company. Frequently asked questions about the Humulin and Humalog pen. Indianapolis, IN: 1999. From the Eli Lilly website/01-about/faq.html). https://www.humulinpen.com/01-about/faq.html)

157. Eli Lilly and Company. About the pen. From the Eli Lilly website/01-about/index.html). https://www.humulinpen.com/01-about/index.html)

158. Bastyr EJ, Johnson ME, Trautman ME et al. Insulin lispro in the treatment of patients with type 2 diabetes mellitus after oral agent failure. Clin Ther. 1999; 21:1703-14. http://www.ncbi.nlm.nih.gov/pubmed/10566566?dopt=AbstractPlus

159. Roach P, Yue L, Arora V et al. Improved postprandial glycemic control during treatment with humalog mix 25, a novel protamine-based insulin lispro formulation. Diabetes Care. 1999; 22:1258-61. http://www.ncbi.nlm.nih.gov/pubmed/10480767?dopt=AbstractPlus

160. Eli Lilly and Company. Humalog Mix75/25 pen patient information. Indianapolis, IN; 2000 Apr 11.

161. Robertson KE, Malone JK, Roach P. Insulin lispro and insulin lispro fixed mixtures-a review of recent clinical experience. S Afr Med J. 2000; 5: 93-101.

162. USP DI: drug information for the health care professional. 20th ed. Englewood, CO: Micromedex, Inc; 2000;1:306.

163. American Diabetes Association. Continuous subcutaneous insulin infusion. Diabetes Care. 2000; 23(Suppl 1):S90.

164. Jovanovic L, Ilic S, Pettitt DJ et al. Metabolic and immunologic effects of insulin lispro in gestational diabetes. Diabetes Care. 1999; 22:1422-7. http://www.ncbi.nlm.nih.gov/pubmed/10480503?dopt=AbstractPlus

165. Eli Lilly and Company. Humalog mix75/25 75% insulin lispro protamine suspension and 25% insulin lispro injection (rDNA origin) prescribing information. Indianapolis, IN; 1999 Dec.

166. American Diabetes Association. Type 2 diabetes in children and adolescents. Pediatrics. 2000; 105:671-80. http://www.ncbi.nlm.nih.gov/pubmed/10699131?dopt=AbstractPlus

167. Wolpert HA, Faradji RN, Bonner-Weir S et al. Metabolic decompensation in pump users due to lispro insulin precipitation. BMJ. 2002; 324:1253. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=113278&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/12028980?dopt=AbstractPlus

168. Bode B, Weinstein R, Bell D et al. Comparison of insulin aspart with buffered insulin and insulin lispro in continuous subcutaneous insulin infusion: a randomized study in type 1 diabetes. Diabetes Care. 2002; 25:439-44. http://www.ncbi.nlm.nih.gov/pubmed/11874927?dopt=AbstractPlus

169. Bode B, Weinstein R, Bell D et al. Comparison of insulin aspart with buffered insulin and insulin lispro in continuous subcutaneous insulin infusion: a randomized study in type 1 diabetes. Diabetes Care. 2002; 25:439-44. http://www.ncbi.nlm.nih.gov/pubmed/11874927?dopt=AbstractPlus

170. American Diabetes Association. Position statement: continuous subcutaneous insulin infusion. Diabetes Care. 2004; 27(Suppl 1):S110..

a. Eli Lilly and Company. Humalog mix75/25 75% insulin lispro protamine suspension and 25% insulin lispro injection (rDNA origin) prescribing information. Indianapolis, IN; 2002 May 31.

b. Eli Lilly. Regular Iletin II (insulin injection, USP, purified pork) information for the patient. Indianapolis, IN; 1999 Aug 13.

c. Novo Nordisk Pharmaceuticals Inc.; Novolog (insulin aspart [rDNA origin]) injection prescribing information. Princeton, New Jersey; 2002 May 15.

d. AHFS drug information 2004. McEvoy GK, ed. Insulins General Statement. Bethesda, MD: American Society of Health-System Pharmacists; 2004:2994-3002.

e. Schilling McCann JA, Publisher. Pharmacists drug handbook. 2nd ed. Philadelphia, PA: Lippincott Williams and Wilkins and American Society of Health-System Pharmacists; 2003.

f. Novo Nordisk Pharmaceuticals Inc.; Novolog (insulin aspart [rDNA origin]) injection prescribing information. Princeton, New Jersey; 2002 May 15.

g. Eli Lilly and Company. Humalog (insulin lispro, rDNA origin) injection (vial) patient information. Indianapolis, IN; 2004 Aug 20.

h. Hirsch IB. Type 1 diabetes mellitus and the use of flexible insulin regimens. Am Fam Physician. 1999; 60:2343-56. http://www.ncbi.nlm.nih.gov/pubmed/10593324?dopt=AbstractPlus

i. Hamann A, Matthaei S, Rosak C et al. A randomized clinical trial comparing breakfast, dinner, or bedtime administration of insulin glargine in patients with type 1 diabetes. Diabetes Care. 2003; 26:1738-44. http://www.ncbi.nlm.nih.gov/pubmed/12766103?dopt=AbstractPlus

j. Rossetti P, Pampanelli S, Fanelli C et al. Intensive replacement of basal insulin in patients with type 1 diabetes mellitus give rapid-acting insulin analog at mealtime: a 3-month comparison between administration of NPH insulin four times daily and glargine insulin at dinner or bedtime. Diabetes Care. 2003; 26:1490-6. http://www.ncbi.nlm.nih.gov/pubmed/12716810?dopt=AbstractPlus

k. Zinman B, Ross S, Campos RV et al. Effectiveness of human ultralente versus NPH insulin providing basal insulin replacement for an insulin lispro multiple daily injection regimen: a double-blind randomized prospective trial. Diabetes Care. 199; 22:603-8.

l. Lalli C, Ciofetta M, Del Sindaco P et al. Long-term intensive treatment of type 1 diabetes with the short-acting insulin analog lispro in variable combination with NPH insulin at mealtime. Diabetes Care. 1999; 22:468-77. http://www.ncbi.nlm.nih.gov/pubmed/10097931?dopt=AbstractPlus

m. Renner R, Pfutzner A, Trautmann M et al. Use of insulin lispro in continuous subcutaneous infusion treatment: results of a multicenter trial. Diabetes Care. 1999; 22:784-8. http://www.ncbi.nlm.nih.gov/pubmed/10332682?dopt=AbstractPlus

n. Murphy NP, Keane SM, Ong KK et al. Randomized cross-over trial of insulin glargine plus lispro or NPH insulin plus regular human insulin in adolescents with type 1 diabetes on intensive insulin regimens. Diabetes Care. 2003; 26:799-804. http://www.ncbi.nlm.nih.gov/pubmed/12610040?dopt=AbstractPlus

o. Chase HP, Dixon B, Pearson J et al. Reduced hypoglycemic episodes and improved glycemic control in children with type 1 diabetes using insulin glargine and neutral protamine hagedorn insulin. J Pediatr. 2003; 143:737-40. http://www.ncbi.nlm.nih.gov/pubmed/14657818?dopt=AbstractPlus

p. Mayfield JA, White R. Insulin therapy for type 2 diabetes: rescue, augmentation, and replacement of beta-cell function. Am Fam Physician. 2004; 70:489-500, 511-2. http://www.ncbi.nlm.nih.gov/pubmed/15317436?dopt=AbstractPlus

q. Alemzadeh R, Ellis JN, Holzum MK et al. Beneficial effects of continuous subcutaneous insulin infusion and flexible multiple daily insulin regimen using insulin glargine in type 1 diabetes. Pediatrics. 2004; 114:e91-5. http://www.ncbi.nlm.nih.gov/pubmed/15231979?dopt=AbstractPlus

r. Hanaire-Broutin H, Melki V, Bessieres-Lacombe S et al. Comparison of continuous subcutaneous insulin infusion and multiple daily injection regimens using insulin lispro in type 1 diabetic patients on intensified treatment: a randomized study. Diabetes Care. 2000; 23:1232-5. http://www.ncbi.nlm.nih.gov/pubmed/10977011?dopt=AbstractPlus

s. Melki V, Renard E, Lassmann-Vague V et al. Improvement of HBA_1c and blood glucose stability in IDDM patients treated with lispro insulin analog in external pumps. Diabetes Care. 1998; 21:997-82.

t. Holcombe JH, Zalani S, Arora VK et al. Comparison of insulin lispro with regular human insulin for the treatment of type 1 diabetes in adolescents. Clin Ther. 2002; 24:629-38. http://www.ncbi.nlm.nih.gov/pubmed/12017407?dopt=AbstractPlus

u. Deeb LC, Holcombe JH, Brunelle R et al. Insulin lispro lowers postprandial glucose in prepubertal children with diabetes. Pediatrics. 2001; 108:1175-9. http://www.ncbi.nlm.nih.gov/pubmed/11694699?dopt=AbstractPlus

v. Roach P, Koledova E, Metcalfe S et al. Glycemic control with Humalog Mix 25 in type 2 diabetes inadequately controlled with glyburide. Clin Ther. 2001; 23:1732-44. http://www.ncbi.nlm.nih.gov/pubmed/11726007?dopt=AbstractPlus

w. Lourens W, Bonnici F, Herz M et al. Improved glycaemic control with Humalog Mix 25 compared with human insulin 30/70 in patients with type 2 diabetes. S Afr Med J. 2000; 5:87-92.

x. Roach P, Trautmann M, Arora V et al. Improved postprandial blood glucose control and reduced nocturnal hypoglycemia during treatment with two novel insulin lispro-protamine formulations, insulin lispro mix25 and insulin lispro mix50. Clin Ther. 1999; 523-34.

y. Herz M, Sun B, Milcevic Z et al. Comparative efficacy of preprandial or postprandial Humalog Mix75/25 versus glyburide in patients 60 to 80 years of age with type 2 diabetes mellitus. Clin Ther. 2002; 24:73-86. http://www.ncbi.nlm.nih.gov/pubmed/11833837?dopt=AbstractPlus

z. Reviewers’ comments (personal observations) on Insulins General Statement 68:20.08.

aa. American Diabetes Association. Insulin administration. Diabetes Care. 2004; 27(Suppl 1):S106-9.

bb. Eli Lilly and Company. Humalog (insulin lispro, rDNA origin) injection prescribing information. Indianapolis, IN; 2004 Aug 4.

cc. Campbell PJ, May ME. A practical guide to intensive insulin therapy. Am J Med Sci. 1995; 310:24-30. http://www.ncbi.nlm.nih.gov/pubmed/7604835?dopt=AbstractPlus

dd. Olefsky JM. Diabetes mellitus. In: Wyngaarden JB, Smith LH Jr, Bennett JC, eds. Cecil textbook of medicine. 19th ed. Philadelphia: WB Saunders Company; 1992:1291-310.

ee. Foster DW. Diabetes mellitus. In: Fauci AS, Braunwald E, Isselbacher KJ et al, eds. Harrison’s principles of internal medicine. l4th ed. New York: McGraw-Hill, Inc; 1998:2060-81.

ff. American Society of Health-System Pharmacists. ASHP therapeutic position statement on strict glycemic control in selected patients with insulin-dependent diabetes mellitus. Am J Health-Syst Pharm. 1995; 52:2709-11. http://www.ncbi.nlm.nih.gov/pubmed/8601269?dopt=AbstractPlus

gg. Carlisle BA, Kroon LA, Koda-Kimble MA. Diabetes mellitus. In: Young LY, Koda-Kimble MA, eds. Applied therapeutics: the clinical use of drugs. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:50-1–50-86.

hh. Davis SN, Granner DK. Insulin, oral hypoglycemic agents, and the pharmacology of the endocrine pancreas. In: Hardman JG, Limbird LE, Molinoff PB et al, eds. Goodman and Gilman’s the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill; 1996:1487-517.

ii. American Diabetes Association. Implications of the diabetes control and complications trial. Diabetes Care. 1997; 20(Suppl 1):S620-4.

jj. Henry RR, Genuth S. Forum one: current recommendations about intensification of metabolic control in non–insulin-dependent diabetes mellitus. Ann Intern Med. 1996; 124:175-7. http://www.ncbi.nlm.nih.gov/pubmed/8554214?dopt=AbstractPlus

kk. American Diabetes Association. Tests of glycemia in diabetes. Diabetes Care. 2002; 25(Suppl 1):S97-9.

ll. Tuominen JA, Karonen SL, Melamies L et al. Exercise-induced hypoglycaemia in IDDM patients treated with a short-acting insulin analogue. Diabetologia. 1995; 38:106-11. http://www.ncbi.nlm.nih.gov/pubmed/7744214?dopt=AbstractPlus

mm. Bohannon NJV, Jack DB. Type II diabetes: tips for managing your older patients. Geriatrics. 1996; 51(March):28-30,33-35. http://www.ncbi.nlm.nih.gov/pubmed/8641590?dopt=AbstractPlus

nn. Diabetes Control and Complications Trial Research Group. Hypoglycemia in the diabetes control and complications trial. Diabetes. 1997; 46:271-86. http://www.ncbi.nlm.nih.gov/pubmed/9000705?dopt=AbstractPlus

oo. Paterson KR, Paice BJ, Lawson DH. Undesired effects of insulin therapy. Adverse Drug React Acute Poisoning Rev. 1983; 2:219-34.

pp. Cryer PE, Gerich JE. Glucose counterregulation, hypoglycemia, and intensive insulin therapy in diabetes mellitus. N Engl J Med. 1985; 313:232-41. http://www.ncbi.nlm.nih.gov/pubmed/2861565?dopt=AbstractPlus

qq. Santiago JV. Intensive management of insulin dependent diabetes: risks, benefits, and unanswered questions. J Clin Endocrinol Metab. 1992; 75:977-82. http://www.ncbi.nlm.nih.gov/pubmed/1400891?dopt=AbstractPlus

rr. Clarke WL, Gonder-Frederick LA, Richards FE et al. Multifactorial origin of hypoglycemic symptom unawareness in IDDM: association with defective glucose counterregulation and better glycemic control. Diabetes. 1991; 40:680-5. http://www.ncbi.nlm.nih.gov/pubmed/2040384?dopt=AbstractPlus

ss. Anon. Hypoglycemia: a pitfall of insulin therapy. West J Med. 1983; 139:688-95. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1010967&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/6362204?dopt=AbstractPlus

tt. Cohen P, Barzilai N, Lerman A et al. Insulin effects on glucose and potassium metabolism in vivo: evidence for selective insulin resistance in humans. J Clin Endocrinol Metab. 1991; 73:564-8. http://www.ncbi.nlm.nih.gov/pubmed/1874934?dopt=AbstractPlus

uu. MacCuish AC, Munro JF, Duncan LJP. Treatment of hypoglycaemic coma with glucagon, intravenous dextrose, and mannitol infusion in a hundred diabetics. Lancet. 1970; 2:946-9. http://www.ncbi.nlm.nih.gov/pubmed/4097595?dopt=AbstractPlus

vv. Yoo J, Peter S, Kleinfeld M. Transient hypoglycemic hemiparesis in an elderly patient. J Am Geriatr Soc. 1986; 34:479-81. http://www.ncbi.nlm.nih.gov/pubmed/3517115?dopt=AbstractPlus

ww. Reviewers’ comments (personal observations) [Insulins General Statement]

xx. American Diabetes Association. Hyperglycemic crises in patients with diabetes mellitus. Diabetes Care. 2004; 27(Suppl 1):S94-102.