Insulin lispro

Insulin lispro is an Anti-diabetic Agent belonging to the pharmacological class of fast-acting insulins.

Insulin lispro is approved for treating diabetes mellitus to boost glycemic control in adults and children with type 1 diabetes mellitus and type 2 diabetes mellitus in those adults who require insulin to control hyperglycemia.

Insulin lispro is quickly absorbed into the circulation after subcutaneous injection, which causes a quick beginning of action. Once distributed, it helps tissues absorb glucose. The liver and kidneys are the chief primary sites of metabolism. The kidneys are used for renal excretion of insulin lispro that has not been metabolised.

Hypoglycemia is one of the most common side effects of insulin lispro. Symptoms of allergy at the injection site, such as redness, swelling, or hard lumps (lipodystrophy), are a few of the side effects. Additionally, some individuals who use insulin might gain weight.

Insulin lispro is available in the form of injectable solutions and injectable pen.

The molecule is available in the United States, Canada, the United Kingdom, France, Japan, Germany and Australia.

Insulin lispro is an Anti-diabetic Agent belonging to the pharmacological class of fast-acting insulins.

A heterotetrameric protein composed of two extracellular alpha units and two transmembrane beta units, the insulin receptor (IR), is what the insulin lispro interacts with. Tyrosine kinase activity inside the beta subunit of the receptor is stimulated by insulin's binding to the alpha subunit of IR. The bound receptor phosphorylates and autophosphorylates a wide variety of intracellular substrates, including the insulin receptor substrates (IRS) proteins, APS, Shc, Cbl, and Gab 1. Downstream signalling molecules like PI3 kinase and Akt are activated due to these proteins being activated. Protein kinase C (PKC) and the glucose transporter GLUT4 play essential roles in metabolism and catabolism, and Akt controls their activity. Hexamers of insulin are the type in which it is kept in people, but only insulin monomers can interact with IR. Proline and lysine residues in natural insulin at positions B28 and B29 can be reversed to reduce hydrophobic contacts and impair certain hydrogen bonds that support the stability of the insulin dimers that make up insulin hexamers. In the presence of zinc and m-cresol, insulin lispro hexamers are created. When injected subcutaneously, these hexamers that are only weakly bound soon dissolve and are absorbed as monomers by vascular endothelial cells. These attributes give insulin lispro its fast-acting properties.

Insulin lispro's onset of action is approximately 10-20 minutes after subcutaneous injection.

The Tmax of Insulin lispro data around 30 to 90 minutes after subcutaneous injection.

The Cmax of Insulin lispro data generally occurs within 30 to 90 minutes after subcutaneous injection.

Insulin lispro is available in the form of injectable solutions and prefilled syringes.

• Injectable solution: To use the insulin lispro injectable solution, prepare the dose, identify an injection site, disinfect it, administer the insulin subcutaneously, and cautiously dispose of the needle. For proper use, adhere to the doctor's recommendations.
• Injectable pen: To use the insulin lispro prefilled pen, identify the injection site, disinfect it, attach a new needle, prepare the pen, dial the dose, inject, and cautiously dispose of the needle. For proper use, adhere to the doctor's recommendations.

The physician determines the exact dosage and timing based on the patient's needs and blood sugar levels.

Diabetes mellitus is a primary condition for which insulin lispro is used. In people with diabetes, including type 1 and type 2 diabetes, it helps decrease high blood sugar levels. This fast-acting insulin analogue is administered to diabetic patients to prevent post-meal glucose rises and keep overall glycemic control.

In Treatment of diabetes mellitus

Insulin lispro is a fast-acting insulin that aids in controlling high blood glucose (sugar) levels, allowing for better post-meal blood sugar control and helping to manage blood sugar spikes effectively. It begins to lower the blood glucose level within 10-20 minutes of injecting it, and the effect can last 3-5 hours.

To effectively manage diabetes, the blood glucose levels must be reduced. Controlling blood sugar levels will lower the likelihood of any of the severe complications of diabetes, including kidney damage, eye damage, nerve problems, and amputation of limbs. The risk of cardiac disease and stroke can be decreased with proper diabetes management. Individuals can live longer if they take this medication consistently and follow a healthy diet and exercise routine.

• Fast-acting human insulin analogue indicated for individuals with type 1 or type 2 diabetes mellitus to enhance glycemic control.
• It is indicated to help regulate and manage blood sugar levels in patients with diabetes, primarily to control post-meal glucose spikes and overall glycemic control.

Parenterally: Insulin lispro is available as injectable solutions and injectable pen that can be administered parenterally.

Preparation

Using 0.9% NaCl for IV, dilute insulin lispro to concentrations between 0.1 and 1 units/mL. Mix sterile 0.9% NaCl with SC. Insulin pump continuous SC infusion: Never dilute or combine insulin lispro while utilising continuous subcutaneous infusion. Ensure to routinely replace the insulin lispro in the pump reservoir and the infusion set. Maintain it away from heat sources exceeding 98.6°F (37°C). Refer to the labelling of the system to confirm compatibility with insulin lispro and follow the particular directions for usage supplied by the insulin infusion pump system.

Administration

Only for SC use: Give the dosage 15 minutes before or immediately following a meal. In most cases, intermediate or long-acting insulin is combined with insulin lispro. Subcutaneously inject medication into the buttocks, upper arm, thigh, or abdominal wall. To lower the risk of lipodystrophy, alternate the injection location within the same area for each consecutive injection.

Only IV: To prevent hypoglycemia and hypokalemia, administer insulin intravenously (IV) under medical supervision while closely monitoring blood potassium levels.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Injection solutions: 100 units/mL

Injectable pen: 100 units/mL or 200 units/mL. KwikPen dose increment: 1 unit; maximum dose per injection is 60 units

Junior KwikPen dose increment: 0.5 unit; maximum dose per injection is 30 units

Insulin lispro is available in the form of injectable solutions and injectable pen.

Dose Adjustment in Adult Patients:

Type 1 Diabetes Mellitus

Divided doses' usual daily maintenance range is 0.5-1 unit/kg/day; non-obese may require 0.4-0.6 unit/kg/day; obese may need 0.8-1.2 units/kg/day.

Insulin with a medium- or long-acting: About one-third of the total daily insulin requirements SC.

Premeal insulin should be used to meet the remaining daily insulin requirements, whether rapid-acting or short-acting.

Type 2 diabetes mellitus

The usual recommendation for intermediate- or long-acting insulin is ten units per night SC (or 0.1–0.2 units/kg per day) at night.

Short-acting insulin: Start with up to 4 units, 0.1 unit/kg SC, within 15 minutes of each meal, or 10% of the basal dosage, as needed; if A1C is less than 8%, consider reducing the basal insulin dose by the same percentage.

Once self-monitoring of blood glucose (SMBG) is accomplished, increase by 1-2 units or 10-15% per week or every two weeks.

Dosing Considerations

Ensure that you are only using NPH insulin when injecting SC.

Don't combine any other insulin with an IV or a continuous SC infusion.

If you want to administer Insulin lispro, DO NOT transfer it from the injectable pen to a syringe. The markings on the insulin syringe won't accurately measure the amount, which might lead to overdosing and dangerous hypoglycemia.

When using Insulin lispro, do NOT perform dosage conversion; the dose window shows the total number of insulin units to be administered, and no modification is necessary.

Insulin lispro and other insulins should NOT be combined.

Avoid using an insulin pump to give Insulin lispro; the insulin pump should only be used to administer Insulin lispro.

NEVER intravenously give Insulin lispro.

Insulin lispro should be used in treating Diabetes Mellitus, along with appropriate nutritional limits.

While taking Insulin lispro, maintain regular meal schedules consistently each day and avoid skipping meals to help stabilize blood sugar levels.

Limit or avoid the intake of alcohol as it can interfere with blood sugar regulation.

Consume foods with a lower glycemic index to help stabilize blood sugar levels.

Limit sugary foods and beverages intake, as they can cause rapid spikes in blood sugar.

Minimize intake of processed foods, which often contain hidden sugars.

It is advised to stay hydrated, maintain a rich, balanced diet with appropriate carbohydrate intake, and consume plenty of vegetables, whole grains, fruits, and lean proteins to help manage your overall health and blood sugar levels effectively.

The dietary restriction should be individualized as per patient requirements.

Insulin lispro may be contraindicated in the following conditions:-

• During episodes of hypoglycemia,
• Severe hypersensitivity to Insulin Lispro or one of its excipients; systemic allergic reactions have also been documented.

• Even if the needle changes, prefilled insulin Lispro pens should never be shared between patients. Sharing needles or syringes is not permitted for patients using Insulin Lispro vials. Transmitting blood-borne infections by sharing is unsafe.
• The markings on the insulin syringe will not accurately estimate the dosage and may cause overdosage and severe hypoglycemia if Insulin lispro is transferred from the injectable pen for administration.
  
• Changes in Insulin Regimen with Hyperglycemia: Adjust the patient's insulin regimen (e.g., insulin strength, type, injection location, or mode of delivery) under strict physician supervision with more frequent blood glucose testing.
• Hypoglycemia is the most common side effect of insulins, including Insulin lispro. Seizures, a threat to one's life, or even death can be brought on by severe hypoglycemia. When these skills are crucial (such as when driving or operating other machinery), hypoglycemia can decrease focus and response time, putting the person and others in danger.
  
• Hypoglycemia can occur abruptly, and each person's symptoms will be different and fluctuate over time. Patients with long-term diabetes, those with diabetic nerve disease, those using drugs that inhibit the sympathetic nervous system, such as beta-blockers, patients with recurrent hypoglycemia, or patients with any of these conditions may have less prominent symptoms of hypoglycemia.
• Hypokalemia: All insulins, including Insulin Lispro, induce a shift in potassium concentration from the extracellular to the intracellular region, which may result in hypokalemia. Hypokalemia can lead to cardiac arrhythmia, respiratory paralysis, and even death. If necessary, check potassium levels in patients at risk for hypokalemia (such as those using potassium-lowering medicines or taking drugs sensitive to serum potassium concentrations).
• Hypersensitivity and Allergic Reactions: Insulins, particularly Insulin Lispro, can cause a severe, perhaps fatal, generalised allergy, including anaphylaxis. If hypersensitivity responses happen, stop using Insulin Lispro. Treat as usual and monitor the patient until the symptoms and warning signs go completely.
• When used with insulin, thiazolidinediones, PPAR-gamma agonists, can produce dose-related fluid retention, leading to or worsening heart failure. Consider stopping thiazolidinediones and checking for heart failure symptoms and warnings.
• Hyperglycemia and ketoacidosis can quickly result from an insulin pump or insulin infusion set malfunction or insulin degradation; it is essential to detect and treat the source of these conditions promptly. Patients utilising continuous SC insulin infusion pump therapy must be taught to inject insulin and have access to alternative insulin therapies if the pump fails. Interim insulin lispro injections may be necessary.

It is unsafe to consume Insulin lispro with alcohol.

There is no sufficient scientific evidence traceable regarding the use and safety of Insulin lispro in breastfeeding.

Safe to use during pregnancy only if the possible benefit outweighs the potential risk to the foetus.

Limit Alcohol consumption. Avoid excessive high-glycemic index foods, sugary snacks, and large meals to prevent rapid glucose spikes.

The adverse reactions related to Insulin lispro can be categorized as:

• Common Adverse Effects: Hypoglycemia (low blood sugar), injection site reactions (e.g., redness, swelling, itching) and weight gain.
• Less Common Adverse Effects: Skin allergies or lipodystrophy.
• Rare Adverse Effects: Severe allergic reactions, anaphylaxis, insulin resistance, angioedema, bronchospasm, or severe hypokalemia.

Reports on Postmarketing

Medication errors inducing hypoglycemia.

Cutaneous amyloidosis that is localised.

The clinically relevant drug interactions of Insulin lispro are briefly summarized here.

• The risk of hypoglycemia may be increased by coadministration of antidiabetic medications with salicylates, sulfonamide antibiotics, monoamine oxidase inhibitors, ACE inhibitors, fluoxetine, pramlintide, disopyramide, fibrates, propoxyphene, pentoxifylline, angiotensin II receptor blocking agents, and somatostatin analogues (such as octreotide).
• Corticosteroids, isoniazid, niacin, atypical antipsychotics, glucagon, phenothiazines, danazol, oestrogens, oral contraceptives, somatropin, protease inhibitors, and thyroid hormones may lessen the effects of insulin lispro's ability to lower blood sugar levels.
• Beta-blockers, clonidine, lithium salts, and alcohol may enhance or reduce the glucose-lowering impact of insulin lispro; pentamidine may produce hypoglycemia, which may occasionally be followed by hyperglycemia. When beta-blockers, clonidine, guanethidine, and reserpine are provided with insulin lispro, the signs and symptoms of hypoglycemia may be minimised.

The most common side effects of Insulin lispro include the following :

• Low blood sugar
• Weight gain
• Swollen hands or feet;
• Itchiness; or
• A thickening or hollowing of the skin where the injection site was administered

• Pregnancy

Pregnancy Category B; Could be acceptable. Either no danger has been shown by animal research, but human studies have yet to be conducted, or some risk has been shown by animal studies but not by human studies.

There are risks to the mother and foetus associated with poorly managed diabetes in pregnancy. However, no published studies have linked insulin lispro usage during pregnancy to significant birth abnormalities, miscarriage, or unfavourable maternal or foetal outcomes.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Pregnant women with poorly managed diabetes have an increased risk of developing diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, premature birth, and other problems. Significant birth abnormalities, stillbirths, and morbidity associated with macrosomia are more likely to occur in foetuses with poorly managed diabetes.

Human Data

The use of insulin lispro during pregnancy has not been linked to severe birth abnormalities, miscarriage, or other adverse maternal or foetal outcomes, according to published data from retrospective studies and meta-analyses. Due to methodological restrictions such as small sample sizes, selection bias, confounding by unmeasured factors, and some lacking comparator groups, these studies cannot conclusively demonstrate or consider the absence of any risk.

Animal Data

Female rats were given SC insulin lispro injections at doses of 5 and 20 units/kg/day (0.8 and 3 times the human SC dose of 1 unit/kg/day, based on units per body surface area, respectively) from two weeks before cohabitation through gestation day 19. Foetal growth retardation was produced at the 20 units/kg/day dose, as evidenced by decreased foetal weight and an increased incidence of foetal runts/litter.

• Nursing mothers:

Data from recently released studies reveals that human milk is contaminated with exogenous human insulin products, such as insulin lispro.

The literature has no reports of adverse responses in breastfed babies, and there is no information on the impact of exogenous human insulin products, such as insulin lispro, on milk supply.

Consider the mother's clinical requirement for insulin, the developmental and health benefits of nursing, and any potential adverse effects on the infant from treatment or an underlying maternal disease.

• Pediatric Use

In children with diabetes mellitus, Insulin Lispro has been confirmed to be safe and effective in lowering blood sugar levels. Evidence from appropriate and well-controlled trials in 831 children with type 1 diabetes mellitus aged three years and older, as well as studies in adults with diabetes mellitus, supports the use of Insulin Lispro for this indication.

Dose Adjustment in Pediatric Patients

Type 1 Diabetes Mellitus

<3 years: No evidence of safety or effectiveness

Children under three years: 0.4–1 unit/kg/day SC of total insulin; greater doses are needed throughout puberty; otherwise, use adult dosage (0.5–1 unit/kg/day)

Type 2 Diabetes Mellitus

Safety and efficacy not established

Dosing Considerations

Use in children under three has been approved for SC daily injections and SC continuous infusion through external insulin pumps.

When using the Insulin lispro, do NOT perform dosage conversion; the dose window indicates the total number of insulin units to be administered, and no modification is necessary.

Insulin lispro should not be used with any other kind of insulin.

Human insulin dosage must be carefully adjusted to get the best outcomes depending on the blood and urine glucose testing findings, which are always stated in USP units.

• Geriatric Use

Twelve per cent (n=338) of the 2,834 patients who participated in all eight clinical investigations of Insulin Lispro were 65 years of age or older. Most of these patients had type 2 diabetes. Age did not affect HbA1c numbers or hypoglycemia rates. Age-related differences in the initial phase of Insulin Lispro activity have not been studied using pharmacokinetic or pharmacodynamic methods.

Dose Adjustment in Kidney Impairment Patients:

Patients with renal impairment may need more frequent adjustments to the dosage of Insulin Lispro and more regular blood glucose monitoring due to an increased risk of hypoglycemia.

Dose Adjustment in Hepatic Impairment Patients:

Patients with hepatic impairment may need more frequent adjustments to the dosage of Insulin Lispro and more regular blood glucose testing due to their higher risk of hypoglycemia.

Signs and Symptoms

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Insulin lispro.

Overconsumption of Insulin lispro may lead to hypoglycemia and hypokalemia.

Management

There is no specific antidote or treatment for excessive intake of Insulin lispro. However, immediate medical attention is essential. Insulin lispro should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake.

Oral glucose is often effective in the treatment of mild hypoglycemia episodes. Changing how one eats, exercises, or takes medication could be necessary. A glucagon product for emergency use or concentrated intravenous glucose may treat more severe episodes, including coma, seizure, or neurologic impairment. Hypoglycemia may return even after a seemingly complete clinical recovery. Thus, continued carbohydrate consumption and monitoring may be recommended. Corrective action must be taken for hypokalemia.

Maintain a healthy lifestyle through proper nutritional diet, regular physical activity, and stress management. These factors can help improve blood sugar control and reduce the risk of hypoglycemia.

Pharmacodynamics:

The hormone insulin is produced naturally from beta cells in the pancreas. A basal insulin level is augmented in non-diabetic people by rises in insulin levels after meals. The metabolic changes that occur as the body switches from a postabsorptive to an absorptive state are brought on by increased insulin secretion after meals. Insulin stimulates amino acid uptake by the liver, muscle, and adipose tissue, which increases cellular uptake of glucose, especially in muscle and fatty tissues. Insulin also promotes energy storage through glycogenesis, fights against the catabolism of energy stores, increases DNA replication and protein synthesis, and modifies the activity of many enzymes involved in glycogen synthesis and glycolysis. The effects of growth hormone, including protein synthesis, cell division, and DNA synthesis, require insulin, which also stimulates growth. An analogue of insulin with a quick onset of action called insulin Lispro is used to simulate postprandial insulin rises in people with diabetes. Insulin lispro starts working between 10 and 15 minutes after injection. Its effect lasts 4-5 hours, with its peak activity occurring 60 minutes after subcutaneous injection.

Insulin lispro acts faster and wears off more quickly than conventional human insulin, compared to both of which it is an improvement. The molar equivalent of human insulin to insulin lispro has also been established. It has been demonstrated that insulin lispro is molar equivalent to human insulin. The glucose-lowering effects of one unit of insulin lispro are identical to those of one unit of conventional human insulin. Studies on healthy volunteers and diabetic patients have shown that when administered subcutaneously, insulin lispro had a quicker start of action and a shorter duration of activity than conventional human insulin.

In a euglycemic clamp study with all healthy subjects, the pharmacodynamics of a single 20-unit dose of insulin lispro at 200 units per mL (HUMALOG U-200) were compared to the pharmacodynamics of a single 20-unit dose of insulin lispro at 100 units/mL (HUMALOG U-100).

In this study, HUMALOG U-200 and HUMALOG U-100 had similar effects on reducing blood sugar in terms of overall, maximum, and time-to-maximum effects. HUMALOG U-200 and HUMALOG U-100 had respective mean areas under the glucose infusion rate curves of 125 g and 126 g (a measure of overall pharmacodynamic impact). The maximal glucose infusion rates for HUMALOG U-200 and HUMALOG U-100 were 534 mg/min and 559 mg/min, respectively, with the corresponding median times (min, max) to the maximum effect being 2.8 h (0.5 h to 6.3 h) and 2.4 h (0.5 h to 4.7 h), respectively.

Pharmacokinetics:

Absorption

Insulin lispro is absorbed more quickly than conventional human insulin at the abdominal, deltoid, or femoral subcutaneous areas, according to studies in healthy volunteers and patients with diabetes. Peak blood levels were seen 30 to 90 minutes after treatment in healthy volunteers who received SC doses of insulin lispro ranging from 0.1 to 0.4 units/kg. Peak insulin levels happened between 50 and 120 minutes after healthy participants were given identical dosages of regular human insulin. When insulin lispro was injected into the belly, blood drug levels were more significant, and the duration of action was shorter than when injected into the deltoid or thigh.

The bioavailability of insulin lispro is comparable to that of conventional human insulin. Including dosages between 0.1 and 0.2 units/kg, the absolute bioavailability following subcutaneous injection ranges from 55% to 77%.

The mean observed area under the serum insulin concentration-time curve from time zero to infinity varied between 2360 pmol hr/L to 2390 pmol hr/L. The associated mean peak serum insulin concentration ranged from 795 pmol/L to 909 pmol/L, and the median duration to maximum concentration was 1.0 hr.

Distribution

Insulin lispro mean volume of distribution (Vd) appeared to decrease with an increase in dose administered intravenously as bolus injections of 0.1 and 0.2 U per kg in two groups of healthy subjects (1.55 and 0.72 L/kg, respectively). This phenomenon contrasts regular human insulin, for which Vd was comparable across two dose groups (1.37 and 1.12 L per kg for 0.1 and 0.2 U per kg dose, respectively).

Vd: 1.55 L per kg (0.1 unit/kg-dose); 0.72 L per kg (0.2 unit/kg-dose)

Metabolism

No research has been done on human metabolism. However, according to animal studies, the metabolism of insulin lispro appears to be the same as that of conventional human insulin.

Elimination

With a mean clearance of 21.0 mL/min/kg and 21.4 mL/min/kg, respectively (0.1 unit per kg dosage), and 9.6 mL/min/kg and 9.4 mL/min/kg, respectively (0.2 unit per kg dose), when given intravenously, insulin lispro and ordinary human insulin showed comparable dose-dependent clearance.

Half-life, SC use: 1 hr

Mean clearance, IV use: 21.0 mL/min/kg (0.1 unit per kg dose); 9.6 mL/min/kg (0.2 unit per kg dose)

Mean half-life: 0.85 hr (0.1 unit per kg); 0.92 hr (0.2 unit per kg)

• Zinman, B. et al. “Insulin lispro in CSII: results of a double-blind crossover study.” Diabetes vol. 46,3 (1997): 440-3. doi:10.2337/diab.46.3.440
• Brunelle, B L et al. “Meta-analysis of the effect of the insulin lispro on severe hypoglycemia in the patients with type 1 diabetes.” Diabetes care vol. 21,10 (1998): 1726-31. doi:10.2337/diacare.21.10.1726
• Thomas Blevins, Qianyi Zhang, et al; for the PRONTO-T2D Investigators, Randomized Double-Blind Clinical Trial Comparing the Ultra Rapid Lispro With Lispro in a Basal-Bolus Regimen in the Patients With Type 2 Diabetes: PRONTO-T2D. Diabetes Care 1 December 2020; 43 (12): 2991–2998. https://doi.org/10.2337/dc19-2550
• Curtis, B.H., Rees, T.M., Gaskins, K.A. et al. Efficacy and safety of insulin lispro in the geriatric patients with type 2 diabetes: A retrospective analysis of 7 randomized controlled clinical trials. Aging Clin Exp Res 26, 77–88 (2014). https://doi.org/10.1007/s40520-013-0125-7

https://www.ncbi.nlm.nih.gov/books/NBK507840/

https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020563s172,205747s008lbl.pdf

https://pubmed.ncbi.nlm.nih.gov/29939617/

https://www.ema.europa.eu/en/medicines/human/EPAR/insulin-lispro-sanofi