Insulin glulisine

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

Insulin glulisine is approved for treating diabetes mellitus in adults and children aged four years and older. It is indicated for improving glycemic control by lowering blood glucose levels with a proper diet and exercise regimen. Insulin glulisine is a rapidly absorbed insulin analogue administered subcutaneously. It has a uniform distribution in the body, is metabolized through enzymatic degradation in the liver and other tissues, and is primarily eliminated via the kidneys.

The most common side effects of insulin glulisine are hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, itching, rash, and upper respiratory tract infections.

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

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

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

The insulin receptor (IR) binds to insulin glulisine, a heterotetrameric protein composed of two extracellular alpha units and two transmembrane beta units. Tyrosine kinase activity inherent to the receptor's beta subunit is stimulated by insulin binding to the alpha subunit of IR. Numerous intracellular substrates, including the insulin receptor substrates (IRS) proteins, APS, Shc, Cbl, and Gab 1, are phosphorylated and autophosphorylated by the attached receptor. Downstream signalling molecules like PI3 kinase and Akt are activated when those proteins are activated. Protein kinase C (PKC) and glucose transporter 4 (GLUT4), both of which are essential for metabolism and catabolism, are controlled by Akt. In humans, insulin is stored in hexamers; however, only insulin monomers may interact with IR. The inclination to form hexamers is reduced, the hormone is stabilised in monomeric form, and the absorption rate and duration of action are increased by changing the arginine at position B3 for lysine and the lysine at position B29 for glutamic acid.

Insulin glulisine onset of action is approximately 10 to 15 minutes, and the total duration of action ranges from about 3 to 5 hours after administration.

The Tmax of Insulin glulisine data occurs 40 to 90 minutes after subcutaneous injection.

The Cmax of Insulin glulisine data was achieved within approximately 1 to 2 hours after subcutaneous injection.

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

Injectable solution: To use the insulin glulisine 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.

Prefilled pen: To use the insulin glulisine 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.

• Individuals with type 1 diabetes use insulin glulisine to help regulate their blood sugar levels.
• Insulin glulisine is used for people with type 2 diabetes, mainly when oral medications or other injectable insulins are insufficient.

In Treatment of diabetes mellitus

Insulin glulisine 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.

Insulin Glulisine is indicated to control high blood sugar levels in those individuals with type 1 diabetes (insulin-dependent) and type 2 diabetes (non-insulin-dependent).

Parenterally: Insulin glulisine is available as an injection solution that can be administered parenterally. Before injection, ensure proper mixing (if required) and inspect for particles or colour changes. Taking subcutaneously within 15 or 20 minutes after starting a meal is also advised to control post-meal blood sugar levels. Administer insulin glulisine as a subcutaneous injection under the skin, usually into the thigh, abdomen, or upper arm, using an insulin syringe, insulin pen, or insulin pump. Change the site of injection within the same region to prevent lipodystrophy. Never combine the shots when using insulin; always give them separately. Insulin and Insulin glulisine injections may be administered in the same area of the body, but they shouldn't be close together.

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

Injection solutions (as 10 mL vial and 3 mL cartridge): 100 units/mL

Prefilled syringe 3 mL pen: 100 units/mL

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

Dose Adjustment in Adult Patients:

Diabetes Mellitus Type I or II

It is indicated to boost glycemic control in adults and children with diabetes mellitus.

Dosing Considerations

When given intravenously, it has the same potency as conventional human insulin (that is, it has the same glucose-lowering effects on a unit-by-unit basis).

Compared to conventional human insulin, insulin glulisine acts faster and wears off more quickly.

Individualised dosage and blood glucose monitoring are required for all individuals undergoing insulin treatment.

The daily insulin demand might change but typically ranges from 0.5-1 unit/kg/day.

The amount of insulin needed may fluctuate under stress, when suffering from a severe disease, or when exercising, eating, or taking medications together.

SC injection

Insulin Glulisine should be given around mealtime, preferably within 15 or 20 minutes after starting a meal. When used as a subcutaneous injection, it's typically part of a regimen that includes intermediate- or long-acting insulin. Administer it in the abdominal area, thigh, or upper arm, and ensure you rotate injection sites within the same region to minimize the risk of lipodystrophy.

Continuous SC injection (insulin pump)

Insulin Glulisine can be administered through continuous subcutaneous infusion in the abdominal wall. Avoid dilution or mixing with other insulins. Rotate the infusion sites within the same region to prevent lipodystrophy. Change the insulin reservoir at least every 48 hours. Ensure it's not exposed to temperatures over 98.6°F (37°C). When starting external insulin infusion pump programming, use the total daily recommended insulin dose from the previous regimen as a guideline. Be cautious about insulin pump or infusion set malfunctions, handling errors, or insulin degradation, which can quickly lead to hyperglycemia, ketosis, and diabetic ketoacidosis.

IV administration

Insulin Glulisine can be given intravenously (IV) under medical supervision to manage blood glucose with vigilant monitoring of glucose and serum potassium levels to prevent low blood sugar and potassium. IV administration should use 0.05-1 unit/mL concentrations in PVC bag infusion systems with 0.9% NaCl (normal saline). Before IV administration, visually inspect for any particles or discolouration, and avoid giving insulin mixtures through IV.

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

While taking Insulin glulisine, maintain regular meal schedules with balanced macronutrient content 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 glulisine may be contraindicated in the following conditions:-

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

• Even if the needle changes, never distribute an insulin glulisine pen among patients.
• 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: Can be fatal. In patients with renal impairment, hepatic impairment, hypoglycemia unawareness, or changes to insulin dose, co-administered glucose-lowering drugs, meal patterns, or physical activity, glucose monitoring should be done more often.
• Hypokalemia: It might be fatal to have hypokalemia. Patients at risk for hypokalemia should have their potassium levels checked and treated as necessary.
• Hypersensitivity and Allergic Reactions: Anaphylaxis, a severe, perhaps fatal, generalised allergy, can happen. Stop using glulisine insulin; monitor; and, if necessary, treat.
• Thiazolidinediones (TZDs) Can Cause Fluid Retention and Heart Failure When Used Together. Monitor for heart failure symptoms. Consider reducing your TZD dosage or stopping it altogether if you notice any.
• Ketoacidosis and hyperglycemia Due to a defective insulin pump device: If the pump malfunctions, monitor the blood sugar and inject insulin glulisine

It is unsafe to consume Insulin glulisine with alcohol.

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

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

Limit Alcohol consumption, and avoid heavy or high-fat meals.

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

• Common Adverse Effects: Hypoglycemia (low blood sugar), Injection site reactions (e.g., redness, swelling, itching)
• Less Common Adverse Effects: Swelling, shortness of breath, and decreased potassium levels.
• Rare Adverse Effects: Severe allergic reactions, Changes in sodium levels in the blood (hyponatremia), difficulty breathing, and heart palpitations.

Reports on Postmarketing

At the injection location, there has been localised cutaneous amyloidosis. Repeated insulin injections into regions with localised cutaneous amyloidosis have been associated with hyperglycemia; however, abrupt changes to an unaffected injection site have been associated with hypoglycemia.

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

• Drugs that Lower Blood Glucose or Increase or Decrease the Risk of Hypoglycemia: Dosage adjustment may be required; regularly check blood glucose.
• Drugs that lower the Signs and Symptoms of Hypoglycemia (such as beta-blockers, clonidine, guanethidine, and reserpine): Additional glucose testing may be necessary.
• Thiazolidinediones: Concomitant use may lead to fluid retention and heart failure. Monitoring for these effects is essential.
• ACE Inhibitors and Angiotensin II Receptor Blockers (ARBs): These medications may enhance the hypoglycemic effects of insulin glulisine.
• Salicylates: High doses of salicylates (e.g., aspirin) can lower blood sugar levels. Frequent blood glucose monitoring is advised.

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

• An allergic response
• Low blood sugar (hypoglycemia).
• Swelling, pain and redness at the site where an injection was administered
• Lipodystrophy (thickened skin or pits where injections were administered)
• Itching
• Rash
• An upper respiratory infection

• Pregnancy

Pregnancy Category C; Use with caution if the benefits outweigh the risks.

There are risks to the mother and foetus associated with poorly managed diabetes during pregnancy. Yet, there is no evidence linking the use of insulin glulisine during pregnancy to severe birth abnormalities, miscarriage, or unfavourable maternal or foetal outcomes.

Pre-gestational diabetes patients experience hypoglycemia and hyperglycemia more frequently during pregnancy; poorly controlled diabetes during pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, delivery complications and poorly controlled diabetes increases foetal risk for significant congenital disabilities, stillbirth, and macrosomia-related morbidity.

Animal Data

Insulin glulisine has been used in studies on animal reproduction in rats and rabbits using the regular human insulin as a comparator. Insulin glulisine was given to the female rats throughout pregnancy at SC doses up to 10 units/kg/day (2 times the average human amount, based on the body surface area comparison), and to rabbits during their organogenesis at SC doses up to 1.5 units/kg/day (0.5 times the average human dose, based on the body surface area comparison) was shown effective.

• Nursing mothers:

The development and health advantages of breastfeeding should be considered, as well as the mother's clinical requirement for therapy and any potential adverse effects on breastfed infants or from underlying maternal illnesses. The information that is currently available from the literature indicates that human insulin products are transmitted into human milk. There are no documented adverse effects in breastfed babies.

• Pediatric Use

In paediatric patients, the safety and effectiveness of insulin glulisine to enhance glycemic control have been proven. Evidence from active-controlled non-inferiority research in paediatric patients four years of age and older with type 1 diabetes mellitus treated with insulin glulisine (n=271) and studies in adults with diabetes mellitus supports using insulin glulisine for this indication.

In the clinical studies, compared to adults with type 1 diabetes mellitus, paediatric children with the condition exhibited a greater prevalence of severe symptomatic hypoglycemia in the two therapy groups.

Dose Adjustment in Pediatric Patients

Type 1 Diabetes Mellitus

Less than four years: No data on safety and effectiveness

During growth phases, children age 4 to 17 may need 0.8 to 1.2 units/kg/day SC; otherwise, use an adult dose (0.5 to 1 unit/kg/day).

• Geriatric Use

In clinical studies, 147 individuals aged 65 or younger and 27 patients aged 75 or older received insulin glulisine. This small group of elderly people primarily had type 2 diabetes. Age did not affect the change in HbA1c readings or the frequency of hypoglycemia.

Nevertheless, care should be used while giving insulin glulisine to elderly people. To lower the risk of hypoglycemia in diabetic geriatric patients, start dosing, dose increases and maintenance dosage should all be cautious.

Dose Adjustment in Kidney Impairment Patients:

Patients with renal impairment may need more frequent adjustments to the dosage of Insulin Glulisine 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 Glulisine 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 glulisine.

Overconsumption of Insulin glulisine may lead to hypoglycemia and hypokalemia, particularly when given intravenously.

Management

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

Oral glucose is often effective in treating mild episodes of hypoglycemia. Modifying the medicine dose, eating habits, or exercise routine may be necessary. An emergency glucagon product or concentrated intravenous glucose may treat more severe hypoglycemic episodes, including coma, seizure, or neurologic impairment. Hypoglycemia may return after a seemingly complete clinical recovery, necessitating continued carbohydrate intake and monitoring. The proper treatment must be given 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 beta cells in the pancreas generate the hormone insulin naturally. A basal insulin level is augmented in non-diabetic people by rises in insulin levels after meals. The metabolic alterations that occur as the body shifts from a postabsorptive to an absorptive state are brought on by postprandial insulin increases. 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 short half-life called insulin glulisine is given to people with diabetes to simulate postprandial insulin increases. Insulin glulisine starts to work after around 15 minutes. Its effect lasts 2-4 hours and peaks 60 minutes after subcutaneous injection.

Pharmacokinetics:

Absorption

The median time maximum concentration (Tmax) was estimated at 60 minutes (range 40 to 120 minutes) in a trial with individuals with type 1 diabetes (n=20) following subcutaneous injection of 0.15 units/kg. In contrast to the median Tmax of 120 minutes (ranging from 60 to 239 minutes) and the Cmax of 50 microunits/mL (range 35 to 71 microunits/mL) for conventional human insulin, the peak concentration (Cmax) for insulin glulisine was 83 microunits per mL (range 40 to 131 microunits per mL). The time-concentration patterns were comparable when subcutaneous injections of insulin glulisine were administered to various body parts. Regardless of the injection site (abdomen 73%, deltoid 71%, or thigh 68%), the absolute bioavailability of insulin glulisine following subcutaneous administration is around 70%.

Bioavailability: 70% following SC

Onset: 20 min (SC abdominal or deltoid injection); 30 min (SC femoral injection)

Peak Plasma Time: 1 hr

Peak Plasma Concentration: 83 microUnits/mL

Duration of action: 5 hr

Distribution

Insulin Glulisine distributed in the body is relatively uniform and acts quickly to lower blood glucose levels.

Protein Bound: 5% (not bound to serum binding-protein, but present as a monomer in plasma)

Vd: 13 L

Metabolism

Insulin glulisine undergoes enzymatic degradation in the liver and other tissues, similar to endogenous insulin. It is broken down into smaller components and rendered inactive.

Liver >50%; kidney 30%; adipose tissue/muscle 20%

Elimination

The elimination of insulin glulisine occurs primarily through the kidneys, where the inactive metabolites are excreted in the urine.

Half-Life: 13 minutes (IV); 42 min (SC)

• Doder, Zoran et al. “Insulin Glulisine in Pregnancy - Experience from Clinical Trials and Postmarketing Surveillance.” European Endocrinology vol. 11,1 (2015): 17-20. doi:10.17925/EE.2015.11.01.17
• Hidvégi, T., Balogh, Z., Vass, V. et al. Insulin Glargine 300 U/mL and Insulin Glulisine Treatment in the Patients with Type 2 Diabetes: A Non-Interventional Study of Effectiveness in Routine Clinical Practice. Diabetes Ther 11, 467–478 (2020). https://doi.org/10.1007/s13300-019-00746-4
• Meneghini, Luigi F et al. “A pragmatic randomized clinical trial of the insulin glargine 300 U/mL vs first-generation basal insulin analogues in insulin-naïve adults with type 2 diabetes: 6-month outcomes of the ACHIEVE Control study.” Diabetes, obesity & metabolism vol. 22,11 (2020): 2004-2012. doi:10.1111/dom.14152
• Garnock-Jones, Karly P, and Greg L Plosker. “Insulin glulisine: a review of its use in managing diabetes mellitus.” Drugs vol. 69,8 (2009): 1035-57. doi:10.2165/00003495-200969080-00006
• Dailey, George et al. “Insulin glulisine provides improved glycemic control in patients with type 2 diabetes.” Diabetes care vol. 27,10 (2004): 2363-8. doi:10.2337/diacare.27.10.2363
• Meyer, Christian et al. “Glulisine versus human regular insulin in combination with the glargine in a noncritically ill hospitalized patients with type 2 diabetes: A randomized, double-blind study.” Diabetes care vol. 33,12 (2010): 2496-501. doi:10.2337/dc10-0957

• https://pubmed.ncbi.nlm.nih.gov/16193096/
• https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021629s030lbl.pdf
• https://products.sanofi.us/apidra/apidra.html