Insulin Glargine

Insulin Glargine is an Antidiabetic Agent belonging to the pharmacological class of long-acting insulin.

Insulin Glargine is approved for treating diabetes mellitus, specifically for lowering blood sugar levels among individuals with type 1 and type 2 diabetes (both of which are insulin-dependent). It provides stable, long-lasting blood sugar management and helps control the body's glucose levels.

After subcutaneous injection, insulin glargine is slowly absorbed and forms microprecipitates that release insulin over time. The liver and kidneys are the main sites of metabolism, which is analogous to endogenous insulin. The urine leaves the body with unmetabolized insulin glargine.

Low blood sugar (hypoglycemia) is Insulin Glargine's most frequent side effect. Other common side effects include peripheral oedema, lipodystrophy, allergic responses, injection site reactions, itching, rashes, and weight gain.

Insulin Glargine is available as an injectable solution and a prefilled pen.

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

Insulin Glargine is an Antidiabetic Agent belonging to the pharmacological class of long-acting insulin.

Insulin glargine binds to the insulin receptor (IR) which is a heterotetrameric protein composed of two extracellular alpha units and two transmembrane beta units. Tyrosine kinase activity in the receptor's beta subunit is stimulated by insulin binding to the alpha subunit of IR. The bound receptor phosphorylates and autophosphorylates a wide range of intracellular substrates, including the insulin receptor substrates (IRS) proteins, Cbl, APS, Shc, and Gab 1. The activation of these proteins triggers the activation of PI3 kinase and Akt or Protein kinase B (PKB), two downstream signalling molecules. Protein kinase C (PKC) and glucose transporter 4 (GLUT4), both of which are essential for metabolism, are controlled by Akt. At pH 4, the injected solution's pH, and at physiological pH 7.4, insulin glargine has poor solubility. The solution is neutralised after subcutaneous injection, which causes the development of microprecipitates. Insulin glargine is released from microprecipitates in minimal volumes, maintaining a reasonably steady concentration over 24 hours with no apparent peak. This release mechanism allows the drug to imitate the body's baseline insulin levels.

Insulin Glargine is available as an injectable solution and a prefilled pen.

Injectable solution: To use the insulin glargine 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 glargine 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.

Diabetes

In individuals with diabetes mellitus, including type 1 and type 2 diabetes, insulin glargine controls high blood sugar. It helps regulate blood glucose levels and is injected into the body to maintain adequate glycemic control.

In Treatment of diabetes mellitus

Insulin glargine is a synthetic insulin variant that controls high blood sugar levels. It takes the place of the body's natural insulin synthesis and provides a constant hormone supply all day. It helps regulate blood sugar levels and synthesises energy from sugar by promoting glucose entry into cells.

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 glargine is indicated to treat adults and children with type 1 diabetes and adults with type 2 diabetes to improve optimal glycemic control.

Parenterally: Insulin Glargine is available as an injectable solution and prefilled pen. that can be taken parenterally. Subcutaneous injections in the abdomen, thigh, or upper arm can be used to provide medication daily. Assess the solution visually for clarity and the absence of particles before use. Avoid using an insulin pump or intravenous (IV) or intramuscular (IM) injection. Do not mix or dilute with additional insulin products. Change the injection location from one injection to the next within the same region to reduce the risk of lipodystrophy. These recommendations should be followed to administer insulin glargine safely and effectively to treat diabetes.

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

• Injectable solution: 100 units/mL
• Prefilled pen: 100 units/mL, 300 units/mL

Dose Adjustment in Adult Patients:

Type 1 Diabetes Mellitus

Initial dose for insulin-naïve patients

• Start with approximately one-third of the daily recommended insulin dose and use the remaining two-thirds of the daily recommended insulin dose for short-acting, premeal insulin.
• The usual starting dose range is 0.2-0.4 units/kg; optimum glucose-lowering action may take five days to appear ultimately, and the first dose of insulin glargine may not be enough to fulfil metabolic demands in the first 24 hours of administration.
• Adjust co-administered glucose-lowering treatments per the standard of care and titrate insulin glargine as indicated.

Type 2 Diabetes Mellitus

Initial dose for insulin-naïve patients

When initiating insulin glargine, start with 0.2 units/kg qDay and, if required, alter the dosage of other diabetes medications to reduce the risk of hypoglycemia.

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

While taking Insulin Glargine, 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.

Avoid consuming sugary foods and beverages, including cereals, snacks, and sweetened beverages, as they can lead to rapid spikes in blood glucose.

It is advised to stay hydrated, maintain a rich, balanced diet low in saturated fats and cholesterol, 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 Glargine may be contraindicated in the following conditions:-

• Known hypersensitivity to Insulin glargine or one of its excipients
• Diabetic ketoacidosis with or without coma
• During episodes of hypoglycemia

• Never Share an Insulin Glargine Prefilled Pen, Syringe, or Needle Between Patients: Even if the needle changes, prefilled insulin Glargine pens should never be shared between patients. Patients utilising vials of insulin glargine must keep needles or syringes private. Pathogens that are transmitted through blood can be spread through sharing.
• Hypoglycemia or Hyperglycemia with Changes in Insulin Regimen: Changes in an insulin regimen (such as insulin strength, manufacturer, type, injection location, or delivery technique) may impact glycemic control and increase the risk of hypoglycemia or hyperglycemia. A sudden change in the injection location (to an unaffected region) has been observed to cause hypoglycemia. In contrast, repeated insulin injections into areas of lipodystrophy or localised cutaneous amyloidosis have been documented to cause hyperglycemia.
• Any adjustments to a patient's insulin regimen should be made closely monitored by a doctor and with more frequent blood glucose checks. Patients who have been injected into localised cutaneous amyloidosis or lipodystrophy repeatedly should be advised to switch the injection location and be constantly watched for hypoglycemia. Changing the dosage of concurrent oral and antidiabetic medications may be necessary for individuals with type 2 diabetes.
• Hypoglycemia: Hypoglycemia, notably in severe episodes, is the primary adverse reaction linked to insulin usage, including Insulin glargine. Severe hypoglycemia can lead to seizures and potentially life-threatening situations. It can also impair cognitive function and reaction time, posing risks in activities requiring concentration, such as driving or operating machinery. Hypoglycemia's onset can be sudden, with varying symptoms among individuals that may evolve. Patients with long-standing diabetes, diabetic neuropathy, sympathetic nervous system-blocking medications (e.g., beta-blockers), or recurrent hypoglycemia may have less noticeable symptomatic awareness of low blood sugar.
• Risk Factors for Hypoglycemia
• With the insulin's length of action peaking when its glucose-lowering impact is most significant, there is a correlation between this risk and the post-injection duration of action. Insulin glargine can drop blood sugar over a more extended period of time than other medications, and it can even change over time in the same person. Injection location, blood supply, and temperature are just a few variables that affect this variance. Changes in meal schedules, levels of physical activity, or coadministered drugs can significantly raise the risk of hypoglycemia, especially in those with renal or hepatic impairment.
• Risk Mitigation Strategies for Hypoglycemia
• Both patients and caregivers must receive education regarding the detection and treatment of hypoglycemia. To prevent and control diabetes, regular blood glucose monitoring is essential. It's recommended to check individuals more frequently if they're at higher risk or have impaired awareness. Insulin glargine's prolonged effect might make hypoglycemia recovery take longer.
• Hypersensitivity and Allergic Reactions: With insulin medications, particularly Insulin glargine, severe, life-threatening generalised allergies, including anaphylaxis, can happen. If hypersensitivity responses happen, stop taking insulin glargine; treat as necessary and continue to monitor things until the symptoms and indications disappear.
• Hypokalemia: All forms of insulin, including insulin glargine, produce a change in potassium concentration from the extracellular to the intracellular space, which may result in hypokalemia. Respiratory paralysis, ventricular arrhythmia, and even death can result from untreated hypokalemia. If necessary, check potassium levels in patients at risk for hypokalemia (patients using potassium-lowering drugs, patients receiving medications sensitive to serum potassium values, etc.).
• When giving this treatment to elderly diabetic patients, use caution. Initial dosage, dose increases, and maintenance dosage should all be vigilant to prevent hypoglycemia.

It is unsafe to consume Insulin Glargine with alcohol.

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

Use caution while administrating Insulin Glargine during pregnancy

Limit Alcohol consumption, reduce or avoid sugary and high-glycemic-index foods and beverages

The adverse reactions related to Insulin Glargine can be categorized as

• Common Adverse Effects: Hypoglycemia.
• Less Common Adverse Effects: Hypokalemia or weight gain.
• Rare Adverse Effects: Lipodystrophy (changes in fat tissue) or hypersensitivity reactions (severe allergic reactions)

Reports on Postmarketing

Localized cutaneous amyloidosis

Pediatric patients: Rhinitis.

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

• Beta-Blockers: The signs of hypoglycemia may be suppressed by beta-blockers (such as propranolol), making it more difficult for you to determine whether your blood sugar is too low. For people with diabetes, this may be very worrying. If using beta-blockers, monitor blood sugar levels and adjust insulin dosage.
• Hypoglycemic Agents: Concomitant use of other hypoglycemic agents, such as sulfonylureas, meglitinides, or other insulins, may higher the risk of hypoglycemia (low blood sugar). Dosage adjustments of both Insulin Glargine and these agents may be necessary to prevent low blood sugar.
• ACE Inhibitors and ARBs: Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) may lower blood glucose levels. Combining them with Insulin Glargine may increase the risk of hypoglycemia.
• Thiazolidinediones: Co-administration of Insulin Glargine with thiazolidinediones (e.g., pioglitazone, rosiglitazone) may increase the risk of fluid retention and heart failure.

The most common side effects of Insulin Glargine include:

• Low blood glucose or hypoglycemia
• Peripheral oedema
• Skin thickening or pits at the site where it was administered are signs of lipodystrophy.
• An allergic response
• Reactions at the injection site (pain, swell, redness)
• Itching
• Rash
• Gaining weight

• Pregnancy

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

According to published studies, there isn't enough evidence to conclusively link insulin glargine usage during pregnancy to poor developmental outcomes. Uncontrolled pregnancy-related diabetes has risks for both the mother and the foetus.

During organogenesis, insulin glargine was administered to rats and rabbits in animal reproduction experiments at 50 and 10 times higher doses than the human subcutaneous dosage of 0.2 units/kg/day, respectively. In general, the effects of insulin glargine were similar to those of conventional human insulin.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Pregnant women with poorly managed diabetes are more likely to experience preeclampsia, spontaneous abortions, preterm birth, and other difficulties during delivery. Significant birth abnormalities, stillbirths, and morbidities associated with macrosomia are more likely in foetuses with poorly managed diabetes.

Human data

There isn't enough evidence in the published data to conclusively link insulin glargine use during pregnancy to severe birth abnormalities, miscarriage, or bad outcomes for the mother or the foetus. These studies' methodological flaws, which include sample sizes that are too small and those that lack control groups, prevent them from conclusively proving that there is no evidence of any potential risk.

Animal Data

Studies on teratology and subcutaneous reproduction in rats and Himalayan rabbits have been carried out using insulin glargine and regular human insulin. Female rats were administered insulin glargine at dosages up to 0.36 mg/kg/day before, during mating, and throughout pregnancy. This is around 50 times the advised human subcutaneous beginning dose of 0.2 units/kg/day (0.007 mg/kg/day), expressed in mg/kg. During organogenesis, dosages of 0.072 mg/kg/day, which are about ten times the suggested human subcutaneous beginning dose of 0.2 units/kg/day on a mg/kg basis, were given to rabbits. In either rats or rabbits, the effects of insulin glargine were mainly similar to those seen with ordinary human insulin. However, five foetuses from two litters of rabbits in the high-dose group showed enlargement of the cerebral ventricles. Early prenatal development and fertility appeared normal.

• Nursing Mothers

No information is available on the presence of insulin glargine in human milk, its effects on breastfed infants, or milk production.

Even if administering insulin glargine while nursing is acceptable, other factors, such as the mother's clinical requirement for medication and any potential negative effects on the breastfed infant from pharmaceuticals or the underlying maternal ailment, should also be considered.

• Pediatric Use

In children with type 1 diabetes of aged 6 to 15 years, Insulin glargine has been shown to be both safe and effective.

Dose Adjustment in Pediatric Patient

Type 1 Diabetes Mellitus

<6 years: Safety and efficacy not established

≥6 years: Start administering 1/3 of the daily insulin dosage; utilise 2/3 of the daily insulin dose on short-acting, premeal insulin; adolescents' average daily maintenance range is 1.2 units/kg/day during growth spurts.

• Geriatric Use

15% of the participants in controlled clinical studies, including patients with type 1 and type 2 diabetes who received insulin glargine, were under 65, while 2% were over 75. The only difference in safety or efficacy between the subset of patients under 65 and the overall trial population was a greater incidence of cardiovascular events in the Insulin glargine and NPH therapy groups, typically encountered in an older population.

The use of Insulin glargine in elderly people should be done with caution, nevertheless. The starting dosage, dose increases, and maintenance dosage for diabetic older individuals should all be cautious to prevent hypoglycemia responses. In elderly people, hypoglycemia may be difficult to detect.

Dose Adjustment in Kidney Impairment Patients:

There are no specific dosage adjustments provided.

Dose Adjustment in Hepatic Impairment Patients:

There are no specific dosage adjustments provided.

Signs and Symptoms

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Insulin Glargine.

Overconsumption of Insulin Glargine could lead to symptoms such as hypoglycemia and hypokalemia.

Management

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

Oral carbohydrates are frequently effective in treating mild episodes of hypoglycemia. Modifying the medicine dose, eating habits, or exercise routine may be necessary.

Glucagon administered intramuscularly, subcutaneously, or concentrated intravenous glucose may treat more severe hypoglycemic episodes, including coma, seizure, or neurologic impairment.

Management typically involves supportive measures and symptomatic treatment. The patient will continue to be monitored for several hours to ensure that blood sugar levels remain stable and that there are no further complications.

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 pancreas' beta cells naturally produce the hormone insulin. In non-diabetics, the pancreas continuously secretes low amounts of basal insulin combined with increased insulin levels after meals. The metabolic adjustments that occur as the body shifts from a postabsorptive to an absorptive state are caused by increased insulin secretion after meals. Insulin stimulates amino acid uptake by liver, muscle, and adipose tissue, which increases protein synthesis and DNA replication. Insulin also encourages cellular uptake of glucose, especially in muscle and adipose tissues. It also promotes energy storage through glycogenesis and fights against the catabolism of energy stores. In addition to promoting development, insulin is necessary for the functions of growth hormones, such as protein synthesis, cell division, and DNA synthesis. Insulin glargine is a long-acting insulin analogue with a flat and predictable action profile. It is used to simulate the basal insulin levels in people with diabetes.

Pharmacokinetics:

Absorption

After administration of Insulin glargine (subcutanously) in healthy volunteers and in patients with history of diabetes, the insulin serum concentrations showed a slower, more prolonged absorption and a relatively stable concentration/time profile over 24 hours with no apparent peak compared to NPH insulin.

Bioavailability: Delay in absorption from the SC site

Onset of action: 3–4 hours

Duration: 24 hours (between 10.8 and >24 hours)

Peak plasma time: Microprecipitates form in fatty tissue from which a small quantity of insulin is progressively released; there are no apparent peaks; the release is steady over more than 24 hours.

Metabolism and Excretion

According to human metabolism research, insulin glargine is partially metabolised at the carboxyl terminus of the B chain in the subcutaneous depot to produce M1 (21A-Gly-insulin) and M2 (21A-Gly-des-30B-Thr-insulin), two active metabolites having in vitro activity comparable to that of human insulin. Both the initially administered medication and their breakdown byproducts are in circulation.

Adipose tissue/muscle; Metabolites (active): M1 (21A-Gly-insulin) and M2 (21A-Gly-des-30BThr-insulin)

Excretion: Urine

• Eledrisi, Mohsen et al. “Twice-daily insulin glargine for patients with uncontrolled type 2 diabetes mellitus.” Journal of Clinical & translational endocrinology vol. 15 35-36. 11 Dec. 2018, doi:10.1016/j.jcte.2018.12.002
• Garg, Satish et al. “Clinical experience with insulin glargine in type 1 diabetes.” Diabetes Technology & therapeutics vol. 12,11 (2010): 835-46. doi:10.1089/dia.2010.0135
• Harris, S.B., Parente,et al. Clinical Use of Insulin Glargine 300 U/mL in Adults with Type 2 Diabetes: Hypothetical Case Studies. Diabetes Ther 13, 913–930 (2022). https://doi.org/10.1007/s13300-022-01247-7
• R. Roussel, R. Ritzel, E. Boëlle-Le Corfec, B. Balkau, J. Rosenstock, Clinical perspectives from the BEGIN and EDITION programmes: Trial-level meta-analyses outcomes with either degludec or glargine 300U/mL vs glargine 100U/mL in T2DM, Diabetes & Metabolism, Volume 44, Issue 5, 2018, Pages 402-409, ISSN 1262-3636, https://doi.org/10.1016/j.diabet.2018.02.002.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Insulin glargine was administered to mice and rats in conventional two-year carcinogenicity trials at doses up to 0.455 mg/kg, which, for the rat, was around 65 times the suggested human subcutaneous beginning dosage of 0.2 units/kg/day (0.007 mg/kg/day on a mg/kg basis). Male rats and mice exposed to groups of acid-containing vehicles developed histiocytomas at injection sites, which are thought to be a reaction to prolonged tissue irritation and inflammation in rodents. Female animals, saline control groups, or insulin comparator groups utilising a different vehicle did not have these tumours.

In tests for chromosomal abnormalities (cytogenetics in vitro in V79 cells and in vivo in Chinese hamsters) and gene mutations in bacteria and mammalian cells (Ames and HGPRT-test), insulin glargine was not mutagenic.

In combined fertility, prenatal, and postnatal study, male and female rats were exposed to subcutaneous doses up to 0.36 mg/kg/day, which is about 50 times the recommended human subcutaneous starting dose of 0.2 units/kg/day (0.007 mg/kg/day), which is associated with maternal toxicity due to dose-dependent hypoglycemia. The rearing rate thus only reduced in the high-dose group. NPH insulin produced comparable results.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020664s011lbl.pdf
• https://www.ncbi.nlm.nih.gov/books/NBK557756/
• https://dailymed.nlm.nih.gov/dailymed/drugInfo
• https://pubmed.ncbi.nlm.nih.gov/32491688/