Introduction
In this article, two important drugs are discussed.
The first one is Insulin glargine, a man-made version of human insulin approved by the FDA to treat children and adults with type 1 diabetes and type 2 diabetes only in adults. Insulin glargine is administered in injection form once daily and provides a basal insulin level throughout the day.
The second drug discussed is Lixisenatide. It stimulates the insulin secretion by the body, reducing the sugar level in the blood. It also reduces the amount of glucagon secretion in the pancreas. Since glucagon induces more sugar production by the liver, a decrease in its concentration reduces the sugar level in the body.
Insulin Glargine
What Is Insulin Glargine?
Insulin glargine is a version of human insulin that is FDA approved to cure type 1 diabetes in adults and children and type 2 diabetes only in adults. It is a long-acting injected insulin administered only once daily and maintains a basal insulin level for the entire day. Regimens of Insulin glargine are combined with rapid-acting Insulin to obtain optimal glycemic control. Insulin glargine is not recommended as a treatment option in diabetes ketoacidosis; in these cases, short-term Insulin is only preferred.
How Does Insulin Glargine Work?
Insulin glargine is an analog of human insulin that binds to the insulin receptors in the body. Insulin glargine has an onset of action of 1.5 to 2 hours, and the duration of action is up to 24 hours.
Uses of Insulin Glargine
The Insulin glargine is administered both in type 1 and type 2 diabetes. Therefore, the function of the drug in both the disorders is explained as follows:
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Type 1 Diabetes: In this disorder, the body cannot produce insulin from the pancreas due to autoimmune destruction of beta cells of the pancreas. This leads to a rapid loss of blood glucose levels. Insulin glargine here functions as a basal glycemic control agent due to its 24 hours duration of action. It works in combination with rapid-acting Insulin that functions as coverage of elevated blood glucose due to its quick onset and short duration of action.
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Type 2 Diabetes: In adults with type 2 diabetes, long-acting Insulin such as Insulin glargine should be administered after two or three oral antidiabetic medications have failed to control glycemic levels or patients with a hemoglobin A1c value higher than 9 %. Insulin glargine can be administered alone or along with rapid-acting Insulin or oral medications.
Dosage
Insulin glargine comes in 100 ml vials or dosing pens containing 3 ml cartridges of medication and is injected subcutaneous only. The drug is available in quantities of 100 ml units per ml. The Insulin glargine is administered daily once at the same time of the day. The injection site should be changed frequently to avoid a condition known as lipodystrophy. Some common injection sites are the back of upper arms, buttocks, abdomen, and top of thighs.
Side Effects of Insulin Glargine
Hypoglycemia (decrease in blood glucose level) is the most common side effect of Insulin glargine. Hypoglycemia can lead to symptoms such as nausea, palpitations, tremors, anxiety, decreased concentrations, lethargy, and diaphoresis. In cases of severe hypoglycemia, there can be seizures, coma, unconsciousness, and death.
For Patients
What Is Diabetes?
Diabetes is a disease that occurs when the blood glucose level is increased too high. Blood glucose is the main energy source of the body and is absorbed from the food eaten. The hormone insulin's stimulation metabolizes glucose in the body.
What Are Different Types of Diabetes?
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Type 1 Diabetes: In cases of type 1 diabetes, the body cannot produce insulin. Body's immune system attacks and destroys the pancreas's insulin-producing beta cells. It is usually diagnosed in children and young adults. People affected by type 1 diabetes need to take Insulin every day.
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Type 2 Diabetes: In cases of this diabetes, the body either does not produce enough insulin or cannot use insulin. Although type 2 diabetes can occur in any age group, it is more common in middle-aged or older people. It is a more common type of diabetes than type 1 diabetes.
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Gestational Diabetes: Diabetes may appear in some women during pregnancy. This type of diabetes is generally cured after the child is born. However, cases of gestational diabetes have a great chance of developing type 2 diabetes later in life.
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Monogenic Diabetes: Some rare forms of diabetes result from gene mutations and are known as monogenic diabetes.
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Cystic fibrosis-related diabetes.
More About the Drug
Following points are very important to mention to the doctor or pharmacist before starting Insulin glargine:
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It is important to inform the doctor about any Insulin allergy already pertaining.
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Consumption of any kind of prescribed or non-prescribed medicines such as vitamins, minerals, herbal products, or nutritional supplements should be informed before starting Insulin glargine.
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Some important drugs that should be considered are angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers (ARBs), and drugs containing alcohol.
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Any nerve damage due to heart failure, diabetes, low blood potassium levels, or other medical conditions.
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While undergoing any surgery, even dental surgery, the doctor should be informed about the usage of Insulin glargine.
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Consumption of alcohol may cause changes in blood sugar, so alcoholic beverages should be either avoided or consumed only after consulting the doctor.
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Any change in diet, exercise, or activity schedule can alter the blood glucose levels, so it should be mentioned to the doctor so that the amount of Insulin glargine is regulated.
How Does Insulin Glargine Work for Diabetes?
Insulin glargine is man-made insulin capable of binding to the insulin receptors in the body and functioning as natural insulin. In type 1 diabetes, Insulin glargine is used with short-acting Insulin because its onset is comparatively slow. Whereas in cases of type 2 diabetes, it should be started with or after oral medications for diabetes. Insulin glargine works like natural insulin; it helps transport glucose to body parts for conversion into energy and prevents the liver from producing more sugar.
How Long Does Insulin Glargine Take to Work?
The onset of action of Insulin glargine is almost 2 hours. However, the drug's duration of action lasts up to 24 hours. Once the Insulin is injected into the body, it slowly releases the soluble protein over 24 hours.
While Taking the Drug
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Insulin glargine should not be used in cases with symptoms of hypoglycemia (low blood sugar).
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The needles should never be reused or shared with anybody else. It should be discharged after a single-use.
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The Insulin glargine should neither be diluted nor mixed with any other type of Insulin.
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It is important to check the vial before injecting; the drug should be clear and colorless. The insulin glargine should not be used if it is colored, cloudy, or contains any solid particles.
How to Take Insulin Glargine?
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Insulin glargine is available in a liquid solution and injected (under the skin).
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The injection is administered once a day at the same time every day.
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The injectable sites for Insulin glargine are the upper arm, stomach, or thigh. It should never be injected into veins or muscles.
What if a Dose of Insulin Glargine Is Missed?
It is important to inform the doctor about the missed dose of Insulin glargine injection, and further instructions should be followed only as advised.
How to Start Insulin Glargine?
The drug should be kept in the container it came packed in and should be out of reach of children. The sealed vials and pens should be stored in the refrigerator but not frozen. If the refrigerator is not available, then the Insulin glargine should be kept at room temperature but away from direct sunlight or extreme heat. The opened vials and pens should be kept at room temperature and should be administered within 28 days.
Common Side Effects of Insulin Glargine
At the Site of Injection: Some effects observed at the sites of injection are:
- Swelling, pain, redness, or itching at the site of injection.
- Skin thickening (building up of fat) or skin depression (breakdown of fat).
Systemic Effects: The side effects of Insulin glargine seen in the body are:
- Fever, sore throat, cough, or other infections.
- A decrease in blood sugar levels (hypoglycemia) may lead to symptoms such as tremors, anxiety, and decreased concentration. It may lead to seizures, coma, or even death in some serious cases.
- Increase in blood sugar levels: some drugs that interact with Insulin glargine can diminish its effects and increase blood sugar levels instead of controlling it.
Overdose of Insulin Glargine
Excessive administration of Insulin glargine leads to hypoglycemia which can be mild or severe.
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In cases of mild hypoglycemia, intake of carbohydrates is sufficient to regulate the glucose levels back. The patient is asked to consume 15 grams of carbohydrates, wait for 15 minutes, recheck the blood glucose levels. If hypoglycemia still persists, the procedure is repeated.
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In cases of severe hypoglycemia, if oral intake is compromised, then Glucagon injections are the only option. Another procedure is extremely severe cases is intravenous Dextrose injections.
For Doctors
Indications for Insulin Glargine
In cases of type 1 diabetes where the body is not able to produce insulin due to autoimmune destruction of beta cells of the pancreas or in cases of type 2 diabetes where the body is either not able to produce sufficient insulin or is not capable of utilizing the insulin present. Both types of diabetes can lead to an uncontrolled increase in blood glucose levels which could be tough to control with the help of oral medications or short-acting insulin alone.
Mechanism of Action
Insulin glargine binds to the body's insulin receptors. As the natural insulin acts on skeletal muscles, liver, and adipose tissue, Insulin glargine also works the same way.
What Is an Insulin Receptor?
It is a tyro kinase receptor with two intracellular catalytic beta domains and two extracellular alpha domains. Changes occur in the beta catalytic domains when the insulin binds, which further activates tyrosine kinase domains, causing auto-phosphorylation of beta subunits. Once the beta subunits are activated, they bind proteins, leading to the activation of phosphatidylinositol-4,5-bisphosphate-3 kinase (PI3k) and an intracellular signaling cascade. It also activates protein kinase B (also called Akt). Akt regulates the activity of protein kinase C (PKC) and glucose transporter 4 (GLUT4), which play an important role in metabolism.
Insulin glargine has a long duration of action (24 hours) due to modifications of amino acids. The modifications are Asparagine to Glycine at position 21 and the addition of two Arginine at positions 31 and 32 of the B-chain. This arrangement helps the Insulin to remain soluble at a pH of 4.0. It gets gradually insoluble at physiologic pH of 7.4.
Pharmacokinetics and Absorption
The subcutaneous injection of Insulin glargine shows a slower and more prolonged absorption of Insulin at a constant concentration for 24 hours with no observed peak concentration compared to naturally produced human insulin.
Metabolism
Insulin glargine is metabolized in the liver with a similar phenomenon as natural insulin. It metabolizes into two active metabolites, 21a-Gly-human insulin (M1) and 21a-Gly-des-30b-threonine insulin (M2). The M1 is a predominant metabolite.
Dosage Forms and Strengths
The estimated first dose of Insulin glargine is generally 0.4 to 0.5 units/kg per day of total Insulin. The amount may differ from patient to patient, as in cases of puberty or obesity. The recent consensus about dosing of basal Insulin is 50 % of the total daily requirement of insulin. However, some studies state that 40 % of total daily insulin is enough to maintain optimal glycemic control.
Drug Interactions
The effect of Insulin glargine varies when used with different drugs such as:
Acetylsalicylic Acid: When Insulin glargine is administered along with Acetylsalicylic acid, the severity of hypoglycemia and its complications increases.
Amitriptyline: It affects the hypoglycemic activities of Insulin glargine and reduces its effects.
Hydroxychloroquine: Insulin glargine's efficacy increases when used with Hydroxychloroquine.
Betaxolol: Interactions of Insulin glargine with Betaxolol increase its therapeutic efficacy.
Insulin Aspart: The hypoglycemia gets severe when Insulin glargine is used with Insulin aspart.
Clinical Trials
The clinical trial was done to study the safety and effectiveness of Insulin glargine initiation and titration in patients with type 2 diabetes.
The objectives of clinical trials were:
- The primary objective is to study the percentage of patients achieving glycosylated hemoglobin (HbA1c) less than 7 % with no serious or nocturnal hypoglycemic episodes in 6 months.
- Secondary objectives of trials are the study of Insulin glargine dose at 3 and 6 months, change in glycosylated hemoglobin from baseline to 6 months, and all types of hypoglycemic episodes.
Randomized clinical trials to compare Basal Insulin peglispro and Insulin glargine in type 2 diabetes patients.
Objectives
To compare the efficacy of basal insulin peglispro and Insulin glargine in patients with type 2 diabetes already treated with basal insulin only or with a few oral antihyperglycemic drugs.
Duration of Trial: 52 weeks.
Results
At 26 weeks, the reduction of HbA1c was more with Basal Insulin peglispro than Insulin glargine. The reduction of HbA1c remained greater with Basal Insulin peglispro even at the end of 52 weeks.
Conclusion
Basal Insulin peglispro provided better glycemic control than Insulin glargine with decreased nocturnal hypoglycemic attacks.
Insulin Glargine in Pregnancy and Lactation
The drug is considered safe in pregnancy and lactating mothers as it does not have an adverse effect on the fetus. However, the drug is not approved by FDA yet in pregnancy but is considered a first-line treatment for gestational diabetes if the lifestyle modifications do not prove to be sufficient in treatment.
Lixisenatide
Overview
Lixisenatide was approved by FDA on July 27, 2016, and is used along with exercise and diet to treat type 2 diabetes. It belongs to a class of medicines known as incretin mimetics. It stimulates the pancreas to secrete insulin when glucose content in the blood is high. Insulin initiates the breakdown of glucose into energy and its transport to different parts of the body. Lixisenatide also affects the appetite by decreasing it and slowing the emptying of the stomach.
For Patients
Before Taking Lixisenatide Injection
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Inform the doctor or pharmacist about any allergy to Lixisenatide, Liraglutide, Exenatide, or any similar drug.
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Information about any supplements intake, such as vitamins, minerals, or herbal products, should be given to the doctor.
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History of alcohol abuse or conditions such as pancreatitis, gastroparesis, gallstones, or any kidney disease should be informed to the doctor.
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Conditions of pregnancy or breastfeeding should be informed to the doctor before starting Lixisenatide.
How Is Lixisenatide Injection Used
Lixisenatide injection comes as a prefilled dosing pen and has to be injected subcutaneously (under the skin). Usually, only one injection is injected daily within 60 minutes before the day's first meal. It is advised to use the injection at almost the same time every day.
Points to Remember While Using Lixisenatide
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Lixisenatide is administered on a low dose and then increases after 14 days.
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Lixisenatide controls diabetes but does not cure it, so the administration of injection has to be continued even after the patient feels better. The injection should not be stopped without the doctor's advice.
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The instructions given by the doctor or pharmacist should be followed properly for injecting the Lixisenatide injection.
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The solution should be observed well before administration. It should be clear, colorless, and free from any solid particles. If the solution is colored, cloudy or thick, it should not be used.
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The Lixisenatide pen should be stored in the refrigerator and must be allowed to reach room temperature before administration.
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The site of injection for Lixisenatide is the abdomen (stomach area), upper thigh, or upper arm.
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The needle should not be reused after injecting the drug.
Side Effects of Lixisenatide
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The drug can cause alterations in blood glucose levels-either, hypoglycemia or hyperglycemia.
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Other side effects are nausea, vomiting, constipation, diarrhea, bloating, or headache.
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Itching and pain with redness at the site of injection.
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Some of the serious side effects are rashes, pounding heartbeat, fainting or feeling dizzy, hoarseness, difficulty swallowing and decreased urination.
For Doctors
Indications
Lixisenatide belonging to the drug family incretin mimetics, is approved for use as an adjunct to exercise and diet in type 2 diabetic adults to control the glycemic levels. It is a glucagon-like peptide 1 (GLP-1) receptor agonist. It encourages the pancreas to secrete insulin to convert glucose into energy after food intake.
Pharmacokinetics
The highest plasma concentration of Lixisenatide occurs after 1.25 to 3.5 hours of subcutaneous injection. The rate of absorption is not injection-dependent. The peak concentration (C max) is dose-dependent.
Mechanism of Action
The activation of the glucose-like peptide-1 receptor by Lixisenatide will result in the activation of adenylyl cyclase. This increases the concentration of CAMP (cyclic adenosine monophosphate) in the cells, which leads to activation of protein kinase A (PKA) and Epac 1 and Epac 2. Protein kinase A, Epac 1, and Epac 2 release Ca 2+ from the endoplasmic reticulum, called the 'amplification' pathway, further increasing insulin release.
Elimination
Lixisenatide is considered to be eliminated by glomerular filtration and proteolytic degradation. The mean half-life of the drug is 3 hours with a clearance rate of 35 L/h. Significant changes in renal function affect the elimination of Lixisenatide in cases of severe renal impairment.
Contraindications
Lixisenatide is contraindicated in patients with the following conditions:
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Hypersensitivity: Increases sensitivity to any external factor, allergens, or drugs.
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Pancreatitis: Inflammation of the pancreas.
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Hypoglycemia (decreased blood sugar levels) with insulin secretagogues.
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Severe Renal Impairment: In these cases, the elimination of drugs is very different.
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Gastroparesis or severe gastrointestinal disease.
Dosage
The initial starting dose of Lixisenatide is 10 mcg subcutaneously once daily for 14 days. On day 15, the dose should be increased to 20 mcg once daily within 1 hour before the day's first meal.
Availability of the Drug
The starter pen of Lixisenatide is available in 50 mcg/ml in a 3 ml solution which delivers 14 doses of 10 mcg/dose of the drug. The maintenance dose contains 100 mcg/ml of 3 ml solution, which delivers 14 doses of 20 mcg/dose.
Drug Interactions
Interaction of Lixisenatide with different drugs are:
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Aceclofenac: It decreases the excretion rate of Lixisenatide, which results in a higher serum level.
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Acetaminophen: Acetaminophen decreases the excretion rate of Lixisenatide, which will result in a higher serum level.
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Carbamazepine: Lixisenatide may decrease the excretion rate of Carbamazepine.
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Dextran: The Lixisenatide's excretion rate decreases, leading to high serum levels.
Clinical Trials
Study details: conducted in 83 centers across 13 countries.
The total number of participants: was 786.
Duration of trial: from June 10, 2013, to July 09, 2014.
The Objective of the Trial
To check the efficacy and safety of Lixisenatide versus placebo on the top of Basal Insulin or oral antidiabetic treatment in older type 2 diabetes patients.
