Bexagliflozin for Type 2 Diabetes

Drug Overview:

Bexagliflozin belongs to a class of drugs that inhibit sodium-glucose co-transporter 2 (SGLT2). By doing so, Bexagliflozin aims to reduce the reabsorption of glucose from the kidneys. This makes glucose to be secreted in the urine, and thus, the levels of glucose in the blood are lowered. Bexagliflozin is used as an adjunct to manage hyperglycemic states in type 2 diabetes patients who are following diet and physical activities. Bexagliflozin was approved for this use in January 2023 by the United States Food and Drug Administration (US FDA).

Dosage and Route of Administration:

A single 20 milligrams (mg) dose of Bexagliflozin is indicated to be taken orally in the morning for treating type 2 diabetes.

For Patients

What Is Type 2 Diabetes?

Type 2 diabetes is an endocrinology disorder that makes the body resistant to taking insulin. In type 2 diabetes, there is an imbalance in the amount of insulin production by the pancreas and the body’s ability to utilize the produced insulin. In recent days, type 2 diabetes has been recognized as a part of a broader metabolic syndrome (conditions that increase the risk of incidence of cardiac issues), which includes high blood pressure, imbalance in lipid levels, and increased abdominal obesity. Drugs are being developed to improve glycemic control and provide protection against cardiovascular and renal (kidney) complications secondary to diabetes.

Why Is Bexagliflozin Given for Type 2 Diabetes?

Bexagliflozin helps manage type 2 diabetes by inhibiting the sodium-glucose transporter 2 (SGLT2). The proximal convoluted tubule contains a protein called SGLT-2. This protein reabsorbs glucose from the renal filtrate after filtration. Under normal circumstances, SGLT-2 reabsorbs around 90 percent of the glucose from the filtrate.

Individuals who are in hyperglycemic states (type 2 diabetes) already have elevated levels of glucose in their blood. The continued high activity of SGLT-2 in these individuals exacerbates the pre-existing hyperglycemic condition by maintaining elevated glucose levels in the blood. This maladaptive response contributes to the persistence and worsening of hyperglycemia in type 2 diabetes.

To prevent the worsening of this state, drugs that inhibit the SGLT-2 protein are advised for patients. Bexagliflozin is one such drug that inhibits this protein and impedes the process of glucose reabsorption in the proximal convoluted tubule. It promotes the excretion of glucose from the renal filtrate rather than being reabsorbed. Thus, this mechanism directly targets the renal contribution to hyperglycemia.

How Should Bexagliflozin Be Taken?

Bexagliflozin should be taken once daily in the morning through the oral route. The recommended dosage of Bexagliflozin for managing type 2 diabetes is 20 mg. The tablet ofBexagliflozin should not be crushed or split.

Drug Storage

Store Bexagliflozin at room temperature (20 to 25 degrees Celsius or 68 to 77 degrees Fahrenheit).

Missed Dose

A missed dose of Bexagliflozin should be taken immediately on remembering. However, if it is time for the next dose of Bexagliflozin, it should be skipped. Double dosing on Bexagliflozin is not indicated.

Overdose

Overdose of Bexagliflozin is an emergency event and should be managed immediately.

What Are the Side Effects of Bexagliflozin?

Major Side Effects:

1. Diabetic Ketoacidosis: Bexagliflozin causes reduced insulin secretion and elevated glucagon levels in the blood. This causes lipolysis and the release of free fatty acids, which are subsequently converted to ketone bodies in the liver. The buildup of these ketone bodies in the blood can induce a state of ketosis. This is also accompanied by acidosis in the body. As a result, the ketone body levels are high and the pH (potential of hydrogen) becomes low.

2. Volume Depletion: Bexagliflozin causes depletion in the blood volume. This is especially common among individuals who have low blood pressure, elderly patients, or people taking loop diuretics.

3. Urinary Tract Infections: As Bexagliflozin promotes the excretion of glucose through urine, the incidence of bacterial and yeast growth becomes high in the urinary tract. The most common urinary tract infection reported among people taking Bexagliflozin is caused by Streptococcal species. This also results in urosepsis (a life-threatening complication secondary to urinary tract infection). Some people are also reported to have a higher incidence of pyelonephritis (inflammation of the renal structures caused by bacterial infection) after taking Bexagliflozin.

4. Acute Renal Failure: In some patients, Bexagliflozin causes acute failure of the kidneys. So, Bexagliflozin is generally not given to people whose filtration rate in the glomerulus is estimated to be less than 30 mL/min/1.73 square meters (milliliters per minute).

5. Lower Limb Amputation: Studies suggest that there has been an increase in the amputation rates of the lower limb in people taking Bexagliflozin. This occurs most commonly in people who have peripheral vascular disease (circulation disorder that causes narrowed blood vessels) or ulcers in the foot (secondary to diabetes mellitus). People who are diagnosed with diabetic neuropathy (nerve damage secondary to diabetes) are also not advised for Bexagliflozin therapy due to the risk of amputation.

6. Genital Infections: Genital mycotic infections are also commonly observed in people taking Bexagliflozin. In females, candidiasis (fungal infection) is seen in vulva and vaginal areas. In males, balanoposthitis (inflammatory condition of the foreskin in the penis) is noted. Tinea cruris (dermatophytic infection in the groin) is also reported in males. Such genital infections cause itching, rashes, or erythematous nodules in the genital areas of males and females.

7. Necrotizing Fasciitis of the Perineum (Fournier’s gangrene): Perineal necrotizing fasciitis is a dangerous bacterial infection that causes the death of tissues in the perineum and surrounding genital and perianal areas. This is a rare complication of people taking Bexagliflozin and occurs due to increased bacterial growth in such regions. This complication requires immediate surgical intervention to remove the necrotic slough from the region.

8. Increased Fracture Incidence: The incidence of fractures, especially in the hip and femur, is common after intake of Bexagliflozin. This may be attributed to the changes brought by Bexagliflozin on the calcium homeostasis in the body and the bone mineral density.

Other Side Effects Noted Are:

• Increased urination frequency.

• Increased thirst.

• Itching.

• Rashes in the skin.

• Increased urination during night times.

• Pain while urinating.

• Erythema (redness of skin) surrounding the genital areas.

• Hypoglycemic state, particularly when insulin or other anti-hyperglycemic drugs are taken along with Bexagliflozin.

• Generalized fatigue.

• Vomiting.

• Stomach pain.

• Breathing difficulties.

• Dehydration.

• Lightheadedness.

• Foul-smelling discharge from the genitals.

• Fast heartbeat.

• Headache.

• Confusion.

• Sweating.

• Irritability.

• Increased hunger.

Laboratory Abnormalities:

• Increased creatinine levels.

• Decreased glomerular filtration rate.

• Increase in low-density lipoprotein levels.

• Increase in hemoglobin levels.

What Are the Precautions to Be Taken Before Taking Bexagliflozin?

• If a major surgery is planned or prolonged fasting is indicated, Bexagliflozin will be temporarily stopped for at least three days.

• The level of ketones in the body should be regulated continuously when people are under Bexagliflozin therapy (to prevent diabetic ketoacidosis). If there is an incidence of ketoacidosis, Bexagliflozin therapy should be terminated immediately.

• The volume status of the patients under Bexagliflozin therapy should be assessed before initiating the therapy.

• People who have ulcers or gangrene in the foot or limb should be cautious before taking Bexagliflozin due to the increased risk of lower limb amputations following Bexagliflozin therapy.

• The genital and perineal areas should be monitored continuously for infections and treated spontaneously.

For Doctors

Indications:

• Bexagliflozin is indicated to manage the glycemic range of patients with T2DM (Type 2 diabetes mellitus). Bexagliflozin is prescribed as a supplement (adjunct) to a healthy diet and regular physical activity.

Contraindications:

• Bexagliflozin is not indicated for achieving glycemic control in patients with type 1 diabetes.

• People with poor renal functioning (glomerular filtration rate less than 30 mL/min/1.73 m2) are not indicated for Bexagliflozin therapy.

• People allergic to any ingredients of Bexagliflozin are not indicated.

• People who are under loop diuretics or hypotensive patients are not indicated as there is a risk of volume depletion following Bexagliflozin therapy.

Drug Ingredients:

Active Ingredient: Bexagliflozin.

Inactive Ingredients:

• Colloidal silicon dioxide.

• Lactose monohydrate.

• Magnesium stearate.

• Glyceryl dibehenate.

• Polyethylene oxide.

• Microcrystalline cellulose.

Half-Life:

The half-life of Bexagliflozin is approximately 12 hours.

Pharmacokinetics

Absorption

Soon after Bexagliflozin intake through the oral route, the drug is absorbed well, and the peak plasma concentration of Bexagliflozin is reached within two to four hours. The bioavailability of Bexagliflozin is high, ensuring that a considerable amount of the drug (Bexagliflozin) enters the systemic circulation.

Distribution

Approximately 93 percent of the ingested Bexagliflozin is bound to plasma proteins and the distribution of Bexagliflozin is not affected by any physiological processes. Bexagliflozin’s ability to target renal tissues specifically is highly necessary for its mechanism of action, as it inhibits the SGLT-2 proteins in the proximal renal tubules, thereby, impeding glucose reabsorption and enhancing glucose excretion through the renal route.

Metabolism

Bexagliflozin undergoes minimal metabolism in the body, and the enzyme involved in this process is UGT1A9.

Excretion

Bexagliflozin is primarily excreted unchanged through the urine, reflecting its minimal metabolism in the body. Approximately 80 to 90 percent of the administered dose of Bexagliflozin is eliminated via the renal route.

Pharmacodynamics:

The pharmacodynamics of Bexagliflozin is based on its function as a selective sodium-glucose co-transporter-2 (SGLT-2) inhibitor. By targeting and blocking the action of the SGLT-2 protein located in the proximal renal tubules, Bexagliflozin impedes the reabsorption of glucose from the urine back into the bloodstream. This inhibition results in increased glucose excretion through the urine. Thus, the pharmacodynamic effects of Bexagliflozin are closely tied to its ability to lower hyperglycemia in patients with type 2 diabetes. Additionally, the reduction in blood glucose is accompanied by a modest decrease in body weight and blood pressure due to the osmotic diuretic effect of increased glucose in the urine caused by Bexagliflozin. Bexagliflozin also has beneficial effects on cardiovascular and renal outcomes, with studies suggesting improvements in cardiovascular risk factors and renal function in diabetic patients. The comprehensive effects of Bexagliflozin thus extend beyond glycemic control by addressing multiple aspects of the metabolic syndrome associated with type 2 diabetes.

Drug Interactions:

• Taking Bexagliflozin along with loop diuretics can cause volume depletion and severe reduction in blood pressure. It can also increase the risk of dehydration as Bexagliflozin itself promotes osmotic diuresis through increased glucose excretion.

• Bexagliflozin, when given with other anti-diabetic drugs, can lower the glucose levels in the blood, thus leading to a hypoglycemic state.

• Drugs that affect renal function or are contraindicated in severe renal impairment may interact with Bexagliflozin. Poor functionality of the renal tissues can significantly impact and decrease the clearance of Bexagliflozin.

• A combination of Bexagliflozin and other anti-hypertensive drugs can also cause hypotension and result in syncope.

• While not a direct interaction, the blood glucose-lowering effects of Bexagliflozin can enhance the effects of Insulin or insulin secretagogues, which may increase the risk of hypoglycemia.

• Bexagliflozin affects renal function, which may influence the renal clearance of lithium. The main route for Lithium elimination from the body is through the kidneys, and any alterations in the functions of the kidney or imbalance in the fluid proportions in the kidney can impact Lithium levels within the blood and potentially lead to either subtherapeutic or toxic levels. Therefore, when Bexagliflozin is used alongside lithium, patients should be looked out continuously for clinical manifestations of Lithium toxicity or inadequate therapeutic response.

Guidelines for Specific Populations:

Pregnancy

Bexagliflozin is not advised for pregnant ladies, especially in the second and third trimesters. Clinical studies done in animals have shown that there can be significant fetal malformations occurring after Bexagliflozin therapy. Women who had pre-gestational diabetes showed increased fluctuations of hypoglycemia and hyperglycemia after Bexagliflozin therapy. There was also an increased risk of preeclampsia, preterm labor, and other delivery-related complications.

Lactation

There is insufficient data on the excretion of Bexagliflozin in human breast milk, but animal studies indicate that the drug does pass into breast milk. Given that kidney development continues in infants both in utero and up to two years after birth, exposure to Bexagliflozin through breastfeeding could pose risks to the proper development of the infant's kidneys. Therefore, Bexagliflozin is not recommended for use during lactation.

Pediatric Population

The safety of Bexagliflozin has not yet been studied in children less than 18 years of age and hence it is not indicated in this population.

Geriatric Population

Geriatric people (older than 65 years of age) who have severe renal impairment are not indicated for Bexagliflozin therapy. People who are also under diuretic therapy or anti-hypertensive therapy are not indicated for Bexagliflozin therapy (due to the risk of severe hypotension). Geriatric people are also prone to developing dehydration and volume loss after taking Bexagliflozin. Hence, constant monitoring of such individuals is required.