Canagliflozin

Blood Sugar Management

Canagliflozin is used along with diet and exercise to lower blood sugar levels in adults with type 2 diabetes. It helps the kidneys remove excess sugar from the body through urine.

Reducing Serious Complications

This medication is also prescribed to reduce the risk of major health events in specific patient populations, including:

• Heart Health: It is used to lower the risk of heart attack, stroke, or death in adults with type 2 diabetes who also have established cardiovascular disease.
• Kidney Protection: It is used to reduce the risk of end-stage kidney disease and the worsening of kidney function in adults with type 2 diabetes and diabetic nephropathy (kidney disease caused by diabetes).
• Heart Failure Prevention: It is used to decrease the risk of hospitalization for heart failure in adults with type 2 diabetes and chronic kidney disease.

Canagliflozin is not used to treat type 1 diabetes or diabetic ketoacidosis.

Mechanism of Action

Canagliflozin belongs to a class of drugs known as sodium-glucose co-transporter 2 (SGLT2) inhibitors. It works by changing the way the kidneys process sugar in the bloodstream.

Under normal conditions, the kidneys filter blood and then reabsorb sugar back into the body so it can be used for energy. In people with type 2 diabetes, blood sugar levels are often too high. Canagliflozin works by:

• Blocking reabsorption: It inhibits the SGLT2 protein, which is primarily responsible for moving sugar from the filtered blood back into the bloodstream.
• Increasing excretion: Because the sugar is not reabsorbed, it remains in the urine and is eventually flushed out of the body during urination.

By increasing the amount of glucose passed out of the body, canagliflozin helps lower overall blood sugar levels. This process works independently of insulin, although the medication is typically used as part of a broader diabetes management plan.

Common Side Effects

• Frequent urination or a strong urge to urinate
• Increased thirst
• Nausea or constipation
• Dry mouth
• Vaginal yeast infections, which may cause itching, discharge, or odor
• Yeast infections of the penis, which may cause redness, itching, swelling, or discharge
• Skin rash

Serious Side Effects

• Ketoacidosis: This is a life-threatening condition involving high levels of acid in the blood. Symptoms include nausea, vomiting, stomach-area pain, confusion, unusual sleepiness, or trouble breathing.
• Amputation Risk: There is an increased risk of lower limb amputations, primarily involving the toes and the middle of the foot. It is important to report any new pain, tenderness, sores, ulcers, or infections in the legs or feet to a healthcare provider.
• Fournier's Gangrene: A rare but serious bacterial infection that damages tissue under the skin in the genital and anal area. Seek medical attention for pain, tenderness, redness, or swelling in these areas along with a fever or feeling unwell.
• Urinary Tract Infections: Serious infections may occur, with symptoms such as burning during urination, pelvic pain, or blood in the urine.
• Dehydration and Kidney Problems: This medication can cause the body to lose too much water, leading to dizziness, fainting, or feeling lightheaded when standing up.
• Bone Fractures: An increased risk of bone fractures has been associated with this medication.
• High Potassium Levels: Some patients may develop high levels of potassium in the blood.
• Allergic Reactions: Seek immediate help for signs of a serious allergic reaction, such as hives, rash, or swelling of the face, lips, or throat.

Amputation Risk

Clinical trials have identified an increased risk of lower limb amputations, primarily affecting the toes and midfoot, in patients taking canagliflozin. While the FDA removed a boxed warning for this risk in 2020, it remains a significant precaution. Factors that may increase this risk include a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. Healthcare providers typically monitor for new pain, tenderness, sores, or infections in the legs and feet.

Ketoacidosis

Canagliflozin can cause ketoacidosis, a serious condition where the body produces high levels of blood acids called ketones. This condition can occur even if blood sugar levels are not significantly elevated (less than 250 mg/dL). Symptoms may include nausea, vomiting, abdominal pain, generalized malaise, and difficulty breathing. Treatment usually requires hospitalization.

Kidney Function and Dehydration

The medication works by increasing glucose excretion through the urine, which can lead to fluid loss and dehydration. This volume depletion may cause low blood pressure (hypotension) and acute kidney injury. Risk factors include pre-existing kidney impairment, older age, low systolic blood pressure, or the use of certain medications like diuretics and ACE inhibitors. Kidney function is typically monitored before and during treatment.

Serious Infections

There is an increased risk of genital yeast infections (mycotic infections) in both men and women. Additionally, a rare but life-threatening bacterial infection called necrotizing fasciitis of the perineum (Fournier's gangrene) has been reported. This condition causes tissue damage in the genital and perianal area and requires immediate medical attention.

Bone Fractures and Mineral Density

An increased risk of bone fractures has been observed in patients taking canagliflozin. This risk may be associated with a decrease in bone mineral density and an increased likelihood of falls related to low blood pressure.

Contraindications and Precautions

Canagliflozin is not recommended for individuals with severe kidney impairment or those receiving dialysis. It is also contraindicated for patients with a history of serious hypersensitivity reactions to the drug. Because it can cause low blood sugar (hypoglycemia) when used with insulin or insulin secretagogues, dosage adjustments of those medications may be necessary.

Pregnancy

There is limited research on the use of canagliflozin in pregnant women. However, animal studies suggest that the medication may cause harm to the developing kidneys of a fetus, particularly when used during the second and third trimesters. Because of these potential risks, healthcare providers typically advise against using canagliflozin during these stages of pregnancy.

If you are pregnant, planning to become pregnant, or discover you are pregnant while taking this medication, you should contact your healthcare provider immediately. They can help you weigh the risks and benefits and may suggest alternative ways to manage your blood sugar levels during pregnancy.

Breastfeeding

It is not known whether canagliflozin passes into human breast milk. Because of the potential for serious adverse reactions in a nursing infant, breastfeeding is generally not recommended while using this medication. You should discuss the best options for feeding your baby and managing your condition with your doctor.

Dosage Forms

Canagliflozin is currently available in the following form for administration:

• Oral Tablet: This medication is a film-coated tablet intended to be swallowed by mouth.

It is typically taken once daily, usually before the first meal of the day. The specific tablet prescribed will depend on the medical condition being treated and the patient's response to the medication.

FDA Approval and Indications

Canagliflozin is FDA-approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It is also indicated to reduce the risk of major adverse cardiovascular events, such as heart attack or stroke, in adults with type 2 diabetes and established cardiovascular disease. Additionally, it is approved to treat diabetic nephropathy (kidney disease) and reduce the risk of hospitalization for heart failure in certain adult patients with type 2 diabetes and diabetic nephropathy.

Safety Labeling Changes

The FDA has monitored and updated the safety profile of canagliflozin since its initial approval:

• Amputation Risk: In 2017, the FDA required a Boxed Warning regarding an increased risk of leg and foot amputations. However, in 2020, the FDA removed this Boxed Warning after reviewing additional clinical trial data. The agency determined that the risk, while still present and listed in the Warnings and Precautions section, was outweighed by the drug's benefits in treating heart and kidney disease.
• Bone Fracture Risk: The FDA has updated the drug's labeling to include warnings about an increased risk of bone fractures and decreases in bone mineral density.

Canagliflozin is not indicated for patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Weight Loss and Canagliflozin

Canagliflozin belongs to a class of drugs known as SGLT2 inhibitors. It works by helping the kidneys remove glucose (sugar) from the bloodstream and excreting it through urine. Because glucose contains calories, this process can lead to weight loss in many patients.

Important considerations regarding weight loss include:

• Primary Use: Canagliflozin is not FDA-approved as a weight-loss medication. Its primary purpose is to improve blood sugar control in adults with type 2 diabetes.
• Lifestyle Factors: This medication is intended to be used in combination with a reduced-calorie diet and regular exercise.
• Mechanism: The weight loss associated with this drug is primarily due to the loss of calories through the urine and the reduction of excess fluid in the body.

While many people experience a reduction in body weight while taking canagliflozin, results vary by individual. Patients should consult their healthcare provider to understand how this medication fits into their overall diabetes management plan.