Canagliflozin is a medication widely prescribed for the management of type 2 diabetes mellitus. It is used together with proper diet and exercise to treat type 2 diabetes and is also used to lower the risk of heart attack, stroke, or death in patients with type 2 diabetes and heart or blood vessel disease. Canagliflozin is also used to lower the risk of end stage kidney disease, worsening of kidney function, and hospitalization for heart failure in patients with type 2 diabetes and diabetic kidney disease with a certain amount of protein in the urine. While this medication offers significant therapeutic benefits, it is essential for patients and healthcare providers to understand the potential side effects associated with its use to ensure safe and effective treatment outcomes.
Understanding How Canagliflozin Works
Sodium-glucose co-transporter 2 (SGLT2) is expressed on the proximal renal tubules and is primarily responsible for the reabsorption of 90% of the glucose filtered by our kidneys. Canagliflozin inhibits the proximal renal tubules' SGLT2 receptors. This action decreases renal glucose absorption and the renal threshold for glucose and increases urinary excretion. By promoting the elimination of excess glucose through urine, canagliflozin helps lower blood sugar levels without directly stimulating insulin production. This unique mechanism of action makes it an effective option for many patients with type 2 diabetes, but it also contributes to some of the side effects associated with the medication.
Common Side Effects of Canagliflozin
Like all medications, canagliflozin can cause side effects in some patients. Understanding these common side effects can help you recognize them early and take appropriate action. Many of these effects are related to the medication's mechanism of increasing glucose excretion through urine.
Urinary Tract Infections
The most commonly reported adverse reactions have included female genital mycotic infections, urinary tract infection, and increased urinary frequency. Urinary tract infections (UTIs) occur more frequently in patients taking canagliflozin because the increased glucose levels in the urine create an environment that promotes bacterial growth. Women are particularly susceptible to UTIs while taking this medication. Symptoms of a UTI may include a burning sensation during urination, frequent urge to urinate, cloudy or strong-smelling urine, and pelvic pain. If you experience these symptoms, it is important to contact your healthcare provider promptly for evaluation and treatment.
Genital Yeast Infections
Canagliflozin can cause serious infections in the penis or vagina. Genital yeast infections, also known as genital mycotic infections, are another common side effect of canagliflozin therapy. These infections occur because the excess glucose in the urine provides an ideal environment for yeast to thrive. While these infections are more common in women, men can also develop genital yeast infections while taking canagliflozin. Symptoms in women may include vaginal itching, burning, redness, discharge, and discomfort during intercourse. Men may experience redness, itching, swelling, or discharge from the penis. Maintaining good hygiene and keeping the genital area clean and dry can help reduce the risk of these infections.
Increased Urination
Increased urination is a direct result of canagliflozin's mechanism of action. As the medication causes the kidneys to eliminate more glucose through urine, the volume of urine produced naturally increases. This side effect is generally expected and indicates that the medication is working as intended. However, the increased urination can be inconvenient for some patients and may disrupt sleep if it occurs frequently during the night. Patients should be prepared for this effect and plan accordingly, especially when traveling or in situations where bathroom access may be limited.
Dehydration and Low Blood Pressure
Elderly patients are more likely to have unwanted effects (eg, lightheadedness, dizziness, fainting, or dehydration), which may require caution in patients receiving canagliflozin. Canagliflozin may cause dizziness, lightheadedness, and fainting when you get up too quickly from a lying position. The increased urination caused by canagliflozin can lead to dehydration if fluid intake is not adequate. Dehydration may manifest as dry mouth, increased thirst, decreased urination despite taking the medication, dark-colored urine, fatigue, and dizziness. You may have very low blood pressure while taking this medicine. Low blood pressure related to dehydration can cause symptoms such as lightheadedness, especially when standing up quickly from a sitting or lying position. Drink plenty of liquids while you are taking canagliflozin. Staying well-hydrated is crucial for patients taking canagliflozin, particularly during hot weather or when exercising.
Hypoglycemia When Combined with Other Medications
You may have low blood sugar (hypoglycemia) and feel very hungry, dizzy, irritable, confused, anxious, or shaky. While canagliflozin alone does not typically cause hypoglycemia (low blood sugar), the risk increases when it is used in combination with other diabetes medications, particularly insulin or sulfonylureas. Your healthcare team may advise reducing the dose of your sulphonylurea or insulin medicine when you start taking canagliflozin to reduce the risk of hypos. Symptoms of hypoglycemia include shakiness, sweating, rapid heartbeat, hunger, irritability, confusion, dizziness, and weakness. Patients taking canagliflozin along with insulin or sulfonylureas should monitor their blood sugar levels regularly and be prepared to treat low blood sugar episodes with fast-acting carbohydrates.
Serious Side Effects Requiring Immediate Medical Attention
While most side effects of canagliflozin are manageable, some serious adverse effects require immediate medical attention. Being aware of these potentially life-threatening complications can help ensure prompt treatment and better outcomes.
Diabetic Ketoacidosis
On 15 May 2015, the FDA issued a warning that certain SGLT2 diabetes drugs, including canagliflozin, may lead to ketoacidosis, a condition where the body produces higher levels of ketone bodies. Diabetic ketoacidosis (DKA) is a rare but serious complication that can occur in patients taking canagliflozin. Serious, life-threatening, and fatal cases of DKA have been reported in patients taking an SGLT2 inhibitor (canagliflozin, dapagliflozin, or empagliflozin). The EU review concluded that this side effect is rare (affecting between 1 in 1000 and 1 in 10,000 patients).
What makes canagliflozin-associated DKA particularly dangerous is that it can occur with relatively normal blood glucose levels, a condition known as euglycemic diabetic ketoacidosis. In several cases, blood glucose levels were only moderately elevated (eg <14mmol/L)—representing an atypical presentation for DKA, which could delay diagnosis and treatment. Because canagliflozin promotes glucosuria, episodes of DKA can present with lower blood glucose levels than expected.
Inform patients of the signs and symptoms of DKA (eg rapid weight loss, feeling sick or being sick, stomach pain, fast and deep breathing, sleepiness, a sweet smell to the breath, a sweet or metallic taste in the mouth, or a different odour to urine or sweat) and advise them to seek immediate medical attention if these symptoms develop. Additional symptoms may include nausea, vomiting, abdominal pain, confusion, and unusual fatigue.
Risk Factors for Ketoacidosis
The following factors may predispose patients taking an SGLT2 inhibitor to DKA: a low beta cell function reserve (eg, patients with type 2 diabetes who have low C-peptide levels, latent autoimmune diabetes in adults [LADA], or a history of pancreatitis) conditions leading to restricted food intake or severe dehydration are among the key risk factors. Predisposing factors for canagliflozin-associated DKA include T1DM, concurrent insulin therapy, and an inciting illness such as gastroenteritis.
Reported triggers for occurrence of ketoacidosis in patients on SGLT-2 inhibitors include acute illness, sepsis, recent surgery, starvation, decrease in carbohydrate intake, decrease in insulin intake, and significant changes in the level of physical activity, or pregnancy. Patients should be particularly vigilant during periods of illness, after surgery, or when dietary intake is reduced.
Your doctor may tell you to stop taking canagliflozin at least 3 days before your scheduled surgery if you will not be able to eat or drink normally for a long time. This precaution helps reduce the risk of developing ketoacidosis during the perioperative period. If you take canagliflozin and become unwell, you should temporarily stop taking it. You need to check your ketones and your blood sugars (if you've been told to do this and have the kit) and speak to your healthcare team. Taking this medication when you're not very well could increase your risk of developing DKA, so you need to know the signs and symptoms of DKA to look out for.
Kidney Problems and Acute Kidney Injury
In June 2016, the FDA strengthened the warning about the risk of acute kidney injury for the type 2 diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). Canagliflozin can affect kidney function, and in some cases, may lead to acute kidney injury. This serious complication can develop suddenly and may require hospitalization.
This is more common if you have kidney disease, low blood pressure, or if you are taking a diuretic (water pill). Patients with pre-existing kidney disease are at higher risk for kidney-related complications. Clinical trials have shown Invokana to be associated with a fall in aGFR (estimated glomerular filtration rate), a marker which indicates how well the kidneys are working. The fall in eGFR for patients taking Invokana indicates that there could be safety issues related to a drop in kidney function with the drug.
Signs of kidney problems may include changes in urination patterns (producing much less urine than usual), swelling in the legs, ankles, or feet, unusual tiredness, confusion, nausea, and shortness of breath. Call your doctor if you are sick with vomiting or diarrhea, or if you are sweating more than usual. These conditions can lead to dehydration, which increases the risk of kidney injury in patients taking canagliflozin.
Regular monitoring of kidney function through blood tests is essential for patients taking canagliflozin. Your healthcare provider will check your kidney function before starting the medication and periodically during treatment to ensure it remains within safe parameters.
Bone Fractures and Decreased Bone Density
On 10 September 2015, the FDA issued a drug safety communication for canagliflozin to address risks for bone fracture and decreased bone density. A label warning for fractures was already included in the Adverse Reactions section; however, the FDA made the addition to the Warnings and Precautions section to reflect new information from a placebo study. Studies have suggested that long-term use of canagliflozin may be associated with an increased risk of bone fractures and decreased bone mineral density.
A 29 June 2016, report on the ongoing cardiovascular outcomes trial for canagliflozin (CANVAS) revealed interim findings of new safety concerns including heightened risk of bone fracture that was found to increase with the duration of treatment. This finding suggests that the risk may accumulate over time with continued use of the medication.
They advised that health care professionals should consider fracture risk factors before prescribing canagliflozin, and patients should disclose any bone fracture risk factors to their doctors, but that patients should not stop taking the medication without first talking to their doctor. Risk factors for bone fractures include older age, history of osteoporosis or previous fractures, vitamin D deficiency, low calcium intake, sedentary lifestyle, smoking, excessive alcohol consumption, and use of certain medications such as corticosteroids.
Patients taking canagliflozin should discuss bone health with their healthcare provider, particularly if they have risk factors for fractures. Measures to maintain bone health may include ensuring adequate calcium and vitamin D intake, engaging in weight-bearing exercise, avoiding smoking and excessive alcohol consumption, and potentially undergoing bone density testing to assess fracture risk.
Lower Limb Amputation Risk
This medicine may increase your risk of having leg, toe, or midfoot amputation (leg removal surgery). Check with your doctor right away if you have pain, tenderness, sores or ulcers, or infections on your leg or foot. Clinical trials have identified an increased risk of lower limb amputations in patients taking canagliflozin compared to those taking placebo.
In the CANVAS trial, amputations per 1000 patients per year in patients receiving canagliflozin (100 mg or 300 mg per day) were 5.8 compared to 2.8 amputations per 1000 patients per year in the placebo group. In the CANVAS-R trials, these numbers were 7.5 and 4.2, respectively. While the absolute risk remains relatively low, it is an important consideration, particularly for patients with existing risk factors for amputation.
Risk factors for lower limb amputation include a history of previous amputation, peripheral vascular disease, neuropathy, diabetic foot ulcers, and poor circulation. Patients taking canagliflozin should practice good foot care, including daily inspection of feet for any cuts, sores, blisters, or signs of infection, wearing properly fitting shoes, keeping feet clean and moisturized, and promptly reporting any foot problems to their healthcare provider. Early detection and treatment of foot problems can help prevent serious complications.
Serious Genital Infections (Fournier's Gangrene)
While genital yeast infections are common and generally mild, canagliflozin has been associated with rare cases of serious genital infections, including a life-threatening condition called Fournier's gangrene (necrotizing fasciitis of the perineum). This is an extremely rare but severe bacterial infection that affects the tissue under the skin in the genital and perineal area.
Get medical help right away if you have burning, itching, odor, discharge, pain, tenderness, redness or swelling of the genital or rectal area, fever as these could be signs of a serious infection requiring immediate medical attention. Fournier's gangrene requires emergency treatment with antibiotics and surgical intervention. While this complication is very rare, patients should be aware of the warning signs and seek immediate medical care if they develop severe genital or perineal pain, swelling, redness, or fever.
Allergic Reactions
Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat. Although rare, serious allergic reactions to canagliflozin can occur. Symptoms of a severe allergic reaction (anaphylaxis) include difficulty breathing or swallowing, swelling of the face, lips, tongue, or throat, severe rash or hives, rapid heartbeat, and dizziness or fainting. Any signs of a severe allergic reaction require immediate emergency medical attention.
Who Should Not Take Canagliflozin
Canagliflozin is not appropriate for everyone with diabetes. Understanding the contraindications and situations where canagliflozin should not be used is crucial for patient safety.
Type 1 Diabetes
Canagliflozin does not help patients who have insulin-dependent or type 1 diabetes. Type 1 diabetic patients must use insulin injections. Canagliflozin is not for treating type 1 diabetes. The medication is specifically approved for type 2 diabetes and should not be used as a treatment for type 1 diabetes. Canagliflozin was associated with an increased incidence of serious AEs of DKA in patients with type 1 diabetes inadequately controlled with insulin.
Pregnancy and Breastfeeding
You should not use canagliflozin during the second or third trimester of pregnancy. You should not breastfeed while using this medicine. Canagliflozin may harm the fetus. Tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. Do not breastfeed while you are taking canagliflozin. If you become pregnant while taking canagliflozin, call your doctor.
Canagliflozin should not be used if you are pregnant of breastfeeding. If you're planning a pregnancy speak with a healthcare professional if you are using this medication. Women of childbearing age should discuss appropriate contraception with their healthcare provider while taking canagliflozin and should inform their doctor immediately if they become pregnant.
Severe Kidney or Liver Disease
If you have kidney disease you might not be able to take canagliflozin or your doses might need to be reduced - this will depend on the stage of your kidney disease; If you have severe liver disease you might not be able to take canagliflozin Patients with severe kidney impairment or those on dialysis should not take canagliflozin, as the medication works through the kidneys and is less effective when kidney function is significantly impaired. Additionally, the risk of side effects increases in patients with reduced kidney function.
History of Diabetic Ketoacidosis
Your doctor will tell you to stop taking canagliflozin if you develop diabetic ketoacidosis, or DKA Patients who have previously experienced diabetic ketoacidosis while taking canagliflozin or other SGLT2 inhibitors should not restart treatment with these medications unless another clear cause for the DKA was identified and resolved.
Drug Interactions and Precautions
Canagliflozin can interact with other medications, potentially affecting how it works or increasing the risk of side effects. It is essential to inform your healthcare provider about all medications, supplements, and herbal products you are taking.
Interactions with Other Diabetes Medications
When canagliflozin is used in combination with insulin or insulin secretagogues (such as sulfonylureas), the risk of hypoglycemia increases significantly. Your healthcare provider may need to reduce the dose of insulin or sulfonylurea when starting canagliflozin to minimize this risk. Close monitoring of blood glucose levels is essential when combining these medications.
Diuretics and Blood Pressure Medications
Canagliflozin has a diuretic effect, meaning it increases urine production. When combined with other diuretic medications (water pills) or blood pressure medications, there is an increased risk of dehydration and low blood pressure. Patients taking these combinations should be monitored closely, especially when starting canagliflozin or adjusting doses.
Alcohol Consumption
Ask your doctor about the safe use of alcoholic beverages while you are taking canagliflozin. Alcohol may cause a change in blood sugar. Alcohol can affect blood sugar levels and may increase the risk of hypoglycemia or ketoacidosis in patients taking canagliflozin. Patients should discuss alcohol consumption with their healthcare provider and understand the potential risks.
Monitoring and Follow-Up Care
Regular monitoring is essential for patients taking canagliflozin to ensure the medication is working effectively and to detect any potential side effects early. Your healthcare provider will establish a monitoring schedule tailored to your individual needs.
Blood Sugar Monitoring
Regular blood glucose monitoring helps assess how well canagliflozin is controlling your diabetes and can alert you to episodes of hypoglycemia or hyperglycemia. Your healthcare provider will recommend how often you should check your blood sugar based on your overall diabetes management plan and other medications you are taking.
Kidney Function Tests
Periodic blood tests to assess kidney function are crucial for patients taking canagliflozin. These tests typically include serum creatinine and estimated glomerular filtration rate (eGFR) measurements. Your healthcare provider will check your kidney function before starting canagliflozin and at regular intervals during treatment to ensure the medication is not adversely affecting your kidneys.
Hemoglobin A1C Testing
Hemoglobin A1C testing provides information about your average blood sugar control over the previous two to three months. This test is typically performed every three to six months to assess the effectiveness of your diabetes treatment plan, including canagliflozin therapy.
Foot Examinations
Given the increased risk of lower limb complications, regular foot examinations are important for patients taking canagliflozin. Your healthcare provider should examine your feet at each visit, and you should perform daily self-examinations at home to check for any cuts, sores, blisters, or signs of infection.
Practical Tips for Managing Side Effects
While side effects can be concerning, there are several practical strategies you can employ to minimize risks and manage common side effects associated with canagliflozin therapy.
Staying Hydrated
Taking plenty of fluids each day may help. Adequate hydration is one of the most important measures for preventing dehydration and related complications. Aim to drink water throughout the day, and increase fluid intake during hot weather, when exercising, or if you are experiencing vomiting or diarrhea. However, avoid excessive consumption of sugary beverages, as these can interfere with blood sugar control.
Maintaining Good Hygiene
Good personal hygiene can help reduce the risk of urinary tract infections and genital yeast infections. Keep the genital area clean and dry, wipe from front to back after using the bathroom, wear breathable cotton underwear, avoid tight-fitting clothing, and change out of wet swimsuits or exercise clothing promptly. For women, avoiding douches, scented feminine products, and bubble baths may also help reduce infection risk.
Taking Medication as Prescribed
Canagliflozin is usually taken once per day, before the first meal of the day. Canagliflozin is a tablet that you take once a day. You should take it with a drink of water and swallow it whole. You can take it at any time of the day, but it is recommended to take it at the same time each day. Taking canagliflozin consistently at the same time each day helps maintain steady medication levels and improves treatment effectiveness. Do not skip doses or stop taking the medication without consulting your healthcare provider.
Rising Slowly from Sitting or Lying Positions
To minimize dizziness and the risk of falls related to low blood pressure, rise slowly when getting up from a sitting or lying position. Sit on the edge of the bed for a moment before standing, and hold onto something stable if you feel dizzy. This is particularly important for elderly patients who may be more susceptible to these effects.
Practicing Good Foot Care
Daily foot care is essential for preventing serious complications. Inspect your feet daily for any cuts, blisters, redness, swelling, or nail problems. Wash your feet daily with lukewarm water and mild soap, dry them thoroughly (especially between the toes), and apply moisturizer to prevent dry, cracked skin (but not between the toes). Wear properly fitting shoes and socks, never go barefoot, and trim toenails straight across. Report any foot problems to your healthcare provider promptly.
When to Contact Your Healthcare Provider
Knowing when to seek medical attention is crucial for preventing serious complications. Contact your healthcare provider if you experience any of the following:
- Signs of ketoacidosis (nausea, vomiting, abdominal pain, unusual fatigue, difficulty breathing, confusion, or fruity-smelling breath)
- Symptoms of a urinary tract infection that do not improve with treatment or that recur frequently
- Signs of kidney problems (changes in urination, swelling, unusual tiredness)
- Severe or persistent genital infections
- Foot pain, sores, ulcers, or signs of infection
- Symptoms of dehydration that do not improve with increased fluid intake
- Frequent episodes of low blood sugar
- Any new or worsening symptoms that concern you
Seek emergency medical care immediately if you experience signs of a severe allergic reaction, symptoms of severe ketoacidosis, chest pain, severe abdominal pain, or any other symptoms that seem life-threatening.
Benefits of Canagliflozin Beyond Blood Sugar Control
Despite the potential side effects, it is important to recognize that canagliflozin offers significant benefits beyond blood sugar control. Canagliflozin is also used to lower the risk of death from heart attack, stroke, or heart failure in adults with type 2 diabetes who also have heart disease. Canagliflozin is also used to reduce the risk of end-stage kidney disease and hospitalization or death from heart problems in adults who also have kidney problems caused by type 2 diabetes.
These cardiovascular and renal protective effects represent major advantages for many patients with type 2 diabetes, particularly those with existing heart or kidney disease. The medication has been shown to reduce the risk of major cardiovascular events and slow the progression of kidney disease in appropriate patient populations. Additionally, many patients experience modest weight loss while taking canagliflozin, which can be beneficial for overall health and diabetes management.
Making Informed Treatment Decisions
The decision to use canagliflozin should be made collaboratively between you and your healthcare provider, taking into account your individual medical history, risk factors, other medications, and treatment goals. While the potential side effects discussed in this article may seem concerning, it is important to remember that not all patients will experience these effects, and many side effects are manageable with appropriate precautions and monitoring.
For many patients, the benefits of canagliflozin in controlling blood sugar, protecting the heart and kidneys, and potentially promoting weight loss outweigh the risks. However, for patients with certain risk factors or contraindications, alternative diabetes medications may be more appropriate. Your healthcare provider can help you weigh the potential benefits and risks based on your specific situation.
The Importance of Open Communication
When you start a new medication always check with your healthcare team that it's suitable for you to take. Your healthcare team should explain your prescription to you but it's important to make sure you ask if you don't feel you know enough. Open and honest communication with your healthcare team is essential for safe and effective use of canagliflozin.
Before starting canagliflozin, discuss your complete medical history with your healthcare provider, including any history of kidney disease, liver disease, heart problems, urinary tract infections, genital infections, bone fractures, or amputations. Inform your provider about all medications, supplements, and herbal products you are taking, as well as any allergies you have. Be honest about your alcohol consumption, dietary habits, and lifestyle factors that may affect your diabetes management.
During treatment, keep your healthcare provider informed about any side effects you experience, even if they seem minor. Do not hesitate to ask questions about your medication, including how it works, what side effects to watch for, and what to do if you experience problems. If you are concerned about any aspect of your treatment, discuss these concerns with your healthcare provider rather than stopping the medication on your own.
Lifestyle Modifications to Support Treatment
While canagliflozin can be an effective tool for managing type 2 diabetes, it works best when combined with healthy lifestyle habits. Taking medication(s), making lifestyle changes (e.g., diet, exercise, quitting smoking), and regularly checking your blood sugar may help to manage your diabetes and improve your health.
A balanced diet that is appropriate for diabetes management, regular physical activity, maintaining a healthy weight, not smoking, limiting alcohol consumption, managing stress, and getting adequate sleep all contribute to better diabetes control and overall health. These lifestyle modifications can also help reduce the risk of some side effects associated with canagliflozin, such as infections and cardiovascular complications.
Work with your healthcare team, including your doctor, diabetes educator, and dietitian, to develop a comprehensive diabetes management plan that includes medication, lifestyle modifications, and regular monitoring. This holistic approach provides the best opportunity for achieving optimal blood sugar control while minimizing the risk of complications.
Conclusion
Canagliflozin is a valuable medication for managing type 2 diabetes and providing cardiovascular and renal protection for appropriate patients. While it can cause side effects ranging from common and manageable issues like urinary tract infections and increased urination to rare but serious complications such as diabetic ketoacidosis and lower limb amputations, understanding these potential effects enables patients and healthcare providers to use the medication safely and effectively.
By staying informed about potential side effects, maintaining open communication with your healthcare team, adhering to monitoring recommendations, practicing good self-care habits, and seeking prompt medical attention when needed, you can maximize the benefits of canagliflozin while minimizing risks. Remember that your healthcare provider has prescribed this medication because they have determined that the benefits outweigh the risks for your specific situation. If you have concerns about canagliflozin or experience any troubling symptoms, do not hesitate to contact your healthcare provider for guidance.
For more information about canagliflozin and diabetes management, consult reputable sources such as the Mayo Clinic, MedlinePlus, the American Diabetes Association, and the Diabetes UK website. These resources provide evidence-based information to help you make informed decisions about your diabetes care.