Dapagliflozin Side effects, Warnings, and Contraindications

Dapagliflozin Side effects, especially infections of the urinary tract and genital yeast infections in females, are among the main factors that limit its use.

Dapagliflozin or Farxiga (brand name) is a drug that belongs to the class of medicines called SGLT2 inhibitors.

SGLT2 inhibitors are new diabetes medicines that act by blocking the reabsorption of filtered glucose from the kidneys back into the plasma.

When more glucose passes via the kidneys and bladder, the chances of urinary tract infection are increased.

Contraindications to the use of Dapagliflozin (Farxiga):

It is important not to use dapagliflozin in a certain group of patients. Using dapagliflozin in the following groups of patients might result in serious side effects or even death:

Allergic to Farxiga:

Individuals who are allergic to dapagliflozin. Allergy can manifest as body itching, hives, rashes, difficulty in breathing, swelling of the face, wheezing, and low blood pressure.

If any of these symptoms are observed after taking the drug, an immediate healthcare expert should be consulted. One should avoid future use of dapagliflozin (Forxiga).

Advanced Kidney disease:

Patients who are either on dialysis or have an estimated GFR of less than 30 ml/minute. Since SGLT2 inhibitors act by inhibiting the sodium-glucose channels in the kidneys, with advanced kidney disease, these drugs are not effective.

They may cause more side effects and are less effective. In some cases, these drugs might lead to further worsening of kidney disease.

Forxiga in pregnancy:

Pregnant patients and individuals with type 1 DM who have brittle diabetes are prone to develop diabetic ketoacidosis.

Farxiga for Type 1 Diabetes Mellitus:

Dapagliflozin was approved by the EMA for the treatment of obese type 1 DM patients who have not had diabetic ketoacidosis over a long time and can monitor their ketones at home.

However, the EMA disapproved its use later because of an increased incidence of euglycemic diabetic ketoacidosis.

It has not been approved by the FDA for the treatment of diabetes mellitus type 1 because of the increased chances of patients developing diabetic ketoacidosis despite normal blood glucose.

Dapagliflozin Side effects:

• Increased Risk of Bone fractures associated with SGLT2 Inhibitors:

In patients with type 2 diabetes mellitus and moderate renal impairment, there was an increased incidence of fractures (eGFR 30-60 mL/minute/1.73m²) in a randomized controlled study[Ref].

The same study did not find any effect of the drug on blood glucose compared to the placebo and fractures were observed in 13 patients in the dapagliflozin group compared to 0 patients in the placebo group.

However, a second randomized controlled trial didn’t confirm the same increased risk in patients who have type 2 diabetes and eGFR 45-60 mL/minute/1.73m² [Ref].

Although dapagliflozin appears to not increase fracture risk in the general population, longer-term data might be needed to confirm this. 

• How to prevent fractures?

It is important to identify patients who may be at risk of developing fractures. These include:

• elderly,
• post-menopausal women,
• patients on corticosteroids and other medicines that cause bone loss, especially men using anti-androgens,
• those with advanced kidney disease, and
• individuals with frequent falls.

It is best to add supplements and advocate weight-bearing exercises in all diabetic individuals and especially those who might be at an increased risk of developing fractures.

Individuals must increase their intake of dairy products. Calcium and vitamin D supplements may be added to the medication list.

Bisphosphonates such as alendronate and pamidronate may be given to individuals at high risk of fractures.

• Genital yeast infection is a common side effect of Dapagliflozin in women:

Dapagliflozin may increase the likelihood of genital mycotic illnesses. These include vaginal candidiasis and vulvovaginal candidiasis, balanitis, and balanoposthitis.

Vaginal and vulvovaginal candidiasis is genital yeast infections in women affecting the vagina or vulva of females.

Females may develop symptoms of whitish discharge and itching of the genitalia. Vaginal and vulval soreness may accompany these symptoms. Some women may notice pain during sexual intercourse.

Balanitis and balanoposthitis is the infection of the penis and glans. These infections are more common in uncircumcised men.

Men who develop these infections may notice itching, redness, swelling, dryness, and thickness of the skin of the penis.

• How to prevent yeast infections in men and women using dapagliflozin (Forxiga)?

All individuals who have frequent genital yeast infections should avoid taking dapagliflozin or any other SGLT2 inhibitor drugs.

It is important to ensure adequate hydration. Taking at least 8 glasses of water is helpful to keep the skin hydrated and enhance healing.

Use loose-fitting underwear and undergarments and change them frequently to maintain good hygiene.

Use food such as yogurt that maintains the body’s normal flora and prevents the growth of harmful organisms.

• Hypotension and Dehydration may develop with the use of SGLT2 Inhibitors:

Dapagliflozin may cause symptomatic hypotension due to intravascular volume depletion, especially in the following patients:

• Patients with renal impairment (ie, eGFR <60 mL/minute/1.73 m²),
• Elderly,
• Patients on other antihypertensives (eg, diuretics, angiotensin-converting enzyme [ACE] inhibitors, or angiotensin receptor blockers), or those with low systolic blood pressure, and
• Patients who develop vomiting or diarrhea

Patients at high risk for hypotension and volume depletion should be assessed and corrected if necessary.

Patients should be monitored for the symptoms of hypotension. These may include dizziness, vertigo, lightheadedness, and blackouts.

• How to treat hypotension?

If volume depletion and hypotension are observed, temporary withholding of dapagliflozin is advised and patients are asked to keep themselves hydrated.

Patients on concomitant medications that might cause dehydration should have their doses reduced when initiating treatment with dapagliflozin.

In severe cases and highly symptomatic individuals, intravenous fluid replacement may be necessary. These patients might also need hospitalization to prevent acute kidney injury as a result of volume depletion.

• Ketoacidosis is one of the severe side effects of dapagliflozin:

Some cases of ketoacidosis have been reported in patients suffering from type 1 or type 2 diabetes mellitus who have received sodium-glucose transporter 2 (SGLT2) inhibitors.

In some cases, patients presented with normal to modestly elevated blood glucose levels (250mg/dL).

Consider the risk factors that could lead to ketoacidosis before you start treatment. These include:

• Insulin-deficient individuals,
• Individuals who reduce their insulin dose or stop insulin
• Caloric restriction and starvation
• Excessive use of alcohol, and 
• Extreme stress events such as surgery or acute febrile illness.

Temporary discontinuation of therapy should be considered at least three days before surgery or any other event that could lead to ketoacidosis.

• How to diagnose and treat patients who develop ketoacidosis?

Patients must be advised to report to the doctor immediately if any of the following symptoms are observed:

• Nausea and vomiting,
• Pain in the abdomen,
• Generalized weakness and malaise, or
• Shortness of breath.

All patients who have the above symptoms should be evaluated for diabetic ketoacidosis regardless of their blood glucose levels.

The term “euglycemic ketoacidosis” is used here as these patients develop ketoacidosis despite normal blood glucose. Patients should have their ketones and blood gases checked to diagnose ketoacidosis.

Patients who develop euglycemic ketoacidosis need hospitalization. These patients need resuscitation with adequate fluids and electrolytes and intravenous insulin infusion with or without dextrose. In those with severe ketoacidosis, intravenous sodium bicarbonate may be administered.

• Lower limb amputation:

There are conflicting data regarding the risk of lower limb amputations when using SGLT2 inhibitor therapy.

Canagliflozin was found to have almost a 2-fold higher risk of lower limb amputations than placebo in the CANVAS and CANVAS-R trials [Ref].

These included patients with type 2 diabetes with high cardiovascular risk. Dapagliflozin has not been shown to increase the risk of lower limb amputation in trials [Ref].

This FDA guidance, which was specifically written for canagliflozin, may be applicable to other SGLT2 inhibitors as well.

Talk to patients about preventative foot care. Patients should also be asked to report any of these signs and symptoms:

• • Pain and tenderness of the bone,
  • Sores or ulcers in the lower limbs, and 
  • Foot or limb deformity.

• Necrotizing Fasciitis is a life-threatening side effect of Dapagliflozin:

Patients with diabetes mellitus who have received dapagliflozin have had cases of necrotizing fasciitis (Fournier Gangrene) of their perineum. This is a serious, but rare, and potentially fatal infection.

Necrotizing Fasciitis or Fournier’s gangrene is an infection of the perineum and genitals that spread via the tissue planes to the surrounding areas.

These patients are usually very toxic and have bloodstream infections as well. Patients are usually received in the emergency department with genital lesions with pus oozing out of the lesions and black necrotic patches.

The skin of the perineum and surrounding areas is red, swollen, and painful to the touch. Air under the skin may be felt when the patients develop gas gangrene. Patients may rapidly develop sepsis and hypotension.

• How to treat Necrotizing Fasciitis?

Patients with necrotizing fasciitis should be hospitalized and treated immediately.

All patients who develop necrotizing fasciitis are put on:

• Insulin,
• Intravenous fluids (+/- vasopressors if they have hypotension or septic shock),
• Broad-spectrum antibiotics especially those that cover anaerobic or gas-forming bacteria,
• Debridement of the wound, and
• Regular wound toilet.

Patients may require oxygen and care in the intensive unit for frequent monitoring of their blood pressure, hemodynamics, and kidney functions.

• Renal effects and AKI with Dapagliflozin Use:

Dapagliflozin and other SGLT2 inhibitors use may result in acute kidney injury. Patients with chronic kidney disease (eGFR 60mL/minute/1.73m ²) and those who use loop diuretics may be at greater risk of developing acute on chronic kidney disease.

Dapagliflozin is not directly toxic to the kidneys, however, volume depletion and hypotension can cause intravascular volume depletion and pre-renal acute kidney injury.

Other abnormalities in renal function, such as decreased eGFR or increased serum creatinine, may occur within weeks of treatment initiation. However, most cases resolve quickly.

• How to diagnose and treat AKI in patients on dapagliflozin?

Before treatment begins, assess the volume status and renal function. Ask the patients to report to their doctor if they develop any of the following symptoms:

• A reduced frequency of urination
• A reduced volume of urination
• Fatigue, listlessness, and shortness of breath
• Leg swelling or swelling around the eyes

All patients should have their drugs discontinued and volume replacement initiated with intravenous saline.

Patients should have urine volume, kidney functions, electrolytes, and blood gases frequently monitored.

Those patients who have severe acidosis, electrolyte derangements especially hyperkalemia, and uremia may require temporary hemodialysis.

• Urinary tract infections are common with Dapagliflozin:

Serious infections such as urosepsis or pyelonephritis that require hospitalization have been reported. Treatment with SGLT2 inhibits and increases the risk of urinary tract infections (UTIs).

In fact, urinary tract infections are the most frequently reported side effects of dapagliflozin.

Individuals who have frequent urinary tract infections especially females should have the risks and benefits of dapagliflozin therapy assessed before treatment initiation.

Other high-risk groups who may not tolerate dapagliflozin because of UTIs include:

• • Individuals with kidney stones
  • Those with anatomical defects of the urogenital tract
  • Patients with a past history of urinary tract infection
  • Patients with symptoms of urinary tract obstruction caused by an enlarged prostate
  • Patients who are immune-compromised such as those patients who are on corticosteroid therapy.

• How to identify and treat patients who develop UTI?

Patients should be asked to report if they develop the following symptoms:

• Increased frequency of urination and especially getting up at night to pass urine
• Urinary urgency or being unable to hold urine
• Urinary hesitancy is also described as being unable to urinate freely. Patients usually have the urge to urinate but when they try, they can not pass urine or pass urine in very small quantities.
• Difficulty in passing urine
• Dribbling of urine
• Pain or burning sensation while urinating
• Fever and fluctuating blood glucose levels

All patients are asked to stop the medicine if they develop the above symptoms. Adequate hydration is advised.

Urine alkalinizes and urinary analgesics are helpful to relieve the symptoms of UTI. Most patients require urinary antiseptics or antibiotics.

Other Side effects of Dapagliflozin:

Other uncommon side effects of dapagliflozin and other SGLT2 Inhibitors include visual changes such as blurred vision, cataract formation, and retinopathy. Most of these ocular side effects are due to fluid changes and blood glucose changes in the body.

Patients have also been observed to develop nasopharyngitis and back pain. Other drug-related side effects include nausea and vomiting.

Dyslipidemias and especially high LDL (low-density lipoproteins) may occur with dapagliflozin and other SGLT2 Inhibitors.

All patients should have a baseline lipid profile checked, be advised a low carbohydrate and low-fat diet, and may require a statin to lower their LDL levels.

A statin is usually advised to high-risk patients such as those with ischemic heart disease, Framingham Risk Score exceeding 10%, and Diabetic individuals with LDL exceeding the recommended levels (usually 100 mg/dl in diabetics and 70 mg/dl in patients with heart diseases).

Dapagliflozin does not cause hypoglycemia. However, when given insulin or another diabetes medicine such as sulfonylureas, it can result in hypoglycemia.

In Summary:

Side effects of Dapagliflozin include UTIs, Genital infections, Euglycemic Ketoacidosis, Hypovolemia and Hypotension, and Acute Kidney Injury.

Hypoglycemia occurs only if the patient is on concomitant Insulin or other medications for diabetes.