Dapagliflozin (Forxiga, Dapa, Dapaglu) is an SGLT2 inhibitor that inhibits the reabsorption of glucose and sodium in the proximal tubules. Other medicines in this group include empagliflozin and canagliflozin. It is used as an adjunct to diet and exercise for glycemic control in adults with type 2 diabetes mellitus.

Dapagliflozin and metformin:

It has also been studied in prediabetic patients. Compared to metformin, only dapagliflozin and exercise reduced post-prandial glucose levels. However, all three interventions reduced HbA1C and fasting blood glucose [Ref]. Dapagliflozin in combination with metformin XR (extended-release) was reviewed. The fixed-dose combination of Dapa and metformin XR improved medication adherence, drug-compliance, and glycemic control [Ref].

Triple Combination regimens - Dapagliflozin with saxagliptin and metformin:

Triple combination regimen that consisted of dapagliflozin, Saxagliptin, and metformin was given to patients who did not achieve their glycemic targets with Dapa and metformin. The triple regimen significantly reduced the HbA1C without additional adverse events or weight gain [Ref]. Currently, only one triple regimen (TRIJARDY XR) containing empagliflozin, linagliptin, and metformin XR has been approved by the FDA and recently marketed in the US.

Does Dapagliflozin cause weight loss?

Yes. Dapagliflozin, like other SGLT2 inhibitors and GLP-1 analogs, can cause significant weight loss. A case report of a 140.8 kg man with a BMI of 40.3 kg/m2 who lost 33 kgs with dapagliflozin highlights the significant role of the drug in the context of Diabesity [Ref]. It has also been studied and proved to have a greater weight loss potential (along with a greater reduction in the systolic blood pressure and triglyceride levels) when given in combination with the GLP-1 analogs [Ref]

Dapagliflozin in Type 1 Diabetic patients:

Recently, European agencies have also approved it in patients with type 1 diabetes mellitus. The following group of patients with type 1 diabetes mellitus may be advised dapagliflozin as per the manufacturer under supervision:

• Patients with inadequate diabetes control despite optimal insulin therapy
• Body mass index of 27 kg/m² or more
• Insulin requirement is more than 0.5 units/kg of body weight
• Patients have completed a structured education program that encompasses the following important points:
  1. Risk factors, signs and symptoms, and when to suspect diabetic ketoacidosis.
  2. How and when to monitor blood ketone levels
  3. What to do if the ketone levels are high

Dapagliflozin benefits in patients with heart failure and a reduced Ejection Fraction:

The DECLARE–TIMI 58 was a very large trial that assessed the cardiovascular outcomes of dapagliflozin in about 17,000 patients. The key findings of the trial were [Ref]:

• Dapagliflozin was non-inferior to placebo in patients with Diabetes Type 2 with respect to the composite safety outcome of Major adverse Cardiovascular events (MACE) (cardiovascular death, myocardial infarction, or ischemic stroke), but it did not result in a significantly lower rate of MACE than placebo.
• Compared to placebo, there was a greater reduction in the number of cardiovascular deaths and hospitalization for heart failure (regardless of a history of heart failure or atherosclerotic cardiovascular disease.
• The risks of amputations, strokes, and fractures were not significantly increased.
• The rates of genital infections and diabetic ketoacidosis were higher, however, the incidence of Fournier's gangrene and bladder cancer was not significant.
• Compared to the EMPAREG trial, the mortality rates were lower with dapagliflozin.

Another recently conducted trial concluded that dapagliflozin reduced hospitalization due to heart failure in Type 2 diabetic patients with a high cardiovascular risk profile regardless of the Ejection Fraction. However, a greater benefit was seen in patients with a reduced EF [Ref].

Dapagliflozin Dose in Adults

Dapagliflozin dose in the treatment of type 2 Diabetes mellitus:

• 5 mg orally once a day.
• The dose may be increased to 10 mg once a day.

Dose in children:

Safety and efficacy not established. Recently, the European Commission has approved its use in a subgroup of type 1 diabetes patients.

Dapagliflozin Pregnancy risk factor C

• Although data regarding the use of SGLT2 inhibitors during pregnancy are limited, animal studies have shown adverse effects on the development of the kidneys in response to SGLT2 inhibitions in the second or third trimester.
• Negative fetal outcomes can also be associated with maternal hyperglycemia.
• Pregnancy should not be interrupted by any medication other than SGLT2 inhibitors.

Use while breastfeeding

• Breastfeeding may be affected by SGLT2 inhibitors.
• It can also cause a decrease in breast milk.

Dapagliflozin Dose in Kidney Disease:

• eGFR of 45 mL/minute/1.73 m² or more :

  • Adjustment in the dose is not necessary.

• eGFR 30 to 45 mL/minute/1.73 m² :

  • Recommendations regarding its use are different in different regions. Most suggest its use with caution, while some experts advised avoiding its use.

• eGFR  of less than 30 mL/minute/1.73 m² :

  • Use is contraindicated.

• ESRD:

  • Use is contraindicated.

• Hemodialysis:

  • Use is contraindicated.

Dapagliflozin Dose in Liver disease:

• It is not necessary to adjust the dose.
• It is not recommended for severe hepatic impairment patients.

Side Effects of Dapagliflozin (Forxiga) Include:

• Endocrine & Metabolic:

  • Dyslipidemia
  • Hyperphosphatemia
  • Hypovolemia

• Gastrointestinal:

  • Nausea

• Genitourinary:

  • Urinary Tract Infection
  • Increased Urine Output
  • Dysuria

• Hematologic & Oncologic:

  • Increased Hematocrit

• Infection:

  • Genitourinary Fungal Infection
  • Influenza

• Neuromuscular & Skeletal:

  • Back Pain
  • Limb Pain

• Renal:

  • Renal Insufficiency

• Respiratory:

  • Nasopharyngitis

Dapagliflozin Side effects (Less common):

• Hypersensitivity:

  • Angioedema
  • Hypersensitivity reaction

• Neuromuscular & skeletal:

  • Bone fracture

• Renal:

  • Decreased estimated GFR
  • Increased serum creatinine

 Dapagliflozin (Forxiga) Contraindication:

• Severe allergic reactions to dapagliflozin and any component of this formulation
• End-stage renal disease or severe renal impairment (eGFR less than 30mL/minute/1.73m2 ), patients on dialysis, or end-stage renal disease.

Forxiga Warnings and Precautions

• Bone fractures

  • SGLT2 inhibitors, particularly canagliflozin, have been linked to an increase in bone fractures, especially among patients with moderate renal impairment (CrCl between 30 and 60 ml/min/1.73 m2).
  • This association was not confirmed by other randomized trials.

• Infections of the genital tract

  • SGLT2 inhibitors can increase the risk of genital infections such as vulvovaginal mycotic infection, vulvovaginitis and vulvovaginal candidiasis.
  • Patients with a history genital infection and uncircumcised males are at higher risk.

• Hypersensitivity reactions

  • Some patients may develop severe allergic reactions such as angioedema or urticaria.
  • If the patient has an allergy to the drug, treatment should be stopped immediately.

• Hypotension

  • It can cause sodium and glucose loss in urine which may lead to hypotension.
  • Patients with renal impairment, elderly patients, and those on antihypertensives such as diuretics or angiotensin receptor blocking drugs are at greater risk for developing hypotension.

• Ketoacidosis

  • It has been reported that ketoacidosis can occur with moderately high blood sugars. This is why the term euglycemic Ketoacidosis was used.
  • There are several patients at high risk for developing euglycemic Ketoacidosis.
    • Insulin deficient patients
    • Patients who stop taking insulin
    • Alcohol
    • Strenuous exercise or hard work
    • Recent stroke, myocardial Infarction, Surgery, Severe Infection
    • Caloric restriction
  • The ADA recommends that SGLT2 inhibitors be withheld for at least 24 hours before events that could lead to ketoacidosis. Experts recommend that SGLT2 inhibitors be withheld for at most 3 - 5 working days.
  • If patients taking dapagliflozin experience nausea, abdominal pain, malaise or shortness in breath, they should be evaluated for ketoacidosis. This can be done by testing urine/ serum ketones, and arterial blood gasses.

• Lipid abnormality

  • Dapagliflozin can cause an increase in LDL-cholesterol (C).
  • It should be monitored and treated accordingly.

• Necrotizing fasciitis

  • SGLT2 inhibitors have been linked to an increase in necrotizing fasciitis (Fournier gangrene)
  • This is a potentially life-threatening infection that has been reported in patients who have received dapagliflozin.
  • Fournier's Gangrene should be treated immediately if patients develop fever, redness and swelling in the perineum.
  • Dapagliflozin should be stopped immediately and the appropriate treatment started.

• Effects on the renal system:

  • Acute kidney injury is possible in patients.
  • Hypovolemia, chronic renal failure, heart disease, and use of nephrotoxic drugs or agents that can cause dehydration are all risk factors for acute kidney damage.
  • Patients with low volume should temporarily stop taking dapagliflozin.
  • It is important to monitor the function of the renal system regularly.

• Infection of the urinary tract:

  • It has been associated with serious urinary infections, including urosepsis and pyelonephritis. These may need hospitalization.
  • If UTI symptoms develop, patients should be immediately assessed and treated.

• Bladder cancer

  • Patients suffering from active bladder cancer should not use it.
  • It is believed that bladder cancer incidences will rise with the increasing use of this drug.

• Hepatic impairment

  • It should not be used in severe hepatic impairment.

• Renal impairment

  • Examining the renal functioning is crucial before utilising them.
  • The glycemic efficacy of patients with compromised renal function may be decreased.

Dapagliflozin: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Risk Factor: C

Monitor:

• Blood glucose
• Glycated hemoglobin is twice a year in patients who have stable glycemic control, and once a quarter in patients who do not meet the glycemic goals.
• Baseline renal functions and periodically thereafter
• LDL-C
• Monitor for genital and urinary tract infections
• Allergy reactions
• Hydration and volume status
• You should monitor for signs and symptoms of ketoacidosis such as nausea, vomiting, malaise and shortness or breath. If clinical signs are present, test blood ketones and arterial pH.

How to take Dapagliflozin (Forxiga)?

• It should be administered orally in the morning with or without food.

 Dapagliflozin (Forxiga) Mechanism of action:

• It inhibits sodium-glucose transporter 2 (SGLT2) within the proximal renal tubes. 
• It also inhibits glucose reabsorption from the kidneys.
• Osmotic diuresis results when excess glucose is eliminated via the kidneys.
• This effect could be beneficial for hypertensive patients, those suffering from cardiac disease, or fluid overload.
• It can also lead to recurrent infections of the urinary tract, volume depletion, or dehydration.

91% of the drug's total is Protein-bound

It is Metabolized mainly by UGT1A9 to inactive metabolites. 

It is bioavailable at 78%, with a half-life of approximately 12.9 hours.

Time to get there Peak plasma concentration: It takes approximately 2 hours.

Excreted: 75% of the drug is excreted in the urine. 21% is excreted through feces.

Dapagliflozin Brand Names International:

• Daflozin
• Dapaglip
• Daparol
• Dapazin
• Diglifloz
• Edistride
• Forxiga
• Sabaglifozin
• Zegapets

Dapagliflozin Brand Names in Pakistan:

Dapa 5 and 10 mg ( Hilton Pharmaceuticals) Xiga 5 and 10 mg (CCL) Dapaglu (scotmann) Daploz (Highnoon)