FORXIGA® (dapagliflozin)

FORXIGA® is a highly selective SGLT2 inhibitor for type 2 diabetes mellitus, with 4-year safety and efficacy data, that removes glucose and its associated calories via the kidney.1

FORXIGA®: Safety and tolerability

Results from an extensive clinical trial programme1

Overview of safety and tolerability

Adverse reactions in placebo-controlled clinical studiesa and postmarketing experience

Pre-specified pooled analysis of 13 placebo-controlled studies with 2,360 patients on FORXIGA® 10 mg and 2,295 patients on placebo.1

Adverse reactions in placebo-controlled studies[a1]
Adverse reactions in placebo-controlled studies[a1]

  • Reactions related to volume depletion were 1.1% with FORXIGA® 10 mg vs. 0.7% with control groups1‡
  • The frequency of hypoglycaemia depended on the type of background therapy used in each study1
  • For studies of dapagliflozin in monotherapy, as add-on to metformin or as add-on to sitagliptin (with or without metformin), the frequency of minor episodes of hypoglycaemia was similar (< 5%) between treatment groups, including placebo up to 102 weeks of treatment. Across all studies, major events of hypoglycaemia were uncommon and comparable between the groups treated with dapagliflozin or placebo. Studies with add-on sulphonylurea and add-on insulin therapies had higher rates of hypoglycaemia1
  • In an add-on to glimepiride study, at weeks 24 and 48, minor episodes of hypoglycaemia were reported more frequently in the group treated with FORXIGA® 10 mg plus glimepiride (6.0% and 7.9%, respectively) than in the placebo plus glimepiride group (2.1% and 2.1% respectively)1
  • In an add-on to insulin study, episodes of major hypoglycaemia were reported in 0.5% and 1.0% of subjects treated with dapagliflozin 10 mg plus insulin at Weeks 24 and 104, respectively, and in 0.5% of subjects treated with placebo plus insulin groups at Weeks 24 and 104. At Weeks 24 and 104, minor episodes of hypoglycaemia were reported, respectively, in 40.3% and 53.1% of subjects who received dapagliflozin 10 mg plus insulin and in 34.0% and 41.6% of the subjects who received placebo plus insulin.1
  • Reactions related to volume depletion (including, reports of dehydration, hypovolaemia or hypotension) were reported in 1.1% and 0.7% of subjects who received FORXIGA® 10 mg and placebo, respectively; serious reactions occurred in <0.2% of subjects balanced between FORXIGA® 10 mg and placebo.1

    a) The table shows up to 24-week (short-term) data regardless of glycaemic rescue.
    b) See corresponding subsection below for additional information.
    c) Vulvovaginitis, balanitis and related genital infections includes. e.g., the predefined preferred terms: vulvovaginal mycotic infection, vaginal infection, balanitis, genital infection fungal, vulvovaginal, candidiasis, vulvogainitis, balanitis, candida, genital candidiasis, genital infection, genital infection male, penile infection, vulvitis, vaginitis bacterial, vulval abscess.
    d) Urinary tract infection includes the following referred terms, listed in order of frequency reported: urinary tract infection, cystitis. Escherichia urinary tract infection, genitourinary tract infection, pyelonephritis, trigonitis, urethritis, kidney infection and prostatitis.
    e) Volume depletion includes e.g. the predefined preferred terms: dehydration, hypovolaemia, hypotension.
    f) Polyuria includes the preferred terms: pollakiuria, polyuria, urine output increased.
    g) Mean changes from baseline in haematocrit were 2.30% for FORXIGA®, 10 mg versus -0.33% for placebo. Haematocrit values >55% were reported in 1.3% of the subjects created with FORXIGA® 10 mg vs 0.4% of placebo subjects.
    h) Mean percent changes from baseline for dapagliflozin 10mg versus placebo, respectively was: total cholesterol 2,5% versus 0.0%; HDL cholesterol 6.0% versus 2.7%; LDL cholesterol 2.9% versus -1.0%; triglycerides 2.7% versus -0.7%.
    j) Adverse reaction was identified through postmarketing surveillance. Rash includes the following preferred terms, listed in order of frequency in clinical trials: rash, rash generalised, rash pruritic, rash macular, rash maculo-papular, rash pustular, rash vesicular, and rash erythematous. In active- and placebo-controlled clinical trials (dapagliflozin, N=5936, All control, N=3403), the frequency of rash was similar for dapagliflozin (1.4%) and all control (1.4%), respectively.

    *Reported in ≥2% of subjects and ≥1% more and at least 3 more subjects treated with FORXIGA® 10 mg compared to placebo.
    **Reported by the investigator as possibly related, probably related or related to study treatment and reported in ≥0.2% of subjects and ≥0.1% more and at least 3 more subjects treated with FORXIGA® 10 mg compared to placebo.

    Urinary tract infections (UTIs) and genital infections (GIs)

    Type 2 diabetes is associated with an increased incidence/prevalence of Gls and UTIs.37-41
    FORXIGA® works by eliminating glucose through the kidneys and is therefore associated with a higher incidence of Gls and UTls compared to placebo.1* Where they occurred, most Gls and UTls were mild to moderate, rarely led to discontinuation and generally responded with a single course of standard treatment.1

    FORXIGA® 10 mg: percentage of UTIs and GIs vs. placebo

    FORXIGA® 10 mg: percentage of UTIs and GIs vs. placebo
    FORXIGA® 10 mg: percentage of UTIs and GIs vs. placebo

    Renal function

    Renal function remained stable (estimated by eGFR) with FORXIGA® up to 2 years versus placebo.41†
    FORXIGA® is not recommended for use in patients with moderate to severe renal impairment (patients with creatinine clearance [CrCI] < 60 ml/min or estimated glomerular filtration rate [eGFR] < 60 ml/min/ 1.73m2).1

    * Genital infections includes, e.g. the predefined preferred terms: vulvovaginal mycotic infection, vaginal infection, balanitis, genital infection fungal, vulvovaginal candidiasis, vulvovaginitis, balanitis candida, genital candidiasis, genital infection, genital infection male, penile infection, vulvitis, vaginitis bacterial, vulval abscess.1
     Small initial decrease in mean baseline eGFR by week 1, followed by a gradual return to baseline.41

    Hypoglycaemia

    FORXIGA® demonstrated a lower incidence of hypoglycaemia vs. a sulphonylurea when added to metformin42

    FORXIGA® demonstrated a lower incidence of hypoglycaemia vs. a sulphonylurea when added to metformin[2]
    FORXIGA® demonstrated a lower incidence of hypoglycaemia vs. a sulphonylurea when added to metformin[2]

    *Major hypoglycaemia was defined as a symptomatic episode requiring external assistance due to severely impaired consciousness or behaviour, with capillary or plasma glucose levels of 54 mg/dl (3.0 mmol/L) and recovery after glucose or glucagon administration.42

    • Minor hypoglycaemia was defined as a symptomatic episode with capillary or plasma glucose levels of 63 mg/dl (3.5 mmol/L), irrespective of the need for external assistance, or an asymptomatic episode with capillary or plasma glucose levels of 63 mg/dL (3.5 mmol/L) that did not qualify as a major episode
    • Other hypoglycaemia was defined as an episode with symptoms suggestive of hypoglycaemia but without measurement confirmation.

    The frequency of hypoglycaemia depended on the type of background therapy used in each study.1

    • For studies of FORXIGA® in monotherapy, as add-on to metformin or as add-on to sitagliptin (with or without metformin), the frequency of minor episodes of hypoglycaemia was similar (<5%) between treatment groups, including placebo up to 102 weeks of treatment. Across all studies, major events of hypoglycaemia were uncommon and comparable between the groups treated with dapagliflozin or placebo. Studies with add-on sulphonylurea and add-on insulin therapies had higher rates of hypoglycaemia
    • In an add-on to glimepiride study, minor episodes of hypoglycaemia were reported more frequently in the group-treated with FORXIGA® 10 mg plus glimepiride (6.0%) than in the placebo plus glimepiride group (2.1%)
    • In an add-on to insulin study, minor episodes were reported more frequently in the group treated with FORXIGA® 10 mg plus insulin (40.3%) than in the placebo plus insulin group (34.0%)
    • In an add-on to metformin and a sulphonylurea study, up to 24 weeks, no episodes of major hypoglycaemia were reported. Minor episodes of hypoglycaemia were reported in 12.8% of subjects who received dapagliflozin 10 mg plus metformin and a sulphonylurea and in 3.7% of subjects who received placebo plus metformin and a sulphonylurea.

    Reactions related to volume depletion (including, reports of dehydration, hypovolaemia or hypotension) were reported in 1.1% and 0.7% of subjects who received dapagliflozin 10 mg and placebo, respectively; serious reactions occurred in <0.2% of subjects balanced between FORXIGA® 10 mg and placebo.1

    In a study comparing FORXIGA® + metformin vs. sulphonylurea + metformin, the FORXIGA® arm showed a significantly reduced incidence of hypoglycaemia compared to glipizide (3.5% vs. 40.8%, p < 0.0001) at 52 weeks.42
    There were no major hypoglycaemic events on the FORXIGA® + metformin arm, compared to 3 episodes on the sulphonylurea + metformin arm.42

    No increased risk of CV events with FORXIGA®43-45

    In a meta-analysis of 21 Phase IIb/III studies, of 9,339 patients with a varying degree of CV risk and duration of T2D, FORXIGA® demonstrated:43-45*

    • No increased risk of CV events in the first 30 days following treatment initiation.43
    • Consistent CV safety profile in patients with established CVD.44
    • No increased risk of CV death or hospitalisation for heart failure (HR=0.70; 95% CI, 0.36 to 1.36 and HR=0.36; 95% CI, 0.16 to 0.84, respectively).43,45

    A randomised trial to evaluate the effect of FORXIGA® on the incidence of cardiovascular events (DECLARE) is ongoing.46

    eGFR mean change from baseline during treatment with FORXIGA
    eGFR mean change from baseline during treatment with FORXIGA

    *FORXIGA® is not indicated to reduce the risk of cardiovascular events.1

    MACE, its components and additional CV events in patients with a history of CVD44*

    A meta-analysis of 21 Phase IIb/III studies in which 34.4% of subjects had a history of CVD (excluding hypertension) at baseline and 67.9% had hypertension.44 Studies that did not have at least one positively adjudicated event were excluded from analysis.45

    MACE, its components and additional CV events in patients with a history of CVD
    MACE, its components and additional CV events in patients with a history of CVD

    *FORXIGA® is not indicated to reduce the risk of cardiovascular events.1