Forxiga: first in new class of diabetes treatments

The SGLT2 inhibitor dapagliflozin (Forxiga) has been licensed for the treatment of type II diabetes.

Forxiga is a once-daily oral tablet that can be taken at any time of day with or without food.
Forxiga is a once-daily oral tablet that can be taken at any time of day with or without food.

It is indicated for use in adults: as monotherapy, when diet and exercise do not provide adequate glycaemic control, and metformin is inappropriate owing to intolerance; and in combination with other glucose-lowering agents including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control

PHARMACOLOGY

Dapagliflozin inhibits sodium-glucose co-transporter 2 (SGLT2), the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. By reducing renal glucose reabsorption and increasing urinary glucose excretion, dapagliflozin improves both fasting and post-prandial plasma glucose levels independent of insulin secretion. The glucuretic effect is continuous over the 24 hour dosing interval and is sustained for the duration of treatment.1

CLINICAL STUDIES

Better than placebo over 24 weeks      

A 24-week placebo-controlled study examined the effects of dapagliflozin in adults with inadequate glycaemic control (HbA1c 7–10% [53–86mmol/mol]) despite metformin treatment. Participants were randomised to receive dapagliflozin 2.5mg, 5mg or 10mg or placebo once daily, added on to metformin. Over 24 weeks, mean HbA1c declined by 0.84% (9mmol/mol) in patients receiving dapagliflozin 10mg (n=132), compared with 0.30% (3mmol/mol) in those on placebo (n=134; p<0.0001). In the subset of patients with baseline HbA1c of 9% (75mmol/mol) or greater, levels decreased by 1.32% (14mmol/mol) with dapagliflozin 10mg (n=18) versus 0.53% (6mmol/mol) with placebo (n=22).2

Events suggestive of genital infection were more common with dapagliflozin than with placebo (8–13% vs 5%) and affected both men and women. Hypoglycaemia was generally mild and occurred at comparable rates in the dapagliflozin and placebo groups (2–4% vs 3%).2

Non-inferior to glipizide

In a 52-week active-controlled non-inferiority study, dapagliflozin was compared to glipizide as add-on therapy in 814 adults with inadequate glycaemic control (HbA1c 6.6–10% [49–86mmol/mol]) on metformin. Doses were titrated up to a maximum of 10mg dapagliflozin and 20mg glipizide daily over 18 weeks. HbA1c declined by a mean of 0.52% (6mmol/mol) in both groups over 52 weeks, indicating the non-inferiority of dapagliflozin to glipizide. Patients receiving dapagliflozin lost a mean of 3.2kg body weight, whereas those given glipizide gained a mean of 1.4kg (p<0.0001). Hypoglycaemia occurred at a more than 10-fold lower rate in the dapagliflozin group than the glipizide group (3.4% vs 39.7%), but symptoms of genital and urinary tract infection were more common with dapagliflozin than glipizide (12.3% vs 2.7% and 10.8% vs 6.4%, respectively).3

Results from a 52-week extension of this study showed a sustained effect of dapagliflozin on glycaemic control at 104 weeks compared with baseline. The initial weight reduction seen with dapagliflozin was sustained and the weight gain with glipizide persisted at 104 weeks.4

Reductions in BP observed

A pre-specified pooled analysis of 12 placebo-controlled studies found that treatment with dapagliflozin 10mg daily for 24 weeks produced reductions in systolic and diastolic blood pressure of –4.4mmHg and –2.1mmHg, respectively, compared with –0.9mmHg and –0.5mmHg, respectively, with placebo.1

Monitor renal function

In patients taking dapagliflozin, monitoring of renal function is recommended before starting treatment and at least yearly thereafter; before starting concomitant treatment with agents that might reduce renal function, and periodically thereafter; and at least two to four times per year in patients with renal function approaching moderate impairment. If renal function falls below CrCl 60ml/min or eGFR 60ml/min/1.73m2, dapagliflozin should be discontinued.1

References

  1. Forxiga Summary of Product Characteristics, November 2012.
  2. Bailey CJ et al. Lancet 2010; 375: 2223–33.
  3. Nauck M et al. Diabetes Care 2011; 34: 2015–22.
  4. Nauck M et al. Poster presented at 71st Scientific Sessions of the American Diabetes Association. San Diego, USA, June 2011; 40-LB.

View Forxiga drug record

Further information: BMS/AstraZeneca

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