For treatment of type 2 diabetes Commissioning guidance:
Commissioners may wish to bear the following in mind when considering the commissioning of dapagliflozin:
Its place in the local care pathway should be defined by local Drug & Therapeutics or Area Prescribing
In the absence of such local guidance, it is the opinion of the committee that dapagliflozin may be suitable as
a third-line agent following treatment with a DPP-4 inhibitor (gliptin’).
It has potential as an alternative treatment in patients with type 2 diabetes who are obese. Current draft NICE guidance on dapagliflozin does not recommend its use because the appraisal committee
require further information from the manufacturer regarding the efficacy and cost-effectiveness of the treatment.
Prescribing guidance: Category B (Q3) Expected BNF: 6.1.2
Dapagliflozin should be initiated by a practitioner with a special interest in diabetes. Following initiation, it is suitable for prescribing in primary care.
Category B: suitable for restricted prescribing under defined conditions Q3 rating: The evidence for the efficacy of dapagliflozin was considered to
be relatively strong. In seven RCTs, it was shown to be more effective at
decreasing glycosylated haemoglobin (HbA1c) levels than placebo as
monotherapy, and as add-on therapy to metformin, glimepiride, pioglitazone and insulin. As add-on therapy to metformin it was non-inferior to a
combination of metformin and glipizide. There is however, no longer-term
outcome data for this treatment. The place in therapy of dapagliflozin has not yet been established.
The Q rating relates to the drug’s position on the effectiveness indicator grid. Strength of evidence for efficacy The strength of the evidence is determined by the quality and quantity of studies that show significant efficacy of the drug compared with placebo or alternative therapy. Its place in therapy in primary care takes into account safety and practical aspects of using the drug in primary care, alternative options, relevant NICE guidance, and the need for secondary care input.Description of technology
diabetes mellitus (~90%) have type 2 diabetes,1
Dapagliflozin is the first in a new class of oral
which is associated with serious long-term
antidiabetic agents that selectively inhibit the human
microvascular and macrovascular complications.
renal sodium glucose co-transporter type 2 (SGLT2),
Patients with type 2 diabetes are two to five times
the major transporter responsible for renal glucose re-
more likely to suffer cardiovascular morbidity.2
absorption. Dapagliflozin lowers plasma glucose by
Dietary and lifestyle modifications form the mainstays
inhibiting the renal re-absorption of glucose in the
of therapy for type 2 diabetes, but 50 to 70% of
proximal tubule, thereby promoting its urinary
patients will also require an antidiabetic drug. Drug
excretion. It is licensed for use in adults aged 18
treatments currently available include sulphonylureas,
years and older with type 2 diabetes mellitus to
metformin, pioglitazone, acarbose, repaglinide,
nateglinide, DPP-4 inhibitors (“gliptins”), exenatide,
monotherapy when diet and exercise alone do not
provide adequate glycaemic control in patients for
Clinical evidence for efficacy and safety
whom metformin is considered inappropriate due to
Eight fully published multicentre, phase III RCTs (n =
4,657) assessed the efficacy and safety of oral
add-on therapy in combination with other glucose-
dapagliflozin 2.5 mg, 5 mg, or 10 mg once daily as
lowering medicinal products including insulin, when
monotherapy (1 trial), or as part of a dual or triple
these, together with diet and exercise, do not
therapy regimen in patients with type 2 diabetes
whose glycosylated haemoglobin levels (HbA1c) were
not well controlled with current therapy (7 trials). Seven trials used a placebo comparator; the eighth
Diabetes mellitus is a common chronic disease,
trial was an active comparator trial.3-8
associated with markedly increased morbidity and mortality. The majority of people in the UK with
The primary outcome in all the trials was the change
February 2013 Page 1 of 2
in HbA1c from baseline to the end of the study.
mg for dapagliflozin-treated patients or 20 mg for
Secondary outcomes included the proportion of
patients achieving a therapeutic response (HbA1c < 53
Results of the trial showed that the combination of
mmol/mol [7%]) and the change from baseline in
metformin plus dapagliflozin was non-inferior to
fasting plasma glucose levels (FPG) and bodyweight.
metformin plus glipizide. There was also no significant
In thedapagliflozin as monotherapy trial,3
difference in the proportion of patients that showed a
dapagliflozin at doses of 5 mg and 10 mg daily
response to treatment (HbA1c < 53 mmol/mol [7%]).
lowered HbA1c levels significantly more than placebo
Significantly more metformin plus glipizide-treated
after 24 weeks’ treatment (placebo-subtracted
patients had at least one hypoglycaemic episode
decreases of 5.9 and 7.3 mmol/mol [0.54% and
compared with metformin plus dapagliflozin-treated
0.66%] respectively from baseline, p < 0.001).3 FPG
patients (40.8% vs. 3.5%, p < 0.0001).
levels were also significantly lowered in the
dapagliflozin 5 mg and 10 mg groups compared with placebo (p < 0.001). There was no significant
In the trials reviewed, the most commonly reported
difference between the dapagliflozin 2.5 mg dose
events leading to discontinuation in patients treated
group and placebo for those outcomes. Mean
with dapagliflozin 10 mg were increased blood
bodyweight decreased in all patients during the trial
creatinine (0.4%), urinary tract infections (0.3%),
with no significant difference between dapagliflozin
nausea (0.2%), dizziness (0.2%), and rash (0.2%).
Considerations for cost impact
As dual or triple therapy, dapagliflozin 5 mg or 10
mg dailywas evaluated in combination with metformin
According to QOF 2011/12 data,10 the estimated
extended-release (XR) formulation in 2 trials (1,236
number of patients with diabetes mellitus in the West
treatment-naïve patients, duration 24 weeks)5; and at
Midlands is 298,514. About 90% of these will have
doses of 2.5 mg to 10 mg in combination with
type 2 diabetes,11 equating to a total of 268,663
standard metformin in a further trial involving 534
patients over 24 weeks.4 Dapagliflozin was also
At current prices, a year’s treatment with
evaluated: as dual therapy with pioglitazone or
glimepiride,6,7 compared with pioglitazone or
glimepiride plus placebo; and as dual or triple therapy
1. Stumvoll MGBJ, van Haeften TW. Type 2 diabetes: principles
with insulin ± oral antidiabetic drugs (OADs)
of pathogenesis and therapy. Lancet 2005;365:1333-1346.
compared with placebo plus insulin ± oral antidiabetic
2. Nathan DM. Initial management of glycemia in type 2 diabetes
mellitus. N Engl J Med 2002;347:1342-1349. et al. Dapagliflozin monotherapy in type 2 diabetic
In all six trials after 24 weeks’ treatment (or 52
patients with inadequate glycemic control by diet and exercise:
weeks in one trial8), the combination treatment
a randomized, double-blind, placebo-controlled, phase 3 trial.
Diabetes Care 2010;33:2217-2224. et al. Effect of dapagliflozin in patients with type 2
baseline than placebo plus individual components.
diabetes who have inadequate glycaemic control with
Placebo-subtracted mean decreases in HbA1c for the
metformin: a randomised, double-blind, placebo-controlled trial.
groups receiving dual or triple therapy were in the
range 4.4 to 9.5 mmol/mol [0.4 to 0.86%] in these
et al. Dapagliflozin, metformin XR, or both: initial
pharmacotherapy for type 2 diabetes, a randomised controlled
trial. Int J Clin Pract 2012;66:446-456.
Across the trials, results were similar for fasting
et al. Effect of dapagliflozin in patients with type 2
plasma glucose decreases compared with placebo.
diabetes who have inadequate glycaemic control with
Bodyweight decreases were in the range 2 to 3 kg
glimepiride: a randomized, 24-week, double-blind, placebo- controlled trial. Diabetes Obes Metab 2011;13:928-938.
for dapagliflozin plus metformin-treated patients and
et al. Effects of dapagliflozin, an SGLT2 inhibitor,
0.9 to 2 kg for dapagliflozin plus glimepiride-treated
on HbA(1c), body weight, and hypoglycemia risk in patients with
patients, or dapagliflozin plus insulin. In combination
type 2 diabetes inadequately controlled on pioglitazone
with pioglitazone, only patients in the dapagliflozin
monotherapy. Diabetes Care 2012;35:1473-1478. et al. Long-term efficacy of dapagliflozin in patients
10 mg-treated group showed a mean decrease in
with type 2 diabetes mellitus receiving high doses of insulin: a
bodyweight of 0.14 kg. Patients treated with
randomized trial. Ann Intern Med 2012;156:405-415.
dapagliflozin 5 mg or placebo plus pioglitazone
et al. Dapagliflozin versus glipizide as add-on
showed a mean weight gain over the trial of 0.09 to
therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week,
double-blind, active-controlled noninferiority trial. Diabetes Care 2011;34:2015-2022.
In the only active comparator trial,9 a combination of
10. Quality and Outcomes Framework - 2011-12. NHS Information
dapagliflozin plus metformin was compared with
Centre. 2012. http://www.ic.nhs.uk/catalogue/PUB08135
glipizide plus metformin in 801 patients over 52
11. Diabetes in the UK 2010: Key statistics on diabetes. Diabetes
weeks. In that trial, doses were titrated to target FPG
UK. 2010. http://www.diabetes.org.uk/ Documents/Reports/Diabetes_in_the_UK_2010.pdf
levels over the initial 18 weeks to a maximum of 10
Manufacturer: Bristol Myers Squibb-AstraZeneca EEIG Ltd WARNING: This sheet should be read in conjunction with the Summary of Product Characteristics This guidance is based upon the published information available in English at the time the drug was considered. It remains open to review in the event of significant new evidence emerging. NICE GUIDANCE ON DAPAGLIFLOZIN WAS NOT AVAILABLE AT TIME OF PUBLICATION OF THIS GUIDANCE School of Pharmacy, Keele University, Keele, Staffordshire ST5 5BG Tel: 01782 734131 Email: [email protected] Web: www.mtrac.co.uk Midlands Therapeutics Review & Advisory Committee Date: February 2013
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