
Sodium-glucose cotransporter-2 (SGLT2) inhibitors (Gliflozins) in Adults with Type 2 Diabetes (T2DM)
The SGLT2 inhibitors canagliflozin, dapagliflozin and empagliflozin are licensed in the UK for adults with T2DM. No head to head trials between the SGLT2 inhibitors have been
conducted. The document summarises the key prescribing considerations.
NICE TA288: Dapagliflozin; TA336: Empagliflozin; TA315: Canagliflozin make recommendations for when SGLT2 inhibitors are options for combination treatment in T2DM:
 Dual therapy in patients with inadequate glycaemic control (HbA1c ≥ 48 mmol/mol [6.5%] or as agreed with the patient) with metformin when either the person does not tolerate
sulphonylurea or a sulphonylurea is contraindicated, or in the case of sulphonylureas, there is a significant risk of hypoglycaemia (as an alternative to pioglitazone or gliptins).
 Canagliflozin and empagliflozin are recommended as triple therapy added to first-line metformin and second-line sulphonylurea or metformin and a thiazolidinedione.
 NICE TA418: Dapagliflozin in triple therapy for treating T2DM
o Recommended as an option for triple therapy in adults, only in combination with metformin and a sulfonylurea.
o This guidance is not intended to affect the position of patients whose treatment with dapagliflozin in other triple therapy regimens was started within the NHS before this
guidance was published.
NICE TA390: Canagliflozin, dapagliflozin and empagliflozin as monotherapies for treating type 2 diabetes May 2016
 Recommended as an option for monotherapy when diet and exercise alone do not provide adequate glycaemic control; metformin, sulfonylureas and pioglitazone are unsuitable; and as
an alternative to DPP-4 inhibitors.
 Adults whose treatment with canagliflozin, dapagliflozin and empagliflozin as monotherapy is not recommended in this NICE guideline, but was started within the NHS before this
guidance was published, should be able to continue treatment until they and their NHS clinician consider it appropriate to stop.
Consider moving to the next level of treatment intensification if addition of SGLT2 inhibitor gives a reduction in HbA1c at 6 months <5.5 mmol/mol [0.5%] (as per NICE NG28, Type 2
Diabetes in Adults: Management, December 2015)
Drug Interactions
Canagliflozin
 Effect of diuretics may be increased. Increased risk of dehydration and hypotension.
 Hypoglycaemic effects of insulin and insulin secretagogues, such as sulphonylureas may be enhanced.
 Plasma digoxin concentrations may increase. No dose adjustment of digoxin is recommended but patients at risk should be monitored for digoxin toxicity.
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Enzyme inducers such as St. John's wort [Hypericum perforatum], rifampicin, barbiturates, phenytoin, carbamazepine, ritonavir and efavirenz may decrease canagliflozin
concentrations and may lead to decreased efficacy.
 Cholestyramine may decrease canagliflozin absorption. Administer canagliflozin 1 hour before or 4 hours after cholestyramine.
Dapagliflozin
 Effect of diuretics may be increased. Increased risk of dehydration and hypotension.
 Hypoglycaemic effects of insulin and insulin secretagogues, such as sulphonylureas may be enhanced.
Empagliflozin
 Effect of diuretics may be increased. Increased risk of dehydration and hypotension.
 Hypoglycaemic effects of insulin and insulin secretagogues, such as sulphonylureas may be enhanced.
Produced by Herts Valleys (HV) and East and North Hertfordshire (ENH) CCG Pharmacy and Medicines Optimisation Teams
This HMMC recommendation is based upon the evidence available at the time of publication. The
recommendation will be reviewed upon request in the light of new evidence becoming available.
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Co-medication with known inducers of UGT enzymes (such as St. John's wort [Hypericum perforatum], barbiturates, phenytoin, carbamazepine, ritonavir, efavirenz) should be
avoided due to a potential risk of decreased efficacy.
NB: This list is not exhaustive; please refer to BNF/SPC for further information http://www.medicines.org.uk/emc/
Produced by Herts Valleys (HV) and East and North Hertfordshire (ENH) CCG Pharmacy and Medicines Optimisation Teams
This HMMC recommendation is based upon the evidence available at the time of publication. The
recommendation will be reviewed upon request in the light of new evidence becoming available.
Comparative data for SGLT-2 inhibitors
28 day cost
for standard
daily doses
Dapagliflozin
Canagliflozin
Empagliflozin
10mg
daily****
£36.59
100mg daily
£36.59
(£39.20 for 30
tablet pack)
10mg daily
£36.59
28 day cost for
increased
daily doses
-
Monotherapy
License
√**
300mg daily*
£36.59
(£39.20 for 30
tablet pack)
25mg daily*
£36.59
√**
√**
NICE
√
√
√
With Insulin
(+/- MET)
License and
NICE
√
√
√
Dual therapy
Renal impairment (CrCl ml/min or eGFR
ml/min/1.73m2)
Triple therapy
Hepatic Impairment
License
√
√
√
NICE
√( with
MET)
√( with
MET)
√( with
MET)
License
√
(exclude
PIO)***
√
√
NICE
√( with
MET or
SU)
√ (with
MET &
SU or
PIO)
√(with
MET &
SU or
PIO)
Mild/moderate – 10mg
daily
Severe – start at 5mg daily,
titrate to 10mg if tolerated
Mild/moderate - No dose
adjustment
Severe – not recommended
Mild/moderate - No dose
adjustment
Severe – not recommended
>60 MILD
≥45 <60
MODERATE
<45 SEVERE
No dose
adjustme
nt needed
New patients Not
recommended.
Existing Patients
- discontinue.
New patients Not
recommended.
Existing Patients
- discontinue.
No dose
adjustme
nt needed
New patients –
Not
recommended
Existing patients
– Adjust/
maintain dose at
100mg daily.
New patients –
Not
recommended
Existing Patients
- discontinue.
No dose
adjustme
nt needed
New patients –
Not
recommended.
Existing patients
–
Adjust/maintain
dose at 10mg OD
New patients –
Not
recommended.
Existing Patients
- discontinue.
MET= metformin; SU= sulphonylurea; PIO=pioglitazone
*=where standard daily dose is tolerated and 'tighter glycaemic control is needed' and CrCl ≥ 60 ml/min
**=where MET is inappropriate.
***=not recommended for use in patients concomitantly treated with pioglitazone (precautionary measure as a result of concerns about bladder cancer rates for both drugs).
****=Dapagliflozin is not recommended in patients >75 years.
All of the SGLT2 inhibitors are available co-formulated with metformin at no additional cost.
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MHRA Drug Safety Update
MHRA Drug Safety update June 2015 reports that serious and life-threatening cases of diabetic ketoacidosis have been reported in patients taking SGLT-2 inhibitors. It advises to test for
raised ketones in patients with acidosis symptoms, even if plasma glucose levels are near-normal. https://www.gov.uk/drug-safety-update/sglt2-inhibitors-canagliflozin-dapagliflozinempagliflozin-risk-of-diabetic-ketoacidosis
MHRA Drug Safety update April 2016: SGLT-2 inhibitors: updated advice on the management of the risk of diabetic ketoacidosis. https://www.gov.uk/drug-safety-update/sglt2-inhibitorsupdated-advice-on-the-risk-of-diabetic-ketoacidosis
MHRA Drug Safety update June 2016: Canagliflozin (Invokana▼, Vokanamet▼): signal of increased risk of lower extremity amputations observed in trial in high cardiovascular risk
patients. https://www.gov.uk/drug-safety-update/canagliflozin-invokana-vokanamet-signal-of-increased-risk-of-lower-extremity-amputations-observed-in-trial-in-high-cardiovascular-riskpatients
Produced by Herts Valleys (HV) and East and North Hertfordshire (ENH) CCG Pharmacy and Medicines Optimisation Teams
This HMMC recommendation is based upon the evidence available at the time of publication. The
recommendation will be reviewed upon request in the light of new evidence becoming available.
EMPA-REG OUTCOME trial
The EMPA-REG OUTCOME trial showed that adding empagliflozin to standard care in people with T2DM and established CV disease reduced the risk of cardiovascular outcomes. This was
driven by a reduction in the risk of cardiovascular death, not MI or stroke. There is currently no cardiovascular safety outcome data for dapagliflozin and canagliflozin.
Produced by Herts Valleys (HV) and East and North Hertfordshire (ENH) CCG Pharmacy and Medicines Optimisation Teams
This HMMC recommendation is based upon the evidence available at the time of publication. The
recommendation will be reviewed upon request in the light of new evidence becoming available.