Amber with Guidance= To be initiated and titrated to a stable dose in secondary care with follow up prescribing and monitoring by primary care where deemed appropriate.
The use of SGLT2 inhibitors in the treatment of type 2 diabetes
· Empagliflozin (Jardiance®), Empagliflozin/Metformin (Synjardy® 5mg/850mg, 5mg/1000mg, 12.5mg/850mg, 12.5mg/1000mg)
· Dapagliflozin (Forxiga®), Dapagliflozin/Metformin (Xigduo® 5mg/850mg, 5mg/1000mg)
· Canagliflozin (Invokana®) and Canagliflozin/Metformin (Vokanamet® 50mg/85mg, 50mg/1000mg)
Please see the full Summary of Product Characteristics for more information.
http://www.medicines.org.uk/emc/
Background Information / NICE have approved the following SGLT2 inhibitors for the treatment of type 2 diabetes.· Empagliflozin in combination therapy for treating type 2 diabetes. TA336. March 2015
· Dapagliflozin in combination therapy for treating type 2 diabetes. TA288. June 2013
· Canagliflozin in combination therapy for treating type 2 diabetes. TA315. June 2015
Although all three SGLT2 inhibitors have been given positive NICE technology appraisals, only empagliflozin has evidence to show positive cardiovascular outcomes. This may be a class effect of the drugs, however, it seems reasonable to suggest that empagliflozin should be used in preference to other SGLT2 inhibitors until further research is published. See trial summary below:
Empagliflozin and cardiovascular outcomes
The randomised controlled trial (n=7020) found that patients at high risk of CV events who were taking empagliflozin in addition to standard care, compared with placebo plus standard care, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care.
The study took place over a median time of 3.1 years. In patients taking empagliflozin there was a:
· 38% relative risk reduction in death from cardiovascular causes
· 35% relative risk reduction in hospitalisation for heart failure
· 32% relative risk reduction in death from any cause
· No significant differences between the groups for MI or stroke
Zinman B, Wanner C, Lachin J et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. EMPA-REG OUTCOME study. New England Journal of Medicine 17th September 2015. Available at: http://www.nejm.org/doi/pdf/10.1056/NEJMoa1504720 Accessed <30.9.15>
BNF therapeutic class / 6.1.2.3 Other antidiabetic drugs
Licensed Indication (Please note this differs to NICE guidance – see below) / Treatment of type 2 diabetes:
· Monotherapy in patients who are unable to take metformin
· Add on combination therapy with insulin or other antidiabetic drugs (if existing treatment fails to achieve adequate glycaemic control).
NICE guidance / Dual Therapy
Empagliflozin, dapagliflozin and canagliflozin can be used in dual therapy in the following situations:
· a sulfonylurea is contraindicated or not tolerated or
· the person is at significant risk of hypoglycaemia or its consequences.
Triple therapy
Empagliflozin and canagliflozin (NOT dapagliflozin) can be used in triple therapy in combination with:
· metformin and a sulfonylurea or
· metformin and a thiazolidinedione.
Empagliflozin, dapagliflozin and canagliflozin, in combination with insulin with or without other antidiabetic drugs is recommended as an option for treating type 2 diabetes. (Dapagliflozin should not be used in combination with GLP-1 receptor agonists or with pioglitazone).
People currently receiving treatment initiated within the NHS with canagliflozin, dapagliflozin or empagliflozin that is not recommended for them by NICE in this guidance should be able to continue treatment until they and their NHS clinician consider it appropriate to stop.
Dosage and administration / Empagliflozin
Adult over 18 years:
10mg od, increase to 25mg od if necessary and if tolerated / Dapagliflozin
Adult over 18 years:
10mg od.
Over 75 years – not recommended / Canagliflozin
Adult over 18 years:
100mg od, increase to 300mg od if needed.
Contraindications / Known hypersensitivity to active substance or to any excipients. Type 1 diabetes mellitus, ketoacidosis, severe gastro-intestinal disease, pregnancy, breast-feeding, children under 18 years, end-stage renal disease or moderate to severe renal impairment (creatinine clearance <60 ml/min), severe hepatic dysfunction.
Cautions / · Dose of concomitant insulin or drugs that stimulate insulin secretion may need to be reduced
· Hepatic impairment: Initiate dapagliflozin at 5mg daily in severe impairment and increase according to response. Canagliflozin and empagliflozin are not recommended in severe hepatic impairment.
· Increase diuresis associated with a modest decrease in blood pressure. This may be more pronounced in patients with very high blood glucose concentrations. Caution should be exercised in patients for whom a drop in blood pressure could pose a risk, such as patients with known cardiovascular disease, patients on anti-hypertensive therapy with a history of hypotension or elderly patients.
· Dapagliflozin is not recommended for use in patients receiving loop diuretics or who are volume depleted, e.g. due to acute illness such as GI illness. Elderly patients are at a greater risk for volume depletion
· Elderly patients are more likely to have impaired renal function, and/or to be treated with anti-hypertensive medicinal products that may cause changes in renal function such as angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II type 1 receptor blockers (ARB).
Adverse Drug Reactions / The most common adverse drug reactions are:
· Hypoglycaemia
· Urogenital infection (UTIs, candidal infection) is increased, although this isn’t usually a reason to discontinue treatment
Adverse drug reactions related to volume depletion (dehydration, hypovolaemia, hypotension) have been reported.
Risk of Diabetic Ketoacidosis (Drug Safety Update June 2015. Available at: https://www.gov.uk/drug-safety-update/sglt2-inhibitors-canagliflozin-dapagliflozin-empagliflozin-risk-of-diabetic-ketoacidosis
When treating patients who are taking an SGLT2 inhibitor:
•be aware that SGLT2 inhibitors are not approved for treatment of type 1 diabetes
•test for raised blood ketones in anyone taking an SGLT2i who is unwell
•if you suspect DKA, stop SGLT2 inhibitor treatment and seek immediate specialist advice
•inform patients of the symptoms and signs of DKA (nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness); advise them to get immediate medical help if these occur.
Monitoring / No specific monitoring is required
Interactions / Diuretics: SGLT2 inhibitors may add to the diuretic effect of thiazide and loop diuretics and may increase the risk of dehydration and hypotension.
Insulin and insulin secretagogues: Insulin and insulin secretagogues, such as sulfonylureas, cause hypoglycaemia. Therefore, a lower dose of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycaemia.
Contact names and details
Contact Name / Telephone number / EmailDr K Sands
Consultant Endocrinologist / 01226 434050 /
Dr E Uchegbu
Consultant Diabetologist / 01226 432598 /
Dr Z Merza
Consultant Endocrinologist and Diabetologist / 01226 435366 /
Prof TH Jones
Consultant Endocrinologist and Diabetologist / 01226 432147 /
Community Diabetes Specialist Nurse Team
Apollo Court – Glenn Nicholson / 01226 209884 /
Gillian Smith
Medicines Information Pharmacist / 01226 432857 /
References
· British National Formulary. Available at: www.medicinescomplete.com/mc/bnf/current/
· Summary of Product Characteristics available at:
o Jardiance® (Empagliflozin). Summary of Product Characteristics. January 2015 Available at: http://www.medicines.org.uk/emc/medicine/28974 Accessed <30.9.15>
o Synjardy® (Empagliflozinmetformin). Summary of Product Characteristics. September 2015 Available at: http://www.medicines.org.uk/emc/medicine/30781 Accessed <30.9.15>
o Forxiga® (Dapagliflozin). Summary of Product Characteristics. October 2014. Available at: http://www.medicines.org.uk/emc/medicine/27188 Accessed <30.9.15>
o Xigduo® (Dapagliflozin/metformin). Summary of Product Characteristics. January 2015. Available at: http://www.medicines.org.uk/emc/medicine/28667 Accessed <30.9.15>
o Invokana® (Canagliflozin). Summary of Product Characteristics. August 2015 Available at: http://www.medicines.org.uk/emc/medicine/28400 Accessed <30.9.15>
o Vokanamet® (Canagliflozin/metformin). Summary of Product Characteristics. August 2015 Available at: http://www.medicines.org.uk/emc/medicine/29368 Accessed <30.9.15>
· NICE Technology Appraisals:
o NICE Technology Appraisal. Empagliflozin in combination therapy for treating type 2 diabetes (TA336). March 2015. Available at: https://www.nice.org.uk/guidance/ta336/ Accessed <30.9.15>
o NICE Technology Appraisal. Dapagliflozin in combination therapy for treating type 2 diabetes (TA288). June 2013. Available at: https://www.nice.org.uk/guidance/ta288 Accessed <30.9.15>
o NICE Technology Appraisal. Canagliflozin in combination therapy for treating type 2 diabetes (TA315). June 2015. Available at: https://www.nice.org.uk/guidance/ta315 Accessed <30.9.15>
Development Process
This guideline was developed following an AMBER-G (Amber with guidance) classification status of canagliflozin, dapagliflozin and empagliflozin for the treatment of type 2 diabetes, by the Barnsley Area Prescribing Committee. This information has been subject to consultation and endorsement by the Endocrinologists in Barnsley and was ratified at the Area Prescribing Committee on 14th October 2015 and the LMC on 10th November 2015.
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Date Prepared: October 2015 Review Date: October 2017