See foot of page for NICE algorithm for blood glucose lowering therapy or download from NG28 above

Therapeutic AreaFormulary ChoicesCost for 28
(unless otherwise stated)		Rationale for decision / comments
BiguanidesFirst-line:
Metformin
Immediate-release		500mg tablets: £0.86 (28)
850mg tablets: £1.20 (56)		Offer standard-release metformin as the initial drug treatment for adults with type 2 diabetes
Gradually increase the dose of standard-release metformin over several weeks
to minimise the risk of gastrointestinal side effects in adults with type 2
diabetes e.g. 500mg daily and gradually titrated to 2g per day (or 3g under specialist supervision).
-Continued in patients with Type 2 DM who require Insulin, as Metformin reduces insulin requirements.
- Use with caution in those at risk of a sudden deterioration in kidney function
Metformin has a risk of lactic acidosis in patients with reduced renal function and is contraindicated below eGFR of 30ml/min. The European Medicines Agency (EMA) has concluded that metformin-containing medicines can now be used in patients with moderately reduced kidney function (GFR [glomerular filtration rate]=30–59 ml/min) for the treatment of type 2 diabetes
Metformin 500mg/5ml oral solution sugar free£15.65 (150ml)
Alternative for patients unable to swallow solid dosage forms
Second-line:
Modified release

as Yaltormin PR®



or Sukkarto SR®
500mg S/R tablets: £2.39 (56)
750mg M/R tablets: £2.88 (56) Tariff is £6.40
1000mg S/R tablets: £3.83 (56)



500mg S/R tablets: £2.38 (56)
750mg S/R tablets: £2.87 (56)
1000mg S/R tablets:£3.82 (56)		If an adult with type 2 diabetes experiences gastrointestinal side effects with
standard-release metformin, consider a trial of modified-release metformin.
SulphonylureasGliclazide40mg tablets: £3.36
80mg tablets: £0.87
NICE NG28 recommends prescribing a sulfonylurea with a low acquisition cost (but not glibenclamide) when a sulfonylurea is indicated.
Please note that NICE does not support quadruple therapy, neither is this licensed by any of the oral medications
Glitazones (thiazolidinediones)
Prescribing of Pioglitazone should be in line with MHRA/EMEA advice ( Dec-07, Jan-11, Aug-11) and NICE guidance NG28
 Pioglitazone should not be started in people who:
○ are at higher risk of fracture
○ have evidence of heart failure
 The incidence of heart failure is increased when Pioglitazone is combined with insulin
 Inform patient of risk of oedema and what to do if this happens. Closely monitor patients during treatment with pioglitazone for signs and symptoms of fluid retention. Discontinue pioglitazone if heart failure develops.
 Following consideration at Somerset Prescribing Forum (Nov 2011) it was agreed that generic versions of pioglitazone may be used for all indications
ThiazolidinedionesPioglitazone15mg tablets: £8.23 (28)
30mg tablets: £10.89 (28)
45mg tablets: £11.71 (28)		The PROACTIVE trial showed improvements in secondary outcomes.
Pioglitazone is licensed for use with insulin
Continue only if there is a reduction ≥ 0.5% points in HbA1c in 6 months
Pioglitazone might be preferable to a DPP-4 inhibitor if there is marked insulin insensitivity, or if DPP-4 inhibitor is contraindicated or not tolerated.
Secondary or tertiary centres may recommend the use of pioglitazone in patients with advanced liver fibrosis whether they have diabetes or not according to NICE NG 49 July 2016. This is an unlicensed use-please note.
DPP-4 inhibitors
(Gliptins)

Please note: SGLT-2 inhibitors (gliflozins) are preferred to DPP-4 inhibitors as they have demonstrated beneficial cardiovascular benefits. Please note: NICE guidance does not allow for a DDP4 and a SGLT2 to be taken together-please see algorithm below
DPP-4 inhibitor may be preferable to a glitazone:
 To prevent weight gain
 If the patient has not responded to, or not tolerated or has a contraindication to a glitazone
NB Group 2 (LGV/PCV) drivers are required to notify DVLA if taking combination of gliptin with sulphonylurea
See below for dose adjustment in renal impairment

Please note that NICE does not support quadruple therapy, neither is this licensed by any of the oral medications
First line

Alogliptin		6.25mg tablets:£26.60
12.5mg tablets:£26.60
25mg tablets: £26.60		As a dual therapy add-on to other agents including insulin. Please note that the licence for alogliptin does not preclude any particular combination including triple therapy with metformin and a sulphonylurea (SU), and the use within this specific combination is not contraindicated. The safety and efficacy of alogliptin when used as triple therapy with metformin and a sulphonylurea have not been fully established.
Monotherapy would be considered “off license”
Second line

Linagliptin		5mg tablets: £33.26Monotherapy if metformin intolerant or C/I. Dual therapy with metformin. Triple therapy with SU and metformin. Can use with insulin with or without metformin
Saxagliptin5mg tablets: £31.60
2.5mg tablets: £31.60		Saxagliptin is is licensed for triple therapy with metformin & sulphonylurea and with insulin +/- metformin
Sitagliptin100mg tablets: £33.26
50mg tablets: £33.26
25mg tablets: £33.26		Sitagliptin is licensed for triple therapy with metformin & sulphonylurea and with insulin +/- metformin
Vildagliptin50mg tablets: £33.35 (56)Twice daily dosing. In dual combination with a sulphonylurea, the recommended dose of vildagliptin is reduced to 50mg once daily administered in the morning.
In this patient population, vildagliptin 100mg daily was no more effective than vildagliptin 50mg once daily
Other options:
Rapid acting insulin secretagogue		Repaglinide500mcg tablets: £9.03 (90)
1mg tablets: £10.62 (90)
2mg tablets: £5.88 (90)		Repaglinide may have a role in patients who fail to achieve target HbA1c with Metformin +/- Sulphonylurea, or when either of these two classes of drug are contra-indicated or not tolerated.
Consideration should be given to a trial of Repaglinide before initiating a glitazone.
Repaglinide may have a particular role in patients with an erratic lifestyle / irregular eating pattern. Repaglinide should be given in the 30 minute period before a meal, up to TDS.
Sodium-glucose
cotransporter-2
(SGLT-2) inhibitor		Type 2 diabetes treatment only
Due to recent studies suggesting an improved cardiovascular outcome, SGLT-2 inhibitors are preferred over DPP-4 inhibitors. NICE does not offer the alternative of combining an SGLT2 with a DPP4 (see algorithm below). Qtern (saxagliptin plus dapagliflozin) is therefore non-formulary. Monotherapy with an SGLT2 is only if all other agents are not tolerated or C/I. There is no intensification possible thereafter.
Treatment with combinations of medicines including sodium–glucose co-transporter 2 (SGLT-2) inhibitors may be appropriate for some people with type 2 diabetes; see the NICE guidance on canagliflozin in combination therapy for treating type 2 diabetes, dapagliflozin in combination therapy for treating type 2 diabetes and empagliflozin in combination therapy for treating type 2 diabetes.
MHRA and EMA have raised the increased risk of Fournier's gangrene with all SGLT-2 inhibitors. Please see here for details
In no particular orderErtugliflozin▼5mg: £29.40 (28)
15mg: £29.40 (28)		NICE suggests that SGLT-2 inhibitors provide cardiovascular protection and, although there are no data on cardiovascular outcomes for ertugliflozin yet, this appears to be a class effect. NICE also suggest that SGLT-2 inhibitors have a protective effect on kidney function. NICE concluded that ertugliflozin offers similar benefits to the other SGLT-2 inhibitors.
• as monotherapy in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications.
• in addition to other medicinal products for the treatment of diabetes.
Most cost effective SGLT-2.
Start with 5mg and increase to 15mg if greater glycaemic control needed.
Initiation is not recommended in patients with an eGFR less than 60 ml/min/1.73 m2 or CrCl less than 60 ml/min
Discontinue when eGFR is persistently less than 45 ml/min/1.73 m2 or CrCl is persistently less than 45 ml/min.
No studies done in patients >75 years
Empagliflozin▼10mg tablets: £36.59
25mg tablets: £36.59		EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial demonstrated that treatment with the SGLT2 inhibitor empagliflozin compared with placebo showed a significant reduction in the risk of major cardiovascular end points and hospitalisation for heart failure for patients with T2DM and existing cardiovascular disease.
- as monotherapy when metformin is considered inappropriate due to intolerance

- in addition to other medicinal products for the treatment of diabetes

• Age limit 85
• Can be used as per NICE TA336 (Mar-15)
• No initiatition if eGFR <60ml/min/1.73m2,and discontinued if patient eGFR falls consistently to <45ml/min/1.73m2
Dapagliflozin5mg tablets: £36.59
10mg tablets: £36.59		DECLARE TIMI 58 study suggests cardivascular outcome improvements with dapagliflozin
For the improvement of glycaemic control treatment of type 2 diabetes mellitus of in adults in accordance with NICE NG28 July 2016
• Monotherapy. When diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to intolerance.
• Add-on combination therapy. In combination with other glucose-lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control
• Not recommended above 75 years
Initiation not recommended with concurrent pioglitazone or if eGFR <60ml/min/1.73m2. Existing patients with eGFR consistently below 45ml/min should be discontinued
Quadruple therapy with metformin, SU and DPP-4 has not been studied so remains non-formulary
Type 1 diabetes- Dapagliflozin 5mg is now licensed for use in type 1 diabetes mellitus as an adjunct to insulin in patients with BMI ≥ 27 kg/m2, when insulin alone does not provide adequate glycaemic control despite optimal insulin therapy.
Canagliflozin
100mg tablets:£39.20 (30 tablets)
300mg tablets:£39.20 (30 tablets)		CANVAS study suggests improved cardiovascular outcomes of canagliflozin
- as monotherapy when metformin is considered inappropriate due to intolerance or contraindications

- in addition to other medicinal products for the treatment of T2 diabetes.

• No age limit by license but elderly patients more at risk of volume depletion and low eGFR
• Can be used as per NICE TA315 (Jun-14)
• No initiatition if eGFR <60ml/min/1.73m2 and should be discontinued if patient eGFR consistently falls to 45 ml/min/1.73m2
SGLT-2 inhibitors may increase the risk of lower-limb amputation (mainly toes) in patients with type 2 diabetes. Evidence does not show an increased risk for dapagliflozin and empagliflozin though manufacturers warn of the increased risk, which may be a class effect. Preventive foot care is important for all patients with diabetes.
MHRA alert March 2017
Please note that NICE does not support quadruple therapy, neither is this licensed by any of the oral medications
GLP-1 mimetic (Glucagon-like peptide-1 analogue)Dietary advice should be given before starting therapy with these agents.
NICE says :If triple therapy with metformin and 2 other oral drugs is not effective, not tolerated or contraindicated, consider combination therapy with metformin, a sulfonylurea and a glucagon-like peptide-1 (GLP-1) mimetic for adults with type 2 diabetes who:
-have a BMI > 35 kg/m2 (adjust accordingly for people from black, Asian and other minority ethnic groups) and specific psychological or other medical problems associated with obesity
or
-have a BMI less than 35 kg/m2 for whom insulin therapy would have significant occupational implications or weight loss would benefit other significant obesity-related comorbidities.
Only continue GLP-1 mimetic therapy if the person with type 2 diabetes has had a beneficial metabolic response (a reduction of at least 11 mmol/mol [1.0%]
HbA1c and a weight loss of at least 3% of initial body weight in 6 months).

NB Group 2 (LGV/PCV) drivers are required to notify DVLA if taking combination of exenatide with sulphonylurea.
Somerset Prescribing Forum approved the use of lixisenatide and exenatide as adjunctive therapy to basal insulin (with or without metformin and/or pioglitazone in adults with Type 2 diabetes) i.e. within the respective licensed indications. Patients are expected to show 0.5% (6mmol/mol) reduction in HbA1c after 6 months to justify continuation.
Do not add GLP-1 treatment to basal insulin plus SU regimen as high risk of hypoglycaemia
First-line:Lixisenatide▼


Once-daily dosing		Treatment initiation pack: £54.14

10mcg prefilled pen: £31.67 (14 doses) 20mcg prefilled pen: £57.93 (2 x 14 doses)		15-26% less expensive than other GLP-1 mimetics
Starting dose: dosing is initiated at 10 mcg once daily for 14 days.
Maintenance dose: a fixed maintenance dose of 20 mcg once daily is started on Day 15. Lyxumia 20 micrograms solution for injection is available for the maintenance dose.
Lixisenatide is administered once daily, within the hour prior to any meal of the day
Second-line:




or		Exenatide
Twice-daily dosing




Modified-release
Once-weekly dosing		5mcg pre-filled pen: £68.24 (60 doses)
10mcg pre-filled pen: £68.24 (60 doses)





2mg vial : £73.36 (4)		Exenatide is indicated for treatment of type 2 diabetes mellitus in combination with:
- metformin
- sulphonylureas
- thiazolidinediones
- metformin and a sulphonylurea
- metformin and a thiazolidinedione
in adults who have not achieved adequate glycaemic control on maximally tolerated doses of these oral therapies.
Also indicated as adjunctive therapy to basal insulin with or without metformin and/or pioglitazone in adults who have not achieved adequate glycaemic control with these medicinal products.
orLiraglutide
Once-daily dosing		6mg/ml pre-filled pen:
£78.48 (2 x 3ml),
£117.72 (3 x 3ml)		Liraglutide 1.2mg daily can be considered for dual therapy (in combination with metformin or a sulphonylurea) only if either metformin or a sulphonylurea is contraindicated or not tolerated, and a DPP-4 inhibitor is contraindicated or not tolerated.
For triple therapy see above.
Monotherapy
When diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to intolerance or contraindications
orDulaglutide▼
Once-weekly dosing		0.75mg and 1.5mg pre-filled pen:
£73.25 (4 doses)		Dulaglutide is indicated in adults with type 2 diabetes mellitus to improve glycaemic control as:
• Monotherapy when diet and exercise alone do not provide adequate glycaemic control in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications.
• Add-on therapy in combination with other glucose-lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control.
orSemaglutide▼
Once-weekly dosing		0.25mg pre-filled pen: £73.25 (4 doses)
0.5mg pre-filled pen: £73.25 (4 doses)
1mg pre-filled pen: £73.25 (4 doses)		For dual therapy. Semaglutide (Ozempic®) is licensed for mono and dual therapy, however NICE only recommend for dual therapy.
Medicines to treat hypoglycaemiaGlucose 40% oral gel 75G
YourGLUCO 40% oral gel £5.00
Glucoboost, Rapilose (3x25G)
£5.49

Clinical considerations for drug classes   Link

BG algorithm