Chapter 6.1.2- Drugs used in Diabetes – Somerset Prescribing Formulary

Related references

Therapeutic Area	Formulary Choices	Cost for 28 (unless otherwise stated)	Rationale for decision / comments
Biguanides	First-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 Glucorex® as Sukkarto SR® or Yaltormin PR®	500mg S/R tablets: £0.95 (28) 500mg S/R tablets: £2.38 (56) 750mg S/R tablets: £2.87 (56) Tariff is £6.40 1000mg S/R tablets:£3.82 (56) 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)	If an adult with type 2 diabetes experiences gastrointestinal side effects with standard-release metformin, consider a trial of modified-release metformin.
Sulphonylureas	Gliclazide	40mg tablets: £3.36 80mg tablets: £0.87	NICE NG28 recommends prescribing a sulfonylurea with a low acquisition cost when a sulfonylurea is indicated.
Glitazones (thiazolidinediones) Prescribing of Pioglitazone should be in line with MHRA/EMEA advice ( 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
Thiazolidinediones	Pioglitazone	15mg tablets: £8.23 30mg tablets: £10.89 45mg tablets: £11.71	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)	Related alert MHRA Dipeptidylpeptidase-4 inhibitors: risk of acute pancreatitis December 2014 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 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: £33.26	Monotherapy if metformin intolerant or C/I. Dual therapy with metformin. Triple therapy with SU and metformin. Can use with insulin with or without metformin. No dose adjustment needed for renal impairment
	Saxagliptin	5mg tablets: £31.60 2.5mg tablets: £31.60	Saxagliptin is is licensed for triple therapy with metformin & sulphonylurea and with insulin +/- metformin
	Sitagliptin	100mg tablets: £33.26 50mg tablets: £33.26 25mg tablets: £33.26	Sitagliptin is licensed for triple therapy with metformin & sulphonylurea and with insulin +/- metformin
	Vildagliptin	50mg 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	Meglitinides such as repaglinide are no longer recommended for use in diabetes in Somerset
Sodium-glucose cotransporter-2 (SGLT-2) inhibitor	Type 2 diabetes treatment 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
SGLT2 inhibitor treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute serious medical illnesses and ketone levels measured, preferably in blood rather than urine. Treatment may be restarted when the ketone values are normal and the patient's condition has stabilised. MHRA alert March 2020 EMA could not find evidence to guide on when to stop or restart SGLT-2s but FDA recommendations are: Canagliflozin,dapagliflozin,and empagliflozin should each be temporarily discontinued at least 3 days prior to scheduled surgery. Ertugliflozin should be temporarily discontinued at least 4 days prior to scheduled surgery. Blood glucose levels should be carefully monitored following discontinuation of the SGLT-2 inhibitor and managed appropriately prior to surgery. The SGLT-2 inhibitor may be restarted once the patient’s oral intake is back to baseline and any other risk factors for ketoacidosis are resolved.
In no particular order	Ertugliflozin ▼	5mg: £29.40 15mg: £29.40	Indicated in adults aged 18 years and older with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control: • 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. NICE concluded that ertugliflozin with metformin and a gliptin could be recommended as an option for type 2 diabetes in adults when it is uncontrolled with metformin and a gliptin, but only when sulfonylureas and pioglitazone are not appropriate. NICE suggests that SGLT-2 inhibitors provide cardiovascular protection and, although there are no data on cardiovascular outcomes for ertugliflozin yet, this may 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. 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 Ertugliflozin with metformin and a dipeptidyl peptidase-4 inhibitor for treating type 2 diabetes
	Empagliflozin	10mg tablets: £36.59 25mg tablets: £36.59	- 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
	Dapagliflozin	5mg tablets: £36.59 10mg tablets: £36.59	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 Recent studies have shown improved cardiovascular and renal outcomes for dapagliflozin Initiation not recommended 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. [TA679] Dapagliflozin for treating chronic heart failure with reduced ejection fraction
	Canagliflozin	100mg tablets:£39.20 (30 tablets) 300mg tablets:£39.20 (30 tablets)	- 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 100mg can be initiated In patients with eGFR >=45ml/min/1.73m2 in absence of severe albuminuria (ACR<30mg/mmol). Discontinue when eGFR falls below 45ml/min/1.73m2 For the treatment of Diabetic Kidney Disease In patients with eGFR >=30ml/min/1.73m2 in presence of severe albuminuria (ACR>30mg/mmol) Continue dosing until dialysis or renal transplantation
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
GLP-1 mimetic (Glucagon-like peptide-1 analogue)	Related references MHRA alert June 2019. GLP-1 receptor agonists: reports of diabetic ketoacidosis when concomitant insulin was rapidly reduced or discontinued 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:	Semaglutide ▼ Injections are once-weekly dosing	250 mcg, 4-dose prefilled pen, 1=£73.25 500 mcg, 4-dose prefilled pen, 1=£73.25 1mg, 4-dose prefilled pen, 1=£73.25 3mg tablets (30) £78.48 7mg tablets (30) £78.48 14mg tablets (30) £78.48	Initially 250 mcg by sc inj once weekly increasing after 4 weeks to 500 microgram once weekly. After ≥4 weeks increase to max 1mg once weekly if required. Combination therapy, consider lower dose of sulfonylurea/insulin. PLEASE NOTE- one syringe will last 4 weeks unlike all the other weekly GLP-1 which only last a week. Suggest on commencement that the 250mcg is issued as acute with a note to titrate up after 4 weeks Type II diabetes inadequately controlled by diet and exercise: as monotherapy when metformin is contraindicated or not tolerated; or with other hypoglycaemics. Initially 3mg daily increasing after one month to 7mg once daily. After a further month increase to max 14mg once daily if required. To be taken on an empty stomach, ≥30 min before food. Combination therapy, consider lower dose of sulfonylurea/insulin.
or	Dulaglutide Once-weekly dosing	0.75mg, 1.5mg, 3mg and 4.5mg (0.5ml 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.
or	Lixisenatide Daily dosing	10 mcg, 14-dose pre-filled pen, 1=£31.67 20 mcg, 14-dose pre-filled pen, 2=£57.93 Treatment initiation pack (1 x 10 mcg and 1 x 20 mcg pre-filled pen), 1=£57.93	Type II diabetes as an adjunct to oral hypoglycaemics and/or basal insulin, when these plus diet and exercise are inadequate. Age 18 plus
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.
Second line	Liraglutide 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

Dose adjustment of DPP-4 in renal impairment