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6.1.2 Antidiabetic drugs

First Line
Second Line
Specialist
Hospital Only

6.1.2.1 Sulfonylureas

All sulfonylureas can cause hypoglycaemia and weight gain. Local specialists report that although severe hypoglycaemic events associated with sulfonylureas are rare other drugs may be preferred for vulnerable patients such as the frail and elderly; note that combining pioglitazone and sulfonylureas may produce 10% weight gain. Local specialists also report that there is evidence that the glucose-lowering effect of sulfonylureas is less durable than some other antidiabetic treatments. If a sulfonylurea has been prescribed for many years it may be reasonable to try replacing it with another treatment, particularly if the patient is keen to delay insulin therapy.

Sulfonylurea-induced hypoglycaemia may persist for many hours and must always be treated in hospital.

Several sulfonylureas are available and choice is determined by side-effects and the duration of action as well as the patient's age and renal function. Accumulation of sulfonylureas may occur in renal impairment, potentially causing increased glucose-lowering and increased risk of hypoglycaemia. Gliclazide is preferred in renally impaired patients due its primarily hepatic metabolism.

Gliclazide
  • Tablets 80mg (£0.99 = 80mg daily)
  • Modified-release tablets 30mg (£2.81 = 30mg daily)

Indications and dose

  • Type 2 diabetes mellitus
    • Immediate-release: Initially 40–80mg daily, adjusted according to response, increased if necessary up to 160mg once daily, dose to be taken with breakfast. Doses higher than 160mg to be given in divided doses; maximum 320mg per day.
    • Modified-release: Initially 30mg daily, dose to be taken with breakfast, adjust dose according to response every 4 weeks (after 2 weeks if no decrease in blood glucose); maximum 120mg per day.

Notes

  1. If necessary, gliclazide which is principally metabolised in the liver, can be used in renal impairment but careful monitoring of blood-glucose concentration is essential.
  2. It is not usually necessary to increase the dose of gliclazide in increments of 40mg.
  3. Gliclazide modified release tablets have been added to aid concordance – they should not be used first line.
  4. Gliclazide modified-release 30mg may be considered to be approximately equivalent in therapeutic effect to standard formulation gliclazide 80mg.
Glimepiride
  • Tablets 1mg, 2mg 3mg, 4mg (£0.96 = 2mg daily)

Dose

  • Initially 1mg daily, adjusted according to response, then increased in steps of 1mg every 1–2 weeks, increased to 4mg daily, dose to be taken shortly before or with first main meal.

Notes

  1. Glimepiride may be a useful treatment option for patients unable to take other sulfonylureas or for whom once daily dosing is beneficial.
Glipizide
  • Tablets 5mg (£1.26 = 5mg daily)

Indications and dose

  • Type 2 diabetes mellitus
    • Initially 2.5mg-5mg daily before breakfast or lunch; adjust according to response up to 20mg maximum daily. Doses up to 15mg may be given as a single dose.

Notes

  1. Glipizide would be a reasonable choice for a patient who does not tolerate gliclazide and for whom a trial of a different sulfonylurea is appropriate

6.1.2.2 Biguanides

Metformin is weight neutral and hypoglycaemia does not usually occur with metformin.

The immediate-release version of metformin should be considered first line treatment, in preference to modified-release metformin. Gastrointestinal side effects are common (up to 15%) with metformin but can be minimised by slow introduction of the immediate-release preparation. Only if a patient experiences gastrointestinal side effects with immediate-release, consideration may be given to a trial of modified-release metformin.

In adults with type 2 diabetes and renal impairment, metformin should be used with caution. Individual Summary of Product Characteristics (SPC) should be consulted for prescribing information.

There is a risk of lactic acidosis with metformin use. Do not use in the circumstances shown below:

  • Uncontrolled heart failure
  • Respiratory failure
  • Recently post myocardial infarction
  • Severe infection, trauma, shock or sepsis
  • Severe dehydration
  • Renal impairment
  • Alcoholism
  • X-ray contrast media - stop for 48 hours afterwards
  • Hepatic failure - jaundice and raised INR not just raised LFTs
  • Pregnancy
Metformin immediate-release (IR)
  • Immediate-release tablets 500mg, 850mg (£2.52 = 500mg three times daily)
  • Oral solution sugar free 500mg/5ml (£51.32 = 500mg three times daily)

Indications and dose

  • Type 2 diabetes mellitus
    • Initially 500mg with breakfast for at least 1 week then 500mg with breakfast and evening meal for at least 1 week then 500mg with breakfast, lunch and evening meal; usual maximum 2g daily in divided doses (maximum licensed dose: 3g daily)
    • Increase dose only when patient has been free of side effects for 1 week.
    • Titrate to maximum tolerated dose as symptoms allow, do not wait for glycaemic change before increasing dose.
    • If GI effects are present, then reduce the dose of metformin to highest dose tolerated
    • Many patients who have failed to tolerate the usual starting dose of metformin, can be successfully managed if the dose is started at 125mg (quarter of a tablet) daily and titrated very slowly.

Notes

  1. The dosage should be slowly increased in weekly increments until the target dosage is achieved, to minimize side effects
    1. Begin with low dose metformin (500mg with evening meal)
    2. Increase dose in 500mg increments every 7 days up to 1000mg twice daily if tolerated
    3. If gastro-intestinal side-effects occur decrease to previously tolerated dose.
  2. Metformin oral solution is considerably more costly than the tablet form and the need for this preparation should be reviewed regularly.
Metformin modified-release (MR)
  • Modified-release tablets 500mg, 750mg, 1g (£2.95 = 2 x 1g daily)

Indications and dose

  • Type 2 diabetes mellitus
    • Initially 500mg once daily, increased every 10–15 days, maximum 2g once daily with evening meal; if control not achieved, use 1g twice daily with meals

Notes

  1. Metformin MR is for the treatment of type 2 diabetes mellitus in adult patients who are intolerant of immediate-release metformin due to GI side effects, and in whom the modified-release tablet allows the use of a dose of metformin not previously tolerated, or in patients for whom a once daily preparation offers a clinically significant benefit.
  2. Review soon after initiation and discontinue if not tolerated or ineffective.
  3. Patients taking less than 2g daily of the immediate-release metformin may start with the same daily dose of the modified-release preparation.

6.1.2.3 Other antidiabetic drugs

Acarbose
  • Tablets 50mg, 100mg

Dose

  • Acarbose should be taken or chewed with the first mouthful of food or swallowed whole with liquid immediately before food. The possibility of GI side effects is reduced by lower incremental dosage increases.

Notes

  1. Acarbose should only be considered as an alternative glucose-lowering therapy in people unable to use other oral drugs.
  2. Flatulence with acarbose tends to decrease with time.

Dipeptidylpeptidase-4 (DPP-4) inhibitors (Gliptins)

There have been reports of acute pancreatitis associated with DPP-4 inhibitors. Patients treated with DDP-4 inhibitors should be informed of the characteristic symptoms of acute pancreatitis – persistent, severe abdominal pain (sometimes radiating to the back). If pancreatitis is suspected, the DPP-4 inhibitor and other potentially suspect medicines should be discontinued. See MHRA Warning, September 2012 for more information.

DPP4-inhibitors usually have no effect on weight, and do not cause hypoglycaemia; they are considerably more expensive than sulfonylureas therefore may be most appropriately targeted to patients where weight gain and risk of hypoglycaemic events are of a particular concern. The dose of concomitant sulfonylurea or insulin may need to be reduced to reduce the risk of hypoglycaemia, when used in combination with a gliptin.

Alogliptin is recommended for first line use, except in patients with renal impairment, when linagliptin is recommended.

Alogliptin
  • Tablets 6.25mg, 12.5mg, 25mg (£26.60 = 25mg daily)

Indications

Dose

  • The recommended dose is 25mg once daily as add-on therapy to metformin, a thiazolidinedione, a sulfonylurea, or insulin or as triple therapy with metformin and a thiazolidinedione or insulin.
  • The manufacturer's SmPC states that the safety and efficacy of alogliptin when used as triple therapy with metformin and a sulfonylurea have not been fully established.
  • An increased risk of hypoglycaemia has been observed when used as triple therapy with metformin and thiazolidinedione. In case of hypoglycaemia, a lower dose of the thiazolidinedione or metformin may be considered.
  • Reduce dose to 12.5mg once daily in patients with moderate renal impairment (creatinine clearance ≥ 30 to ≤ 50 mL/min), or 6.25mg once daily in patients with severe renal impairment (creatinine clearance < 30mL/min) or with end-stage renal disease (ESRD) requiring dialysis. Alogliptin may be administered without regard to the timing of dialysis. Alogliptin has not been studied in patients undergoing peritoneal dialysis.

Notes

  1. Alogliptin is not licensed for use as monotherapy.
Sitagliptin
  • Tablets 25mg, 50mg, 100mg (£3.12 = 100mg daily)

Indications and dose

  • Type 2 diabetes mellitus
    • The dose is 100mg once daily
    • Reduce dose to 50mg once daily in patients with moderate renal impairment (creatinine clearance ≥ 30 to <50mL/min).
    • For patients with severe renal impairment (creatinine clearance < 30mL/min) or with end-stage renal disease requiring haemodialysis or peritoneal dialysis, the dose should be reduced to 25mg once daily. Treatment may be administered without regard to the timing of dialysis.

Notes

  1. In a meta-analysis, sitagliptin was associated with an increased risk of all-cause infection, including infection of the upper and lower respiratory tracts.
Linagliptin
  • Tablets 5mg (£33.26 = 5mg daily)

Indications and dose

Sodium-glucose co-transporter 2 (SGLT2) Inhibitors

SGLT-2 inhibitors may be suitable for initiation in primary care. SGLT-2 inhibitors may be initiated in primary care in patients co-prescribed insulin after discussion with a specialist.

SGLT-2 inhibitors increase renal glucose excretion. They lower blood glucose and reduce weight through calorie excretion (with an average 2-3kg decrease over 6-12 months). Efficacy is reduced in renal impairment. There is an increased risk of hypoglycaemia when SGLT-2 inhibitors are used with insulin and/or a sulfonylurea; consider reduction in dose of insulin/sulfonylurea.

Side-effects include polyuria, genital irritation and increased risk of UTI. Temporary interruption of treatment with a SGLT-2 inhibitor should be considered in patients with complicated urinary tract infections.

Due to their mechanism of action, SGLT2 inhibitors induce osmotic diuresis which may lead to a small decrease in blood pressure. Be aware of this for patients for whom a drop in blood pressure could pose a risk, such as patients on anti-hypertensive therapy with a history of hypotension, patients on diuretics, patients with renal impairment and elderly patients (≥ 65 years of age). Frail elderly patients may be particularly at risk of volume depletion and postural hypotension.

Treatment of heart failure with dapagliflozin and empagliflozin in patients with or without type 2 diabetes

See dapagliflozin and empagliflozin entries below. Dapagliflozin and empagliflozin increase diuresis which may lead to a modest decrease in blood pressure in the range of 2mmHg for patients with chronic heart failure. Be aware of this for patients for whom a drop in blood pressure could pose a risk, such as patients on anti-hypertensive therapy with a history of hypotension or elderly patients.

In case of intercurrent conditions that may lead to volume depletion (e.g. gastrointestinal illness), careful monitoring of volume status (e.g. physical examination, blood pressure measurements, laboratory tests including haematocrit and electrolytes) is recommended. Temporary interruption of treatment is recommended for patients who develop volume depletion until the depletion is corrected

MHRA Drug Safety Updates for SGLT2 Inhibitors
Risk of diabetic ketoacidosis:

MHRA Drug Safety Updates (June 2015 and April 2016): When treating patients who are taking a sodium-glucose co-transporter 2 (SGLT2) inhibitor (canagliflozin, dapagliflozin, or empagliflozin):

  • Be aware that SGLT2 inhibitors are not approved for treatment of type 1 diabetes
    • MHRA Drug Safety Update (December 2021): Dapagliflozin (Forxiga): no longer authorised for treatment of type 1 diabetes mellitus
  • Inform patients of the signs and symptoms of diabetic ketoacidosis (DKA) and advise them to seek immediate medical advice if they develop any of these:
    • nausea and/or vomiting
    • anorexia
    • rapid weight loss
    • abdominal pain
    • excessive thirst
    • difficulty breathing
    • confusion
    • unusual fatigue or sleepiness
    • sweet smell to the breath
    • sweet or metallic taste in the mouth
    • different odour to urine or sweat
  • Discuss the risk factors for DKA with patients, and use SGLT2 inhibitors with caution in patients who have them:
    • a low beta cell function reserve (eg, patients with type 2 diabetes who have low C-peptide levels, latent autoimmune diabetes in adults [LADA], or a history of pancreatitis)
    • conditions leading to restricted food intake or severe dehydration
    • sudden reduction in insulin
    • increased insulin requirements due to acute illness
    • surgery
    • alcohol abuse
  • Test for raised ketones in patients with symptoms of diabetic ketoacidosis (DKA) even if plasma glucose levels are near-normal; omitting this test could delay diagnosis and treatment of DKA
  • Discontinue treatment with the SGLT2 inhibitor immediately if DKA is suspected or diagnosed
  • If DKA is confirmed, take appropriate measures to correct the DKA and to monitor glucose levels
  • Do not restart treatment with any SGLT2 inhibitor in patients who experienced DKA during use, unless another cause for DKA was identified and resolved
  • Interrupt treatment with the SGLT2 inhibitor in patients who are hospitalised for major surgery or acute serious illnesses; treatment may be restarted once the patient's condition has stabilised

MHRA Drug Safety Update (March 2020): monitor ketones in blood during treatment interruption for surgical procedures or acute serious medical illness

  • interrupt sodium-glucose co-transporter 2 (SGLT2) inhibitor treatment in patients who are hospitalised for major surgical procedures or acute serious medical illnesses
  • monitor ketones during this period – measurement of blood ketone levels is preferred to urine
  • restart treatment with the SGLT2 inhibitor once ketone values are normal and the patient's condition has stabilised
Risk of lower-limb amputation (mainly toes):

MHRA Drug Safety Update (March 2017): Canagliflozin 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, but the risk may be a class effect. Preventive foot care is important for all patients with diabetes.

  • carefully monitor patients receiving canagliflozin who have risk factors for amputation, such as poor control of diabetes and problems with the heart and blood vessels
  • consider stopping canagliflozin if patients develop foot complications such as infection, skin ulcers, osteomyelitis, or gangrene
  • advise patients receiving any sodium-glucose co-transporter 2 (SGLT2) inhibitor about the importance of routine preventive foot care and adequate hydration
  • continue to follow standard treatment guidelines for routine preventive foot care for people with diabetes
Reports of Fournier's gangrene:

MHRA Drug Safety Update (February 2019): SGLT2 inhibitors: reports of Fournier's gangrene (necrotising fasciitis of the genitalia or perineum)

  • post-marketing cases of Fournier's gangrene (necrotising fasciitis of the genitalia or perineum) have been associated with the use of SGLT2 inhibitors
  • Fournier's gangrene is a rare but serious and potentially life-threatening infection
  • if Fournier's gangrene is suspected, stop the SGLT2 inhibitor and urgently start treatment (including antibiotics and surgical debridement as required)
  • urogenital infection or perineal abscess may precede necrotising fasciitis
  • advise patients to seek urgent medical attention if they experience severe pain, tenderness, erythema, or swelling in the genital or perineal area, accompanied by fever or malaise
Canagliflozin
  • Tablets 100mg, 300mg (£36.59 = 100mg daily)

Indications

Dose

  • Adult: 100mg once daily initially
  • In patients tolerating canagliflozin 100mg once daily who have an eGFR ≥ 60mL/min/1.73m2 and need tighter glycaemic control, the dose can be increased to 300mg once daily orally
  • Renal impairment:
    • eGFR below 60mL/min/1.73 m2: do not initiate
    • In patients tolerating canagliflozin whose eGFR falls persistently below 60mL/min/1.73m2 after initiation: adjust to max 100mg once daily.
    • eGFR falls persistently below 45mL/min/1.73m2: stop treatment.
  • Do not use in patients with end stage renal disease (ESRD) or those on dialysis

Notes

  1. Canagliflozin may be initiated in primary care in patients co-prescribed insulin after discussion with a specialist.
  2. Renal function and risk of volume depletion should be taken into account in patients aged ≥ 65 years.
  3. Monitoring of renal function is recommended by the manufacturing product license as follows:
    1. Prior to initiation of canagliflozin and at least annually, thereafter
    2. Prior to initiation of concomitant medicinal products that may reduce renal function and periodically thereafter
    3. For renal function approaching moderate renal impairment, at least 2 times to 4 times per year.
  4. NICE TA315: Canagliflozin in combination therapy for treating type 2 diabetes (June 2014):
    1. Canagliflozin in a dual therapy regimen in combination with metformin is recommended as an option for treating type 2 diabetes, only if:
      1. a sulfonylurea is contraindicated or not tolerated or
      2. the person is at significant risk of hypoglycaemia or its consequences.
    2. Canagliflozin in a triple therapy regimen is recommended as an option for treating type 2 diabetes in combination with:
      1. metformin and a sulfonylurea or
      2. metformin and pioglitazone.
    3. Canagliflozin in combination with insulin with or without other antidiabetic drugs is recommended as an option for treating type 2 diabetes.
  5. NICE TA390: Canagliflozin as monotherapy is recommended as options for treating type 2 diabetes in adults for whom metformin is contraindicated or not tolerated and when diet and exercise alone do not provide adequate glycaemic control (May 2016), only if:
    1. a dipeptidyl peptidase-4 inhibitor would otherwise be prescribed and
    2. a sulfonylurea or pioglitazone is not appropriate
Dapagliflozin
  • Tablets 5mg, 10mg (£36.59 = 10mg daily)

Indications and dose

  • Type 2 diabetes mellitus – see notes below
    • Adult: 10mg once daily
    • Dapagliflozin may be initiated in primary care in patients co-prescribed insulin after discussion with a specialist
    • Renal impairment: glycaemic efficacy is dependent on renal function. Where prescribed primarily for glucose lowering, if eGFR falls below 45mL/min/1.73m2, additional glucose-lowering treatment should be considered if needed. Glycaemic effect is likely absent in severe renal impairment.
    • There is limited experience with initiating treatment below eGFR 25mL/min/1.73m2. Initiation is not recommended in patients with eGFR below 15mL/min/1.73m2 due to lack of experience.
    • Hepatic impairment: starting dose of 5mg for severe hepatic impairment, if well tolerated increase to 10mg
  • Chronic kidney disease – in line with NICE TA775, see notes below
    • Adult: 10mg once daily
    • Renal impairment: No dose adjustment required. There is limited experience with initiating treatment below eGFR 25mL/min/1.73m2. Initiation is not recommended in patients with eGFR below 15mL/min/1.73m2 due to lack of experience.
    • Hepatic impairment: starting dose of 5mg for severe hepatic impairment, if well tolerated increase to 10mg
  • Chronic heart failure (specialist): - in line with NICE TA679, see notes below
    • Adult: 10mg once daily
    • Renal impairment: No dose adjustment required. There is limited experience with initiating treatment below eGFR 25mL/min/1.73m2. Initiation is not recommended in patients with eGFR below 15mL/min/1.73m2 due to lack of experience.
    • Hepatic impairment: starting dose of 5mg for severe hepatic impairment, if well tolerated increase to 10mg

Notes

  1. Management of type 2 diabetes
    1. NICE NG28 guidance includes the use of SGLT2 inhibitors earlier in the type 2 diabetes pathway for patients with chronic heart failure, or established atherosclerotic cardiovascular disease, or at high risk of cardiovascular disease. Refer to the formulary guidance for type 2 diabetes.
    2. Monitoring of renal function is recommended by the Summary of Product Characteristics:
      1. Prior to initiation of dapagliflozin and at least yearly, thereafter
      2. Prior to initiation of concomitant medicinal products that may reduce renal function and periodically thereafter
      3. For renal function with GFR <60mL/min, at least 2 to 4 times per year.
  2. Management of chronic kidney disease
    1. In patients who are being treated with dapagliflozin for both chronic kidney disease (CKD) and type 2 diabetes, additional glucose-lowering treatment should be considered if GFR falls persistently below 45mL/min
    2. NICE TA775 recommends dapagliflozin as an option for treating CKD only if it is an add-on to optimised standard care including the highest tolerated licensed dose of angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs), unless these are contraindicated. There are additional TA775 criteria which must be met (see note 8). NICE guidance for chronic kidney disease (NG203) recommends:
      1. For adults with CKD and diabetes (type 1 or type 2), offer an ACE inhibitor or ARB for patients with a confirmed ACR of 3mg/mmol or more.
      2. For adults with CKD but without diabetes, offer an ACE inhibitor or ARB for patients with an ACR of 70mg/mmol or more.
    3. Patients with CKD should be monitored in line with NICE guidance on chronic kidney disease (NG203).
    4. Refer to the Summary of Product Characteristics for patient groups in which dapagliflozin has not been studied for the treatment of CKD.
  3. Management of heart failure
    1. Treatment with dapagliflozin should be started on the advice of a heart failure specialist. Ongoing management and monitoring of the patient may be performed in primary care.
    2. Following stabilisation on a maximum tolerated dose, patients should be monitored in line with the NICE clinical guideline on chronic heart failure (NG106)
    3. In patients with type 1 diabetes mellitus, dapagliflozin is not recommended for the treatment of heart failure
    4. In patients who are being treated with dapagliflozin for both heart failure and type 2 diabetes mellitus additional glucose-lowering treatment should be considered if GFR falls persistently below 45mL/min
    5. Severe renal impairment (GFR <30mL/min) was an exclusion criterion for the dapagliflozin clinical trial for heart failure (DAPA-HF).
  4. NICE TA288: Dapagliflozin in combination therapy for treating type 2 diabetes (June 2013):
    1. Dapagliflozin (Forxiga) in a dual therapy regimen in combination with metformin is recommended as an option for treating type 2 diabetes (June 2013), only if:
      1. a sulfonylurea is contraindicated or not tolerated or
      2. the person is at significant risk of hypoglycaemia or its consequences
    2. Dapagliflozin in combination with insulin with or without other antidiabetic drugs is recommended as an option for treating type 2 diabetes
  5. NICE TA390 (May 2016): Canagliflozin (Invokana), dapagliflozin (Forxiga), and empagliflozin (Jardiance) as monotherapies are recommended as options for treating type 2 diabetes in adults for whom metformin is contraindicated or not tolerated and when diet and exercise alone do not provide adequate glycaemic control, only if:
    1. a dipeptidyl peptidase-4 (DPP-4) inhibitor would otherwise be prescribed and
    2. a sulfonylurea or pioglitazone is not appropriate
  6. NICE TA418 (Nov 2016): Dapagliflozin (Forxiga) in a triple therapy regimen is recommended as an option for treating type 2 diabetes in adults, only in combination with metformin and a sulfonylurea.
  7. NICE TA679 (Feb 2021): Dapagliflozin (Forxiga) is recommended as an option for treating symptomatic chronic heart failure with reduced ejection fraction in adults, only if it is used as an add-on to optimised standard care with:
    1. angiotensin-converting enzyme (ACE) inhibitors or angiotensin-2 receptor blockers (ARBs), with beta blockers, and, if tolerated, mineralocorticoid receptor antagonists (MRAs), or
    2. sacubitril valsartan, with beta blockers, and, if tolerated, MRAs
  8. NICE TA775 (Mar 2022): Dapagliflozin is recommended as an option for treating chronic kidney disease (CKD) in adults. It is recommended only if:
    1. it is an add-on to optimised standard care including the highest tolerated licensed dose of angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs), unless these are contraindicated, and
    2. people have an estimated glomerular filtration rate (eGFR) of 25mL/min/1.73m2 to 75mL/min/1.73m2 at the start of treatment and:
      1. have type 2 diabetes or
      2. have a urine albumin-to-creatinine ratio (uACR) of 22.6mg/mmol or more.
  9. NICE TA902 (June 2023): Dapagliflozin is recommended, within its marketing authorisation, as an option for treating symptomatic chronic heart failure with preserved or mildly reduced ejection fraction in adults.
  10. MHRA Drug Safety Update (Dec 2021): Dapagliflozin (Forxiga): no longer authorised for treatment of type 1 diabetes mellitus
    1. dapagliflozin should be reviewed and discontinued in patients with type 1 diabetes by or in consultation with a physician specialised in diabetes care as soon as clinically practical. After stopping dapagliflozin treatment, frequent blood glucose monitoring is recommended
    2. an increased insulin dose may be needed, which should be undertaken carefully to minimise the risk of hypoglycaemia or hyperglycaemia
Empagliflozin
  • Tablets 10mg, 25mg (£36.59 =25mg daily)

Indications and dose

  • Type 2 diabetes mellitus - see notes below
    • Adult: 10mg once daily initially. In patients tolerating empagliflozin 10mg once daily who have an eGFR ≥60ml/min/1.73m2 and need tighter glycaemic control, the dose can be increased to 25mg once daily.
    • May be initiated in primary care in patients co-prescribed insulin after discussion with a specialist
    • Renal impairment:
      • In patients tolerating empagliflozin whose eGFR falls persistently below 60mL/min/1.73m2: adjust to max 10mg once daily.
      • Glycaemic effect is dependent on renal function: Where prescribed primarily for glucose-lowering, if eGFR falls below 45mL/min/1.73m2, additional glucose-lowering treatment should be considered if needed. Glycaemic effect is likely absent below 30mL/min/1.73m2.
      • Initiation is not recommended in patients with eGFR below 20mL/min/1.73m2 due to limited experience.
    • Hepatic impairment: no dose adjustment required. Not recommended in severe hepatic impairment due to limited experience.
  • Chronic kidney disease – in line with NICE TA942, see notes below
    • Adult: 10mg once daily
    • Renal impairment: initiation not recommended in patients with eGFR below 20mL/min/1.73m2 due to limited experience.
    • Hepatic impairment: no dose adjustment required. Not recommended in severe hepatic impairment due to limited experience
  • Chronic heart failure (specialist) – in line with NICE TA773, see notes below
    • Adult: 10mg once daily
    • Renal impairment: initiation not recommended in patients with eGFR below 20mL/min/1.73m2 due to limited experience 
    • Hepatic impairment: no dose adjustment required. Not recommended in severe hepatic impairment due to limited experience

Notes

  1. Management of type 2 diabetes
    1. NICE NG28 guidance includes the use of SGLT2 inhibitors earlier in the type 2 diabetes pathway for patients with chronic heart failure, or established atherosclerotic cardiovascular disease, or at high risk of cardiovascular disease. Refer to the formulary guidance for type 2 diabetes.
    2. Monitoring of renal function is recommended by the Summary of Product Characteristics as follows:
      1. Prior to empagliflozin initiation and periodically during treatment, i.e. at least yearly
      2. Prior to initiation of any concomitant medicinal product that may have a negative impact on renal function.
  2. Management of chronic kidney disease
    1. In patients who are being treated with empagliflozin for both chronic kidney disease (CKD) and type 2 diabetes, additional glucose-lowering treatment should be considered if eGFR falls persistently below 45mL/min/1.73m2.
    2. NICE TA942 recommends empagliflozin as an option for treating CKD only if it is an add-on to optimised standard care including the highest tolerated licensed dose of angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs), unless these are contraindicated. There are additional TA942 criteria which must be met (see note 8). NICE guidance for chronic kidney disease (NG203) recommends:
      1. For adults with CKD and diabetes (type 1 or type 2), offer an ACE inhibitor or ARB for patients with a confirmed ACR of 3mg/mmol or more.
        ii. For adults with CKD but without diabetes, offer an ACE inhibitor or ARB for patients with an ACR of 70mg/mmol or more. 
    3. Patients with CKD should be monitored in line with NICE guidance on chronic kidney disease (NG203).
    4. Patient groups excluded from the EMPAG-CKD trial included those receiving maintenance dialysis, or with a functioning kidney transplant, or with polycystic kidney disease. Also, patients who had received intravenous immunosuppressive therapy in the last 3 months or were receiving >45mg prednisolone or equivalent.
  3. Management of heart failure
    1. Treatment with empagliflozin should be started on the advice of a heart failure specialist. Ongoing management and monitoring of the patient may be performed in primary care.
    2. Following stabilisation on a maximum tolerated dose, patients should be monitored in line with the NICE clinical guideline on chronic heart failure (NG106).
    3. In patients with type 1 diabetes mellitus, empagliflozin is not recommended for the treatment of heart failure.
    4. In patients who are being treated with empagliflozin for both heart failure and type 2 diabetes mellitus additional glucose-lowering treatment should be considered in moderate or severe renal impairment.
  4. NICE TA336:
    1. Empagliflozin in a dual therapy regimen in combination with metformin is recommended as an option for treating type 2 diabetes, only if:
      1. a sulfonylurea is contraindicated or not tolerated, or
      2. the person is at significant risk of hypoglycaemia or its consequences.
    2. Empagliflozin in a triple therapy regimen is recommended as an option for treating type 2 diabetes in combination with:
      1. metformin and a sulfonylurea or
      2. metformin and pioglitazone
    3. Empagliflozin in combination with insulin with or without other antidiabetic drugs is recommended as an option for treating type 2 diabetes.
  5. NICE TA390: Empagliflozin as monotherapy is recommended as options for treating type 2 diabetes in adults for whom metformin is contraindicated or not tolerated and when diet and exercise alone do not provide adequate glycaemic control, only if:
    1. a dipeptidyl peptidase-4 inhibitor would otherwise be prescribed and
    2. a sulfonylurea or pioglitazone is not appropriate
  6. NICE TA773 (Mar 2022): Empagliflozin is recommended as an option for treating symptomatic chronic heart failure with reduced ejection fraction in adults, only if it is used as an add-on to optimised standard care with:
    1. an angiotensin-converting enzyme (ACE) inhibitor or angiotensin 2 receptor blocker (ARB), with a beta blocker and, if tolerated, a mineralocorticoid receptor antagonist (MRA), or
    2. sacubitril valsartan with a beta blocker and, if tolerated, an MRA.
    3. Start empagliflozin for treating symptomatic heart failure with reduced ejection fraction on the advice of a heart failure specialist. Monitoring should be done by the most appropriate healthcare professional.
  7. NICE TA929 (November 2023): Empagliflozin is recommended, within its marketing authorisation, as an option for treating symptomatic chronic heart failure with preserved or mildly reduced ejection fraction in adults.
  8. NICE TA942 (December 2023): Empagliflozin is recommended as an option for treating chronic kidney disease (CKD) in adults, only if:
    1. it is an add-on to optimised standard care including the highest tolerated licensed dose of angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs), unless these are contraindicated, and
      1. people have an estimated glomerular filtration rate of:
        1. 20ml/min/1.73m2 to less than 45ml/min/1.73m2 or
        2. 45ml/min/1.73m2 to 90ml/min/1.73m2 and either:
          1. a urine albumin-to-creatinine ratio of 22.6mg/mmol or more, or
          2. type 2 diabetes.
    2. If people with the condition and their clinicians consider empagliflozin to be 1 of a range of suitable treatments (including dapagliflozin), after discussing the advantages and disadvantages of all the options, use the least expensive. Take account of administration costs, dosage, price per dose and commercial arrangements.
Ertugliflozin
  • Tablets 5mg, 15mg (£29.40 = 5mg daily)

Indications

Dose

  • Adult: 5mg once daily; increased to 15mg once daily if necessary and if tolerated, dose to be taken in the morning
  • Renal impairment:
    • Avoid initiation if eGFR less than 60mL/minute/1.73m2
    • Avoid if eGFR is persistently less than 45mL/minute/1.73m2

Notes

  1. Manufacturer advises to determine renal function before treatment and periodically thereafter
  2. Manufacturer advises monitor volume status and electrolytes during treatment in patients at risk of volume depletion
  3. NICE TA572: Ertugliflozin (Steglatro) as monotherapy or with metformin for treating type 2 diabetes (Mar 2019):
    1. Ertugliflozin as monotherapy is recommended as an option for treating type 2 diabetes in adults for whom metformin is contraindicated or not tolerated and when diet and exercise alone do not provide adequate glycaemic control, only if:
      1. a dipeptidyl peptidase 4 (DPP 4) inhibitor would otherwise be prescribed and
      2. a sulfonylurea or pioglitazone is not appropriate
    2. Ertugliflozin in a dual-therapy regimen in combination with metformin is recommended as an option for treating type 2 diabetes, only if:
      1. a sulfonylurea is contraindicated or not tolerated or
      2. the person is at significant risk of hypoglycaemia or its consequences
  4. NICE TA583: Ertugliflozin (Steglatro) with metformin and a dipeptidyl peptidase-4 (DPP-4) inhibitor is recommended as an option for treating type 2 diabetes in adults when diet and exercise alone do not provide adequate glycaemic control, only if (Jun 2019):
    1. the disease is uncontrolled with metformin and a DPP-4 inhibitor, and
    2. a sulfonylurea or pioglitazone is not appropriate

Glucagon-like peptide-1 receptor agonists (GLP-1 mimetics)

The GLP-1 mimetics may be initiated in primary care. In adults with type 2 diabetes, only offer a GLP-1 mimetic in combination with insulin with specialist advice and support.

Treatment with GLP-1 mimetics is associated with the prevention of weight gain and possible promotion of weight loss which can be beneficial in overweight patients.

When a GLP-1 mimetic is added to a sulfonylurea or insulin, a reduction in the dose of sulfonylurea or insulin should be considered to reduce the likelihood of hypoglycaemia. See also MHRA Drug Safety Update below.

Gastrointestinal side effects are common. Nausea was reported in 40-50% of patients in clinical trials but the frequency and severity of nausea decreased with continued use.

Prescribers need to be aware of the possibility of pancreatitis with GLP-1 mimetics. If suspected, discontinue the drug as soon as possible. If pancreatitis is confirmed, GLP-1 should not be restarted until an alternative aetiology for the pancreatitis is identified.

Only 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 of 35kg/m2 or more (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 35kg/m2 but insulin therapy would pose significant occupational problems, 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 11mmol/mol in HbA1c and a weight loss of at least 3% of initial body weight in 6 months).

MHRA Drug Safety Update (June 2019): GLP-1 receptor agonists: reports of diabetic ketoacidosis when concomitant insulin was rapidly reduced or discontinued.

  • serious and life-threatening cases of diabetic ketoacidosis have been reported in association with exenatide, liraglutide, and dulaglutide, particularly after discontinuation or reduction of concomitant insulin
  • blood glucose self-monitoring is necessary when adjusting the dose of insulin, particularly when GLP-1 receptor agonist therapy is initiated and insulin is reduced
  • if the insulin dose is to be reduced, a stepwise approach is recommended
  • discuss with patients the risk factors for and signs and symptoms of diabetic ketoacidosis and advise them to seek immediate medical advice if these develop

National Patient Safety Alert (3rd January 2024): Shortage of GLP-1 receptor agonists update 

  • Supply is not expected to return to normal until at least the end of 2024.
  • The supply issues have been caused by an increase in demand for these products for licensed and off-label indications.
  • Please refer to the SPS Prescribing available GLP-1 receptor agonists for an up-to-date supply stock situation and the SPS Medicines Supply Tool for a summary of the current situation and advice, and clinical guidance on alternative treatment options.
  • Where an alternative glucose lowering therapy needs to be considered, use the principles of shared decision making as per NICE guidelines in conjunction with the Clinical Guidance from a collaboration of The Primary Care Diabetes Society (PCDS) and Association of British Clinical Diabetologists (ABCD), here.
  • If switching a patient on to insulin, ensure an insulin is chosen as per information on the Specialist Pharmacy Service page on prescribing available insulins as not all suppliers are able to manage an uplift in demand.
  • Where there is reduced access to GLP-1 RAs, support people with type 2 diabetes to access structured education and weight management programmes where available.

Medicines Supply Notification (MSN/2024/031) 18 March 2024: Semaglutide (Ozempic); Dulaglutide (Trulicity); Liraglutide (Victoza)

Actions required:

  • only prescribe GLP-1 RAs for their licensed indication; 
  • proactively engage with patients established on GLP-1 RAs impacted by shortage and consider prioritising for review based on the criteria set out in NICE NG28 and: 
    • discuss stopping the GLP-1 RA if patients have not achieved treatment goals as per NICE NG28.
    • do not double up a lower dose preparation where a higher dose preparation of a GLP-1 RA is not available;
    • do not switch between strengths of a GLP-1 RA solely based on availability; and
  • do not prescribe more than one month’s supply unless there is clear reason to do so in order that the risks to the supply chain are minimised and the needs of patients acknowledged (see supporting information).

Where patients are prescribed Victoza or Byetta or where patients are unable to obtain Ozempic or Trulicity for 2 weeks or more, prescribers should:

  • consider prescribing either Rybelsus tablets or Mounjaro KwikPens (ensuring that the patient is prescribed appropriate needles), which can support the market during this time, if appropriate;
  • if prescribing Mounjaro or Rybelsus, ensure that the patient is not intolerant to any of the excipients (refer to product SPC) and that the dose regimen, including administration volumes where applicable is specifically discussed (see supporting information); and
  • if the above options are not considered appropriate, or if prescribers in primary care require further clinical advice, they should liaise with specialists on management options.
Ozempic

(Semaglutide)

  • Solution for injection 1.5ml pre-filled pens, 0.25mg/0.19ml, 0.5mg/0.37ml (£73.25 = 1 pre-filled pen (4 doses))
  • Solution for injection 3ml pre-filled pens, 1mg/0.74ml (£73.25 = 1 pre-filled pen (4 doses))

Indications

Dose

  • To be administered by subcutaneous injection. Initially, 0.25mg semaglutide once weekly. After 4 weeks the dose should be increased to 0.5mg once weekly. After at least 4 weeks with a dose of 0.5mg once weekly, the dose can be increased to 1mg once weekly to further improve glycaemic control.
  • 1 pre-filled pen provides 4 doses (4-weeks' supply)

Notes

  1. Medicines Supply Notification (MSN/2024/031) 18 March 2024:
    1. New patient initiations cannot be supported for semaglutide (Ozempic) 0.25mg, 0.5mg and 1mg solution for injection in a pre-filled pen. 
    2. Semaglutide (Ozempic) 0.25mg and 1mg solution for injection in a pre-filled pen are available but will have intermittent supply throughout 2024. 
    3. Semaglutide (Ozempic) 0.5mg solution for injection in a pre-filled pen is out of stock until early June 2024. This product will then have intermittent supply until the end of 2024. 
    4. Where patients are unable to obtain Ozempic for 2 weeks or more, prescribers should: 
      1. consider prescribing either Rybelsus tablets or Mounjaro KwikPens (ensuring that the patient is prescribed appropriate needles), which can support the market during this time, if appropriate. 
      2. See above for further advice for clinicians.
  2. Prescribe by brand (to aid identification where products contain multiple ingredients, or to prevent confusion where multiple brands contain similar ingredients and / or have different licensed indications and dosing regimens):
    1. Ozempic and Rybelsus are licensed for the treatment of type 2 diabetes mellitus and should not be prescribed for weight management
    2. Wegovy is licensed for weight management, see section 4.5 Drugs used in the treatment of obesity
  3. In adults with type 2 diabetes, only offer semaglutide in combination with insulin with specialist advice and support.
  4. Semaglutide 0.25mg is not a maintenance dose. Weekly doses higher than 1.0mg are not recommended.
  5. No dose adjustment needed in elderly patients, hepatic impairment, or those with mild to moderate or severe renal impairment.
  6. NICE does not recommend semaglutide for monotherapy (although it is a licensed indication).
  7. The routine commissioning of semaglutide is accepted in Devon for patients with type 2 diabetes as described for glucagon-like peptide-1 (GLP-1) mimetics in NICE guideline NG28 (see Commissioning Policy for more details).
  8. For use of semaglutide (Wegovy) for managing overweight and obesity, see section 4.5 Drugs used in the treatment of obesity.
  9. MHRA Drug Safety Update (November 2023): Ozempic (semaglutide) and Saxenda (liraglutide): vigilance required due to potentially harmful falsified products
    1. Falsified Ozempic and Saxenda products have been found in the UK, including falsified pens containing insulin. Ozempic and Saxenda from legitimate supply chains are unaffected.
    2. Remain vigilant for symptoms linked to hypoglycaemia in patients who may have obtained a falsified product.
    3. Remind patients using these products to always obtain prescription medicines from a qualified healthcare provider and not to use products they suspect are falsified. The legitimacy of a pharmacy, including those on-line, can be verified by referring to the GPhC website pharmacy registry.
    4. Refer to the safety update for additional advice to patients.
Rybelsus

(Semaglutide)

  • Tablets 3mg, 7mg, 14mg (£73.25 = 14mg)

Indications

Dose

  • Initially 3mg once daily for one month. After one month, the dose should be increased to a maintenance dose of 7mg once daily. After at least one month with a dose of 7mg once daily, the dose can be increased to a maintenance dose of 14mg once daily to further improve glycaemic control.

Notes

  1. Medicines Supply Notification (MSN/2024/031) 18 March 2024:
    1. Semaglutide (Rybelsus) 3mg, 7mg and 14mg tablets are available and can support increased demand for both new patient initiations and any patients unable to obtain their existing GLP-1 RA therapy.
  2. Prescribe by brand (to aid identification where products contain multiple ingredients, or to prevent confusion where multiple brands contain similar ingredients and / or have different licensed indications and dosing regimens):
    1. Rybelsus and Ozempic are licensed for the treatment of type 2 diabetes mellitus and should not be prescribed for weight management
    2. Wegovy is licensed for weight management, see section 4.5 Drugs used in the treatment of obesity
  3. In adults with type 2 diabetes, only offer semaglutide in combination with insulin with specialist advice and support
  4. Tablets should be taken whole on an empty stomach, with a sip of water. Patients should wait at least 30 minutes after a dose before eating, drinking or taking other oral medicines
  5. Unlike the subcutaneously administered preparation (Ozempic), Rybelsus has not been demonstrated to significantly reduce the incidence of cardiovascular outcomes. Its use is therefore recommended only for patients who are unable to use injectable therapy
  6. The bioavailability of oral semaglutide is highly variable, some patients may have no exposure and therefore gain no benefit from the treatment
  7. Due to the high pharmacokinetic variability of oral semaglutide, the effect of switching between oral and subcutaneous semaglutide cannot easily be predicted.
  8. Taking two 7mg tablets to achieve the effect of a 14mg dose has not been studied and is therefore not recommended.
  9. No dose adjustment needed in elderly patients, hepatic impairment, or those with mild to moderate or severe renal impairment.
  10. NICE does not recommend semaglutide for monotherapy (although it is a licensed indication).
  11. The routine commissioning of Rybelsus is accepted in Devon for the treatment of type 2 diabetes who are suitable for treatment with a GLP-1 mimetic, as described in NICE guideline NG28, but for whom injectable therapy is not suitable (see Commissioning Policy for more information)
  12. For use of semaglutide (Wegovy) for managing overweight and obesity, see section 4.5 Drugs used in the treatment of obesity
Dulaglutide
  • Solution for injection pre-filled pens, 0.75mg/0.5ml, 1.5mg/0.5ml, 3mg/0.5ml, 4.5mg/0.5ml (£73.25 = 4 pre-filled pens (4 doses))

Indications

Dose

  • To be administered by subcutaneous injection. Add-on therapy in combination with metformin and a sulfonylurea: 1.5mg once weekly (or for potentially vulnerable populations, such as patients 75 years of age and older, 0.75mg once weekly can be considered as a starting dose)
  • For additional glycaemic control, the 1.5mg dose may be increased after at least 4 weeks to 3mg once weekly, then after at least 4 weeks to 4.5mg once weekly. The maximum dose is 4.5mg once weekly.

Notes

  1. Medicines Supply Notification (MSN/2024/031) 18 March 2024: 
    1. Dulaglutide (Trulicity) 0.75mg, 1.5mg, 3mg and 4.5mg solution for injection in a pre-filled pen are available but will have intermittent supply throughout 2024. New patient initiations cannot be supported. 
    2. Where patients are unable to obtain Trulicity for 2 weeks or more, prescribers should: 
      1. Consider prescribing either Rybelsus tablets or Mounjaro KwikPens (ensuring that the patient is prescribed appropriate needles), which can support the market during this time, if appropriate. 
      2. See above for further advice for clinicians
  2. In adults with type 2 diabetes, only offer dulaglutide in combination with insulin with specialist advice and support.
  3. No dose adjustment needed in elderly patients, hepatic impairment, or those with mild, moderate or severe renal impairment (eGFR ≥ 15mL/min/1.73m2). Not recommended in end stage renal disease.
  4. NICE does not recommend dulaglutide for monotherapy (although it is a licensed indication).
  5. The routine commissioning of Dulaglutide (Trulicity) is accepted in Devon for the treatment of type 2 diabetes, for use in line with NICE guideline NG28 (see Commissioning Policy for more details).
Exenatide
  • Bydureon BCise prolonged-release suspension for injection pre-filled pens, 2mg/0.85ml (£73.36 = 4 pre-filled pens)

Indications

Dose

  • To be administered by subcutaneous injection.
  • 2mg once weekly

Notes

  1. Medicines Supply Notification (MSN/2024/031) 18 March 2024:
    1. Exenatide (Bydureon BCise) 2mg/0.85ml prolonged-release pre-filled pens remain available for patients stabilised on therapy but are not able to support new patient initiations. 
    2. Exenatide (Byetta) 5micrograms/0.02ml and 10micrograms/0.04ml pre-filled pens will be discontinued at the end of March 2024. See above for more advice for clinicians.
  2. In adults with type 2 diabetes, only offer exenatide in combination with insulin with specialist advice and support.
  3. Prescribe by brand. Patient familiarity with one brand is important; instructions for use vary between preparations and patient training is required
  4. Renal impairment: avoid if CrCl less than 30mL/minute
  5. There have been reports of necrotising and haemorrhagic pancreatitis in people taking exenatide some of which were fatal. If pancreatitis is suspected, treatment with exenatide should be suspended immediately; if pancreatitis is diagnosed, exenatide should be permanently discontinued. Diagnosed pancreatitis with an unexpectedly prolonged course, haemodynamic instability, fever, failure of medical therapy, or presence of fluid collections on CT suggest possible necrosis (MHRA alert 2009).
Victoza

(Liraglutide)

  • Solution for injection 3ml pre-filled pens, 6mg/ml (£78.48 = 2 x 3ml pen (60 doses))

Indications and dose

  • Type 2 diabetes mellitus (See above)
    • To be administered by subcutaneous injection. Initially given at a dose of 0.6mg once daily, increased after at least one week to 1.2mg once daily. Some patients are expected to benefit from an increase in dose from 1.2mg to 1.8mg and based on clinical response, after at least one week, the dose can be increased to 1.8mg to further improve glycaemic control

Notes

  1. Medicines Supply Notification (MSN/2024/031) 18 March 2024:
    1. Liraglutide (Victoza) 6mg/ml solution for injection in a pre-filled pen is out of stock until end of 2024.
    2. Where patients are prescribed Victoza, prescribers should:
      1. consider prescribing either Rybelsus tablets or Mounjaro KwikPens (ensuring that the patient is prescribed appropriate needles), which can support the market during this time, if appropriate. 
      2. See above for more advice for clinicians
  2. Prescribe by brand (to aid identification where products contain multiple ingredients, or to prevent confusion where multiple brands contain similar ingredients and / or have different licensed indications and dosing regimens):
    1. Victoza is licensed for the treatment of type 2 diabetes mellitus and should not be prescribed for weight management
    2. Saxenda is licensed for weight management, see section 4.5 Drugs used in the treatment of obesity
  3. In adults with type 2 diabetes, only offer liraglutide in combination with insulin with specialist advice and support.
  4. Renal impairment: No dose adjustment is required for patients with mild, moderate or severe renal impairment. There is no therapeutic experience in patients with end-stage renal disease, and liraglutide is therefore not recommended for use in these patients.
  5. For use of liraglutide (Saxenda) for managing overweight and obesity, see section 4.5 Drugs used in the treatment of obesity

Thiazolidinediones

Pioglitazone
  • Tablets 15mg, 30mg, 45mg (£1.42 = 30mg daily)

Indications

Dose

  • Initially 15–30 mg once daily, adjusted according to response to 45 mg once daily.
  • The safety and efficacy of pioglitazone should be reviewed after 3–6 months; pioglitazone should be stopped in patients who do not respond adequately to treatment.
  • Dose of concomitant sulfonylurea or insulin may need to be reduced.

Notes

  1. Pioglitazone is associated with an increased risk of bone fractures (most relevant for osteoporosis or post-menopausal women).
  2. Pioglitazone may cause oedema, and has been associated with decreased visual acuity. Note that oedema may limit use in advanced renal impairment.
  3. Pioglitazone results in an average 2-3kg increase weight gain over 12 months. Note that combining pioglitazone and sulfonylureas often produces 10% weight gain.
  4. Pioglitazone does not usually cause hypoglycaemia.
  5. In adults with type 2 diabetes, do not offer or continue pioglitazone if they have hepatic impairment or diabetic ketoacidosis.
  6. 2011 MHRA Drug safety update: Pioglitazone: risk of bladder cancer
    1. There is a small increased risk of bladder cancer associated with pioglitazone use. However, in patients who respond adequately to treatment, the benefits of pioglitazone continue to outweigh the risks. Pioglitazone should not be used in patients with active bladder cancer or a past history of bladder cancer, or in those who have uninvestigated macroscopic haematuria. Pioglitazone should be used with caution in elderly patients as the risk of bladder cancer increases with age.
    2. Before initiating treatment, assess patients for risk factors of bladder cancer (including age; current or past history of smoking; exposure to some occupational or chemotherapy agents such as cyclophosphamide; or previous irradiation of the pelvic region) and any macroscopic haematuria should be investigated.
    3. Patients should be advised to report promptly any haematuria, dysuria, or urinary urgency during treatment.
  7. 2011 MHRA Drug Safety Update: Insulin combined with pioglitazone: risk of cardiac failure
    1. Pioglitazone should not be used in patients with heart failure or a history of heart failure.
    2. The incidence of heart failure is increased when pioglitazone is combined with insulin especially in patients with predisposing factors e.g. previous myocardial infarction. If the combination is used, patients should be closely monitored for signs of heart failure, weight gain and oedema; treatment should be discontinued if any deterioration in cardiac status occurs.

Meglitinides

Repaglinide
  • Tablets 500 micrograms, 1mg, 2mg

Notes

  1. Repaglinide has a rapid onset of action and a short duration of activity. It should be administered shortly before each main meal.
  2. Repaglinide may have a role in attaining tight glucose control in patients with non-routine daily patterns or in patients unable to take sulfonylureas.
  3. Repaglinide should not be used in combination with sulfonylureas.

GIP/GLP-1 receptor agonists

Tirzepatide is recommended by NICE for the management of type 2 diabetes only.

When tirzepatide is added to a sulfonylurea or insulin, a reduction in the dose of sulfonylurea or insulin should be considered to reduce the likelihood of hypoglycaemia.

DPP-4 inhibitors and GLP-1 receptor agonists have a similar mechanism of action to tirzepatide. Do not combine either a DPP-4 inhibitor or a GLP-1 receptor agonist with tirzepatide.

Acute pancreatitis has been reported in patients receiving tirzepatide. If suspected, discontinue the drug as soon as possible. If pancreatitis is confirmed, tirzepatide should not be restarted.

Tirzepatide
  • KwikPen solution for injection 2.4ml pre-filled pens
    • 2.5mg/0.6ml, 5mg/0.6ml (£92.00 = 1 pen (4 doses)); 7.5mg/0.6ml, 10mg/0.6ml (£107.00 = 1 pen (4 doses)); 12.5mg/0.6ml, 15mg/0.6ml ((£122.00 = 1 pen (4 doses))
    • Needles are not provided and will need to be prescribed, see section 6.1.1 for pen needles

Indications

Dose

  • To be administered by subcutaneous injection.
  • Initially 2.5mg once weekly for 4 weeks, then increased to 5mg once weekly for at least 4 weeks, then increased if necessary up to 15mg once weekly, dose to be increased in steps of 2.5mg at intervals of at least 4 weeks
  • One KwikPen provides 4 weeks supply

Notes

  1. Tirzepatide 2.5mg is not a maintenance dose. The recommended maintenance doses are 5mg, 10mg and 15mg once weekly. The maximum weekly dose is 15mg.
  2. No dose adjustment is needed in elderly patients, in hepatic impairment, or in renal impairment. There is limited experience with the use of tirzepatide in patients with severe hepatic or renal impairment.
  3. Tirzepatide is not recommended during pregnancy and in women of childbearing potential not using contraception. For further information, see tirzepatide SmPC. Also, see SmPC section 4.5 for advice on contraception during treatment initiation and dose escalation for patients with obesity or overweight.
  4. NICE does not recommend tirzepatide for monotherapy (although it is a licensed indication).
  5. NICE TA924: Tirzepatide is recommended for treating type 2 diabetes alongside diet and exercise in adults (October 2023) when it is insufficiently controlled only if:
    1. triple therapy with metformin and 2 other oral antidiabetic drugs is ineffective, not tolerated or contraindicated, and
    2. they have a body mass index (BMI) of 35kg/m2 or more, and specific psychological or other medical problems associated with obesity, or
    3. they have a BMI of less than 35kg/m2, and:
      1. insulin therapy would have significant occupational implications, or
      2. weight loss would benefit other significant obesity-related complications.
  6. Use lower BMI thresholds (usually reduced by 2.5kg/m2) for people from South Asian, Chinese, other Asian, Middle Eastern, Black African or African-Caribbean family backgrounds.
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