6.1.2 Antidiabetic drugs

6.1.2.1 Sulfonylureas

All sulphonylureas can cause hypoglycaemia and weight gain. Local specialists report that although severe hypoglycaemic events associated with sulphonylureas are rare other drugs may be preferred for vulnerable patients such as the frail and elderly; note that combining pioglitazone and sulphonylureas may produce 10% weight gain. Local specialists also report that there is evidence that the glucose-lowering effect of sulphonylureas is less durable than some other antidiabetic treatments. If a sulphonylurea 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 sulphonylureas 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 (£0.82 = 80mg daily)

Indications

Dose

  • Immediate release: Initially 40–80mg daily, adjusted according to response, increased if necessary up to 160 mg once daily, dose to be taken with breakfast. Doses higher than 160 mg to be given in divided doses; maximum 320mg 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.
Glipizide
  • Tablets 5mg (£2.06 = 5mg daily)

Indications

Dose

  • Initially 2.5mg-5mg daily before breakfast or lunch; adjust according to response up to 20mg maximum daily. Doses up to 15 mg 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 sulphonylurea 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 standard-release, consideration may be given to a trial of modified-release metformin.

In adults with type 2 diabetes, review the dose of metformin if eGFR is below 45 ml/minute/1.73m2:

  • Prescribe metformin with caution for those at risk of a sudden deterioration in kidney function and those at risk of eGFR falling below 45 ml/minute/1.73m2.
  • Stop metformin if the eGFR is below 30 ml/minute/1.73m2.

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; monitor if serum Cr 150-200, if greater than 200, stop metformin
  • Alcoholism
  • X-ray contrast media - stop for 48 hours afterwards
  • Hepatic failure - jaundice and raised INR not just raised LFTs
  • Pregnancy
Metformin
  • Immediate release tablets 500mg, 850mg (£2.58 = 500mg three times daily)

Indications

Dose

  • 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. 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)
  • Sukkarto® tablets 500mg, 1g (£2.77 = 1g daily)
  • Tablets 750mg (£6.40 = 56 tablets)

Indications

Dose

  • 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 standard-release metformin due to GI side effects, and in whom the prolonged-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. Any new prescription of the MR preparation should be reviewed soon after initiation and discontinued if not tolerated or ineffective.
  3. Patients taking less than 2g daily of the standard release metformin may start with the same daily dose of the slow release preparation.
  4. Generic prescribing is advised in secondary care but in primary care there is a significant cost reduction by prescribing Sukkarto® for the 500mg and 1g preparations

6.1.2.3 Other antidiabetic drugs

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

There have been reports of acute pancreatitis associated with DPP-4 inhibitors. Patients treated with DPP-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.

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 sulphonylurea, or insulin or as triple therapy with metformin and a thiazolidinedione or insulin. The safety and efficacy of alogliptin when used as triple therapy with metformin and a sulphonylurea have not been fully established.
  • The safety and efficacy of alogliptin when used as triple therapy with metformin and a sulphonylurea 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 < 30 mL/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.
  2. The routine commissioning of alogliptin is accepted in Devon for the treatment of Type 2 diabetes (see Commissioning Policy for more details).
Sitagliptin
  • Tablets 25mg, 50mg, 100mg (£33.26 = 100mg daily)

Indications

Dose

  • The dose is 100mg once daily
  • Reduce dose to 50mg once daily in patients with moderate renal impairment (creatinine clearance ≥ 30 to < 50 mL/min).
  • For patients with severe renal impairment (creatinine clearance < 30 mL/min) or with end-stage renal disease requiring haemodialysis or peritoneal dialysis, the dose should be reduced to 25 mg 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

Dose

  • The dose is 5mg once daily (no dose adjustment is required for patients with renal impairment)

Sodium-glucose co-transporter 2 (SGLT2) Inhibitor

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. SGLT-2 inhibitors have a small blood-pressure lowering effect.

There is an increased risk of hypoglycaemia when SGLT-2 inhibitors are used with insulin and/or a sulphonylurea; consider reduction in dose of insulin/sulfonylurea.

Side-effects include polyuria, genital irritation and increased risk of UTI. For those patients at risk of volume depletion, concomitant use with loop diuretics should be avoided. Frail elderly patients may be particularly at risk of volume depletion and postural hypotension.

In patients aged 85 years and older, initiation of empagliflozin therapy is not recommended due to the limited therapeutic experience.

In patients ≥ 75 years of age, a higher incidence of adverse reactions associated with volume depletion (e.g., postural dizziness, orthostatic hypotension, hypotension) was reported. In addition, in such patients greater decreases in eGFR were reported (see sections 4.2 and 4.8).

MHRA Drug Safety Alerts (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
  • Inform them 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 Alerts (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
  • report any suspected side effect with SGLT2 inhibitors or any other medicine on a Yellow Card
Canagliflozin
  • Tablets 100mg, 300mg (£36.59 = 100mg daily)

Indications

Dose

  • Adult: 100mg once daily initially
  • In patients tolerating canagliflozin 100 mg once daily who have an eGFR ≥ 60 mL/min/1.73 m2 and need tighter glycaemic control, the dose can be increased to 300 mg once daily orally
  • Renal impairment:
    • eGFR below 60 mL/min/1.73 m2: do not initiate
    • In patients tolerating canagliflozin whose eGFR falls persistently below 60 mL/min/1.73 m2 after initiation: adjust to max 100 mg once daily.
    • eGFR falls persistently below 45 mL/min/1.73 m2: 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:
    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, 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

Dose

  • Adult: 10mg once daily
  • Renal impairment: avoid if eGFR less than 60mL/minute/1.73m2

Notes

  1. Dapagliflozin 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 for patients aged ≥ 65 years. Due to the limited therapeutic experience in patients ≥75 years, initiation of dapagliflozin therapy is not recommended.
  3. Monitoring of renal function is recommended by the manufacturing product license as follows:
    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 approaching moderate renal impairment, at least 2 to 4 times per year.
  4. NICE TA288 (June 2013): Dapagliflozin 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.
    3. Dapagliflozin in combination with insulin with or without other antidiabetic drugs is recommended as an option for treating type 2 diabetes.
  5. NICE TA390: Dapagliflozin 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 a dipeptidyl peptidase-4 inhibitor would otherwise be prescribed and a sulfonylurea or pioglitazone is not appropriate
  6. NICE TA418 (November 2016): Dapagliflozin 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.
Empagliflozin
  • Tablets 10mg, 25mg (£36.59 =25mg daily)

Indications

Dose

  • Adult: 10mg once daily initially. In patients tolerating empagliflozin 10 mg once daily who have an eGFR ≥60 ml/min/1.73 m2 and need tighter glycaemic control, the dose can be increased to 25 mg once daily.
  • Renal impairment:
    • eGFR below 60 mL/min/1.73 m2: do not initiate
    • In patients tolerating empagliflozin whose eGFR falls persistently below 60 mL/min/1.73 m2: adjust to max 10mg once daily.
    • eGFR falls persistently below 45 mL/min/1.73 m2: stop treatment.
    • Do not use in patients with end stage renal disease (ESRD) or those on dialysis

Notes

  1. Empagliflozin may be initiated in primary care in patients co-prescribed insulin after discussion with a specialist.
  2. In patients 75 years and older, an increased risk for volume depletion should be taken into. In patients aged 85 years and older, initiation of empagliflozin therapy is not recommended due to the limited therapeutic experience.
  3. Monitoring of renal function is recommended by the manufacturing product license 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.
  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.
    1. 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
    1. 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 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 exenatide, liraglutide, and lixisenatide is associated with the prevention of weight gain and possible promotion of weight loss which can be beneficial in overweight patients. They are given by subcutaneous injection for the treatment of type 2 diabetes mellitus. Lixisenatide is the lowest acquisition cost GLP-1 mimetic.

When a GLP-1 mimetic is added to a sulphonylurea or insulin, a reduction in the dose of sulphonylurea or insulin should be considered to reduce the likelihood of hypoglycaemia.

Gastrointestinal side effects are common. In trials, lixisenatide was associated with fewer GI side effects than exenatide and liraglutide. 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 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 in HbA1c and a weight loss of at least 3% of initial body weight in 6 months).

Lixisenatide
  • Injection, 50 micrograms/ml, 10 micrograms/dose pre-filled pen (£31.67 = 14 doses)
  • Injection 100 micrograms/ml, 20 micrograms/dose pre-filled pen (£28.97 = 14 doses)

Indications

Dose

  • 10 micrograms once daily within one hour of any meal of the day for 14 days, then 20 micrograms once daily thereafter.

Notes

  1. In adults with type 2 diabetes, only offer lixisenatide in combination with insulin with specialist advice and support.
  2. Use with caution in patients with eGFR less than 30-50mL/minute/1.73m2; avoid in patients with eGFR below 30mL/minute/1.73m2 due to limited experience in this patient group
Dulaglutide
  • Injection (Trulicity®), 0.75 mg/ 0.5ml solution for injection in pre-filled pen (£73.25)
  • Injection (Trulicity®) 1.5 mg/0.5ml solution for injection in pre-filled pen (£73.25)

Indications

  • Type 2 diabetes mellitus

Dose

  • Add-on therapy in combination with metformin and a sulfonylurea: 1.5mg once weekly (or for potentially vulnerable populations, such as patients ≥ 75 years, 0.75 mg once weekly can be considered as a starting dose)

Notes

  1. In adults with type 2 diabetes, only offer dulaglutide in combination with insulin with specialist advice and support.
  2. No dose adjustment needed in elderly patients, hepatic impairment, or those with mild to moderate renal impairment. Not recommended in severe renal impairment (eGFR below 30ml/min/1.73m2) or end stage renal disease.
  3. NICE does not recommend dulaglutide for monotherapy (although it is a licensed indication).
  4. The routine commissioning of dulaglutide has been 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
  • Standard release injection (Byetta®) 5 micrograms, 10 micrograms, pre-filled pen (£68.24 = 60 doses)
  • Modified release injection (Bydureon®) 2mg vial, 2mg pre-filled pen (£73.36)

Indications

Dose

  • Standard release: initiate at 5 micrograms twice daily for at least one month in order to improve tolerability. The dose can then be increased to 10 micrograms twice daily to further improve glycaemic control. Doses higher than 10 micrograms twice daily are not recommended. Administer at any time within the 60-minute period before the morning and evening meal (or two main meals of the day, approximately 6 hours or more apart).
  • Modified release: 2mg once weekly, on the same day each week.

Notes

  1. In adults with type 2 diabetes, only offer exenatide in combination with insulin with specialist advice and support.
  2. Patients should be started with the short acting formulation of exenatide and then changed to the long acting version if suitable for the patient. They should be counselled that they may initially experience transient increases in blood glucose when they change over.
  3. Initiation of long acting exenatide is recommended to be either commenced by or on the advice of secondary care.
  4. Renal impairment:
    1. Standard-release injection, use with caution if CrCl 30–50 mL/minute; avoid if CrCl less than 30 mL/minute
    2. Modified-release injection, avoid if CrCl less than 50 mL/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).
Liraglutide
  • Injection 6mg/ml, pre-filled pen (£78.48, 2 x 3ml pens = 30 doses of 1.2mg)

Indications

Dose

  • 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 1.2 mg to 1.8 mg and based on clinical response, after at least one week, the dose can be increased to 1.8 mg to further improve glycaemic control.

Notes

  1. In adults with type 2 diabetes, only offer liraglutide in combination with insulin with specialist advice and support.
  2. There is no therapeutic experience in patients with severe renal impairment (CrCl below 30 ml/min), avoid use in this group of patients.

Thiazolidinediones

Pioglitazone
  • Tablets 15mg, 30mg, 45mg (£1.99 = 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 sulphonylureas 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. 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.

 

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