6.1.2 Antidiabetes drugs

General Notes
  • Refer to the Lothian Diabetes Handbook 2010, prepared by the Lothian Diabetes Network
  • First–line treatment for management of type 2 diabetes is usually a trial of dietary therapy unless there is intercurrent infection, severe hyperglycaemia or severe osmotic symptoms.
  • Patients commencing blood glucose lowering agents may need to inform the DVLA and their vehicle insurance company. Advise patients to check with their insurer and the DVLA website.
  • Women with type 2 diabetes who become pregnant whilst taking antidiabetes medication should be referred urgently for specialist advice. It is safe to continue metformin.
(a) biguanides

First Choice:
metformin
Formulations/Dose
  • metformin tablets 500mg, 850mg: initially 500mg once or twice daily after meals; gradually increased every 10-15 days to usual maintenance dose 1g twice daily; max 3g daily in divided doses.
Prescribing Notes
  • Metformin is the first choice oral hypoglycaemic drug. It is the only oral antidiabetic drug which has a proven survival advantage. It does not need to be limited to overweight patients.
  • Metformin may cause gastro–intestinal adverse effects; it should be started at low dose and taken with or after meals, and the dose gradually increased every 10-15 days if tolerated. Hypoglycaemia is not a problem with metformin monotherapy.
  • Metformin modified release tablets can be tried in patients who are unable to tolerate immediate release metformin.
  • Metformin oral solution should be restricted to patients unable to swallow tablets.

  • Due to the rare but serious risk of lactic acidosis, metformin must be avoided in patients with: significant renal impairment (estimated glomerular filtration rate (eGFR) less than 30mL/min); alcoholism with previous pancreatitis; severe cardiac/respiratory disease producing tissue hypoxia; severe liver disease with potential for hepatic failure.
  • The precipitant of a lactic acid crisis is often in the eGFR range 30 to 45mL/min when the patient develops what would have been a trivial illness (such as diarrhoea and vomiting) which compromises renal function and causes acute renal failure. This is compounded if the patient is also taking diuretics and/or ACE inhibitors in combination with metformin. Unlike acute illnesses in type 1 diabetes (where insulin treatment MUST be continued) stopping the drugs for a day or two will NOT cause any immediate problem for the patient and will protect renal function until the patient improves. Blood glucose estimation should be used to assess any glycaemic deterioration. In circumstances where renal impairment is suspected, NSAIDs should NOT be used as they can further compromise renal function.
(b) sulphonylureas

First Choice:
gliclazide
orglipizide
Formulations/Dose
  • gliclazide tablets 80mg: initially 40–80mg daily before main meal, max 320mg daily; doses above 160mg daily should be divided.
  • glipizide tablets 5mg: initially 2.5–5mg daily before main meal, max 20mg daily; doses above 15mg daily can be divided.
Prescribing Notes
  • Sulphonylureas should be taken before meals.
  • Gliclazide 30mg m/r (Diamicron® MR) should be reserved for patients with demonstrable compliance problems.
  • Patients should be informed that sulphonylureas can cause hypoglycaemia. The risk of hypoglycaemia increases with age.
(c) Other antidiabetes drugs
(i) dipeptidyl peptidase-4 inhibitor (DPP-4 inhibitors)

First Choice:
sitagliptin
Formulations/Dose
  • sitagliptin tablets 100mg,  50mg, 25 mg: normal renal function or mild renal impairment (CrCl > 50ml/min)100mg once daily; moderate renal impairment (CrCL > 30ml/min to 50ml/min) 50mg once daily; severe renal impairment  (CrCl < 30ml/min) or End Stage Renal Disease requiring haemodialysis or peritoneal dialysis 25mg once daily.
Prescribing Notes
  • There are five DPP-4 inhibitors available, they differ in which of their licensed indications are approved for use by the Scottish Medicines Consortium.
  • In Lothian sitagliptin is approved for use:

    • in combination with metformin, where the addition of a sulphonylurea is not appropriate
    • in combination with a sulphonylurea, where the addition of metformin is not appropriate
    • in combination with metformin and a sulphonylurea
    • as monotherapy, where metformin or a sulphonylurea are not appropriate.
  • Janumet® (sitagliptin and metformin) is a fixed dose combination product.
  • DPP-4 inhibitors have been shown to reduce HbAlc levels, but there is no data on morbidity, mortality or long-term adverse effects.
  • DPP-4 inhibitors are considered to be weight neutral.
  • There have been reports of acute pancreatitis associated with DPP-4 inhibitors. Patients should be informed of the characteristic symptoms of pancreatitis and encouraged to inform their healthcare professional if they experience these symptoms.
(ii) glitazones (thiazolidinediones)

First Choice:
pioglitazone
Formulations/Dose
  • pioglitazone tablets 15mg, 30mg, 45mg: initially 15–30mg once daily, increased to 45mg once daily according to response.
Prescribing Notes
  • Pioglitazone can cause significant weight gain and fluid retention. It must not be used in patients with heart failure or history of heart failure. Macular oedema has also been associated with its use.
  • Pioglitazone should not be used in patients with current or a history of bladder cancer or in patients with uninvestigated macroscopic haematuria.
  • Due to a reduction in bone mineral density in post-menopausal women with a subsequent increase in fracture risk, pioglitazone should be avoided in elderly women with high fracture risk, irrespective of cardiovascular risk.
  • Liver function should be checked before initiating pioglitazone and periodically thereafter based on clinical judgement. It should not be initiated in anyone with ALT > 2.5 times the upper limit of normal or with other evidence of liver disease.
  • The balance of risks and benefits should be considered both before initiating and during treatment.  Prescribers should review patients after three to six months (and regularly thereafter) to ensure only patients who are benefiting from treatment continue.
  • Pioglitazone can be used in combination with insulin in patients with type 2 diabetes mellitus, who have insufficient glycaemic control on insulin, in whom metformin is inappropriate because of contraindications or intolerance.
  • Competact® (pioglitazone and metformin) may be prescribed for patients on metformin who require pioglitazone due to a sulphonylurea not being an appropriate choice.
  • There is an increased risk of hypoglycaemia when combined with a sulphonylurea.
(iii) Glucagon-like peptide (GLP-1) agonist (injectable)

Weekly
First Choice:
dulaglutide  
Daily
First Choice:
liraglutide
Formulations/Dose
  • dulaglutide 0.75mg and 1.5mg solution for injection in a prefilled pen: 1.5mg by subcutaneous injection once weekly. For potentially vulnerable populations such as patients aged at least 75 years, 0.75mg once weekly can be considered as a starting dose.
  • liraglutide 6mg/mL solution for injection in a 3mL prefilled syringe: 600micrograms once daily for at least a week, then increased to 1.2mg once daily for at least 1 week, then increased if necessary up to 1.8mg once daily. As an alternative to 1.8mg daily, a switch to dulaglutide could be considered.
Prescribing Notes
  • Dulaglutide or liraglutide are approved for use by prescribers with a specialist interest in diabetes, in combination with other antidiabetic medicines. See Lothian Diabetes Handbook for treatment algorithm.   
  • Dulaglutide has been shown to be more cost effective than liraglutide, however some patients may prefer a daily preparation. As an alternative to1.8mg liraglutide daily, a switch to dulaglutide could be considered. Liraglutide 1.8mg is significantly more expensive and is no more effective than dulaglutide.
  • Dulaglutide is administered once weekly, at any time of the day, with or without meals. The day of weekly administration can be changed if necessary, as long as the last dose was administered at least three days before.
  • Liraglutide is administered once a day independent of food intake.

  • Gastric emptying may be delayed, therefore, the rate and extent of absorption of other oral drugs administered at the same time may be affected. For oral drugs that require threshold concentrations for efficacy, patients should take these medicines at least one hour before.
  • Patients should be reviewed at 6 months and only continue therapy in those with a ≥0.5% reduction in HbAlc and/or ≥3% reduction in body weight.
  • Upper gastro-intestinal side-effects are common with incretin mimetics. Acute pancreatitis has been associated with GLP-1 agonists, patients should be informed of the warning signs to look for. 
  • There is an increased risk of hypoglycaemia when combined with a sulphonylurea.
  • Long-term studies are needed to determine the effects of GLP-1 agonists on disease-related morbidity and mortality.
(iv) sodium-glucose co-transporter 2 (SGLT2) inhibitor

First Choice:
empagliflozin
Dose
  • empagliflozin 10mg, 25mg tablets: 10mg once daily, increased to 25mg once daily if necessary and if tolerated.
Prescribing Notes
  • Sodium-glucose co-transporter 2 (SGLT2) inhibitors reversibly inhibit sodium-glucose co-transporter 2 in the kidneys to reduce glucose reabsorption and increase glucose excretion.

  • Empagliflozin is approved for use in Lothian in type 2 diabetic patients,

    o     as dual therapy in combination with metformin, when a sulphonylurea is inappropriate

    o     as dual therapy in combination with insulin

    o     as triple therapy in combination with metformin plus standard of care

  • Reduce dose to 10mg once daily if eGFR falls persistently below 60mL/min/1.73m2. Treatment should not be initiated in patients with eGFR <60mL/min/1.73m2. Avoid if eGFR is persistently below 45mL/min/1.73m2
  • Patients with a past history of genito-urinary tract infection are not suitable for treatment with SGLT2 inhibitors.

  • Empagliflozin is also licensed for monotherapy, but has only been assessed as cost effective by the Scottish Medicines Consortium for the indications above.
  • Synjardy® (empagliflozin and metformin) is a combination product which may be appropriate for patients taking the individual drugs, to reduce pill burden or improve compliance.