6.1.2 Antidiabetic Drugs
METFORMIN (usual approach)
SULFONYLUREAS (if intolerant of metformin or if weight loss/osmotic symptoms)
Links to guidance:
Refer to Grampian Guidelines and SIGN 116 for further information.
- Grampian Guidelines for the Management of Diabetes Mellitus (2011)
- Grampian Guidelines for the Management of Diabetes
- SIGN 116: Management of diabetes
- SIGN 116 algorithm for glucose-lowering in people with type 2 diabetes
In this section:
Antidiabetic drugs
Antidiabetic drugs are suitable for people with type 2 diabetes when blood glucose control through dietary and lifestyle measures proves inadequate. Even when taking antidiabetic drugs diet and lifestyle issues remain of key importance.
Since in practice, the majority of patients are overweight, metformin is usually the drug of first choice. Sulfonylureas would be the usual second choice due to cost and safety factors. Pioglitazone, DPP4 inhibitors or GLP-1 analogues are newer available alternatives that are expensive and have a limited history of long-term usage (and safety) and so should usually be considered as third-line choices.
Biguanides
Metformin (tablets, oral powder, m/r tablets, combination tablet with pioglitazone see below).
Works principally by reducing insulin resistance. It is the treatment of choice for overweight type 2 diabetics, and can be used as an adjuvant to other hypoglycaemic therapy in type 2 patients. Metformin may be continued in some obese patients with type 2 diabetes who ultimately require insulin therapy, to maximise insulin sensitivity and minimise weight gain on insulin.
The dose is often limited by diarrhoea. Metformin should be taken with or after food to minimise gastro-intestinal effects.
Common side-effects of metformin are diarrhoea, lethargy, anorexia, malabsorption of vitamin B12 and folate. Lactic acidosis is a very rare but often fatal side-effect.
Modified-release tablets are more expensive and should be restricted to use for patients who are intolerant of standard-release metformin and in whom prolonged-release allows the use of a dose not previously tolerated, or in patients for whom a once-a-day preparation offers a clinically significant advantage over standard-release tablets. Not suitable if dose of standard-release tablets more than 2g daily.
Oral powder is more expensive and its use should be restricted for patients who are unable to swallow the solid dosage formulation.
Risk of lactic acidosis: Review dose if eGFR <45mL/min/1.73m2, avoid if eGFR <30mL/1.73m2. Withdraw or interrupt treatment in those at risk of tissue hypoxia or sudden deterioration in renal function such as those with dehydration, severe infection,shock, sepsis, acute heart failure, respiratory failure or hepatic impairment, or those who have recently had an MI.
Iodine containing X-ray contrast media: Administration carries a risk of reduced renal function which can increase the risk of lactic acidosis with metformin. Suspend metformin prior to the test, restart no earlier than 48 hours after the test if renal function has returned to baseline.
Sulfonylureas
Glipizide (tablets), gliclazide (tablets, modified-release tablets) and glimepiride (tablets)
Sulfonylureas potentiate the pancreatic beta-cell insulin release in response to glucose. They are the primary drug treatments for non-obese patients with type 2 diabetes and for overweight type 2 patients unable to tolerate usual first-line agents. They are also used as adjuvant therapy with other agents, particularly in addition to metformin. The most common side-effects of sulfonylureas are hypoglycaemia and weight gain.
Sulfonylureas should usually be taken before meals, ideally 20 to 30 minutes before eating. Glimepiride has the advantage of once-daily dosing across the dose range at similar cost to other agents. Gliclazide modified release tablets, which are more expensive then regular sulfonylurea tablets are taken once per day but have little or no advantage over glimepiride. Gliclazide 30mg m/r is equivalent to 80mg of the normal release tablets. Glibenclamide is particularly prone to causing hypoglycaemia and should no longer be initiated and its continued use should be reviewed periodically.
Other antidiabetic drugs
Third-line agents (thiazolidinediones, GLP-1 analogues and DPP4 inhibitors) should only be continued if either individualised target is achieved OR HbA1c falls >0.5% (5.5 mmoL/mol) in 3 to 6 months.
- Thiazolidinedione
- DPP4 inhibitors
- GLP-1 analogues
- Acarbose
- Selective and reversible inhibitor of sodium-glucose co-transporter 2
Thiazolidinedione
Pioglitazone (15mg, 30mg, 45mg tablets, combination tablet with metformin (Competact®)).
It acts at the level of PPARgamma receptor to promote insulin sensitivity. To be effective, patients require to have sufficient endogenous insulin production. The maximum therapeutic benefit may not be apparent until after eight weeks.
Pioglitazone is the treatment choice for overweight individuals with type 2 diabetes as monotherapy (where metformin and sulfonylureas are contra-indicated or not tolerated). It is also suitable for use as dual or triple therapy in combination with metformin and/or sulfonylureas. Also see letter regarding the prescribing of generic pioglitazone.
Advice on the risk of bladder cancer with pioglitazone - 22nd July 2011. Prescribers should review the safety and efficacy of pioglitazone in individuals after 3 to 6 months of treatment to ensure that only patients who are deriving benefit continue to be treated. Patients who are already receiving pioglitazone should also commence a similar programme of monitoring. Pioglitazone should be stopped in patients who do not respond adequately to treatment (e.g. reduction in glycosylated haemoglobin, HbA1c).
It is contra-indicated in patients with heart failure (of any severity), previous or active bladder cancer and uninvestigated macroscopic haematuria.
Pioglitazone 15mg/metformin 850mg hydrochloride (Competact®) is a potentially useful combined preparation for patients requiring both agents. This combination product costs the same as equivalent doses of the individual constituent preparations and offers a more convenient, though less flexible, dosing regimen.
GLP-1 analogues
Exenatide
- Byetta®
solution for injection (pre-filled pen, exenatide 250 micrograms/mL) administered s/c within one hour before main meals twice daily.
- Bydureon®
modified-release injection (exenatide 2 mg powder and solvent for prolonged-release suspension for injection) administered s/c once a week on the same day each week, with or without food. This preparation requires reconstitution prior to administration and is therefore more complicated to prepare.
Exenatide is an analogue of the incretin hormone (glucagon-like peptide 1 or GLP-1) which increases insulin secretion, reduces glucagon secretion, slows gastric emptying, and may decrease food intake.
Avoid if eGFR <30mL/minute/1.73m2 use with caution if eGFR 30 - 50mL/minute/1.73m2.
It is restricted to use as a third-line antidiabetic agent
- available for restricted use under specialist supervision for the treatment of type 2 diabetes mellitus in combination with metformin and a sulfonylurea or a thiazolidinedione in adult patients who have not achieved adequate glycaemic control on maximally tolerated doses of these oral therapies.
- Byetta® is also indicated as adjunctive therapy to basal insulin with or without metformin and/or pioglitazone in adults who have not achieved adequate glycaemic control with these agents.
It is an injectable agent and could be considered in individuals willing to consider injectable therapy and who have a BMI >30kg/m2. It can be considered at a lower BMI in non-caucasians and tried in individuals who need to avoid insulin therapy for occupational reasons.
Liraglutide solution for injection (pre-filled pen, liraglutide 6mg/mL (Victoza®) is another GLP-1 analogue.
Avoid if eGFR <60mL/minute/1.73 m2
It is available for restricted use under specialist supervision for the treatment of adults with type 2 diabetes mellitus:
- in combination with metformin and/or a sulfonylurea, in patients with insufficient glycaemic control despite maximal tolerated doses of these therapies.
- in combination with metformin and pioglitazone in patients with insufficient glycaemic control despite dual therapy.
It is restricted to use as a third-line antidiabetic agent, and in NHS Grampian, up to a dosage of 1.2 mg/day.
It is administered s/c once-daily independent of food intake.
DPP4 inhibitors
Dipeptidyl peptidase 4 (DPP4) inhibitors result in prolonged action of endogenously released GLP-1 (glucagon-like peptide 1).
Sitagliptin (25mg, 50mg, 100mg tablet, Januvia®) is the first-choice DPP4 inhibitor.
It is available for restricted use for the treatment of adults with type 2 diabetes mellitus, to improve glycaemic control:
As dual oral therapy in combination with
- metformin when diet and exercise, plus metformin, do not provide adequate glycaemic control and when the addition of sulfonylureas is not appropriate;
- a sulfonylurea when diet and exercise plus maximal tolerated dose of a sulfonylurea alone do not provide adequate glycaemic control and when metformin is inappropriate due to contraindications or intolerance.
As triple oral therapy in combination with:
- a sulfonylurea and metformin when diet and exercise plus dual therapy with these agents do not provide adequate glycaemic control.
As monotherapy:
- where metformin and a sulfonylurea are contraindicated or not tolerated.
Dose (18 years and over): 100mg once daily, if eGFR > 50mL/minute/1.73 m2;
- reduce to 50mg once daily if eGFR 30 to 50mL/minute/1.73 m2;
- reduce to 25mg once daily if eGFR <30mL/minute/1.73 m2.
SPECIAL INDICATIONS
Saxagliptin (2.5mg tablet, Onglyza®) is available for restricted use as add on therapy in combination with metformin when there is good reason to avoid the use of a sulfonylurea and the patient has moderate renal failure (eGFR <50 mL/minute/1.73 m2 but >30 mL/minute/1.73 m2). Dose (18 years and over): 2.5mg once daily.
Acarbose
Acarbose (50mg, 100mg tablets) is an alpha-glucosidase inhibitor, which acts within the gut to slow digestion and absorption of carbohydrates. Acarbose is the primary drug treatment for patients with type 2 diabetes (especially the obese) if other drugs are contra-indicated. It can also be used as an adjuvant to other oral agents or insulin. It does not cause hypoglycaemia. It should be taken with the first mouthful of food or swallowed whole with a little water immediately before food.
Caution: Insulin- or sulfonylurea-induced hypoglycaemia in patients taking acarbose must be treated with glucose, e.g. dextrose (Dextro Energy tablets), not a disaccharide such as sucrose (sugar) or lactose (milk).
Selective and reversible inhibitor of sodium-glucose co-transporter 2 (SGLT2)
Dapagliflozin (5mg,10mg tablets, Forxiga®
) is a highly potent selective and reversible inhibitor of sodium-glucose co-transporter 2 in the kidney. It inhibits reabsorption of glucose from the glomerular filtrate back into the circulation, leading to increased urinary glucose excretion.
Dapagliflozin is a new anti-diabetic drug available
only as add-on combination therapy
for patients with type 2 diabetes. Use is restricted to combination with metformin, when metformin alone with diet and exercise does not provide adequate glycaemic control and a sulfonylurea is inappropriate.
Dose (18 - 75 years): 10mg once daily at any time of day with or without food (in patients with severe hepatic impairment, a starting dose of 5 mg is recommended). Avoid in patients with moderate to severe renal impairment (patients with CrCl < 60mL/min or eGFR < 60mL/min/1.73m2). Due to the limited experience in patients 75 years and older, initiation of dapagliflozin therapy is not recommended.
GERIATRIC NOTES - ANTI-DIABETIC DRUGS
Hypoglycaemia may occur in patients taking sulfonylureas and is often under-reported in the elderly when the symptoms are non-specific and are confused with another condition, e.g. TIAs. Hypoglycaemia may occur following initial treatment; admission to hospital may be required. Glibenclamide is not recommended, and is unsuitable for use in the elderly. Over-enthusiastic attempts at glycaemic control are particularly likely to lead to hypoglycaemia which is especially likely to have serious consequences in frail, elderly patients and those with multiple co-morbidities.