Biguanides

Metformin is the only drug licensed in this group. The dose of metformin should be stepped up over several weeks to minimise the risk of gastrointestinal side-effects. A trial of extended-absorption metformin may be used if gastrointestinal tolerability prevents the person from continuing with metformin. The dose should be reviewed if serum creatinine rises to above 130 μmol/L or estimated glomerular filtration rate (eGFR) drops to less than 45 ml/minute/1.73 m². Metformin should be stopped if serum creatinine rises to above 150 μmol/L or the eGFR drops to below 30 ml/minute/1.73 m².^[3] 

• Benefits and indications:
  • Metformin is the only oral hypoglycaemic shown to reduce macrovascular complications and death.^[6]
  • It is associated with fewer hypoglycaemic attacks than sulphonylureas and does not cause weight gain.
  • It is more effective than sulphonylureas in reducing any diabetes endpoint, all-cause mortality, and stroke. These improvements have not been explained entirely on the basis of glycaemic control.^[7]
• Risks:
  • There is no evidence that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared to other antihyperglycemic treatments.^[8] 
  • Gastrointestinal side-effects occur commonly with metformin at higher doses, and may necessitate a change of drug.

Insulin secretagogues

Sulphonylureas

Sulphonylureas are thought to act by enhancing pancreatic islet cell function. They are also thought to act on the liver, stimulating the glycolytic pathway and inhibiting the production of glucose. They generally have a duration of action of 12-24 hours.

• Benefits and indications:
  • Sulphonylureas may be used as a first-line drug where oral hypoglycaemic medication is required, particularly in patients who cannot tolerate metformin or in whom it is contra-indicated.^[3] 
  • Newer drugs in this group, such as glipizide and glimipramide, appear to afford similar efficacy as the older drugs such as gliclazide.
  • Chlorpropamide is no longer recommended, as it has more side-effects than other members of this group.
• Risks:
  • The main risk with sulphonylureas is hypoglycaemia. This is increased in older age groups, mild-to-moderate hepatic impairment, and renal impairment.
  • Glibenclamide, a long-acting sulfonylurea, is associated with a greater risk of hypoglycaemia and therefore should be avoided in the elderly, and shorter-acting alternatives, such as gliclazide or tolbutamide, should be used instead.^[9]  
  • Other problems can include weight gain, liver dysfunction and gastrointestinal disturbance.

Rapid-acting insulin secretagogues - postprandial glucose regulators

The two meglitinides licensed for use in the UK are repaglinide and nateglinide. They are relatively short-acting stimulators of insulin secretion (<6 hours). They act by binding to various sites on pancreatic beta cells.

• Benefits and indications:^[9]  
  • Meglitinides are characterised by short duration and rapid onset of action, which requires them to be taken before a main meal.
  • Repaglinide may be suitable as monotherapy for non-obese patients in whom metformin is contra-indicated or not tolerated, or in combination with metformin.
  • Nateglinide is licensed only for use in combination with metformin.
• Risks: as with the sulfonylureas, the main risk with meglitinides is hypoglycaemia.

Thiazolidinediones

Thiazolidinediones (TDZs) or 'glitazones' - pioglitazone is the only one currently licensed in the UK. Its mechanism of action is still subject to debate but is thought to act in a similar manner to metformin, increasing hepatic sensitivity to insulin, and enhancing glucose clearance. Unlike metformin, it appears to have an effect on insulin-mediated glucose uptake at all insulin levels, making it effective in patients with insulin resistance. A TDZ may be preferable to a DPP-4 inhibitor if the patient has marked insulin insensitivity.^[3]

• Benefits and indications:
  • TDZs are usually used in combination with a sulphonylurea or metformin. It has also been licensed as monotherapy.
  • The combination with metformin or a sulphonylurea should only be used in patients unable to tolerate metformin and sulphonylurea in combination therapy, or in whom either metformin or a sulphonylurea is contra-indicated.
    • In such cases, the TDZ should replace whichever drug in the combination is poorly tolerated or contra-indicated.
    • A TDZ plus metformin is a useful combination for obese patients. The introduction of a TDZ may cause a deterioration of blood glucose control temporarily when used in combination therapy.
  • Pioglitazone may be considered with insulin therapy in patients who have previously had a marked glucose-lowering response to TDZ therapy or in those on high-dose insulin therapy and whose blood glucose is inadequately controlled.^[3]
• Risks:^[9] 
  Do not commence or continue a TDZ in patients who have heart failure, or who are at higher risk of fracture:^[3]
  • Cardiovascular: the risk of heart failure is increased when pioglitazone is combined with insulin and in patients with a history of cardiovascular disease. Patients who take pioglitazone should be closely monitored for signs of heart failure, and treatment should be stopped immediately if any deterioration in cardiac status occurs. Pioglitazone should not be used in patients with heart failure or a history of heart failure.
  • Risk of bladder cancer: there is a small increased risk of bladder cancer associated with pioglitazone use. Pioglitazone should not be used in patients with active bladder cancer, a past history of bladder cancer or for patients with uninvestigated macroscopic haematuria. .
  • There have been rare reports of liver failure, but large-scale trials have shown no difference in incidence between TDZs and other oral hypoglycaemics.^[10] Baseline LFTs and periodic monitoring are recommended.
  • There is an increased risk of fractures, especially in women.

Only continue with a TDZ if there has been a beneficial metabolic response (HbA1c falling 0.5% in 6 months).^[3]

Acarbose

• Acarbose acts by inhibiting intestinal alpha glucosidases, which delays the absorption and digestion of sucrose and starch.
• Acarbose is usually only used when other oral glucose-lowering medications cannot be used.^[3] 
• The use of acarbose is limited by its gastrointestinal adverse effects but these do decrease with time.

Dipeptidylpeptidase-4 inhibitors (linagliptin, saxagliptin, sitagliptin, and vildagliptin)

• Linagliptin, saxagliptin, sitagliptin, and vildagliptin inhibit dipeptidylpeptidase-4 to increase insulin secretion and lower glucagon secretion.
• Linagliptin is licensed for use in type 2 diabetes as monotherapy (if metformin is inappropriate), or in combination with metformin when metformin alone provides inadequate glucose control), or with both metformin and a sulfonylurea (when additional treatment is required).
• Saxagliptin, sitagliptin, and vildagliptin are licensed for use in combination with metformin, a sulfonylurea (if metformin is inappropriate) or pioglitazone when additional treatment is required.
• Sitagliptin and vildagliptin are licensed for use as monotherapy (if metformin is inappropriate). Sitagliptin is licensed for use in combination with both metformin and a sulfonylurea, or both metformin and pioglitazone when dual therapy with fails to achieve adequate glycaemic control.
• Sitagliptin or saxagliptin in combination with insulin (with or without metformin) is licensed for use when insulin has not provided adequate glycaemic control.

• Benefits and indications:
  • They may be appropriate ahead of a TDZ when the latter is contra-indicated, or if further weight gain would cause or exacerbate significant problems associated with a high body weight. In these circumstances, they are considered as a third-line therapy in combination with metformin and sulfonylurea when glycaemic control is still inadequate.^[3]
  • They can be considered second-line with metformin in patients at particular risk of hypoglycaemia (elderly patients living alone; other patients working at heights or with heavy machinery), or second-line in combination with a sulfonylurea in patients intolerant of metformin.^[3]
• Risks:
  • Hypersensitivity reactions may occur (anaphylaxis, angioedema and Stevens-Johnson syndrome).

Only continue DPP-4 inhibitor therapy if there has been a beneficial metabolic response (HbA1c falling 0.5% in 6 months).^[3]

Glucagon-like peptide-1 mimetics (exenatide and liraglutide)

Exenatide and liraglutide are both given by subcutaneous injection. They activate the glucagon-like peptide-1 (GLP-1) receptor to increase insulin secretion, suppress glucagon secretion, and slow gastric emptying. Treatment is associated with the prevention of weight gain and possibly even with weight loss.^[9]  

• Benefits and indications:
  • It may be a particularly useful step in patients who hold LGV or PCV driving licences, who would lose them if converted to insulin.
  • Can cause significant weight loss (rather than gain). Hence, it is most appropriate in patients with BMI ≥35.0 kg/m².^[3]
• Risks:
  • May cause significant gastrointestinal disturbance and there are reports of associated severe acute pancreatitis.
  • There is an interaction with warfarin (monitor INR carefully).
  • The long-term safety is not yet established.

Only continue GLP-1 mimetic treatment if there has been a beneficial response (HbA1c fall of 1% and a weight loss of at least 3% of initial body weight at six months).^[3]