Diabetes, Oral Hypoglycaemic Agents and Exenatide

See related article Insulin Regimens

Oral hypoglycaemic agents are the group of drugs that may be taken singly or in combination to lower the blood glucose in type 2 diabetes. Type 2 diabetes can be due to increased peripheral resistance to insulin or to reduced secretion of insulin.
Oral hypoglycaemics should be used together with changes in diet and lifestyle to achieve good glycaemic control, and it is customary to monitor such changes for three months before considering medication.

Oral hypoglycaemic agents are not usually used in type 1 diabetes,¹ but metformin may be of use in overweight type 1 diabetics.²
The following groups of oral hypoglycaemics are currently available:

Metformin is the only drug licensed in this group.³ Various theories for the mechanism of action have been advanced, the most widely accepted being that it acts at the level of skeletal muscle by increasing glucose transport across the cell membrane.⁴ It only acts in the presence of endogenous insulin, and is therefore only effective when there are residual functioning pancreatic islet cells. Manufacturers state it should not be used in renal failure (where creatinine clearance < 60 ml/min).³ Local guidelines may vary e.g. stop metformin if serum creatinine ≥150 μmol/l.

• Benefits There is good evidence to support the use of metformin as a first-line drug in overweight patients when strict dieting has failed.^5,6 There is a growing body of support for the use of metformin as first-line in all type 2 diabetic patients.
  
  A summary of the evidence base is indicated below:
  • Metformin is the only oral hypoglycaemic shown to reduce macrovascular complications and death.⁵
  • It is associated with fewer hypoglycaemic attacks than sulphonylureas and does not cause weight gain.⁷
  • It is more effective than sulphonylureas in reducing any diabetes endpoint, all-cause mortality, and stroke. These improvements were not explained entirely on the basis of glycaemic control.^8,9
• Risks
  • The main problem with metformin is the risk of lactic acidosis and this is commoner in patients with renal insufficiency, cardiovascular disease, peripheral vascular disease, liver disease, pulmonary disease and age over 65 (see individual drug monograph for full list).¹⁰
    The risk is negligible if the contra-indications are rigorously followed, but does mean that approximately 50% of people needing an oral hypoglycaemic would be excluded from using metformin.⁶ It should be remembered that there is a temporary increased risk of lactic acidosis in situations where increased tissue hypoxia occurs, e.g. myocardial infarct, infection or respiratory depression.
  • Gastro-intestinal side-effects occur commonly with metformin at higher doses, and may necessitate a change of drug.

Sulphonylureas

Sulphonylureas are thought to act by enhancing pancreatic islet cell function.¹¹ They are also thought to act on the liver, stimulating the glycolytic pathway and inhibiting the production of glucose.¹² They generally have a duration of action of 12-24 hours.¹³

• Benefits
  • 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.¹² Their beneficial effects on reducing glycosylated haemoglobin (HbA1c) over a ten year period is well documented.¹⁴
  • Newer drugs in this group such as glipizide and glimipramide appear to afford similar efficacy to the older drugs such as gliclazide.^15,16
  • Chlorpropamide is no longer recommended, as it has more side effects than other members of this group. Tolbutamide is a shorter acting member of the group (half-life 4.5 to 6.5 hours).
  As mentioned above, the group as a whole is outperformed by metformin in terms of clinical outcomes.
• Risks
  • The main risk with sulphonylureas is hypoglycaemia. This is increased in older age groups, mild to moderate hepatic impairment, and renal impairment. The risk can be reduced by using a short-acting drug such as tolbutamide, or one of the newer sulphonylureas such as glimepiride.^15,16
  • Other problems can include weight gain, liver dysfunction and gastrointestinal disturbance.

Postprandial glucose regulators (Meglitinides)

The two drugs licensed for use in the UK are repaglinide and nateglinide. They are relatively short acting stimulators of insulin secretion(<6 hours).¹³ They act by binding to various sites on pancreatic beta cells.¹⁷

• Benefits
  • Meglitinides are characterised by short duration and rapid onset of action, which requires them to be taken before a main meal.
  • Repaglinide may suitable as monotherapy for non-obese patients in whom metformin is contraindicated or not tolerated, or in combination with metformin.¹⁸
  • Nateglinide is licensed only for use in combination with metformin.¹⁹ Head to head trials suggest that meglitinides may be of some use in patients with irregular lifestyles (eating habits) or where sulphonylureas are contraindicated.^13,20
• Risks
  • The main problem with meglitinides is hypoglycaemia but the evidence base is small. The trials that have been done indicate that the incidence of hypoglycaemia is equivalent to that of the older sulphonylureas.²¹

The two drugs licensed for use in the UK are pioglitazone²² and rosiglitazone.²³ Their mechanism of action is still subject to debate but they are thought to act in a similar manner to metformin, increasing hepatic sensitivity to insulin, and enhancing glucose clearance. Unlike metformin, they also appear to have an effect on insulin-mediated glucose uptake at all insulin levels, making them particularly effective in patients with insulin resistance.¹⁷ This latter effect is thought to be mediated via peroxisome proliferator-activated gamma (PPRA-gamma) receptors, of which the glitazones are agonists.²⁴

• Benefits
  • Thiazolidinediones are usually used in combination with a sulphonylurea or metformin, but not recommended with insulin.²⁵ Both drugs have now 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 thiazolidinedione should replace whichever drug in the combination is poorly tolerated or contra-indicated.
    • A thiazolidinedione plus metformin is a useful combination for obese patients. The introduction of a thiazolidinedione may cause a deterioration of blood glucose control temporarily when used in combination therapy.
  • Rosiglitazone may reduce the development of diabetes in patients with impaired fasting glycaemia.²⁶
• Risks
  • The MHRA advises that the thiazolidinediones should not be used in patients with any history of heart failure, as they can cause fluid retention and precipitate congestive cardiac failure.^25,27 This risk seems more related to long-term use,²⁸ and coterminous use of insulin.²⁹
  • There have been rare reports of liver failure, but large scale trials have shown no difference in incidence between thiazolidinediones and other oral hypoglycaemics.^30,31 Baseline LFTs and periodic monitoring are recommended.^22,23
  • Rosiglitazone has been associated with a significantly increased risk of MI and heart failure (but not cardiovascular death), and should not be used in patients with symptoms of coronary ischaemia.²³
  • The MHRA also warns that trial data showed a small increase in risk of fractures (mainly foot or arm) in women treated with rosiglitazone or pioglitazone, so they are not ideal treatment options for women with other risk factors for fracture.

Acarbose acts by inhibiting intestinal alpha glucosidases, which delays the absorption and digestion of sucrose and starch.³²

• Benefits Use acarbose for patients who cannot use other oral hypoglycaemics. Trials suggest that it can significantly improve glycaemic control over a three year period irrespective of other therapy.³³ It can also be used as an adjunct to metformin or sulphonylureas.
• Risks The use of acarbose is limited by its gastrointestinal adverse effects. The UKPDS study reported an incidence of 30% flatulence and 16% diarrhoea.³³ The side effects do however decrease with time.

These inhibit dipeptidylpeptidase-4, increases insulin secretion and lower glucagon secretion (enhancing the levels of active incretin hormones).³⁵ They are licensed for use in type 2 diabetes with combined with metformin and/or sulphonylurea, or with a thiazolidinedione when treatment with these alone fails to achieve adequate glycaemic control.^36,37

• Benefits:
  • Can be considered as a third line therapy in combination with metformin or a glitazone when glycaemic control is still inadequate. There is no evidence for use as a triple therapy, nor comparison with any of the alternative multiple drug regimens above so their place in the armoury is not well established at present, and may be clarified when the NICE guidance is reviewed.
• Risks:
  • Hypersensitivity reactions may occur (anaphylaxis, angioedema and Stevens-Johnson syndrome).

This is a synthetic form of exendin-4, is also an incretin mimetic, licensed for use in type 2 diabetes, in combination with metformin and/or sulphonylureas.³⁸ It is given as a twice daily subcutaneous injection up to an hour before meals (but not afterwards). It can be considered as an alternative to insulin therapy in obese patients who have failed to achieve adequate glycaemic control on maximal doses of established oral treatment regimens.

• Benefits:³⁹
  • It may be a particularly useful step in patients who hold HGV or PSV driving licenses who would lose them if converted to insulin.
  • It has a comparable efficacy to insulin - and may offer some advantages due to its fixed dose regimen and can cause significant weight loss (rather than gain).
• Risks:
  • It can cause significant hypoglycaemia (consider reducing dose of other hypoglycaemics).³⁹
  • Gastrointestinal side effects are common (particularly nausea).
  • There is an interaction with warfarin (monitor INR carefully).
  • The long term safety of the drug is not yet established.