Oral hypoglycaemic agents

Glycaemic control is one aspect of diabetes management, and the United Kingdom Prospective Diabetes Study (UKPDS), published in 1998, provides evidence that we can reduce complication rates in diabetes by improving HbA_1c levels. Oral hypoglycaemic agents (OHAs) are used in people with type 2 diabetes after an initial 3 month trial of diet and exercise (except in those who are severely symptomatic who require earlier intervention). Table 1 recommends which OHA should be introduced at which point in diabetes management, following the National Institute of Clinical Excellence (NICE) National Clinical Guidelines for Type 2 diabetes – management of blood glucose recommendations.

Metformin, the only oral treatment available in the biguanide group, reduces hepatic glucose output and increases tissue sensitivity to insulin, thereby reducing the overall demand for insulin. It is contraindicated in renal impairment (defined by NICE as a creatinine level of >130μmol/l), and gastro-intestinal intolerance is common, although this can be reduced by introducing and titrating the dose slowly.

Insulin secretagogues include sulphonylureas and the more rapid-acting nateglinide and repaglinide. Sulphonylureas have long been the main stay of oral treatment alongside metformin, and act by stimulating the
β cells to increase insulin secretion. Second-generation agents such as gliclazide, glimepiride and glipizide are more commonly used, with varying doses and frequency (Table 1). Side-effects include hypoglycaemia, and health professionals should be alert to this. Weight gain can also occur although the incidence of both these side-effects varies with different preparations.

Prandial glucose regulators, nateglinide and repaglinide, have a shorter duration of action and are therefore taken with each meal. They increase insulin secretion through different pathways from sulphonylureas, are rapidly absorbed and quickly eliminated, thereby reducing the risk of hypoglycaemia and weight gain. Nateglinide is an amino acid derivative and repaglinide is a meglitinide. They are recommended in people who have irregular lifestyles (Table 2).

Thiazolidinediones, often referred to as glitazones or insulin sensitisers, include rosiglitazone and pioglitazone. They increase tissue uptake of glucose and fatty acids (among other actions), thereby potentially reducing cardiovascular risk as well as glucose levels. Their effect is slow to develop over several weeks of treatment, adverse effects include weight gain and fluid retention, and liver function needs to be monitored. They are currently only licensed for use in combination treatment with other OHAs, and contraindicated in combination with insulin.

Acarbose is the only α-glucosidase inhibitor available in the UK, and delays the digestion of complex carbohydrates. Acarbose has a high incidence of gastro-intestinal side-effects including flatulence and diarrhoea, although these can be lessened if the dose is increased slowly. The side-effects mean that acarbose is often discontinued by the patient before it has any significant effect.

Table 2 details the NICE recommendations on how different oral treatments should be introduced. NICE recommends that people with diabetes should have individual HbA_1c targets set of between 6.5% and 7.5%. The guidelines also acknowledge that concordance with treatment is problematic with all glucose-lowering drugs, so the diabetes review should offer opportunities to check whether tablets are actually being taken. The guidelines also state that all oral treatments should be prescribed on a trial basis and the patient’s response should be monitored with HbA_1c readings, so a check of HbA_1c 3 months after any change in treatment should be carried out.

When glycaemic control is unsatisfactory, NICE recommends that another treatment should be added rather than substituted. It is worth noting that in the UKPDS, approximately 50% of people with diabetes were taking more than one glucose-lowering drug 3 years after diagnosis, and this rose to 75% by 9 years after diagnosis. Multiple drug treatment is therefore to be expected, and a significant number of people will also require the introduction of insulin if their target HbA_1c level is not maintained. 

Insulin should no longer be considered a last resort, and greater acceptance of insulin treatment by people with diabetes can be achieved by discussing it as a treatment option early in the disease process.

Case study 1
Tony White is a 48-year-old businessman with a BMI of 25 who was diagnosed with type 2 diabetes 3 years ago. He has not been prescribed any OHAs to date, although is taking anti-hypertensive medication. His HbA_1c was 6.8% a year ago and has now risen to 8%. 

a) What treatment and lifestyle goals would you choose for Tony and why?
b) What would be your treatment plan over the next 6 months?

Case study 2
Judy Walsh is 63 years old, works at a local charity shop, and was diagnosed with type 2 diabetes 6 months ago, at which time she had an HbA_1c of 9.5%. Her BMI is 32, and she started taking metformin (500mg) twice daily 3 months ago. Her HbA_1c has dropped to 8.5% but she has had diarrhoea since starting the metformin.

a) What treatment and lifestyle goals would you choose for Judy and why?
b) What would be your treatment plan over the next 6 months?