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The right diabetes regimen: do you know the options?

Jill Lankester
RGN
Lead Diabetes Specialist Nurse
Whittington Hospital
London

The UKPDS showed that tight glycaemic control and tight blood pressure control reduced diabetes complications.(1) Tight glucose control reduced any diabetes endpoint by 12%, microvascular disease by 25% and myocardial infarction by 16%. Based on the findings of this study, we should be discussing with our patients ways of achieving an HbA1c target of 7% or less. To achieve this, most of their preprandial sugars will need to be 4-7 mmol/l, and postprandial 4-8 mmol/l.
However, these tight targets may not always be appropriate, and we need to take account of what is possible and safe for our patients. For example, in those with a relatively short life expectancy it may be inappropriate to impose strict targets when these may impair their quality of life.
It is the task of the health professional to choose a treatment plan that will achieve glycaemic control that is as good as possible, that is acceptable to the patient and that, as far as possible, prevents weight gain. It is important that patients are aware of the progressive nature of diabetes and that good glycaemic control to avoid complications is the continued aim of management, whether it takes lifestyle measures alone or the addition of tablets and insulin.

Pathophysiology of type 2 diabetes

Insulin resistance, hyperinsulinaemia and hyperglycaemia
Insulin resistance is a fundamental cause of type 2 diabetes and is strongly associated with central obesity.(2)  In order to understand the available treatment regimens, it is helpful to understand insulin resistance.
Insulin resistance is a decrease in the sensitivity of tissues such as the liver, skeletal muscle and body fat to the action of insulin. In the liver, impaired sensitivity to insulin causes an increase in glucose production, and the extra glucose enters the blood stream. In the other tissues insulin resistance decreases their ability to take up glucose from the blood. Both processes lead to a rise in blood sugar.
In response to this rise, the pancreatic beta cells secrete more insulin. This state is called hyperinsulinaemia and precedes the development of diabetes by some years. The extra insulin produced is just able to keep up with the rise in blood sugar levels. People with hyperinsulinaemia have been shown to have an increased risk of cardiovascular disease.(3)
Eventually, as insulin resistance continues or increases, the beta cells fail to compensate fully. Glucose levels begin to rise, leading to hyperglycaemia and the development of diabetes. During a patient's life with diabetes, beta cell failure increases and, with the continued presence of insulin resistance, good glycaemic control becomes increasingly difficult to achieve.

Treatment choices
Treatment choices available to our patients with type 2 diabetes can be divided largely into two groups.

Treatments that help to reduce insulin ­resistance:

  • Dietary advice for weight reduction.
  • Encouragement to increase physical activity.
  • Education about diabetes self-management.
  • Oral medication: metformin and glitazones ­(thiazolidinediones).

Treatments that help to counter or compensate for beta cell failure:

  • Oral medications that stimulate insulin production - insulin secretagogues: sulphonylureas and ­prandial glucose regulators.
  • Insulin therapy.

In addition, acarbose can be used as a first-line therapy if diet fails, or with another oral agent, or with insulin. It delays the digestion and absorption of starch and sucrose and thus alters the rise of blood sugar levels after a meal containing carbohydrate.
As diabetes progresses, patients may need a combination of many of these treatments to achieve optimum control.

Selecting the right treatment regimen at ­diagnosis

Does the patient need insulin?
Many people with type 2 diabetes are diagnosed, through screening, before they have any symptoms of hyperglycaemia. When a patient presents with symptoms we need to decide whether they are likely to need insulin straight away. If people have two or more of the following they are likely to need insulin, and would normally be referred to secondary care for management:

  • Moderate or large ketonuria.
  • Severe symptoms of hyperglycaemia.
  • A short history (a few weeks).
  • Significant weight loss.

It is important to remember that, although type 1 diabetes presents more usually in childhood or young adulthood, it can present at any age, and that includes old age.

Patients who don't need insulin
For these patients management of their diabetes is a stepwise process:

  • Weight reduction and increased physical activity - continue while HbA1c remains
  • Addition of oral monotherapy.
  • Combined oral therapy.
  • Insulin and oral therapy.

The treatment plan, which you may wish to discuss in some detail with your patient, will depend on whether they are overweight or normal weight (see Boxes 1 and 2).

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Oral antidiabetic medications

Tablets that reduce insulin resistance

Biguanides (metformin)

  • Metformin reduces hepatic glucose output and increases tissue sensitivity to insulin.
  • This is the tablet of choice in overweight patients and in other insulin-resistant groups (black African/ Caribbean and Asian).
  • Gastrointestinal side-effects are common and can be reduced by introducing it at a low dose and increasing slowly, and by advising the patient to take it with or after a meal.
  • There is a risk of lactic acidosis if renal or hepatic function is significantly impaired or the patient is hypoxic. It is therefore contraindicated if the ­creatinine level is above 130mmol/l, and should be avoided if patients have heart or respiratory ­failure or are very elderly.(4)
  • This tablet, if it is the only diabetic medication, does not cause hypoglycaemia.

Thiazolidinediones - often referred to as glitazones (eg, rosiglitazone, pioglitazone)

  • Glitazones decrease insulin resistance by ­increasing the uptake of glucose and fatty acids by muscle and fat cells and the liver. They therefore potentially reduce cardiovascular risk as well as glucose levels.
  • Their effect develops slowly over several weeks.
  • Adverse effects include fluid retention and weight gain. They should be avoided in people with heart failure.
  • Liver function must be monitored every 2 months in the first year of use, as severe liver toxicity was reported in an earlier glitazone that was ­subsequently withdrawn.
  • Glitazones are safe if the patient has mild-to- ­moderate renal failure.
  • They are currently licensed for use only in combination treatment with other oral hypoglycaemic agents.(5)
  • Triple combination therapy has been used ­successfully, particularly with patients who are very unhappy about taking insulin.
  • They are not licensed for use with insulin.

Insulin secretagogues

Sulphonylureas (eg, gliclazide, glibenclamide, ­tolbutamide, glimeparide)

  • Sulphonylureas have long been the mainstay of oral treatment, alongside metformin. They ­stimulate the beta cells to secrete more insulin.
  • Side-effects include increased appetite, weight gain and hypoglycaemia.
  • In renal impairment or the elderly, gliclazide or tolbutamide should be used as these are metabolised in the liver and are shorter acting.
  • Glimeparide and gliclazide MR are useful once-daily preparations for patients for whom this is an advantage.

Prandial glucose regulators (eg, nateglinide, ­repaglinide)

  • These have a short duration of action and are designed to be taken before 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 licensed for use only with ­metformin. Repaglinide may be used as a monotherapy.
  • These agents are useful for patients who have irregular or missed meals. If a meal is missed the dose should be missed.

When to add insulin
The addition of insulin is normally discussed with the patient when control is suboptimal on maximum doses of a combination of metformin and a sulphonylurea.
If the patient is introduced to the concept of adding insulin in an appropriate way, shown the easy devices available and given the opportunity to feel what it is like to insert an insulin needle, they are normally happy to give it a go.
Commonly, metformin, and often the sulphonylurea, is continued and a small dose of isophane or glargine insulin added before bed.

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Conclusion
The correct treatment regimen for diabetes may involve, progressively, diet, diet and tablets, or diet tablets and insulin in order to achieve an HbA1c as near as possible to 7%. But treatment with medication is only one aspect of the management of glycaemic control.
The Diabetes NSF is the first to make structured education and self-management the key to chronic disease management.(6) Advising and supporting our patients in making health-enhancing changes are fundamental to the care we give.

References

  1. United Kingdom Prospective Diabetes Study 33. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet 1998;352:837-53.
  2. Haffner SM. Epidemiological studies on the effect of ­hyperglycaemia and improvement of glycaemic control on macrovascular events in type 2 diabetes. Diabetes Care 1999;22 Suppl 3:54-6.
  3. Ruige JB, Assendelft WJ, Dekker JM, et al. Insulin and risk of cardiovascular disease: a ­meta-analysis. Circulation 1998;97:996-1001.
  4. National Institute for Clinical Excellence (NICE). National Clinical Guideline for Type 2 diabetes - management of blood glucose. September 2002.
  5. NICE Technology Appraisal ­guidance No 63. August 2003.
  6. Department of Health. The National Service Framework for Diabetes: Delivery Strategy. Department of Health: London; 2002.