The study demonstrated that in both the conventional and intensive treatment groups, there was a steady increase in fasting blood glucose and glycated haemoglobin (HbA1c) over the period of the study. Type 2 diabetes is therefore a progressive disease associated with worsening metabolic control over a number of years (Fig. 4.1). This implies that metabolic control can be maintained in type 2 diabetes only by progressive increases in doses of medications and the utilisation of multiple therapies, including insulin. The different treatment modalities showed little difference on their effect on fasting blood glucose or HbA1c. Only people treated with chlorpropamide had significantly improved metabolic control when compared with other sulphonylureas or insulin.

The intensively treated group showed an 11% reduction in HbA1c when compared to the conventional group (HbA1c 7.0% compared to 7.9%). For every 1% increment in HbA1c the study demonstrated a:

Furthermore, the UKPDS (1998a) demonstrated that benefits could be achieved by reducing HbA1c results no matter how low they were to start with; in other words the lower the HbA1c the better. Microvascular risk became low when HbA1c reached levels of 7–8% whereas macrovascular risk continued to fall, down to HbA1c levels of 6–7%.

The difference in HbA1c results between the conventional and intensive treatment groups was associated with a significantly reduced frequency of microvascular endpoints; the reduction in diabetes-related mortality or macrovascular endpoints did not quite reach statistical significance. However, the group of obese people who were treated intensively with metformin showed a significant reduction in cardiovascular risk.

Metformin was the only treatment that was not associated with weight gain and raised circulating concentrations of plasma insulin. Sulphonylureas and insulin treatments were associated with increased plasma insulin concentrations and insulin resistance, and this might therefore have accounted for their poorer influence on long-term cardiovascular morbidity.

Exercise confers the well-established benefit of improved insulin sensitivity for people with or without diabetes. As with weight loss, improved insulin sensitivity is associated with reduction in blood pressure and improvement in lipid profiles, thus reducing cardiovascular risk. Improved fitness and exercise are associated with a reduction in coronary disease in the general population, but evidence for such a decrease among people with diabetes has not appeared.

The addition of exercise training to a conventional diet has been shown to be beneficial (Blonk 1994) with people showing greater weight loss and improved HbA1c. However, weight loss tends to be modest in most people and only a minority maintain their weight loss over a 3-year period (Stevens et al 2001).

Increased insulin sensitivity allows glucose to enter muscle cells more efficiently both acutely and chronically with exercise. Improvements in glucose tolerance testing have been shown in type 2 diabetes after as little as 1 week of aerobic training. Increased insulin sensitivity begins to decline however, in as little as 1 or 2 days without exercise.

Exercise can therefore improve diabetic control and allow lower doses of oral hypoglycaemic drugs or insulin. However, the exercise must be maintained and this requires both self-motivation by the individuals and continuing encouragement by their families, friends and health carers. The optimal methods for maintaining motivation are still to be identified.

The finding of a random blood glucose above 11.1 mmol/L in a person with osmotic symptoms confirms diabetes. Bernard’s elevated blood glucose might be the cause of his lethargy. In addition to his diabetes, his unhealthy lifestyle will further increase his risk of vascular catastrophe in the future unless he makes major alterations to the way he lives.

Bernard’s case history is fairly typical of the person with type 2 diabetes. There is a strong family history of diabetes and he has the associated risk factor of being overweight. He is likely to have other features of the metabolic syndrome; namely hypertension and hyperlipidaemia. His initial management will involve appropriate changes to his lifestyle including diet and exercise.

As Bernard has a sedentary lifestyle, he should be encouraged to increase his exercise activity. It is recommended that all individuals (including those with diabetes) undertake aerobic physical activity on a minimum of 3 days per week with sessions lasting 20–60 minutes. However, our 52-year-old taxi driver might have to start with low intensity exercise for shorter periods of time. In some areas of the UK, general practitioners can prescribe an exercise programme at a local gym. It is important to undertake a pre-exercise assessment of people with diabetes prior to entry into any such programme. Watch for signs and symptoms of peripheral vascular disease, such as intermittent claudication, cold feet, decreased or absent peripheral pulses. Diminished light touch, pin-prick or vibration sense might signal a peripheral neuropathy. Such people might be at risk of foot ulceration if asked to undertake exercise. Eyes should be examined to identify new vessel formation (see Chapter 9).

A history of postural hypotension, hypoglycaemia unawareness, gustatory sweating or impotence might signal the presence of autonomic neuropathy which, if present, could make exercise dangerous because of risks to the heart.

An exercise stress test is recommended for people at risk of heart disease who anticipate engaging in moderate to intense exercise. Among people with diabetes who are considered at risk are those who are older than 35 years, who have had type 2 diabetes for longer than 10 years and those who have had type 1 diabetes for longer than 15 years.

Metformin lowers blood glucose concentrations by several mechanisms. Its most important effect is to enhance insulin sensitivity in peripheral tissues, in particular the liver and skeletal muscles. By improving insulin action on the liver, metformin inhibits glucose production and release. It also stimulates insulin uptake by skeletal muscle. It might have direct or indirect effects on reducing appetite (Bailey 1992).

The UKPDS included a subgroup of overweight people who were allocated to treatment with metformin, sulphonylureas (chlorpropamide or glibenclamide) or insulin therapy. Only metformin therapy was associated with improved insulin sensitivity and reduced circulating concentrations of insulin.

Reduced insulin resistance would be expected to improve cardiovascular risk and, indeed, the UKPDS showed that metformin had the greatest effects on any diabetes-related end point, on overall mortality due to any cause and also on the incidence of stroke. The UKPDS also reported that, in overweight people, metformin was not associated with weight gain and produced fewer hypoglycaemic attacks than sulphonylureas or insulin therapy (UKPDS 1998b). It is therefore recommended that metformin is used as first-line treatment in overweight people if lifestyle changes fail to improve diabetic control.

Metformin is likely to reduce blood glucose concentrations by 2–3 mmol/L when prescribed for people in whom diet has failed. This is a comparable blood glucose lowering effect to sulphonylureas. About 30% of people so treated will achieve good diabetic control. However, in a further 5–10% of people per year, metformin treatment will fail to achieve adequate control.

Metformin is available in the UK as 500- and 850-mg tablets. The drug should be taken with meals and the dose increased gradually to lessen side effects. A typical starting dose would be 850 mg once daily or 500 mg once or twice daily. The dosage can be increased in a stepwise fashion over a period of several weeks to prevent adverse drug effects. Garber et al (1997) showed that metformin lowered HbA1c and fasting blood glucose in a dose-related manner, up to 2000 mg per day. Beyond this dosage there is little therapeutic gain but a much higher incidence of side effects.

The most common side effects of metformin are gastrointestinal in origin. About 20% of people experience diarrhoea, flatulence or abdominal pain, whereas others complain of a metallic taste, nausea or anorexia. Although a reduction in appetite might be desirable in the overweight person, for the sake of compliance any nausea or anorexia must be considered seriously. These disturbances are generally transient and can be minimised by starting treatment at a low dosage and taking the drug with food.

Metformin can cause the blood lactate levels to rise. However, if it is prescribed taking into account recognised contraindications, there is no increased risk of serious lactic acidosis or increased levels of lactate compared to other antihyperglycaemic agents (Aguilar et al 1992). Metformin is normally excreted through the kidneys and is contraindicated in people with impaired renal function (e.g. serum creatinine > 130 micromol/L) as this can result in accumulation of the drug in the body, enhancing its effect on lactate production. Liver disease is also a contraindication, because adequate hepatic function is required to metabolise the increased lactic acid. People with cardiac failure perfuse their tissues poorly and the resulting tissue hypoxia causes lactic acid production. It is therefore unwise to prescribe metformin for such individuals. Metformin should be temporarily withdrawn in people undergoing surgery or radiology procedures requiring injection of contrast.

Before making additions to Annie’s current therapy, it is important to determine if she is actually taking her current prescribed medication. Further dietary assessment should also be undertaken to determine her understanding, identify any necessary changes to be made and to assess her motivation and adherence.

One of the most important findings of the UKPDS was the demonstration that type 2 diabetes is a progressive condition. All modalities of therapy were associated with a relentless rise in HbA1c with duration of disease (see Fig. 4.1). This results in the need for increasing doses of medication and the introduction of multiple therapies to maintain diabetic control. UKPDS (1990) suggested that 3 years after diagnosis approximately half of people controlled on diet alone were failing in their control and required more than one glucose-lowering drug. After 9 years this increased to 75% of people requiring multiple therapies to achieve HbA1c levels averaging 7.0%. Following the failure of metformin to control Annie’s diabetes, the introduction of an insulin secretogogue is recommended (NICE 2004).

Sulphonylureas have been used to treat type 2 diabetes for more than 50 years. In recent years, understanding of their mode of action has developed. Sulphonylureas bind to cell membrane receptors on the beta cell. This causes the potassium channel across the membrane to close and the membrane to depolarise. In turn, this causes calcium influx and insulin granule release into the extracellular medium. Therefore the effect of sulphonylureas is limited to people with preserved pancreatic cell function. The pancreas can only be squeezed to produce more insulin if there are functioning beta cells there to be squeezed!

It is generally recommended that sulphonylureas are ingested about 30 minutes before meals as this will stimulate insulin production to coincide with the time of eating. This in turn has been shown to reduce the postprandial rise in blood glucose (Melander et al 1989). Most drugs in this group are given twice daily when used at higher doses. The maximum therapeutic effect of most sulphonylureas is achieved at relatively low doses. This is likely to be due to cell receptors for the drug becoming saturated at low doses and further increases in drug dose have no additional effects. A person who shows poor glycaemic control on a dose of gliclazide 160 mg daily or glibenclamide or glipizide 10 mg daily is unlikely to respond optimally to higher doses and a decision to start additional therapy should not be delayed unnecessarily.

Glinides, such as repaglinide and nateglinide, are recently introduced insulin secretogogues. Like the sulphonylureas, they bind to the sulphonylurea receptor on the surface of the beta cell. The binding, however, occurs at a different position on the sulphonylurea receptor. Nevertheless, their action is similar to that of the sulphonylureas, causing closure of the transmembrane, potassium channel and subsequent release of insulin from the beta cell.

These drugs are short acting and should be taken before main meals. Their function is mainly to reduce postprandial rises in blood glucose. There is some evidence to support the hypothesis that rapid rises in blood glucose levels are particularly important in the development of diabetic complications. Therefore, drugs that can reduce postprandial glucose excursions might be important in reducing the morbidity and mortality associated with diabetes. However, this theory is at present unproven and controversial.