3: Management of diabetes

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Section 3 Management of diabetes

Type 1 diabetes – initiating therapy

Type 2 diabetes – initiating therapy

Glycaemic monitoring

Principles of education in diabetes

Organization of diabetes care

Type 1 diabetes – initiating therapy

Home-based instruction of the newly diagnosed child or young person appears to be at least as effective as inpatient instruction in terms of glycaemic control, acceptable to the family and/or carers and cost-effective. There is no evidence for a sustained effect of any specific insulin regimen on glycaemic control during the first few months after diagnosis.

Dietary advice as part of a comprehensive management plan is recommended to improve glycaemic control. A dietitian should give specialist dietetic advice with expertise in type 1 diabetes, and all patients should be able to access such training locally and, ideally, at their own diabetes clinic.

Glycaemic targets

There is compelling evidence that good glycaemic control reduces the risk of microvascular and macrovascular complications in people with type 1 diabetes. However, there is no agreed single target for glycaemic control in type 1 patients. Targets recommended by different authorities vary between 6.5% and 7.5%. However, individual preferences, general treatment goals, co-morbidities and other patient factors may require modification of glycaemic goals. In addition, targets also vary within an individual even over a very short period of time, depending on a variety of clinical and non-clinical circumstances.

The overall aim is to achieve the lowest possible HbA1c that does not interfere with the patient’s quality of life.

Insulin regimens

Evidence regarding the impact of an intensive insulin regimen upon long-term control is derived principally from the Diabetes Control and Complications Trial (DCCT), which also involved a comprehensive patient support element (diet, exercise plans and monthly visits). Intensive insulin therapy (four injections or more per day, or insulin pump) significantly improved glycaemic control over a sustained period compared with conventional insulin therapy (two injections per day). However, it is difficult to separate the benefits of intensive insulin therapy from the intensive support package.

The choice of insulin regimen and dose depends on several factors: what type of diabetes a person has; their weight; their age; how often they check or intend to check their blood glucose; and, finally, what goals they are trying to achieve.

The principle of insulin replacement is to mimic insulin secretion in a person without diabetes and to achieve the best possible control of blood glucose without causing significant hypoglycaemia. After eating, there is normally a rapid rise in insulin to limit glucose levels after meals. Overnight, low steady levels of insulin (the background or ‘basal’ insulin level) are sufficient to limit glucose production by the liver.

Appropriate combinations of the above insulins can be tailored to the individual; a certain element of this will be trial and error, but close liaison with the health-care provider usually results in the right regime for that person (Table 3.1). The pre-mixed insulins are a popular starting regimen, and the timing of onset, peak and duration of action will depend on the component parts.

Table 3.1 Insulin types, names and profiles of insulin action

Conventional therapy for type 1 diabetes (twice-daily insulin with support from a multidisciplinary health-care team and regular diabetes and health monitoring) is associated with variable results.

Both basal (e.g. glargine and detemir) and rapid-acting (e.g. lispro, aspart and glulisine) insulin analogues are prescribed widely in the management of type 1 diabetes.

Insulin injection sites

The recommended sites for insulin injection are shown in Figure 3.1. Injection should be given into a pinched-up skin fold using thumb, index and middle finger, taking up the skin and leaving the muscle behind. This will avoid intramuscular injection. Too shallow an injection will be delivered intradermally, and can be painful.

• Insulin absorption is fastest in the abdomen and slowest in the arms and buttocks. Short-acting insulin is best given into the abdomen, and long-acting insulin into the thigh or arm; however, this can be varied according to the most practical site available.

• Most importantly, the injection sites should be ‘rotated’: if the abdomen is the site used most often then rotating around different points regularly is a good idea. This should avoid lipohypertrophy (an accumulation of fat under the skin), which occurs if the same injection site is used repeatedly. If this occurs, it can be unsightly and increases the variability of insulin absorption.

• If a person rotates from limb to limb, it is good idea to try to stick to a schedule whereby the same area is injected at the same time of day, for example morning injection in the abdomen, teatime injection in the leg.

• Insulin absorption may also be accelerated by exercising that part of the body (e.g. injecting legs and then jogging/running).

Figure 3.1 Recommended sites for subcutaneous insulin injection.

Different insulin delivery systems

There are four main devices for insulin injection: needle and syringe; insulin pens (now most commonly used); jet injection devices; and external pumps.

Needle and syringe

This is the traditional method of delivery. The following steps are recommended:

1. Clean the rubber stopper of the bottle with alcohol. If intermediate-acting or long-acting insulin is being used (cloudy insulins), mix by rolling or rotating the bottle.

2. Open the syringe to the number of units that is needed so that there is air to this point in the syringe.

3. Turn the insulin bottle upside down and inject the stopper with the needle.

4. Push the air inside and withdraw the insulin dose required.

5. Give the syringe a few taps with your finger to get the bubbles to the top, and push the bubbles back into the bottle.

6. Pinch up the area of skin to be injected.

7. Insert the needle at a right angle to the skin and push it in; then push down the plunger to administer the insulin.

There are now several aids to needle and syringe delivery: spring-loaded syringe holders; syringe magnifiers to help the visually impaired; syringe-filling devices that click when the insulin has been taken up; and needle guides for when a person cannot see the rubber stop on the bottle where the needle is inserted to take up insulin.

Insulin pens

These pens come with a cartridge already inserted that contains 3.0 mL of the specific insulin and the patient can dial the amount of insulin to be taken. Each unit (or 2 units) is accompanied by a click so that people with visual impairment can hear the number of units; the number will also appear in a window on the pen. The pens allow delivery of 30–70 units; a new needle can be screwed on as necessary. There are several different pens available and it is best to view them and try them out with a diabetes specialist nurse to see which is most suitable.

Jet injection device

These are expensive but good for people who cannot perform the injection for themselves. The device holds a large quantity of insulin to be used for multiple treatments. After dialing up the amount of insulin to be delivered, the device is held against the skin and, on pressing a button, a jet of air forces the insulin through the skin into the tissue underneath. The device is occasionally leaky, with insulin staying above the skin; others report that the injection can be painful.

Traditionally patients are advised to rotate the location of their injection sites; this helps to avoid local reactions to insulin, which are, principally:

• Allergy. Local allergic reactions are uncommon with modern insulin preparations; reactions to diluent or preservatives are sometimes thought to be of relevance; a change of brand may help, but many cases resolve spontaneously. Transient tender nodules developing at the injection site are suggestive; generalized allergic reactions are exceedingly uncommon. Testing kits are available from insulin manufacturers. Major insulin resistance due to high titres of anti-insulin antibodies that cause antigen–antibody complexes is very uncommon; corticosteroids may be useful.

• Lipohypertrophy. Localized areas of lipohypertrophy, although comfortable to inject into, are thought to cause erratic absorption of insulin from the site. The hypertrophy is attributed to the trophic effects of insulin on fat metabolism. Avoidance of the area may lead to regression; liposuction has been used.

• Lipoatrophy. This has become rare since the introduction of highly purified, and more recently human sequence, insulins. It may be improved by the injection of highly purified soluble insulin around the edge of the lesion.

Patients occasionally complain of recurrent minor local bleeding or bruising, which rarely presents any real cause for concern.

Renal failure

Care is required with insulin treatment in patients with progressive renal impairment. Decreased insulin degradation by the failing kidneys, anorexia with decreased caloric intake and reduced renal gluconeogenesis may all contribute. Sometimes substantial reductions in insulin dose may be required.

Progressive renal failure necessitates reduction in insulin dose.

Some patients with end-stage renal failure on continuous ambulatory peritoneal dialysis (CAPD) inject their insulin into the dialysate bags, thereby delivering insulin intraperitoneally. Insulin requirements vary enormously between patients and are in part dependent on the strength of dialysate used; hypertonic solutions contain high concentrations of glucose.

Disposal of needles

Clipper devices are available for the safe disposal of used syringe needles. Boxes designed to contain used sharps should be disposed of appropriately. Some local authorities offer a needle disposal service.

Altering insulin doses

Patients vary in their capacity and willingness to adjust their own insulin doses. Some will never make an adjustment; the advice of the specialist nurse can be helpful in such cases and close telephone contact is reassuring. Other patients alter doses too frequently according to their latest home capillary readings – this can lead to a ‘roller-coaster’ effect with glycaemic instability, and is best avoided. Although there are some general principles to be followed, there are no hard-and-fast rules; caution and common sense are guiding principles.

• Alter one insulin dose at a time.

• Alter the appropriate insulin based on knowledge of the pharmacokinetics of the insulin preparations being used. For example, on twice-daily mixtures of short- and medium-acting insulin:

• Allow a few days to observe the effect of the change; daily fluctuations must be taken into account.

• A relatively small change (2–4 units) is generally safe; larger changes may be indicated in some instances, but care should be taken to avoid inducing hypoglycaemia. Such small alterations are not always appropriate; the magnitude of the increase or decrease should reflect the overall insulin dose. For example, for a patient stabilized on a daily dose of 40 units, a change of 4 units is 10% of the total; for a patient on 100 units, a proportionately similar change would be 10 units. Moreover, when insulin has just been initiated, tiny daily increases in dose may be too cautious. However, experience is required in judging whether larger increases are indicated.

• If recurrent hypoglycaemia occurs at the higher dose, the patient should drop back to the previous dose.

• Remember that increasing the dose of a pre-mixed insulin preparation will increase both the short- and the longer-acting components.

• Be prepared for discrepancies between theory based on insulin pharmacokinetics and the realities of clinical practice.

Unwanted effects of insulin therapy

Weight gain

This is a common consequence of insulin (and sulphonylurea) treatment. In patients with type 1 diabetes, some regain of lost body weight is appropriate; this reflects the physiological anabolic effects of insulin. However, in patients with type 2 diabetes, the initiation of insulin therapy because of inadequate glycaemic control with oral agents is often associated with unwelcome weight gain. Dietary countermeasures may be partially effective, particularly when combined with an exercise programme. Weight gain is not inevitable but it can detract from the sense of achievement for some patients. It tends to plateau after a few months, possibly reflecting the resetting of a physiological homeostatic mechanism.

Insulin oedema

This is a rare complication of insulin therapy. Oedema of the feet and legs develops shortly after the initiation of insulin and resolves with continued therapy. The aetiology is uncertain but insulin-mediated sodium and water retention by the kidney has been postulated.

Transient deterioration of retinopathy

A rapid and sometimes marked transient deterioration in pre-existing retinopathy may follow the institution of improved glycaemic control, for example when insulin is commenced after tablet failure. This appears to be due to a reduction in retinal blood flow that occurs with improved glycaemic control. As a result, already compromised areas of retinal circulation become more ischaemic and further damage may occur.

Insulin neuritis

An uncommon complication is so-called insulin neuritis, wherein acute symptomatic neuropathy, which may be very unpleasant, develops following the institution of insulin treatment. Histological studies in acute painful neuropathies have demonstrated actively regenerating neurons, which are thought to be the origin of the symptoms. Rapid alterations in osmotically active intraneural molecules (e.g. sorbitol) are also thought to be relevant. The prognosis appears to be generally favourable with continued good glycaemic control. Symptomatic treatment may be required until recovery, which may not always be complete; subclinical neuropathy predating the improved control may have been present in some cases.

Postural hypotension

A clinically significant fall in blood pressure shortly after insulin injection is very rare. The vasodilator effects of insulin have been implicated, but the pathophysiology remains uncertain.

Severe insulin resistance

The definition is arbitrary. When daily insulin doses (in excess of 200 units) were needed to control glycaemia, it was considered to reflect severe insulin resistance; this is now largely of historical interest. The concept of insulin resistance is discussed in Section 1.

• Severe insulin resistance syndromes. Specific causes of severe insulin resistance, congenital or acquired, are very rare.

• Brittle diabetes. Whether this entity exists is regarded as contentious by some. Apparently high insulin requirements with swings in control are a feature of some patients with idiopathic brittle diabetes.

• Hormonal stress response to intercurrent illness. Transient insulin resistance may arise in the course of intercurrent illnesses (e.g. sepsis); temporary increases in insulin doses, sometimes necessitating a change to intravenous or multiple subcutaneous doses of short-acting insulin, are required. Insulin may be required during the course of such an illness in patients previously well maintained on oral antidiabetic agents; this will usually be undertaken in the hospital setting. With resolution of the acute episode, reintroduction of oral therapy may be possible.

• Anti-insulin antibodies. The role of acquired anti-insulin antibodies, once thought to be an important mechanism of insulin resistance, has faded with modern, less antigenic, insulin preparations.

• Obesity. Clinical insulin resistance is confined largely to patients with type 2 diabetes whose obesity and associated insulin resistance limits attainment of glycaemic targets despite large doses of insulin. However, type 1 patients can become obese and develop insulin resistance – possible ‘double diabetes’.

Insulin regimens

This is the schedule of insulin that a person will decide upon with their health-care professional, and is based on the type of diabetes, physical needs and lifestyle (in particular eating patterns and activity). The variables include type of insulin, timing and dose (Fig. 3.2). There are many regimens, but the most common examples are:

• Insulin added to oral medication. This combination is worthwhile in those with type 2 diabetes where the fasting blood glucose begins to rise despite maximum oral medication. It most often means a dose of long-acting insulin at bedtime.

• Twice-daily insulin. This is either two doses of an intermediate-acting insulin or two doses of a mixed insulin to give more control over postprandial increases in blood glucose (Fig. 3.3). The latter is often used in type 1 diabetes when the individual wants to avoid taking insulin at work/school at lunchtime.

• Basal-bolus insulin. This is essentially intensive insulin therapy and is discussed below (Fig. 3.4).

Figure 3.2 Action profiles of injectable insulins. NPH, neutral protamine Hagedorm.

Figure 3.3 Twice-daily insulin. B, breakfast; L, lunch, S, supper; HS, hora somni (bedtime); NPH, neutral protamine Hagedorm.

Figure 3.4 Basal-bolus insulin replacement.

If recurrent hypoglycaemia occurs at the higher dose, it should be dropped back to the previous dose. If there is a significant change in diet and weight, this can increase or decrease insulin requirements significantly.

If no change in results is observed, check your insulin (expiry and pen device), plus review your injection site and technique with a health-care professional.

Adverse effects of insulin therapy

Although insulin is no doubt life-saving to many and provides a dramatic improvement in symptoms, to others it is good to be aware of the following adverse effects:

• Hypoglycaemia. This is the most common disadvantage of insulin therapy and occurs when the amount of insulin taken is too much for the amount of food ingested, exercise undertaken or starting level of blood sugar. It may also occur as a consequence of excess alcohol intake (see Section 4).

• Weight gain. When insulin is started, a person will begin to retain fat; this is normal to some extent. People will find they are unable to eat as much as they did previously without putting on weight and therefore they should beware of overeating. Also, eating snacks to avoid hypoglycaemia should be limited as much as possible. It is usually better to reduce the insulin dose rather than eating to justify it.

• Insulin allergy. This is now extremely rare due to the use of human insulin.

Rapid-acting insulin analogues

Rapid-acting insulin analogues have a small but statistically significant effect on glycated haemoglobin (HbA1c) that, in the context of long-term glycaemic control, is unlikely to be clinically significant. However, there is a reduction in hypoglycaemia associated with their use, and insulin analogues have been associated with an improvement in treatment satisfaction scores.

Basal insulin analogues

Basal insulin analogues appear to offer no clinically significant improvement in glycaemic control, but are associated with fewer severe hypoglycaemic episodes, particularly nocturnal episodes. Insulin detemir is associated with less weight gain than neutral protamine Hagedorm (NPH) insulin, but many individuals require twice-daily dosing. Basal insulin analogues appear to offer greater patient satisfaction but no clear change in quality of life.

Basal insulin analogues should be used in adults with type 1 diabetes who are experiencing severe or nocturnal hypoglycaemia. In type 1 diabetic patients who are not experiencing severe or nocturnal hypoglycaemia, NPH insulin could be considered.

Rapid-acting and basal insulin analogues in children and adolescents

In children and adolescents, the use of rapid-acting and basal insulin analogues offers similar glycaemic control, rates of overall hypoglycaemia, and rates of nocturnal hypoglycaemia to that of regular human insulin. Therefore, children and adolescents should be offered insulin analogues, regular human insulin and NPH preparations, or an appropriate combination of these.

The insulin regimen should be tailored to the individual to achieve the best possible glycaemic control without disabling hypoglycaemia.

Intensive insulin therapy should be delivered as part of a comprehensive support package. In general this refers to regular contact between patients and their families/carers and the local multidisciplinary diabetes team delivering specific health-care strategies.

Continuous subcutaneous insulin infusion therapy

Continuous subcutaneous insulin infusion (CSII) or ‘insulin pump’ therapy allows programmed insulin delivery with multiple basal infusion rates and flexible bolus dosing of insulin with meals. In developed countries its usage is increasing in patients with type 1 diabetes who are expert at carbohydrate counting or have undertaken an appropriate structured education course. Carbohydrate counting is an essential skill to support intensified insulin management in type 1 diabetes, by either multiple daily injections (MDI) or CSII. CSII therapy requires considerable input from the patient along with the diabetes nurse specialists and dietitians, in addition to the purchase of a pump and consumables.

Pumps are often the size of a pager and are worn on a belt or in the clothing, with thin plastic tubing coming from the pump to a needle that penetrates the skin, usually in the abdomen. It is in place 24 hours a day, and this device is as close as one can get to the constant gradual administration of insulin that is taking place in the body.

Some important points to know about pumps

• They do not measure blood sugar and so the pump still needs to be directed by blood sugar measurements with a meter and dose adjustments.

• There are two basic rates of delivery: the basal rate, which is a slow, continuous trickle when a person is not eating, and the bolus rate, which is a much higher flow rate delivered when a meal is about to be eaten.

• Much guidance is required, especially at the start, from the diabetes specialist nurse and/or doctor, in addition to a dietitian.

• National Institute for Health and Clinical Excellence (NICE) guidelines recommend that pumps be considered in those where other insulin regimes have ‘failed’ – where it is not possible to reduce HbA1c to less than 7.5% without causing ‘disabling hypoglycaemia’. Pumps should also be considered only for patients who are committed to gaining the considerable expertise and competence that the effective use of a pump requires.

Advantages of pumps

• They are flexible and good for people whose meal times are unpredictable.

• They have built-in safety devices to stop overdosage.

• They generally do improve control, reducing uncomfortable swings in blood sugar, and result in a better HbA1c.

Disadvantages of pumps

• Skin infections can occur as the infusion set is left in situ for a few days.

• Ketoacidosis can occur rapidly if the pump disconnects, as short-acting insulin is the only form given.

• Blood glucose must be measured frequently to adjust the pump for best control.

• They are expensive (more than £2500, with annual costs of about £1200).

• Limited availability of pumps supplied from the National Health Service.

Concerns have been raised over the lack of independent studies to allow objective comparison of MDI and CSII.

However, in patients with type 1 diabetes, CSII therapy has been associated with an improvement in glycaemic control with reported mean falls in HbA1c of between 0.2% and 0.4% (2.2–4.4 mmol/mol) or greater mean treatment satisfaction scores.

CSII therapy should be considered for patients unable to achieve their glycaemic targets and in patients who experience recurring episodes of severe hypoglycaemia. Pump therapy management requires a local multidisciplinary pump clinic for patients who have undertaken structured education. Patients using CSII therapy should agree targets for improvement in HbA1c and/or reduction in hypoglycaemia with their multidisciplinary diabetes care team. Progress against targets should be monitored and, if appropriate, alternative treatment strategies should be offered.

An insulin pump is recommended for those with very low basal insulin requirements (such as infants and very young children) where even small doses of basal insulin analogue may result in hypoglycaemia.

Inhaled insulin

A number of drug companies have developed inhaled insulins. In principle, this was a way of avoiding giving insulin by injection, but the dose of insulin needed is about seven times the amount needed, compared with injection. The accuracy of dosing has proved difficult and, because the insulin is being absorbed through the lungs, there has been some doubt about long-term safety – it would be difficult to know for many years whether inhaling insulin might impair lung function.

One preparation has been recently withdrawn from the market, but inhaled insulins continue to be developed. Currently there are no preparations available for use.

Type 2 diabetes – initiating therapy

The immediate purpose of lowering blood glucose is to provide relief from symptoms (thirst, polyuria, nocturia and blurred vision). Thereafter, the aim is to prevent microvascular complications: retinopathy, nephropathy and neuropathy.

Hyperglycaemia, along with hypertension and dyslipidaemia, is associated with macrovascular complications (myocardial infarction (MI), stroke and peripheral arterial disease). The effects of glucose-lowering therapies on cardiovascular morbidity and mortality are therefore of major importance (and not just on glucose-lowering).

Oral hypoglycaemic agents

Modifications to diet and lifestyle are seldom sufficient to produce good, long-term, metabolic control in patients with type 2 diabetes. Thus, pharmacological adjuncts are required in the majority of patients early in their management. Historically, orally active agents are usually employed first-line, whereas insulin is reserved for patients in whom tablets prove insufficient.

The choice of drug depends on both clinical and biochemical factors; as with all pharmacological agents, antidiabetic therapy should be initiated only following careful consideration of the possible benefits and risks of treatment for the individual patient.

Selection of oral antidiabetic agents should be based on the potential benefits and risks to the patient.

Classification

Oral antidiabetic drugs may usefully be classified by their actions as being either:

• hypoglycaemic agents, or

• antihyperglycaemic agents.

This distinction, which reflects differences in chemistry and hence mode of action, is clinically relevant. Drugs in the latter category do not usually cause hypoglycaemia when used as monotherapy. It should be noted that other drugs, not used primarily as antidiabetic agents, may also lower plasma glucose concentrations (Table 3.2). The latter agents may potentiate the glucose-lowering effects of other drugs.

Table 3.2 Hypoglycaemic and antihyperglycaemic drugs used to treat type 2 diabetes

Hypoglycaemic drugs	Antihyperglycaemic drugs
Sulphonylureas	Biguanides
Repaglinide	α-Glucosidase inhibitors
	Thiazolidinediones
	GLP-1 analogues/DPP-4 inhibitors

GLP, glucagon-like peptide; DPP, dipeptidyl peptidase.

Antihyperglycaemic agents may potentiate the hypoglycaemic actions of other drugs.

Combination oral agent therapy

For patients inadequately controlled by monotherapy, biguanides and sulphonylureas may be usefully combined; the effect may be synergistic (i.e. greater than a simple additive effect). Combination therapy is more likely to be effective in patients with less severe degrees of fasting hyperglycaemia. However, many patients will still not attain adequate glycaemic control. In these circumstances, the addition of a third agent will often result in further improvement.

Metformin and sulphonylureas may be usefully combined in patients with type 2 diabetes.

The time-honoured conventions concerning the clinical use of oral antidiabetic agents have attracted criticism, and the optimal order of selection of therapy for patients with type 2 diabetes remains uncertain. However, the benefits of improved glycaemic control with either oral antidiabetic agents or insulin, particularly on microvascular complications, are clear. However, most clinicians would agree that metformin is the drug of choice for overweight patients.

Additional benefit from oral antidiabetic agents is rarely obtained by escalating doses; consider adding an agent from another class, or consider insulin therapy.

Use of insulin in type 2 diabetes

The question of when to either abandon oral agents in favour of insulin or to add in insulin therapy is a particularly difficult one. This is especially so in the case of an obese patient who continues to have inadequate glycaemic control despite strenuous nutritional and lifestyle advice. The morbidly obese patients may require very high insulin doses to achieve satisfactory glycaemic control.

The waning of response to oral agents reflects the gradual attrition of endogenous insulin secretion that characterizes type 2 diabetes. Dietary compliance is also likely to be important in some cases. Non-obese patients masquerading as type 2 patients may have sufficient β-cell reserve at diagnosis to have a satisfactory response to oral agents. A proportion of these middle-aged to elderly patients have autoimmune markers associated with type 1 diabetes. These patients represent a subgroup called latent autoimmune diabetes in adults (LADA; see p. 59).

Failure of an adequate therapeutic response to oral antidiabetic agents supports the case for insulin treatment.

Contraindications to oral antidiabetic agents

There are a number of acute or temporary clinical situations where oral antidiabetic agents are contraindicated in patients with type 2 diabetes; insulin therapy should be instituted in these circumstances (Table 3.3). After resolution or recovery, a satisfactory therapeutic response may be attained following the reintroduction of oral agents.

Table 3.3 Indications for insulin in type 2 diabetes

Clinical indication	Rationale for insulin therapy
Major acute intercurrent illness (e.g. septicaemia, MI)	Deterioration in metabolic control with sulphonylureas and risk of lactic acidosis with biguanides
Pregnancy	Inadequate metabolic control with oral antidiabetic agents; safety concerns about medication other than metformin and glibenclamide
Surgery	Risk of perioperative hypoglycaemia (especially with long-acting sulphonylureas); risk of lactic acidosis with biguanides
Acute major metabolic decompensation (DKA or HONK/HHS)	Absolute or marked relative insulin deficiency in concert with insulin resistance mandates insulin therapy

DKA, diabetic ketoacidosis; HONK, hyperosmolar non-ketotic coma; HHS, hyperosmolar hyperglycaemic state; MI, myocardial infarction.

Biguanides

Although the data for clinically relevant outcomes with metformin are limited, they are stronger than for any other oral agent for the treatment for type 2 diabetes. Metformin (dimethylbiguanide) should be considered as the first-line oral treatment option for overweight patients (body mass index (BMI) > 25 kg/m²; Asians > 23 kg/m²) with type 2 diabetes.

Metformin has been the only biguanide available in the UK since the late 1970s. It was introduced into the USA only in 1995.

The metabolic actions of metformin are complex and remain incompletely understood. It can be used either as monotherapy or in combination with other therapies such as sulphonylureas – where the effect on glycaemia is greater than that observed with either drug alone. It is also used as an adjunct to insulin therapy. Metformin’s mode of action, pharmacokinetics and its adverse effects are distinct from those of the sulphonylureas.

Mode of action

In contrast to the sulphonylureas, metformin does not increase insulin secretion. Metformin suppresses gluconeogenesis, thereby reducing hepatic glucose output, which is the principal determinant of fasting plasma glucose levels. In addition, metformin appears to improve insulin action and serves to limit postprandial plasma glucose excursions by promoting tissue glucose uptake with oxidation or storage as glycogen. These effects appear to be due mainly to intracellular actions of the drug distal to the interaction between insulin and its membrane receptor.

Effects on fatty acid metabolism may also contribute to the improvement in glycaemia through decreased activity of the glucose–fatty acid (Randle) cycle in muscle and liver; these substrates compete for uptake and oxidation (see Section 1, p. 45). Through increasing insulin sensitivity, metformin has effects on some of the components of the metabolic syndrome. In addition, the beneficial effects of metformin therapy in overweight patients previously demonstrated are not explained solely by improvement in glycaemia. In particular, metformin appears to have a cardioprotective role in overweight type 2 patients.

In summary, metformin decreases hepatic glucose production and may improve peripheral glucose disposal while suppressing appetite and promoting weight reduction. Activation of the energy-regulating enzyme AMP-kinase in liver and muscle is a principal mode of action.

Metformin has beneficial effects on some components of the metabolic syndrome.

Pharmacokinetics

Metformin is absorbed predominantly from the small intestine, attaining high local concentrations. The bioavailability of an oral dose is 50–60%; the mean plasma half-life is between 2 and 3 hours, necessitating 2–3 daily doses. Metformin is not bound to plasma proteins and is therefore not subject to displacement by other drugs such as sulphonylureas. No hepatic metabolism occurs, with virtually the entire drug dosage being excreted unchanged in the urine by the renal tubules.

Adverse effects

Metformin is a safe and well tolerated drug.

Gastrointestinal disturbances

Symptoms include nausea, anorexia, abdominal discomfort and diarrhoea. The absolute risk increase of diarrhoea is approximately 7% and the symptoms resolve rapidly on withdrawal. A minority of patients are unable to tolerate these effects. Metformin is available as a slow-release (SR) preparation that is associated with fewer side-effects. Introduction of metformin at a low dose (500 mg daily for the first week) can help to reduce the frequency and severity of gastrointestinal symptoms, which may be transient and self-limiting – ‘Start low, go slow’. Other side-effects are rare; although reduced serum concentrations of vitamin B₁₂ and folate are well documented, anaemia is virtually never encountered and in practice the clinical risk can be ignored.

Lactate metabolism

The principal contraindication is renal impairment, as this leads to accumulation of the drug. Metformin is contraindicated in patients with an estimated glomerular filtration rate (eGFR) of 30 units or less. Renal function should be checked at least annually.

Metformin therapy does not lead to an increase in lactic acid levels and there is no evidence that it increases the risk of developing lactic acidosis (see p. 161). However, metformin should be avoided in clinical conditions in which lactate production is increased (e.g. cardiopulmonary disease) or hepatic clearance impaired (e.g. alcohol abuse).

Renal impairment is the principal contraindication to metformin therapy.

Hypoglycaemia

When used as monotherapy, metformin is associated with a low risk of hypoglycaemia. However, metformin does potentiate the hypoglycaemic risks of oral hypoglycaemic agents such as sulphonylureas.

Glycaemic control

Metformin, sulphonylureas, insulin, meglitinides and α-glucosidase inhibitors all have similar effects on HbA1c. In non-obese patients, metformin monotherapy reduces postprandial glycaemia, hypercholesterolaemia and hyperinsulinaemia.

Sulphonylureas

Sulphonylureas increase endogenous release of insulin from pancreatic β-cells. The drugs available are classed according to their date of release: first generation (acetohexamide, chlorpropamide, tolbutamide, tolazamide), second generation (glipizide, gliclazide, glibenclamide (glyburide), gliquidone, glyclopyramide) and third generation (glimepiride). The first-generation agents are now rarely used.

Sulphonylureas should be considered as oral agents especially in patients who are not overweight, who are intolerant of, or have contraindications to, metformin.

Mode of action

Sulphonylureas bind to an ATP-dependent K⁺ (KATP) channel on the cell membrane of pancreatic β-cells inhibiting the tonic, hyperpolarizing efflux of potassium. This causes the electric potential over the membrane to become more positive. This depolarization opens voltage-gated Ca^2 + channels. The rise in intracellular calcium leads to increased fusion of insulin granulae with the cell membrane, and therefore increased secretion of (pro)insulin.

There is some evidence that sulphonylureas also sensitize β-cells to glucose, that they limit glucose production in the liver, that they decrease lipolysis (breakdown and release of fatty acids by adipose tissue) and decrease clearance of insulin by the liver.

Hypoglycaemia/weight gain/adverse effects

Patients taking sulphonylureas have a higher rate of major hypoglycaemia (defined as requiring third-party help or medical intervention) than patients on diet alone. Weight gain is also significantly greater. A recent population-based study showed that 1 person in every 100 treated with a sulphonylurea each year experienced an episode of major hypoglycaemia, compared with 1 in every 2000 treated with metformin and 1 in every 10 treated with insulin. Weight gain of approximately 5 kg was observed in the sulphonylurea arm versus the placebo arm.

Cardiovascular morbidity

There have been concerns regarding the cardiovascular safety of sulphonylureas dating from the early 1970s. In 1970, the University Group Diabetes Program (UGDP) reported a detrimental effect of the sulphonylurea, tolbutamide, on cardiovascular disease (CVD). It was reported that CVD mortality was higher in patients given tolbutamide than in those given insulin (12.7% versus 6.2%, respectively). In a further large retrospective cohort study, there was a 24–61% excess risk for all-cause mortality with sulphonylureas in comparison with metformin. However, other studies, including the UKPDS, have not confirmed this.

Meglitinide analogues

Meglitinides act on the same β-cell receptor as sulphonylureas, but have a different chemical structure. They have not been assessed for their long-term effectiveness in decreasing microvascular or macrovascular risk, and are more expensive than other glucose-lowering agents. Weight gain is more common and hypoglycaemia is more frequent in those treated with meglitinides compared with metformin.

Repaglinide

The carbamoylmethyl benzoic acid derivative, repaglinide, is a rapid-acting insulin secretagogue (meglitinide being the non-sulphonylurea portion of the glibenclamide molecule). Repaglinide binds to a distinct portion of the ATP-dependent K⁺ channel in the β-cell membrane. However, unlike sulphonylureas, repaglinide does not stimulate exocytosis of insulin.

Nateglinide

This is a phenylalanine derivative that also produces rapid and brief secretion of insulin when administered with meals. In the UK, a limited licence restricts its use to combination therapy with metformin.

Pharmacokinetics

Repaglinide is rapidly absorbed, has a short plasma half-life (less than 60 min), is hepatically metabolized and is excreted principally (90%) in the bile. It is designed for use only when a meal is consumed; if a meal is skipped, no drug is taken. The tablet should ideally be taken 30 min before the meal. This mealtime dosing allows for more flexibility than is possible with once- or twice-daily sulphonylureas, which have much longer duration of action (Table 3.4). Thus, repaglinide can be viewed as a prandial glucose regulator.

Table 3.4 Plasma half-lives, duration of action and metabolism of the sulphonylureas

Clinical efficacy

Repaglinide achieves reductions in fasting glucose levels, postprandial glucose levels and reductions in HbA1c concentrations similar to those of metformin, sulphonylureas, insulin and α-glucosidase inhibitors. As with sulphonylureas, selection of patients is important; there should be sufficient β-cell reserve to allow effective stimulation of endogenously synthesized insulin. Combining repaglinide with metformin results in control that is superior to the control obtained with either agent used alone.

Repaglinide allows flexible dosing with meals for patients with type 2 diabetes.

Safety and tolerability

Repaglinide is generally well tolerated. Side-effects include hypoglycaemia and weight gain. Contraindications are similar to those for sulphonylureas. Repaglinide appears to be a relatively safe choice in mild-to-moderate renal impairment. However, cautious dose titration is recommended.

α-Glucosidase inhibitors

α-Glucosidase inhibitors are oral glucose-lowering agents that specifically inhibit α-glucosidases in the brush border of the small intestine. These enzymes are essential for the release of glucose from more complex carbohydrates. As a result they inhibit postprandial glucose peaks, thereby leading to decreased post-load insulin levels, especially in comparison with sulphonylureas. Acarbose, miglitol and voglibose are the α-glucosidase inhibitors available commercially, and as monotherapy reduce HbA1c by approximately 0.8% (8.7 mmol/mol) compared with placebo.

Compared with placebo, α-glucosidase inhibitors have minimal effects on body weight. As predicted from their mechanism of action, hypoglycaemic adverse effects do not occur. Abdominal discomfort (flatulence, diarrhoea and stomachache) are the most frequently occurring adverse effects inhibitors and are dose-related.

Thiazolidinediones

Mode of action

Thiazolidinediones (pioglitazone and rosiglitazone) increase whole-body insulin sensitivity by activating nuclear receptors and promoting esterification and storage of circulating free fatty acids in subcutaneous adipose tissue.

The thiazolidinediones lower glucose by two main mechanisms:

• increased glucose disposal in peripheral tissues (the principal effect)

• decreased hepatic glucose production.

These actions are mediated via effects of the drugs with a specific nuclear receptor – the peroxisome proliferator-activated receptor (PPAR)-γ. Activation of this receptor increases the transcription of certain insulin-sensitive genes, influencing adipocyte differentiation and function. Binding of thiazolidinediones to this complex induces a conformational change that ultimately alters the expression of genes involved in the regulation of lipid metabolism, including:

• lipoprotein lipase

• fatty acid transporter protein

• fatty acyl-CoA synthetase

• malic enzyme

• glucokinase.

Effects on glucose transporter (GLUT)-4 and adipocyte leptin expression have also been reported. The combined effect is to increase the uptake of non-esterified fatty acids and increase lipogenesis within adipocytes. However, the precise mechanisms through which these drugs improve insulin sensitivity in glucose metabolism remains to be determined.

Effects on the glucose–fatty acid cycle is an attractive possibility; amelioration of insulin resistance via reduction in adipocyte-derived or possibly through tumour necrosis factor-α is another. Combining a thiazolidinedione (TZD) with a sulphonylurea or metformin is beneficial and enhances the glucose-lowering effect.

Glycaemic control

Thiazolidinediones require the presence of a sufficient amount of insulin in order to exert a therapeutic effect. Pioglitazone can be added to metformin and sulphonylurea therapy, or substituted for either in cases of intolerance. When combined with insulin therapy in insulin-treated obese patients, insulin doses may be reduced substantially with a concomitant improvement in glycaemic control.

Pioglitazone is effective at lowering HbA1c as monotherapy, and in dual or triple therapy when combined with metformin, sulphonylureas or insulin. However, there is no convincing evidence that pioglitazone monotherapy has benefits over metformin or sulphonylurea monotherapy.

Cardiovascular effects

A meta-analysis of 84 published and 10 unpublished trials of pioglitazone compared with placebo or other therapy, and excluding the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive trial), reported a reduction of all-cause mortality with pioglitazone, but no significant effect on non-fatal coronary events. A further meta-analysis with 16 390 patients found a reduction in the primary composite endpoint (death, MI or stroke) with pioglitazone versus control. However, the PROactive trial suggested a reduction in fatal and non-fatal MI in the subgroup with previous MI. In patients with previous stroke, subgroup analysis showed that pioglitazone reduced fatal or non-fatal stroke, whereas there was no effect on stroke risk in patients with any history of previous stroke.

Studies on congestive heart failure (CHF) found an increased risk of CHF in TZD therapy in comparison with placebo or other medications, with an overall relative risk of 1.72. The PROactive study found that, although more patients treated with pioglitazone had a serious heart failure event compared with placebo (P = 0.007), mortality due to heart failure was similar to that with placebo. Pioglitazone does not have a negative inotropic effect on the heart. The cardiac failure appears, mostly, to be due to the increased plasma volume induced by TZD treatment.

Pioglitazone should not be used in patients with heart failure.

Weight gain

Increases of several kilograms in body weight have been reported in clinical trials. This appears to be due to the insulin-sensitizing and lipogenic effects of TZD therapy; improved glycaemic control may also reduce urinary glucose losses. Thiazolidinediones appear preferentially to increase subcutaneous fat deposits, whereas visceral adiposity is reduced.

Hypoglycaemia

Thiazolidinediones are classed as antihyperglycaemic rather than oral hypoglycaemic agents. The risk of hypoglycaemia exists when the drugs are combined with agents such as sulphonylureas or insulin; careful monitoring of blood glucose is required and doses of other agents doses may have to be reduced, sometimes substantially.

Fractures

Pioglitazone treatment is associated with an increased risk of peripheral fracture in both women and men.

Incretins

It has been known for many years that glucose administered orally gives rise to much higher insulin levels than glucose given intravenously despite similar or even higher plasma glucose levels. This increase is due to the release of intestinal humoral substances. Incretins are a group of gastrointestinal hormones that cause this increase in the amount of insulin released from the β-cells of the islets of Langerhans. This increase occurs before blood glucose levels are increased. These intestinal humoral substances also slow the rate of absorption of nutrients into the bloodstream by reducing gastric emptying, and in many patients directly reduce food intake by central effects on satiety. They also inhibit glucagon release from the α-cells of the islets of Langerhans. The two main candidate molecules that fulfil criteria for the incretin effect are glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic peptide (GIP). Both GLP-1 and GIP are inactivated rapidly by the enzyme dipeptidyl peptidase (DPP)-4. Type 2 patients have a blunted incretin response, and infusion studies have shown that GIP is ineffective in type 2 diabetes (Fig. 3.5).

Figure 3.5 Effect of incretin on insulin secretion

(Source: Nauck et al. (1996). © Springer. Redrawn with permission.)

Glucagon-like peptide-1 agonists

GLP-1 is produced in the intestinal α-cells in the small intestine. It is one of the key ‘incretin’ hormones – a group of rapidly metabolized peptides secreted from the gut in response to food that amplify secretion of insulin from pancreatic β-cells and inhibit inappropriate glucagon secretion. GLP-1 also slows gastric emptying, resulting in slowed absorption of glucose following meals, and reduce appetite. GLP-1 agonists mimic endogenous GLP-1 activity, but are resistant to breakdown by the DPP-4 enzyme, resulting in more prolonged action.

Glycaemic control

Two GLP-1 agonists are currently available:

• Both need to be administered subcutaneously.

• Exenatide, which requires twice-daily injection, has a half-life of 4 h.

• Liraglutide, which requires once-daily injection, has a half-life of 11–13 h.

Both exenatide 10 μg (twice daily) and liraglutide 1.2/1.8 mg (once daily) added to oral glucose-lowering agents (metformin and sulphonylureas) reduce mean HbA1c by over 1%.

Hypoglycaemia/weight gain/adverse effects

GLP-1 agonists are generally well tolerated. The most frequent adverse events are gastrointestinal, especially nausea, which is generally reported as mild to moderate and settles in 8–10 weeks. If the patient is warned about this potential side-effect, the medication is usually well tolerated. Severe hypoglycaemia is rare and occurs only when sulphonylureas are co-prescribed. Mild to moderate hypoglycaemia occurs in approximately 10% of patients.

GLP-1 agonist treatment often results in weight loss. Weight loss was reported in study participants in the range of 1.6–3.1 kg. Hence, weight loss is a possible advantage of GLP-1 agonist therapy compared with insulin therapy and other oral glucose-lowering drugs, such as sulphonylureas and thiazolidinediones.

GLP-1 agonists may be used to improve glycaemic control in obese adults (BMI ≥35 kg/m²) with type 2 diabetes who are already prescribed metformin and/or sulphonylureas. A GLP-1 agonist may be added as a third-line agent in those who do not reach target glycaemia on dual therapy with metformin and sulphonylureas (as an alternative to adding insulin therapy).

There have been suggestions that GLP-1 agonists are associated with increased risk of pancreatitis. However, there is insufficient evidence to determine whether these agents increase the background rates of acute pancreatitis in patients with diabetes.

Dipeptidyl peptidase-4 inhibitors (gliptins)

DPP-4 inhibitors are oral agents that inhibit activity of the enzyme DPP-4 and hence prolong the actions of endogenous GLP-1. Three DPP-4 inhibitors are currently available: sitagliptin, vildagliptin and saxagliptin.

Glycaemic control

Compared with placebo, sitagliptin, vildagliptin, alogliptin, linagliptin, and saxagliptin have all been shown to be effective at lowering HbA1c by nearly 0.7 to 1%.

Hypoglycaemia/weight gain/adverse effects

DPP-4 is a membrane-associated peptidase that is expressed widely in tissues such as liver, lung, intestine and kidney. It is also known as CD26 and is distributed on T-cells, β-cells and natural killer cells. DPP-4 inhibitors, in the trials undertaken, have been well tolerated. However, they have so many roles that careful monitoring is necessary.

No severe hypoglycaemia was reported in study participants taking DPP-4 inhibitors alone. In combination with metformin, rates of hypoglycaemia were 6–10-fold lower with gliptins than with sulphonylureas. Gliptins are weight-neutral.

Published studies for sitagliptin and vildagliptin have medium-term follow-up (maximum 2 years); therefore, the long-term effects of these drugs on microvascular complications, cardiovascular disease and mortality are unknown. There is a statistically significant increase in all-cause infection following treatment with sitagliptin, but not with vildagliptin or saxagliptin.

Sodium–glucose co-transporter inhibitors: flozins

Phlorizin is a naturally occurring phenol glycoside first isolated from the bark of an apple tree in 1835. Early studies in animals showed that oral ingestion of phlorizin caused renal glycosuria and weight loss without hyperglycaemia; these findings were later confirmed in humans. The therapeutic potential of phlorizine is limited by poor oral bioavailability because of its tendency to be hydrolysed in the gut to its aglycone, phloretin. Because the majority of filtered glucose is reabsorbed in the early proximal convoluted tubule, and because non-selective sodium-glucose co-transporter (SGLT) inhibitors may also block GLUT-1, research has focused specifically on SGLT2 as a molecular target to increase urinary glucose excretion. Chemically, most SGLT2 inhibitors are glycosides derived from the prototype, phlorozin.

There are now several SGLT2 inhibitors in early clinical development, among which the leading compounds are sergiflozin and dapagliflozin. These novel SGLT2 inhibitors are pro-drugs that require conversion to the active ‘A’ form for activity against SGLT2 receptors. SGLT2 inhibitors potentially have the advantage of lowering plasma glucose levels irrespective of the underlying pathology of hyperglycaemia, and therefore may be useful in both type 1 and type 2 diabetes. They should also combine easily with both other oral and injectable treatments for diabetes.

Evidence for the safety of renal glycosuria on long-term kidney function comes from individuals with familial renal glycosuria. The prolonged excretion of urine with high sugar concentrations is classically reputed to be a risk factor for the development of genitourinary infections. So far, an approximate doubling of episodes of vulvovaginitis and balanitis has been reported, although it is less clear whether urinary tract infections are also increased in frequency or severity. Clinic development will also have to include testing SGLT2 inhibitors in diabetic patients with impaired renal function and/or microalbuminuria, who are at risk of further renal and cardiovascular disease.

Other potential adverse affects of SGLT2 inhibitors relate to the non-selective inhibition of GLUT pathways outside the kidneys. For example, non-specific inhibition of SGLT by phlorozin affects glucose uptake in the brain and inhibits the activation of the ventromedial hypothalamic responses to hyperglycaemia. Phlorozin has also been reported to inhibit alveolar fluid absorption in the lungs. Therefore, SGLT2 specificity is important for new agents entering clinical development.

Glycaemic monitoring

Blood glucose monitoring

Many different strips and dedicated meters are available and will continue to progress and improve. Some meters simply measure the blood glucose, whereas others can store a lot of additional information such as exercise and extra carbohydrate intake. Stored information can be downloaded and graphs created. Adequate training and a system of quality control are vital. Even when trained health professionals use such systems, misleading results are possible, particularly in the lower range of blood glucose results. The diagnosis of diabetes cannot be made on the basis of a meter reading.

Practical limitations to self-testing include:

• inadequate manual dexterity (e.g. deforming rheumatoid arthritis or advanced neuropathy; post-stroke)

• intellectual inability or incapacity

• visual handicap.

When to test?

In type 1 diabetes, single readings are of relatively limited value, except to confirm or, sometimes importantly, to exclude the possibility of acute hypoglycaemia (see p. 126). More useful is a ‘profile’ of tests performed at different times of the day, usually in close relation to meals, typically:

• before breakfast

• before lunch

• before evening meal

• before retiring to bed.

In addition, a test at 0200–0300 hours, although inconvenient, may be important for patients in whom nocturnal hypoglycaemia (which may be asymptomatic) is suspected. Tests before and after exercise can be used to guide reductions in insulin dose or need for additional carbohydrate (see p. 74).

In patients in whom particularly ‘tight’ glycaemic control is required (e.g. pregnancy in diabetes) patients are often asked to test 2–3 hours postprandially.

Self-monitoring of blood glucose (SMBG) is a commonly used strategy for both type 1 and type 2 diabetes. It is a fundamental and established component of self-management in people with type 1 diabetes. The frequency and accuracy of testing vary considerably between patients; records vary from non-existent to meticulously charted profiles from dedicated (and sometimes obsessional) individuals. Fabricated results are well recognized. Discomfort and inconvenience are the main factors that discourage regular testing in many patients; expense is another consideration for patients in some countries. Self-monitoring guides adjustment of insulin or other medication for patients and health professionals as part of a comprehensive package of diabetes care, encourages self-empowerment and promotes better self-management behaviours. Frequent blood glucose monitoring is associated with an improvement in glycaemia.

Occasionally self-monitoring may fail to improve diabetes control and has been associated with negative psychological outcomes. Other methods of self-monitoring include self-monitoring of urine glucose (SMUG) and measurement of blood or urine ketones. Continuous monitoring of interstitial glucose (CMG) is an alternative for people with type 1 diabetes who have persistent problems with glycaemic control.

The importance of SMBG whilst driving should be reinforced in people with type 1 diabetes.

Self-monitoring of blood glucose in people with type 1 diabetes

Continuous glucose monitoring

Although SMBG is a vital part of the management of glycaemia in people with type 1 diabetes, many patients do not routinely monitor glucose levels either postprandially or overnight, which may leave undetected episodes of hyperglycaemia and hypoglycaemia, respectively. Systems using continuous monitoring of glucose are generally considered for use only by patients who experience particular difficulties in maintaining normal glucose levels or who have been transferred to continuous subcutaneous insulin infusion therapy.

Self-monitoring in people with type 2 diabetes

The evidence for the benefit of SMBG in people with type 2 diabetes is conflicting. The impact of SMBG on management of glycaemic control is positive but small for patients not on insulin: the benefit in glycaemic control is greatest for those using insulin. However, it is difficult to use the evidence base to define which groups of patients with type 2 diabetes will gain most benefit from SBGM. Extrapolation from the evidence would suggest that specific subgroups of patients might benefit. These include those who are at increased risk of hypoglycaemia or its consequences, and those who are supported by health professionals in acting on glucose readings to change health behaviours, including appropriate alterations in insulin dosage.

Motivated patients with type 2 diabetes who are using sulphonylureas may benefit from routine use of SMBG to reduce risk of hypoglycaemia. SMBG may be considered in the following groups of people with type 2 diabetes who are not using insulin:

• those at increased risk of hypoglycaemia

• those experiencing acute illness

• those undergoing significant changes in pharmacotherapy of fasting, for example during Ramadan

• those with unstable or poor glycaemic control (HbA1c > 8.0% (64 mmol/mol))

• those who are pregnant or planning pregnancy.

SMGB is recommended for patients with type 1 or type 2 diabetes who are using insulin and have been educated in appropriate alterations of insulin dosage.

Fingerprick devices

Sterile, disposable, single-use lancets may be used in conjunction with simple, hand-held, mechanical devices by which a fingerprick sample is obtained with a minimum of discomfort. This aids compliance and helps to ensure that an adequate sample is obtained. The depth of the puncture can be adjusted. Used lancets must be disposed of appropriately.

Routine self-monitoring of blood glucose in people with type 2 diabetes who are using oral glucose-lowering drugs (with the exception of sulphonylureas) is not recommended.

Urine glucose monitoring in patients with type 2 diabetes

Some old studies suggest that urine testing is equivalent to blood testing, but these studies were generally carried out in an era when HbA1c levels were higher than would now be considered acceptable, limiting the applicability of these data to current practice. There is no evidence describing an impact of urine monitoring on rates of hospital admission, rates of diabetic ketoacidosis (DKA), or mortality.

Routine self-monitoring of urine glucose is not recommended in patients with type 2 diabetes.

Blood and urine ketone monitoring

Ketone monitoring using urine, or more recently blood, is generally accepted practice in the management of type 1 diabetes. Detection of ketones can assist with insulin adjustments during illness or sustained hyperglycaemia to prevent or detect DKA.

Blood ketone measurement is a more accurate predictor of ketosis/acidosis than urine ketone measurement. Blood ketone monitoring with increased health-care professional support is preferable to urine ketone monitoring in young adults with type 1 diabetes.

There is insufficient evidence to advise on the routine measurement of ketones in patients with type 1 or type 2 diabetes.

Principles of education in diabetes

Education in adults with diabetes

It is recommended that structured patient education should be available to all people with diabetes and their carers at the time of initial diagnosis, and then as required on an ongoing basis, based on a formal, regular assessment of need.

There is insufficient evidence currently available to recommend a specific type of education or provide guidance on the setting for, or frequency of, sessions. There is good evidence, at least in the short term, that diabetes education improves clinical outcomes and quality of life. The model has moved from primarily didactic presentations to more empowerment-based models.

NICE clinical guideline CG66 on type 2 diabetes (2010, update) recommends that a patient education programme is selected that meets the criteria laid down by the Department of Health and Diabetes UK report on structured patient education in diabetes. Although these guidelines were written with type 2 in mind, the principles for type 1 diabetes should be no different.

The programme should:

• have a person-centred, structured curriculum that is theory-driven and evidence-based, resource-effective, has supporting materials, and is written down

• be delivered by trained educators who have an understanding of education theory appropriate to the age and needs of the programme learners, and are trained and competent in the delivery of the principles and content of the programme they are offering, including the use of different teaching media

• provide the necessary resources to support the educators, and that the educators are properly trained and given time to develop and maintain their skills

• have specific aims and learning objectives and should support development of self-management attitudes, beliefs, knowledge and skills for the learner, their family and carers

• be reliable, valid, relevant and comprehensive

• be flexible enough to suit the needs of the individual, for example including the assessment of individual learning needs, and to cope with diversity, for example meeting the cultural, linguistic, cognitive and literacy needs in the locality

• offer group education as the preferred option, but with an alternative of equal standard for a person unable or unwilling to participate in group education

• be familiar to all members of the diabetes health-care team and integrated with the rest of the care pathway, and that people with diabetes and their carers have the opportunity to contribute to the design and provision of local programmes

• be quality-assured and reviewed by trained, competent, independent assessors who assess it against key criteria to ensure sustained consistency

• have its outcomes audited regularly.

Multidisciplinary teams providing education should include, as a minimum, a diabetes specialist nurse (or a practice nurse with experience in diabetes) who has knowledge of the principles of patient education, and a dietitian. Although not formally assessed in this appraisal, input from other disciplines, such as podiatry, has potential value. The composition of the team and the way that members interact may vary between programmes, but team functioning should be tailored to the needs of different groups of people with diabetes.

Education is considered to be a fundamental part of diabetes care. People with diabetes, whether they are using insulin or other means of achieving glycaemic control, have to assume responsibility for the day-to-day control of their condition. It is therefore critical that they understand the condition and know how to treat it, whether this is through an appreciation of the basis of insulin replacement therapy and its optimal use, or through lifestyle management, including nutrition and physical activity. The aim of education for people with diabetes is to improve their knowledge and skills, enabling them to take control of their own condition and to integrate self-management into their daily lives. The ultimate goal of education is improvement in the following areas:

• control of vascular risk factors, including blood glucose, blood lipids and blood pressure

• management of diabetes-associated complications, if and when they develop

• quality of life.

Education in adults with type 1 diabetes

Structured education based on principles of adult learning (including patient empowerment and experiential learning) is associated with improved psychosocial well-being, reduced anxiety and overall improvement in quality of life in people with type 1 diabetes. Adults with type 1 diabetes experiencing problems with hypoglycaemia or who fail to achieve glycaemic targets should have access to structured education programmes.

In recent years the DAFNE (Dose Adjustment for Normal Eating) education programme has been introduced for adults with type 1 diabetes. Patients taking part in the DAFNE programme obtained an average 1% improvement in HbA1c, overall improvement in quality of life and improved dietary freedom. No effect was noted in frequency of severe hypoglycaemia or patient-perceived hypoglycaemia.

Other packages such as BITES (Brief Intervention in Type 1 Diabetes – Education for Self-efficacy) and BERTIE (Bournemouth Type 1 Intensive Education) have been introduced as part of the education package for adults with type 1 diabetes. Patients participating in these programmes have found varying or no improvement in terms of satisfaction, HbA1c, rates of hypoglycaemia, blood pressure, lipids, weight, BMI or use of insulin.

A number of structured education programmes have also been developed specifically for patients who have significant problems with hypoglycaemia. These include Hypoglycaemia Anticipation, Awareness and Treatment Training (HAATT), HyPOS and Blood Glucose Awareness Training (BGAT). Improvements in hypoglycaemia rates and hypoglycaemia awareness seen in these programmes are not associated with a deterioration in overall glycaemic control.

Education for children and adolescents with type 1 diabetes

Structured education based on developing problem-solving skills has a positive effect on a number of behavioural outcomes (including frequency of SMBG, better compliance with sick-day rules, increased levels of exercise, dietary intake and improved medication adherence) and overall quality of life.

There appears to be no difference as to whether group or individual (one-to-one) structured education is associated with better outcomes.

Children and adolescents should have access to programmes of structured education that has a basis in enhancing problem-solving skills.

Education in patients with type 2 diabetes

Structured education based on principles of adult learning (including patient empowerment and experiential learning) is associated with improved psychosocial well-being, reduced anxiety, and overall improvement in quality of life in patients with type 2 diabetes. The best known type 2 education package is the DESMOND (Diabetes Education and Self-Management for Ongoing and Newly Diagnosed). This programme did not lead to improvement in HbA1c after 12 months but was associated with around 1 kg greater weight loss, 5% less cigarette smoking, a greater understanding of diabetes and a lower prevalence of depression.

Most education interventions are associated with some HbA1c improvement, particularly in the short term – the magnitude of change is usually in the range of 0.3% (3 mmol/mol) to 1.0% (11 mmol/mol) improvement. The programmes may lead to patients reducing their diabetes medication, improving their knowledge outcomes, increasing the number of days exercising and an improvement in patient empowerment.

Organization of diabetes care

Diabetes centres

Patients (and their families) require education backed up by readily available expert assistance from a multidisciplinary diabetes care team. Arrangements for care vary markedly between countries with differing health-care systems. Purpose-built, hospital-based diabetes centres have proved to be popular in the UK and elsewhere. Such centres fulfil a multitude of functions:

The aim is to provide these services in an accessible and comfortable environment. The active participation of patients, both as individuals and collectively, is to be encouraged; more generally, the concept of self-care is important in the management of a chronic disorder such as diabetes for which the patient, suitably educated and supported, is ultimately largely responsible. Diabetes care may be regarded as a cooperative process between the patient and the health-care system. Thus, although patients rightly deserve minimum standards of care (e.g. the European Patients’ Charter), it is also recognized that they have certain obligations to ensure that appropriate care is delivered by acquiring knowledge to enable self-care on a day-to-day basis and to maintain regular contact with the health-care team.

The philosophy of self-management for patients with diabetes should be actively encouraged.

Specialized care

Special clinics (sometimes outside normal office hours) for adolescents and young adults are held in many centres. Care of special groups of patients such as children and pregnant women may be located either in the diabetes resource centre or in another hospital department, according to local circumstances.

Staff

Staffing of the diabetes centre will typically include:

• consultant diabetologist – specialist training in diabetes; team leader

• specialist diabetes nurse – most health districts in the UK have at least one, and often more. Responsibilities include education and provision of day-to-day practical direction and support for patients, both in hospital and in the community, organization of staff training, development and implementation of local policies, commissioning of new equipment, introduction and evaluation of new treatments and technologies, research and audit. The diabetes specialist nurse should be well versed in counselling and education skills. Nurses may elect to concentrate on special groups such as children.

In addition, the services of other specialists will also be required as necessary:

• nephrologist

• obstetrician

• vascular surgeon

• ophthalmic surgeon

• cardiologist

• psychologist.

Shared clinics, for instance between a diabetologist and a nephrologist or an obstetrician, are popular and may help to reduce the number of visits while facilitating the sharing of relevant information.

Inpatient care

The problems surrounding inpatient care for people with diabetes have been long established. There are a number of concerns; these include disempowerment, distress, a lack of staff knowledge including in the management of acute diabetes complications, issues with food and food and medication timing, medicines mismanagement, and a lack of information provision. It is vital that these issues are addressed to ensure people with diabetes receive high-quality care.

Diabetic patients account for a disproportionate amount of hospital inpatient activity. Hospital admission is now rarely required for initiation of insulin therapy, but is necessary for the management of acute metabolic emergencies (see Section 4). Hospitalization is also frequently required for the management of serious acute microvascular and macrovascular complications, notably foot ulceration (see p. 188). Other common conditions such as unstable coronary heart disease and cardiac failure usually necessitate emergency or elective admission.

Surgery is required more often by diabetic patients (see above); close liaison between the surgical and diabetes services is obviously desirable. Written protocols for the management of diabetes during surgery or MI (see p. 207), DKA (see p. 148) or labour (see p. 250) should be agreed upon, implemented, audited and refined. This should be a continual process aiming not just to maintain but also to raise standards of care.

Diabetes UK recently published standards of care in hospital. The principles should be of a level that ensures:

• pre-assessment planning for elective admissions is undertaken and implemented

• every person with diabetes has an assessment and care plan for their hospital stay that is regularly updated as appropriate

• coordination and administration of medications and food in a timely manner

• access to food and snacks appropriate for maintaining good diabetes management

• protocols are in place for the timely prevention and management of hypoglycaemia and hyperglycaemia, including self-management of these complications where appropriate

• people are supported to optimize blood glucose control during their hospital stay

• information about the inpatient stay is provided to people with diabetes

• people with diabetes have access to the specialist diabetes team and education

• effective multidisciplinary communication between staff

• a discharge and follow-up plan is developed for each individual.

Supported self-management of diabetes

People with diabetes wishing to self-manage:

• should be supported to do so where appropriate

• should have access to their self-monitoring equipment

• should have access to education, including information about how to access a structured education programme.

In order to support the delivery of the above, there needs to be:

• the implementation of diabetes training for all medical and nursing staff to ensure health-care professionals are equipped with the necessary competencies

• the development and implementation of protocols and/or systems to cover: communication, ongoing referral, surgery, prevention, and the timely and effective management of acute complications

• the implementation of audit and the commissioning of models of care shown to be effective.

Diabetes inpatient specialist nurse (disn)

Patients with diabetes should have evaluation of their glycaemic control and support in the management of their diabetes from a diabetes nurse specialist in an effort to reduce length of stay.

The inception of the diabetes inpatient specialist nurse (DISN) has led to an improvement in the management of inpatients with diabetes along with a significant reduction in inpatient bed-days. The role of the DISN has been to:

• act as a resource for expert advice and training for nursing staff, medical staff and other health-care professionals

• provide a highly specialized diabetes management and education service to patients referred within secondary care

• lead and contribute to strategic issues relating to diabetes care

• carry out audit and research work in connection with all aspects of diabetes care and participate in quality assurance programmes

• communicate with all areas, both professional and voluntary

• work as part of the diabetes team to provide a multidisciplinary service input with extended knowledge and skills in diabetes management.

Diabetes in primary care

The long-term management of diabetic patients in the UK is increasingly being supervised in whole or in part in primary care; this is regarded as particularly appropriate for patients with type 2 diabetes who have satisfactory glycaemic control and no significant diabetic complications. Problems with metabolic control or the detection of complications should prompt consideration of specialist advice. Various models of care have been described, for example:

• miniclinics – performed in general practice but based on hospital clinics

• integrated care systems – wherein patient management is shared between the primary and secondary sectors to a greater or lesser degree.

Local circumstances will influence the arrangements within a particular health district. This approach requires close cooperation between hospital-based and primary provision to ensure high standards of care. Ready access to the hospital service and diabetes specialist nurses is necessary. An effective patient register and recall system are crucial components of successful diabetes care within a general practice setting. Regular audit of process and outcome is required; this pertains to hospital-based clinics as well as primary care clinics.

A dynamic and regular process of audit is necessary to identify deficiencies and ensure improvements in practice.

Some studies have shown that prompted management of diabetes in primary care can result in good rates of attendance and satisfactory performance of blood pressure measurement and retinal examination. Conversely, unstructured care can lead to losses to follow-up, inferior glycaemic control and increased mortality rates.

A prompted recall system is regarded as a prerequisite for successful care of diabetes in primary care.

Out-of-hours support

Experience of dedicated diabetes hotlines shows that parents of younger children and patients with a short duration of diabetes are more likely to use this service. However, there is no evidence suggesting that a dedicated diabetes helpline prevents acute complications and hospital admissions.

Transition from paediatric to adult services

Young people with diabetes often move from the paediatric services to the adult health-care system at a time when diabetes control is known to deteriorate. There is consensus that the needs of adolescents and young people need to be managed actively during this transition period. Transition models have evolved according to local circumstances and beliefs, and their complexity makes comparison very difficult. There is little evidence available on the different adolescent transition models and their benefits, and there is no evidence to recommend a particular transition model.

• Patients and their families favour a structured transition from paediatric to adult services together with adequate information along the way.

• A structured transition process appears to improve clinic attendance and reduces loss to follow-up in the adult services.

Paediatric and adult services should work together to develop structured transition arrangements that serve the needs of the local population.

Management of diabetes at school

Educational and health services should work together to ensure that children with diabetes have the same quality of care within the school day as outside it. There is no reason, if appropriate planning, education and training of school personnel are in place, why diabetic schoolchildren cannot full participate in the school experience.

Intensification of diabetes management requires increased monitoring and insulin use and, as this significantly improves glycaemic control, appropriate facilities should be available to all children while at school, including the treatment of hypoglycaemia.

Related

Churchills Pocketbook of Diabetes 2e