When and how to start insulin therapy in type 2 diabetes

Transcription

1 When and how to start insulin therapy in type 2 diabetes Anne Kilvert MD, FRCP Most patients with type 2 diabetes will eventually require insulin due to the progressive decline in betacell function. Dr Kilvert describes when to introduce insulin in type 2 diabetes and how the regimen needs to be tailored to the individual patient. Figure 1. Decline in beta-cell function will eventually lead to insulin being required Insulin resistance, usually as a consequence of obesity, is a major factor in the development of type 2 diabetes, but it is progressive betacell failure that leads to worsening hyperglycaemia over time. Although lifestyle changes and tablets are usually effective initially, insulin is almost always required in the long term as endogeus insulin production falls. The UK Prospective Diabetes Study (UKPDS) documented a steady rise in HbA 1c with time in both the tight control and the conventional treatment groups (see Figure 1) 1 and was able to show that this was due to beta-cell failure (see Figure 2), 2 thus confirming that type 2 diabetes is a progressive disease. The study 18 Prescriber 5 October

2 proved that tight blood glucose control (HbA 1c <7.0 per cent) reduced the risk of microvascular and macrovascular complications. However, six years from diagsis, 50 per cent of patients in the study required insulin to achieve good control. Prior to the UKPDS, most insulin initiation and patient education took place in secondary care by diabetes specialist nurses. The combination of ever-increasing numbers of people with type 2 diabetes and recognition of the need for tight blood glucose control has led to a dramatic rise in the number of people requiring insulin. As a result, primary care has taken responsibility for the management of type 2 diabetes and many GPs and practice nurses are becoming experts in insulin initiation. When to introduce insulin The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) have produced a consensus algorithm for the initiation and adjustment of antidiabetic therapy in type 2 diabetes. (see Figure 3). 3 This advises escalation of treatment if the HbA 1c is above 7.0 per cent. The GP Quality and Outcomes Framework (QOF) targets are also based on HbA 1c (<7.5 per cent). However, tight control of diabetes increases the risk of severe hypoglycaemia, and management decisions focussed solely on the HbA 1c target, without considering personal circumstances, may t be in the best interests of the individual. The following factors should be taken into account when assessing whether a person is likely to benefit from insulin: patient preference/attitude to diabetes, including cultural beliefs capacity to cope with insulin HbA 1c (%) conventional Figure 2. Rise in HbA 1c in conventional and intensive treatment groups 1 safely, including risk of hypoglycaemia (frail older people, learning disability) severity of hyperglycaemic symptoms (insulin may be unavoidable) life expectancy vs risk of longterm complications employment (eg HGV driver) obesity (risk of further weight gain without achieving good control). Which insulin regimen? There are several options when first starting insulin and the regimen should be tailored to the individual patient, taking into account the blood glucose profile and patient preference (see Table 1). These are: once-daily long-acting analogue or isophane (basal only therapy) usually added to existing oral therapy (see te on glitazones below) basal bolus (short-acting insulin with meals and long-acting basal insulin taken once or twice daily) premixed insulin (usually twice daily). intensive 6.2% upper limit of rmal range Years from randomisation The following factors should be taken into account when advising on the most suitable insulin for an individual patient: patient preference for (or resistance to) number of injections patient lifestyle and need for flexibility (basal bolus is generally more flexible) pattern of hyperglycaemia (fasting or postprandial) HbA 1c (mir elevation more likely to respond to once-daily insulin) patient s capacity to take insulin and make decisions about insulin dose risk of hypoglycaemia. Be prepared to change the regimen if the first choice is t successful. Insulin initiation Although the HbA 1c provides only a rough guide to the choice of insulin regimen, a high level indicates that the patient is unlikely to be controlled on once-daily insulin. There are little data available to 20 Prescriber 5 October

3 guide a decision but experience suggests that an HbA 1c of 9.5 per cent can be used as an arbitrary cut-off. Asymptomatic patients with HbA 1c <9.5 per cent This group of patients may respond to once-daily basal insulin, particularly if the predominant abrmality is fasting hyperglycaemia. A long-acting analogue or bedtime isophane may be effective. Start at a dose of 10 units and titrate upwards every few days, aiming for a fasting blood glucose of 5-7mmol per litre. Continue oral antidiabetic agents (see below). If the HbA 1c remains above 7.0 per cent when the fasting target has been achieved, this is likely to be due to postprandial hyperglycaemia and mealtime insulin may be needed. If the bedtime blood glucose is >10mmol per litre, try a shortacting insulin or rapid-acting analogue with the evening meal starting at a dose of 4-10 units. The initial dose will depend on the degree of hyperglycaemia and the patient s body weight: the higher the body mass index (BMI), the more insulin resistant the patient will be. If in doubt, start with 4 units but be prepared to titrate up every couple of days if the blood glucose does t respond. Aim for a bedtime blood glucose of 7-8mmol per litre. As beta-cell function declines, it may be necessary to introduce insulin with other meals. Most people are happy to increase the number of injections once they have become used to the idea of taking insulin to cover a meal. Sulphonylureas can be stopped at this stage but metformin should be continued. Symptomatic hyperglycaemia or HbA 1c >9.5 per cent Beta-cell function (%) Years from randomisation Figure 3. Reduction in beta-cell function in patients treated with a sulphonylurea and diet only, presaging the eventual need for insulin therapy 2 Once-daily insulin is unlikely to be effective. Discuss the options of basal bolus (more flexible) or twice-daily premixed insulin (requires fewer decisions about dose). Start basal bolus insulin with 4-6 units of short-acting insulin or a rapid-acting analogue with meals and 6 units of isophane or long-acting analogue at bedtime (see practical hints below). Premixed insulin can be started at 8-10 units twice daily. Titrate the dose every two to three days depending on response. A skilled practice nurse will aim to empower the patient to make their own decisions about dosage increases and will encourage them to take ownership of their diabetes. Less confident patients may need more support until they are ready to take responsibility for decisionmaking. Practical hints If rapid-acting analogues are used in a basal bolus system, it is important to ensure that background insulin lasts for the full 24 hours. Isophane must be taken twice daily, though long-acting analogues can sulphonylurea diet only usually be given once daily. An understanding of carbohydrate counting will help decisions about the dose of mealtime insulin. Some patients prefer to graze rather than to eat three meals a day and a conventional short-acting insulin, such as Humulin S or Actrapid, may suit them better than an analogue because of the lower peak and longer duration of action. Combining oral antidiabetic agents with insulin can reduce HbA 1c and hypoglycaemia and limit weight gain. 4,5 Metformin should be continued whenever possible. Sulphonylureas are usually discontinued when prandial insulin is introduced. Glitazones and insulin Insulin resistance is a major factor in type 2 diabetes and some patients, particularly those with central obesity, require large doses of insulin to control the blood glucose. In such cases, addition of a glitazone can significantly reduce the HbA 1c. 6 Both insulin and glitazones cause fluid retention and the combination may precipitate heart failure. However, the use of Prescriber 5 October

4 diagsis lifestyle intervention plus metformin add basal insulin (most effective) add sulphonylurea (least expensive) add glitazone ( hypoglycaemia) intensify insulin therapy add glitazone add basal insulin add sulphonylurea add basal insulin or intensify insulin therapy intensive insulin therapy plus metformin with or without glitazone Figure 4. Recommended drug treatment of type 2 diabetes (ADA/EASD, 2006) 22 Prescriber 5 October

5 Insulin type Rapid-acting analogues, eg Humalog, NovoRapid Short-acting, eg Humulin S, Actrapid (only available via syringe) Isophane, eg Humulin I, Insulatard Long-acting analogues, eg Levemir, Lantus Comments used as bolus insulin with meals used as bolus insulin with meals used as basal insulin used as basal insulin choices are once-daily long-acting insulin or twice-daily isophane or premixed insulin. Older patients are at particular risk of hypoglycaemia, which may lead to neurological impairment, sometimes presenting as a stroke or collapse. Chronic hypoglycaemia often leads to confusion or cognitive impairment. It is important to ensure that the fasting blood glucose is above 5mmol per litre, since levels below this are suggestive of cturnal hypoglycaemia. Premixed, eg Humalog Mix25, Humalog Mix50, NovoMix 30 insulin with a glitazone should be safe provided: patients with previous heart failure are excluded the two medications are t introduced together patients are warned to seek medical help if they have symptoms suggestive of fluid overload. Obese patients This group of patients is particularly difficult to treat. They usually require large amounts of insulin because of severe insulin resistance and further weight gain is common. An attempt should be made to encourage weight loss by lifestyle advice and pharmacological treatments before resorting to insulin. Some patients may benefit from combining insulin with a glitazone. Older people This potentially vulnerable group requires special consideration. HbA 1c targets are less relevant in those with reduced life expectancy as a result of co-morbidities and the risks of hypoglycaemia are greater. Many older patients are unable to used when prandial short-acting insulin required but patient unwilling or unable to take basal bolus insulin Table 1. Examples of insulin in common use (available as cartridges for pens or as disposable pens, except where stated) cope with insulin adjustment and administration and may need the help of a relative or district nurse. The general health of the patient needs to be taken into account when setting targets. In frail or confused patients, aim to avoid the symptoms of high or low blood sugars rather than to achieve a rigid HbA 1c target. The best Key points most patients with type 2 diabetes require insulin eventually patients needing insulin at or soon after diagsis need to be identified consider individual patient circumstances when assessing the need for insulin combination of once-daily insulin with oral agents may be effective in patients with mildly elevated HbA 1c basal bolus or premixed insulin should be recommended for patients with symptomatic hyperglycaemia older patients are particularly vulnerable to hypoglycaemia Inhaled insulin The first inhaled insulin, Exubera, was launched in the UK in Inhaled insulin is effective in lowering HbA 1c when used as a substitute for short-acting insulin at mealtimes, but large doses are required and long-term safety data are lacking. It should t be prescribed for people with pre-existing lung disease or for smokers. All patients should have baseline lung function tests which should be repeated after six months. The National Institute for Health and Clinical Excellence (NICE) has recommended that inhaled insulin should be reserved for people with needle phobia diagsed by a diabetes specialist or mental health professional, or for those with severe and persistent problems with injection sites. 7 Type 1 or type 2? Type 1 diabetes may present at any age and may be mistaken for type 2 diabetes. It is important to recognise these people rapidly, or they will have a miserable time with symptomatic hyperglycaemia while tablet therapy is gradually escalated. If the patient has rapid onset of symptoms with severe weight loss, low BMI or ketonuria, insulin should be introduced promptly. If 24 Prescriber 5 October

6 in doubt seek advice from the specialist diabetes team. Conclusion Most patients with type 2 diabetes will need insulin eventually and this should be discussed at the time of diagsis. Treatment guidelines are target driven but personal circumstances should be taken into account when deciding on the need for insulin, with the regimen tailored to the individual. References 1. UKPDS 33. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UKPDS Group. Lancet 1998;352: UKPDS 16. Overview of six years therapy of type 2 diabetes a progressive disease. UKPDS Group. Diabetes 1995;44: Nathan DM. Thiazolidinediones for initial treatment of type 2 diabetes? N Engl J Med 2006;355: Johnson JL, Wolf SL, Kabadi UM. Efficacy of insulin and sulphonylurea combination therapy in type 2 diabetes. A meta-analysis of the randomised placebo controlled trials. Arch Intern Med 1996;156: Yki-Jarvinen H, Ryysy L, Nikkila K, et al. Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus. A randomised controlled trial. Ann Intern Med 1999;130: Raskin P, Rendell M, Riddle MC, et al; Rosiglitazone Clinical Trials Study. A randomised trial of rosiglitazone therapy in patients with inadequately controlled insulin-treated type 2 diabetes. Diabetes Care 2001;24: NICE. Techlogy Appraisal 113. Inhaled insulin for the treatment of diabetes (types 1 and 2). December Ackwledgement I would like to thank Dr Charles Fox for his constructive comments. Dr Kilvert is a consultant diabetologist at Northampton General Hospital 26 Prescriber 5 October