Abstract
Insulin therapy for people with type 1 diabetes is life saving and without insulin the condition is terminal. Insulin treatment is also needed in a significant number of people with type 2 diabetes to optimize glycaemic control. As more people with diabetes are now being managed exclusively in primary care, GPs and those training to become GPs need to have an understanding of insulin and its use in type 1 and type 2 diabetes.
The GP curriculum and insulin
Describe and implement the key national guidelines that influence health care provision for diabetes (e.g. NICE guidelines and quality markers) Describe the role of particular groups of medication, such as insulin, in the management of diabetes Communicate about diabetes with patients and their families and other professionals both within the primary health care team and in secondary care Manage acute diabetic emergencies such as hypoglycaemia
This article will review the types of insulin that are available, their formulation and their methods of delivery and will discuss their place in treatment all in the light of National Institute of Clinical Excellence (NICE) guidelines on the treatment of type 1 and type 2 diabetes.
Types of insulin
The large majority of people today use human-sequence insulin. It is manufactured using recombinant DNA technology in which the human insulin genes are inserted into yeast or bacterium cells, which can then be grown in bulk and allowing human insulin to be harvested from the cells. They are now sometimes termed traditional insulins. Pork and beef insulin, extracted and purified from the animal pancreas, is still available for those who need it. Traditional and animal insulins are available in short-acting (clear), longer acting (cloudy) and mixtures of short-acting and longer acting formulations.
In recent years, analogue insulins have been developed. They are made from human-sequence insulin by alterations or substitutions of specific amino acids. The analogue insulins produced may be ‘long acting’ or ‘rapid acting’.
Human soluble insulin
Human soluble insulins are also known as clear or soluble insulins. They have a peak action 2–6 hours after injection and should be given 20–30 minutes before meals. One of the best-known examples is Human Actrapid.
Human longer acting insulins
Human longer acting insulins are also known as cloudy insulins. They are made by precipitating insulin or protamine-insulin [neutral protamine Hagedorn (NPH) insulins, named after the person who invented them] in the presence of zinc. This forms insoluble crystals that are injected as a suspension and absorbed slowly. These insulins have a peak action at around 8 hours after injection, but in some people their effect can last for up to 18 hours.
Premixed insulins
Premixed insulins contain combinations of soluble, short-acting and crystalline long-acting insulin. A combination of 30% short-acting and 70% long-acting is one that is often used, but 10:90, 15:85, 20:80, 25:75, 40:60 and 50:50 combinations have been produced by different companies.
Short-acting insulin analogues
Short-acting insulin analogues have been developed by minor alterations to the amino acid sequences of human insulin to produce insulins that have a quicker onset of action and shorter duration of action than normal soluble insulin. Three are available:
Insulin lispro, which is identical to human insulin apart from inversion of lysine and praline residues at positions B28 and B29 on the B chain of the insulin molecule Insulin aspart, which is identical to human insulin apart from the substitution of praline at position B28 with aspartic acid Insulin glulisine, which is identical to human insulin apart from the substitution of asparagine at position B3 with lysine and lysine at position B29 replaced by glutamic acid.
These three short-acting analogues have similar pharmacokinetic profiles, with quicker onset and shorter duration of action than traditional soluble insulin. Their peak action is around 1 hour after injection and their effect wanes after 4 hours. This means that they can be injected just before a meal, and they reduce the risk of postprandial hypoglycaemia (Oiknine et al., 2005). Short-acting insulin analogues are now also available premixed with longer acting cloudy insulins, in varying combinations, for those using a twice-daily premix regime.
Long-acting insulin analogues
Two long-acting insulin analogues have been developed and marketed. One, insulin glargine, is the same as human insulin apart from a substitution of glycine for asparagines at the A chain of the insulin molecule at position A21 and the addition of two arginine molecules at the C-terminal end of the B chain. This results in a change in properties of insulin glargine. It is soluble at acidic pH and so is the first clear long-acting insulin. When it is injected, it forms a microprecipitate within the more neutral pH of the subcutaneous tissues. This results in slow absorption from the injection site.
It has a flat profile of action with no pronounced peaks, has a duration of action of around 24 hours and is subject to less interperson and intraperson variability than previous cloudy long-acting insulins. As a result, there is often a reduction in hypoglycaemic episodes in people using insulin glargine as compared with NPH insulin (Hamann et al., 2003).
The other, insulin detemir, is acylated with a fatty acid at the C-terminus of the insulin B chain. The fatty acid binds to albumin, which slows insulin absorption and prolongs the circulation time. Insulin detemir has a flat profile of action and reduces the number of hypoglycaemic episodes as compared with long-acting cloudy NPH insulins (Vague et al., 2003).
Insulin delivery systems
Most insulins are available in 10 ml vials, pen cartridges and disposable pens. A good analogy is that of pen and writing. Vials are like dipping a quill into ink, insulin cartridges are like cartridge pens and disposable pens are biros! Pen technology enables insulin to be carried about easily and enables injections to be given where and when required. Insulin doses can be dialled up more accurately using the pen devices, and it is easier to teach people to use pen devices than it is to draw up insulin into a syringe from a vial. Most people moving on to insulin when offered a choice prefer pen devices and they are now commonly being prescribed for initiation of insulin in both type 1 and type 2 diabetes. Some health care professionals prefer cartridges and others the disposable pens. Patient choice should inform the decision as to which to use.
A few people with type 1 diabetes use continuous infusion pumps, which give a slow steady infusion of short-acting insulin. Pump technology has developed significantly in the past few years. However, it is expensive and there are limited NHS funds for it. Such people will be under the care of a secondary or tertiary diabetes care centre.
Advice about insulin injections
Insulin needles are nowadays very thin and short, enabling the injection to be almost ‘pain-free’. Insulin is usually injected at right angles into the subcutaneous tissue of the lower abdomen or the upper outer thighs. The upper outer arms or buttocks can also be used if necessary. Repeated injection into the same site can cause accumulation of fat (called lipohypertrophy). This can be a cosmetic embarrassment and can cause variability in the absorption of insulin. Injection sites should therefore be rotated to avoid this possible complication.
Insulin regimes
Basal bolus therapy is the insulin regime in which an injection of short-acting insulin is given just before each meal, with one injection of long-acting insulin at night. People using this regime usually have four injections a day. It gives flexibility to cope with different meal times, size of meals and exercise and is the insulin regime that many adults with type 1 diabetes find best suits their lifestyle.
Another regime is to have two daily injections of premixed insulin, one before breakfast and the other before the evening meal. Some children may initially manage on one injection of long-acting insulin each day and then move to two injections of mixed insulin per day.
The variety of different insulins available is considerable and can make prescribing complex. This is one reason why insulin treatment has been the territory of the specialist rather than the GP. However, it is important to understand the principles outlined in these paragraphs as you, as a GP, may be required to adjust insulin dosages and issue repeat prescriptions.
Type 1 diabetes
The NICE guideline for the management of type 1 diabetes in childhood and adults is a vital resource document for anyone requiring more detail on diabetes management of type 1 diabetes (NICE, 2004).
Type 1 diabetes in children
Children newly diagnosed with type 1 diabetes should be referred to secondary care services for same day assessment and insulin initiation. Children with diabetes are then virtually always managed on an ongoing basis in paediatric hospital clinics. Most areas of the UK will have a specialist multidisciplinary team lead by a paediatrician with an interest in diabetes to look after such children, often with specialist outreach nurse support to assist the child and family at home. However, the GP will usually be issuing prescriptions for insulin and accessories and will be caring for the children when they develop acute illness so the GP needs a broad understanding of insulin therapy in childhood. Insulin regimes are often targeted at keeping good glucose control with as few injections as necessary in childhood.
Type 1 diabetes in adults
Adults with type 1 diabetes have traditionally received most of their routine follow-up in secondary care. Results from their secondary care clinic attendance will therefore arrive in letters to the practice. These results need to be put on the practice's clinical computer system, as adult patients with type 1 diabetes are included in all the Quality and Outcomes Framework clinical indicators for diabetes.
A number of people with type 1 diabetes disengage from follow-up during the teenage years. They may occasionally attend primary care, but often this is only for acute illness unrelated to diabetes. It is vital to try to re-engage with them and every opportunity needs to be taken to discuss their diabetes and its control. Primary care will be issuing prescriptions for insulin, so repeat prescription monitoring may offer an opportunity to see and review these patients, to offer the chance to discuss their care and to encourage them to re-engage with diabetes services.
Insulin in type 2 diabetes
When insulin is needed in someone with type 2 diabetes, the preference of the individual and lifestyle need to be taken into consideration when discussing insulin regimes and delivery systems. The most straightforward way to start is to continue metformin and sulphonylurea oral medications and add once daily basal insulin. Continuing the oral agents when adding insulin reduces the number or units of insulin required, reduces the weight gain associated with insulin therapy and reduces hypoglycaemia episodes (Gadsby, 2003).
The long-acting NPH insulins (e.g. insulatard) are the cheapest and so are commended as the basal insulin of choice in the new NICE guideline (NICE, 2009). They do, however, cause more hypoglycaemia as compared to the new long-acting insulin analogues (insulin glargine and insulin detemir), and these insulins may be preferred where hypoglycaemia is a concern or where hypoglycaemia is a problem on NPH insulin.
Insulin initiation used to require referral to secondary care but training programmes have been established to enable GPs and practice nurses to acquire these skills and gain experience so that they can initiate insulin in people with type 2 diabetes (Warwick Medical School, 2009). Patient-initiated up-titration algorithms, usually starting with a dose of basal insulin of 10 U, have been shown to be safe and effective in getting people to an optimal dose of long-acting insulin (Davies et al., 2005).
Plan for initiating insulin in type 2 diabetes
All practice team members starting insulin in the community should have received appropriate training. Before starting insulin, teach home blood glucose monitoring if the patient is not already doing it, and revise and reinforce dietary principles. When initiating insulin
Continue on metformin and sulphonylurea oral agents Teach the patient insulin injection technique, using an injection pen Start with a dose of 10 U of long-acting insulin Give verbal and written instructions (patient-initiated up-titration algorithm) about increasing the insulin dose depending on self-monitored fasting glucose levels. A sample regime is included in Box 1, but local policies vary. Teach the patient and/or carers about safe disposal of sharps (Box 2) Teach the patient about hypoglycaemia symptoms and their management Give the patient and/or carer a contact telephone number for advice and help
Follow up all patients initiating insulin by phone after a couple of days and then individualize frequency of calls depending on progress, need to alter insulin dose and blood glucose control. Check an HBA1c every 3 months until the patient is stabilized on insulin.
Simple insulin up-titration algorithm
After starting insulin treatment (usually with 10 U daily) the dose should be titrated every 3–7 days according to a simple schedule, until the target is achieved. For example:
Safe disposal of sharps
Manufacturers recommend that needles for insulin injection should be used once only.
It is important that the patient and/or carer is informed of the risk of sharps injury to family members, household visitors and refuse collectors. Careful and appropriate handling and disposal of sharps is of paramount importance.
One litre sharps bins are available on prescription. Check your local policy for disposing of full bins. In some places, they can be returned to GP surgeries, provided the premises are licensed with the Environment Agency. The BD Safe Clip, which cuts off used needles, is available on prescription.
What if once daily basal insulin does not give adequate glycaemic control?
In type 2 diabetes, if once daily basal insulin at adequate dosage (say around 1 U/kg body wt) does not give adequate overall glycaemic control (as measured by HBA1c), it is often because of elevated blood glucose levels after the main meal of the day. One way of addressing this problem is to suggest that a small dose of rapid-acting insulin be given with the main meal of the day. Self-monitored blood glucose levels around 2 hours after the main meal can be measured to up-titrate the dose of rapid-acting insulin until any postprandial ‘spike’ of blood glucose is controlled.
Sometimes a second injection of rapid-acting insulin in addition to once daily long-acting insulin may be needed with the second largest meal of the day to achieve excellent glycaemic control. In some individuals a third injection of rapid-acting insulin may be needed, giving the full basal bolus therapy regime of four injections a day which is the most flexible regime in adults with type 1 diabetes.
Recognizing and treating hypoglycaemia
The most common complication of insulin treatment is hypoglycaemia. Symptoms include, sweating, a pounding heart, shakiness or tremor, hunger, confusion, drowsiness, difficulty with speech and in coordination. A mixture of symptoms usually occur together. Many people begin to develop these symptoms when their blood glucose levels fall below 3.8 mmol/l. The management of hypoglycaemia depends on the level of consciousness and cooperation.
If the person is conscious and cooperative
Give a sugary drink, e.g. glass of milk with four spoons of sugar in it or three or four glucose sweets Follow this with a substantial snack or meal high in carbohydrate Check blood glucose levels to ensure that they have returned to normal
If the person is conscious but uncooperative
Use dextrose gel (Glucogel) Insert the gel into the mouth, using around a third of the bottle Massage the gel gently around the cheeks to aid absorption of the gel through the buccal mucosa Then treat as for the conscious and co-operative patient
If the person is unconscious
Give a glucagon injection subcutaneously or intramuscularly Place the person in the recovery position and await return of consciousness, which usually occurs in 15–20 minutes
If glucagon does not render the person conscious
Call for ambulance support If available, start an intravenous infusion of glucose, usually in the form of 20 ml of 25 or 50% glucose solution given into a large vein through a wide-bore needle. Great caution is needed with venous access as concentrated glucose solutions can damage tissue if they leak out of a vein, so care must be given to ensure that this does not occur.
Once hypoglycaemia has been recognized and treated, follow up to try to identify the cause. If the cause is thought to be too much insulin, reduce the insulin dosage appropriately.
Key points
GPs need to have a greater understanding of insulin as more people with diabetes using insulin are being managed in primary care People newly diagnosed with type 1 diabetes will be initiated on insulin in secondary care People with type 2 diabetes requiring insulin are now often initiated on insulin in the community Training programmes for insulin initiation in type 2 diabetes for GPs and practice nurses are available The most straightforward way to start insulin in someone with type 2 who requires insulin is add once daily long-acting insulin Hypoglycaemia is the most common side effect of insulin therapy. It needs to be recognized and managed appropriately