The pharmokinetics of insulin analogues and pumps

Insulin was discovered – in Canada – by Banting and Best, working together. Similarly, a team approach is necessary for pump therapy to be successful; nobody does pump therapy successfully by themselves. The best way of delivering insulin with meals and delivering basal insulin is with a pump. When insulin is delivered by subcutaneous injection, physiological production is duplicated in a very poor way. The analogues of insulin have less pharmacokinetic variability than insulin itself and the recent emphasis has been to use these rather than bovine, porcine and human insulin. Competition between the three major insulin companies is intense, with all three having recently produced new analogues. The analogues represent the switching of two amino acids on the B chain of the insulin molecule. The result of this switch is that the hexamer insulin molecule dissociates more quickly to dimers and monomers. These are absorbed rapidly. In this way, fast increases in serum insulin concentrations can be maintained, thus simulating physiological mealtime insulin peaks of concentration. Patients are usually recommended to take their insulin 30–40 minutes before eating. However, the majority find it difficult to comply with this instruction. The insulin analogues allow the adoption of a paradigm of diabetes care that it is critical for the successful implementation of CSII. The current education method for people with diabetes focuses on the patient as the decision maker, adjusting the therapy to the meal. This approach will only work if an insulin preparation is available that allows the therapy to be adjusted in response to different nutrients. There should be no ‘diabetic diet’ for patients with type 1 diabetes (except for adjustments for obesity) and no need for a fixed regimen. How do the insulin analogues work in pumps? A double-blind, randomised trial comparing insulin lispro with regular insulin in 30 patients showed that better postprandial glucose responses were obtained with the analogue than with regular insulin (Figure 1). With regular insulin, a bedtime snack is essential, which results in hyperglycaemia overnight and slightly higher morning glucose. This increase is due to the pharmacokinetics; the insulin peaks after four hours. Therefore, if dinner is consumed at 7 or 8 pm, the peak action of insulin occurs in the early hours of the morning. But an elegant demonstration has shown that patients on insulin lispro at dinner had elevated glucose throughout the night, compared to those on regular insulin (Figure 2). So, in effect, a bedtime snack is not essential with the analogues. This is a very important change in how diabetes is treated. A cut-off level for blood glucose of 7mmol/l is used. If the blood glucose level is below that figure, a bedtime snack is recommended. Comparing regular insulin with insulin lispro in a pump, a small but significant fall in HbA1c levels is seen with lispro. Insulin lispro vs regular insulin Glycosylated haemoglobin levels and rate of hypoglycaemia in 30 CSII patients However, diabetes is not just about hyperglycaemia. With regular insulin, abnormal fatty acid production occurs and this excess production could play an important role in type 2 diabetes, as free fatty acids are known to mediate insulin resistance (Figure 3). Hypoglycaemia has been a concern of the insulin analogue manufacturers when a pump is used. But a trial has shown that after three months, the hypoglycaemia rate was the same whether a pump patient used an analogue or regular insulin. Test meal (520 kcal) In conclusion, intensive therapy, either by pump or multiple daily injection, will only work when diabetes education focuses on self-care behaviour within the context of existing lifestyle practices. Current diabetes education emphasises patient problem-solving and decision-making. The patient must feel comfortable with this concept and be able to make decisions on a daily basis. There is an emphasis on a systematic approach to matching insulin with food and exercise, rather than following a fixed regimen. Most patients can learn to accommodate to their daily variation in lifestyle. Ultimately, the patient should ‘think like a pancreas’. We used to see a lot of local reactions at the site of the pump needle's implantation. Some of these were as a result of infection but some appeared to be as a result of the insulin itself. Do you get differences with the analogues? These reactions are more rare now, mainly because patients are changing their tubing more frequently – usually every two days. If you leave it any longer than three days, the risk of getting an abscess at the infusion site is substantial. And there can be irritation caused by allergies to the tape which holds the tubing in place. I have not seen any reactions to the insulin analogues. In controlled trials, selection often means that the patients are already well controlled, with baseline HbA1cs tending to be better than those seen in regular practice. Do patients in ‘real life’ tend to do so well on pump therapy? It is true that in clinical studies the patients are often past the pre-contemplation state. They are very well motivated and know what they want. However, in my experience in everyday clinical practice, it is those individuals who are not coping well with multiple injections and who are having excessive hyperglycaemias and hypoglycaemias who benefit the most from pump therapy. It is essential that patients selected for pump therapy should already be regularly monitoring their glucose: at least four times a day. With this proviso, patients on pump therapy tend to do very well. Could you briefly describe the process of education for pump therapy? We have radically changed our process for diabetes education. We have four classes –each about one and a half hours – which we use as a menu. An initial ‘getting started’ class explains both multiple injection and CSII therapy. The other key classes cover pattern management, scales and supplements, and carbohydrate counting. We have a maximum of four patients per class, who participate actively, share their life experiences and problem solve. There is then continual contact with the nurse educator – by e-mail, phone or fax – for two to three weeks. Following this transition period, the aim is that the patients should know what to do themselves, and we then see them every three months. You showed the difference in the time-action profile of regular insulin and insulin lispro. Is there evidence about the depot action of insulin lispro? The size of the depot is not so much of a factor as far as the duration of action is concerned. You can match increasing carbohydrate content by increasing the size of the depot. We use about one unit of lispro to approximately ten grammes of carbohydrate. This has to be individualised: between seven and 15 grammes. There is no question that the newer insulins have allowed a more appropriate implementation of CSII.

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