Diabetes and the pharmaceutical industry

Clinical use of insulins

Human insulins now dominate the treatment of both type 1 and type 2 diabetes, although animal insulins are still available, and problems of antibody production, allergy and antibodymediated resistance to insulin have been practically eliminated.

Because food intake causes a surge in blood glucose, as dietary carbohydrates are absorbed and broken down, a rapid-acting or short-acting insulin is usually injected subcutaneously shortly before each main meal, to prevent hyperglycaemia in both type 1 and type 2 diabetes.

The need for a background level of insulin is catered for by using a longer-acting type, to maintain a normal glucose level in the hours between meals and also overnight. This so-called basal-bolus approach tries to mimic insulin secretion in a person without diabetes.

Both the rate of release of insulin from its subcutaneous injection site into the circulation and the metabolic need for blood glucose vary between one person and another and from one day to another, depending on diet, exercise and other factors. It is therefore necessary to fine-tune the type, amount and timing of insulin injections for each individual. Learning to make appropriate adjustments from day to day is part of the self-care process for those with diabetes, especially those with type 1 diabetes.

For example, if too much insulin is taken before a meal, the blood glucose level may later drop below normal, inducing a hypo. Equally, too much basal insulin, which is usually injected at bedtime, may produce hypoglycaemia during the night, whereas too little or too short a duration of action will result in hyperglycaemia on waking.

Tight control of blood glucose, necessary to minimise the development of complications, depends on careful self-monitoring and appropriate choice of the insulin preparations used. The clinical benefits of choosing a target level close to normal must, however, be balanced against the risk of provoking hypoglycaemia.

In type 1 diabetes, the US Diabetes Control and Complications Trial (DCCT) showed that those given intensive insulin treatment had a threefold higher risk of hypoglycaemia than those on a non intensive insulin regimen. They also had a more than 70 per cent higher risk of becoming overweight. However, when the same patients were followed (on non-intensive therapy) for a further eight years (in the EDIC study) after completing the 6.5 years of the DCCT, the benefits of intensive treatment were still highly significant, with an 84 per cent reduction in the risk of developing albuminuria (a sign of kidney disease) and significantly fewer cases of high blood pressure.

The introduction of the short- and long-acting insulin analogues over the past ten years has helped to alleviate some of the problems of intensive therapy.

Insulin lispro (Eli Lilly), launched in 1996, was the first rapid-acting insulin analogue to become available in the UK. Its structure is the same as that of human insulin, except that the order of two of its amino acids has been reversed. This small change makes it diffuse more rapidly out of the site of injection. It has a faster onset and shorter duration of action than unmodified human insulin. Other rapid-acting insulin analogues are insulin aspart (Novo Nordisk), introduced in 1999, and insulin glulisine (sanofi-aventis), introduced in 2005. They also have slightly different structures from human insulin.

Rapid-acting analogues are taken immediately (0- 15 minutes) before or just after eating and this has been reported to reduce post-meal hyperglycaemia, as compared with NPH insulin, in both type 1 and type 2 diabetes. An improvement in long-term glycaemic control, as measured by HbA1C levels, has mainly been seen in type 1 diabetes.

Long-acting insulin analogues have been introduced more recently. The first, insulin glargine (sanofi-aventis), was launched in 2000. It has a slow and flat, peakless release into the circulation, enabling once-daily use as basal insulin.

Insulin glargine is used in both type 1 and type 2 diabetes as basal insulin, normally given once daily in the evening. In type 2 diabetes it may be used in combination with oral hypoglycaemic agents. Comparative studies in type 1 diabetes have typically found lower average HbA1C and fasting blood glucose levels than with NPH insulin, with fewer nocturnal hypoglycaemic episodes and less tendency to weight gain. Similar results have been reported in type 2 diabetes, although evidence for a reduced incidence of hypoglycaemia is currently stronger than for better glycaemic control.

Insulin detemir (Novo Nordisk), introduced in 2004, is the second long-acting analogue insulin to be made available. Insulin detemir gives a longer, dose-dependent duration of action (up to a day) than NPH insulin and can also be used in both type 1 and type 2 diabetes. It appears to produce lower fasting blood glucose levels, less weight gain and a lower risk of nighttime hypoglycaemia than NPH insulin, but not lower HbA1C levels. Insulin detemir is given once or twice daily, depending on insulin requirements.

The recent introduction of insulin analogues means that there are fewer data available on their longterm safety and efficacy than for natural insulins. However, recent studies have shown that, for example, a short-acting analogue insulin can be used in gestational diabetes without increased risk of damage to the baby, and insulin analogues can be a useful addition to therapeutic choices for both type 1 and type 2 diabetes.

Insulins are typically supplied in cartridges, vials, or pre-loaded pens. In addition to the single insulins, there are a variety of pre-mixed biphasic insulins, consisting of a rapid-acting analogue or short-acting insulin mixed with an isophane insulin. For chemical reasons, insulin glargine is never mixed with any other type of insulin.

Continuous infusion pumps can provide a highly effective way of delivering insulin for intensive control of glycaemia, especially in type 1 diabetes. Using a pump can reduce the number of hypoglycaemic episodes as compared with multiple injection regimens. Both basal and meal-time requirements can be catered for in this way. However, the cost of purchasing such a pump may limit their wider use.