Type 1 diabetes: Are long-acting insulin analogues better than regular long-acting human insulin?

There is no scientific proof that long-acting insulin analogues are better than long-acting human insulin. There is also a lack of long-term trials looking at the effects of using insulin analogues for many years.

People who have type 1 diabetes need to inject insulin because their pancreas only produces very little insulin, or none at all. Having high blood sugar levels over long periods of time increases the risk of diabetes complications. Small blood vessels in the body are particularly vulnerable to damage. The eyes, kidneys and nerves are most noticeably affected by this. It is mainly the sensory nerves in the legs and feet that become damaged, as well as the parts of the nervous system that regulate the internal organs in the body. This can affect things like the digestive system and heart.

Nowadays, most people with type 1 diabetes inject insulin using a so-called insulin pen. This device has a fine needle and looks a bit like a fountain pen. It can be used more than once. Generally speaking, people who have type 1 diabetes need to inject insulin several times a day. If their blood sugar is reduced to the recommended levels over longer periods of time, this can also lower the risk of developing complications in the long term. You can find out more about diabetes treatment in our feature.

Different kinds of insulin

People who have diabetes now have a choice of different kinds of insulin. Up until the mid 1980s, insulin was developed from the pancreas of pigs and cattle. After that, artificially produced insulin, so-called human insulin, became more commonly used. Human insulin is chemically virtually identical to the insulin that humans produce naturally. Nowadays, most people who have diabetes use human insulin. In many countries, including Germany, animal insulin is no longer used much.

There is also another kind of insulin, the so-called insulin analogue. Several insulin analogues have been licensed for diabetes since the mid 1990s. Insulin analogues are produced artificially too but, unlike human insulin, their chemical structure is modified. The main aim of modifying the structure is to influence how long it takes for the insulin to start lowering blood sugar levels after being injected, as well as how long the effect lasts. Long-acting insulin analogues are meant to have a more steady effect than long-acting human insulin. The goal is to try to prevent the blood sugar levels from going up and down too much.

Insulin products can be grouped into three main categories according to how long they work for:

• short-acting (or rapid-acting)
• intermediate-acting and
• long-acting insulin.

Short-acting insulin is used to lower blood sugar levels relatively quickly, for example just before a meal. Intermediate-acting and long-acting insulin, also known as “basal insulin”, is taken to cover the body’s basic insulin needs throughout the day.

Two kinds of long-acting insulin analogues are currently available in Germany, called insulin glargine (brand name: “Lantus”) and insulin detemir (brand name: “Levemir”). These medications are meant to have a longer and more steady effect than long-acting human insulin. Like human insulin, they can be used in combination with other types of diabetes medication (oral diabetes medication in type 2 diabetes) or with short-acting insulin.

Research on long-acting insulin analogues

The Institute for Quality and Efficiency in Health Care (IQWiG) in Germany – the publisher of this website – wanted to find out how effective long-acting insulin analogues are in people with type 1 diabetes. IQWiG was commissioned by the German Federal Joint Committee (G-BA) to do this, and worked on it together with researchers at the Medical University of Graz in Austria.

They looked for randomised controlled trials (RCTs) in which one group of patients used insulin analogues and another group used human insulin. In this kind of trial, the participants are randomly assigned to one of the groups. The different groups have different treatments and are then compared with each other. You can read about why this kind of research is important here. The researchers were only interested in trials that lasted at least 24 weeks. They looked for trials that tested whether episodes of seriously low blood sugar (hypoglycaemia, or “hypos”) were less or more common in people who were using human insulin. Hypoglycaemia can be harmful in the short and long term.

The researchers also looked for trials that tested whether the different kinds of insulin had different effects on quality of life and/or complications and deaths. They looked for trials that directly compared the two insulin analogues with each other as well.

Overall, the researchers found 12 relevant trials involving about 4,300 adults in total, as well as 5 trials involving roughly 1,300 children and teenagers. Most of the trials (15 out of 17 trials) compared human insulin with an insulin analogue. Insulin glargine was used in 8 of the trials, and insulin detemir was used in 7 of them. Two of the trials in adults directly compared insulin glargine with insulin detemir.

In the trials that involved adults, the treatment usually lasted between 6 and 12 months. One trial (testing insulin detemir) lasted more than 2 years. In the trials that involved children and teenagers, the treatment lasted between 6 and 7 months in 4 of the trials, and 12 months in a trial of insulin detemir. The IQWiG researchers did not find any trials on the effects of long-term treatment with insulin analogues on diabetes complications in children and teenagers or adults.

No strong proof that insulin analogues are more effective

In some of the trials, human insulin was used in a way that is not typical or recommended in Germany. For example, the participants did not always adjust the number of injections according to their individual insulin needs. This means that the results of these trials are not applicable to everyday clinical practice in Germany.

Complications and life expectancy

Because there were not enough long-term trials, the researchers were not able to say whether the different kinds of insulin had different effects on life expectancy and complications associated with diabetes. The trials also did not provide any information about whether people who use insulin analogues need to go to hospital for treatment more or less often than people who use human insulin.  

Hypoglycaemia

All of the trials looked at how the different kinds of insulin affected people’s HbA1c levels and the frequency of hypoglycaemia. HbA1c levels indicate how high your blood sugar has been over the last three months. Because low blood sugar increases the risk of hypoglycaemia, the reports of hypoglycaemia were always considered together with the HbA1c data. It is important to know whether the people in the two treatment groups have similar blood sugar levels. Only then is it possible to assess whether the risk of hypoglycaemia increases or decreases because of the treatment.  

In the trials, insulin glargine was injected once a day, and insulin detemir was injected once or twice a day. Both kinds of insulin analogues were compared with long-acting human insulin. The outcome: neither the trials in adults nor the trials in children found scientific proof that people who use insulin analogues have fewer episodes of hypoglycaemia compared to people who use human insulin. One trial in adults came to the conclusion that severe hypoglycaemia was less common in patients who used insulin detemir compared to those who used human insulin, particularly at night. But because the people in the trials used insulin detemir in a way that is not recommended in Germany, these results are not applicable to the way people use insulin in Germany. The frequency of mild hypoglycaemia was similar for both kinds of insulin.   

The two insulin analogues, detemir and glargine, were also directly compared with each other. In the trials, which involved adults only, insulin detemir was used twice a day and insulin glargine was used once a day. But these trials also did not find any proof that one of the two insulin analogues was associated with fewer episodes of hypoglycaemia.

Quality of life and satisfaction with treatment

Three trials looked at how the different kinds of insulin affected the health-related quality of life of adults. No difference was found. There was also no difference between people’s satisfaction with their treatment.

Other adverse effects

The IQWiG researchers looked at other possible effects of using these kinds of insulin. The trials suggest that skin reactions at the site of injection in adults were more common in people who used insulin detemir. People who used insulin detemir also gained a bit less weight than people who used human insulin. This was about 0.7 kilos on average in adults. Children and teenagers who took insulin detemir were also found to put on less weight. It is not known why insulin detemir was associated with less weight gain in the trials. So it is still not clear whether this is an advantage or disadvantage.

People might be more likely to stop their treatment if they have unpleasant adverse effects or feel like it is too complicated. In the trials, there was no difference between the number of people taking insulin analogues who stopped their treatment and the number of those who took human insulin who stopped their treatment.

Long-term trials needed

It is currently not possible to say what effect insulin analogues have on life expectancy and the possible complications associated with diabetes. It is also not clear how safe insulin analogues are in the long term. The trials that looked into this were too small and did not last long enough. This means that longer and bigger trials are urgently needed, particularly so that we can find out more about the long-term safety of insulin analogues. There are some suspicions that the insulin analogue glargine could encourage the growth of cancer cells. Researchers around the world have different opinions about this matter and it is still being discussed controversially. More research is needed to be sure about whether insulin glargine really influences the growth of cancer cells.


Author: German Institute for Quality and Efficiency in Health Care (IQWiG)

Note

This health information is a summary of a scientific report published by IQWiG. It is not an assessment of the right to have health care services reimbursed by statutory health insurance funds in Germany. By law, decisions about the reimbursement of diagnostic and therapeutic procedures can only be made by the German Federal Joint Committee (G-BA). The Federal Joint Committee takes IQWiG reports into consideration in its decision-making process. You can find information about the decisions of the German Federal Joint Committee on its English-language website, www.english.g-ba.de.
 

© IQWiG (Institute for Quality and Efficiency in Health Care)