Type 2 diabetes: What are the advantages and disadvantages of lowering blood sugar with glitazones?

Glitazones have not been shown to be better than other medications at preventing the complications of type 2 diabetes. The drug rosiglitazone was taken off the market because of its unfavourable risk-benefit ratio. There are also safety concerns about the drug pioglitazone, so drug agencies are advising against its use.

People who have type 2 diabetes no longer make enough insulin and have usually also become resistant to the insulin they make. This means that the glucose (sugar) in their blood can no longer be transported into their cells properly, so they have high levels of sugar in their blood (hyperglycemia). Typical symptoms of severe high blood sugar include extreme thirst, needing to go to the toilet a lot, tiredness and itching. But the main problem is that very high blood sugar levels can damage blood vessels over time, which in turn can damage important organs such as the eyes and kidneys. People with type 2 diabetes also have a higher risk of cardiovascular diseases (heart and circulation problems) like heart attacks and strokes.

People do not always need medications to control their blood sugar. Losing some weight and doing more exercise often already makes a difference. If that is not enough, tablets that lower blood sugar levels (so-called oral antidiabetics) can be used. Some people who have type 2 diabetes need insulin too. You can read more about type 2 diabetes, its symptoms, and what medications can help in our feature.

Many different medications are available in the form of tablets for the treatment of type 2 diabetes. The most common of these are metformin and sulfonylureas. Medications called glitazones are among the more recent options. Only one glitazone is still licensed for use in Germany: pioglitazone. Yet the German regulatory body – The Federal Institute for Drugs and Medical Devices (in German: Bundesinstitut für Arzneimittel und Medizinprodukte, or BfArM) – has since June 2011 been advising against taking medications containing the drug pioglitazone. It is suspected that it increases the risk of bladder tumors. You can find more information (in German) on this at BfArM and further below on this page.

The European Medicines Agency (EMA) already decided in September 2010 to take the drug rosiglitazone off the market. One of the main reasons for this was that people who took rosiglitazone had more heart disease and fatal heart attacks. Overall, the risk-benefit ratio of this drug was found to be unfavorable.

In 2008 the German Institute for Quality and Efficiency in Health Care (IQWiG) – the publisher of this website – looked into whether patients with type 2 diabetes benefit from long-term treatment with glitazones. IQWiG was commissioned to do so by the German Federal Joint Committee (G-BA).

What glitazones do and how they are used

Glitazones make the cells in fat, muscle and liver tissue more sensitive to insulin. This means that more sugar is transported from the blood into fat and muscle cells, so the level of sugar in the blood goes down. At the same time, less sugar is released from the liver.

Glitazones were not the first choice for diabetes medication right from the start, so they have not been approved for widespread use in Germany from the beginning: they are only allowed to be prescribed as a stand-alone treatment (monotherapy) if patients had a bad reaction to metformin or if there were other medical reasons why they were not able to take metformin.

Research on glitazones

Researchers from the German Institute for Quality and Efficiency in Health Care (IQWiG) looked for research on the effects of long-term treatment with glitazones in people who have type 2 diabetes. They wanted to know how glitazones work compared to a dummy drug (placebo) and other blood-sugar-lowering medications and strategies. They were also interested in how pioglitazone and rosiglitazone compare to each other. They only looked for studies that lasted at least 24 weeks, and in which the use of glitazones was in line with the approved conditions of use mentioned above.

Their search was restricted to certain kinds of studies called randomized controlled trials. In this kind of study, participants are randomly assigned to different groups. The people in one group use glitazones, and people in the other group(s) use a placebo (dummy treatment), a different medication, or a different combination of medications. In this way researchers can be quite sure that any differences between the groups are due to the different medications they are using.

The IQWiG researchers searched medical databases for this kind of trial and also asked the manufacturers of these medications if there had been any other trials. Of the randomized controlled trials that they found, 7 looked at pioglitazone and 16 looked at rosiglitazone. None of the trials directly compared the two glitazones with each other. A total of more than 11,000 people took part in the trials, all between the ages of 51 and 67. Most of the trials lasted between half a year and a year. Only one trial – the PROactive study, involving over 5,000 participants – monitored people for almost three years on average. But this trial only looked at pioglitazone, and not rosiglitazone.

The advantages and disadvantages of glitazones

Once they had analyzed the trials described above, the IQWiG researchers concluded that, overall, rosiglitazone and pioglitazone have not been shown to have an additional benefit compared to other treatments. They based this conclusion on the research results about deaths and complications caused by damage to blood vessels, such as heart disease, strokes, as well as eye and kidney problems. 

The PROactive study provided some data suggesting that people who used pioglitazone to optimize their treatment may have an advantage in terms of deaths, non-fatal heart attacks and strokes if these factors are grouped together. In this study, the participants in the treatment group used pioglitazone on top of the blood-sugar-lowering medication they had been using before. The aim was to optimize their therapy, in other words to reduce their blood sugar to below a certain level. Pioglitazone also seems to benefit people who have already had a stroke: when used to optimize therapy, further strokes were less common.

Pioglitazone and rosiglitazone were found to have an additional benefit when it comes to the risk of hypoglycemia: people who use a combination of metformin and glitazones have fewer episodes of low blood sugar than people who use a combination of metformin and sulfonylureas, although both combinations decrease blood sugar levels by about the same amount. If someone has hypoglycemia, their blood sugar levels drop too low, which can make them turn pale, feel shaky, have difficulties concentrating and even pass out if it is severe.

Adverse effects of glitazones

However, this possible additional benefit may be outweighed by more serious risks: there is some evidence that heart failure (cardiac insufficiency) is more common in people who take pioglitazone to optimize their therapy than it is in people who do not take pioglitazone. This condition was sometimes very serious, and more of the people who took pioglitazone went to hospital because of it. Fluid retention (edema swelling) was more common in people who took glitazones too. This could be related to heart failure. The PROactive study found that more of the patients who took pioglitazone had to stop the treatment because of edema swelling. Bone fractures also seemed to be more common in women who took pioglitazone than they were in the other group. People who use glitazones put on weight, too.

There is evidence that serious adverse effects are more common from the combination of pioglitazone and metformin when compared with treatment using vildagliptin (another newer anti-diabetic drug) and metformin. Serious adverse effects are those adverse effects that are life-threatening or that require hospitalization, for example. Heart trouble (including but not limited to heart attacks and heart pain) also seems to be more likely in comparison with the combination of sulfonylurea and metformin.

Regulatory authority safety warnings

Over the past few years, the US regulatory authority FDA has issued warnings about both pioglitazone and rosiglitazone, drawing attention to the higher risk of heart disease associated with these drugs. In September 2010 rosiglitazone was taken off the market in Germany following a decision by the European drug regulator EMA.

In early 2011 the FDA voiced further safety concerns about pioglitazone. For some time it has been suspected that the use of pioglitazone increases the risk of bladder cancer. A French trial has supported this suspicion. For this reason, the German Federal Institute for Drugs and Medical Devices (BfArM) has since June 2011 been advising against taking medications containing the drug pioglitazone. These medications include Actos, Competact and Tandemact. Doctors should not prescribe these medications to anyone according to BfArM. BfArM also recommends that people taking these medications not stop using them without first consulting with their doctor. This could lead to an uncontrolled increase in blood sugar levels and health risks.

Long-term effects unclear

The long-term effects of drugs are an important factor for people with diabetes because they will use medication for years, or often even decades. Short trials that last 6 months or one year can give results about a treatment’s quality in that timeframe, but they are not very powerful instruments for looking at long-term effects. The IQWiG had already pointed out in its report that a better assessment of the benefits and harms of diabetes medications is only possible when data from long-term trials is available.

If you would like to stop taking prescription drugs for type 2 diabetes, it is important to talk to your doctor first. You can read more about other diabetes treatments and the long-term use of medication here.


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

(This update is based on the new decisions made by EMA, BfArM and the FDA. The information about the advantages and disadvantages of glitazones was not updated.)


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)