There is so far a lack of scientific evidence that glitazones are better than alternative therapies at reducing mortality or complications caused by blood vessel damage in people with type 2 diabetes. As long-term studies are lacking, reliable conclusions on the long-term benefit or harm of these oral antidiabetics are presently possible only to a limited extent. Available studies provide indications that patients could benefit from one of the two currently approved active substances (pioglitazone); however, these studies also provide indications of potential disadvantages, including an increased risk of heart failure. This is the conclusion of a report by the German Institute for Quality and Efficiency in Health Care (IQWiG), Cologne, which was published in January 2009 and for which an English-language summary is now available.
No antidiabetic of first choice
Glitazones improve insulin sensitivity in the adipose tissue, skeletal muscle, and liver. As a result, glucose uptake by the adipose tissue and muscle tissue increases, while the release of glucose from the liver is inhibited. However, glitazones, which are available as tablets, are not regarded as an antidiabetic of first choice and therefore have only limited approval in Europe. They are only allowed to be used as monotherapy if patients do not tolerate metformin or if other contraindications for the use of this drug exist.
In combination therapy, glitazones should only be prescribed if blood-glucose levels are insufficiently controlled by metformin or a sulfonylurea alone. A 3-drug therapy in combination with sulfonylurea and metformin is also possible: however, glitazones are only approved in this therapy regimen if a previous combination of sulfonylurea and metformin failed to achieve the desired success. Pioglitazone can also be used in combination with insulin.
Long-term use has not been sufficiently tested
The aim of the report, which was commissioned by the German Federal Joint Committee, was to assess the benefit of the long-term treatment of pioglitazone and rosiglitazone versus placebo, or versus other blood-glucose lowering drug or non-drug interventions, or versus each other.
A total of 7 eligible studies on pioglitazone and 16 eligible studies on rosiglitazone were identified and included in the evaluation. However, in IQWiG’s opinion, the long-term benefit and harm of glitazones have still not been sufficiently investigated.
Results from studies on rosiglitazone are only available for a treatment period of up to 12 months; however, oral antidiabetics are used for several years, if not decades. A 4-year study on rosiglitazone (ADOPT study) does not correspond to the current approval status in Europe and therefore could not be evaluated.
Only one large long-term study on pioglitazone available
The current evidence is slightly better for pioglitazone. Although only a small number of clinical comparisons have been conducted, these include a long-term study lasting 34.5 months that recruited about 5000 patients (PROactive study). The PROactive study was a comparison of a therapy optimization regimen with and without pioglitazone (including the potential use of other blood-glucose lowering drugs such as metformin or a sulfonylurea). However, according to IQWiG, the results of this study also need to be verified and confirmed in further clinical comparisons.
Both manufacturers of glitazones, GlaxoSmithKline (rosiglitazone) and Takeda Pharma (pioglitazone), supported IQWiG’s benefit assessment by providing comprehensive, previously unpublished data.
No proof of an additional benefit with regard to mortality and late vascular complications
IQWiG found no proof in the available study data of an additional benefit of glitazones with regard to late micro- and macrovascular complications of type 2 diabetes (e.g., cardiac disease, stroke, eye or kidney damage) or mortality.
However, the findings provide indications of an advantage of pioglitazone for a composite outcome of all-cause mortality, non-fatal myocardial infarction (excluding silent myocardial infarction), and stroke. In addition, patients who had previously suffered a stroke seemed to benefit from pioglitazone, as strokes recurred less frequently in patients using this treatment. These indications were inferred from secondary outcomes of the PROactive study; no superiority of pioglitazone was shown for the primary outcome.
Advantage of glitazones with regard to hypoglycaemia
IQWiG sees proof of an additional benefit of glitazones with regard to the outcome “hypoglycaemia” both for pioglitazone and rosiglitazone. According to the findings, patients with type 2 diabetes experience hypoglycaemic events less frequently if they use metformin and a glitazone than if they use a combination of metformin and a sulfonylurea (with comparable lowering of blood-glucose levels).
Potential disadvantages: heart failure, oedema, and bone fractures
However, this potential additional benefit is counteracted by indications of higher risks: in the PROactive study, more cases of heart failure were diagnosed in the treatment arm receiving therapy optimization with pioglitazone, in part including cases of serious heart failure leading to hospitalization. In addition, oedema occurred, which is why more participants discontinued the study. Moreover, women more often experienced fractures.
In addition, for the combination of pioglitazone and metformin, the findings provide indications of more serious adverse events compared with metformin and vildagliptin, another new antidiabetic. Moreover, other heart diseases (e.g., heart attacks and angina pectoris) seem to be more common than in the combination of metformin and a sulfonylurea.
Weighing benefits and harms
In the opinion of the Institute and the external experts involved in the report, the potential benefits and harms of glitazones must be carefully weighed against each other. In order to make reliable statements on their advantages and disadvantages, good quality studies lasting several years are definitely needed. The risk potential of glitazones has been discussed in an increasingly controversial manner over the past 2 years, in particular concerning the possibly higher rate of heart attacks in patients treated with rosiglitazone, though at present there is still a lack of large studies of good methodological quality to make reliable conclusions about these risks. However, in the next few years several such clinical comparisons will be completed.
Procedure of report production
The preliminary results (preliminary report) were published by IQWiG in mid-June 2008 and interested parties were invited to submit comments. After the end of the commenting procedure, the preliminary report was revised and the final report sent to the contracting agency, the Federal Joint Committee, at the end of November 2008. The documentation of the written comments will be published in a separate document simultaneously with the final report.