First assessment of the established drug market: advantage for sitagliptin

There are hints of a minor added benefit of sitagliptin in free combination with metformin versus sulfonylureas if the treatment goal is to lower blood glucose to near-normal levels. In comparison with the sulfonylurea glipizide, which is not approved in Germany, the added benefit in men is even "major". In contrast, an added benefit is not proven for other drugs from the group of gliptins. This is the conclusion reached by the German Institute for Quality and Efficiency in Health Care (IQWiG), which presented the first dossier assessments pursuant to the Act on the Reform of the Market for Medicinal Products (AMNOG) for the so-called established market. These assessments dealt with drugs from the group of gliptins.

Comprehensive commission package on gliptins

Three drugs were examined, either as a single agent or in fixed combination with metformin: vildagliptin and vildagliptin/metformin, sitagliptin and sitagliptin/metformin, and saxagliptin. These drugs were approved in Germany between 2007 and 2009 for the treatment of people with type 2 diabetes mellitus. They are an option if those affected cannot lower their blood glucose levels with dietary changes and exercise alone or do not tolerate other oral antidiabetics.

At the same time, IQWiG also completed a dossier assessment of the fixed combination of saxagliptin and metformin. This fixed combination first entered the German market in the end of 2011 and has been assessed by IQWiG. In the beginning of 2013, it was approved for an additional therapeutic indication, which has now also been investigated by IQWiG.

Available studies unsuitable for the benefit assessment

With the exception of sitagliptin as a single agent, no added benefit can be derived for any of the gliptins from the study data presented. Many of the studies conducted are unsuitable to answer the question of the added benefit.

This has numerous reasons: For some therapeutic indications, the manufacturers themselves did not present data in the dossier because there are no corresponding studies. This is the case, for example, for sitagliptin and vildagliptin, each in combination with a sulfonylurea. In other cases, the manufacturers presented studies that did not investigate the patient group of interest (e.g. vildagliptin in monotherapy).

Comparator therapies often not administered in accordance with Summary of Product Characteristics

Some of the studies were unsuitable because the drugs in the comparator group were not administered in accordance with their Summary of Product Characteristics. Sometimes the dosage of the drugs was too high, sometimes the dose was increased to rapidly, risking side effects. This put the comparator therapy at a disadvantage. In contrast to what is often claimed, there are mostly reasons with regards to content, and not just "formal" reasons, when IQWiG does not accept this kind of data as evidence of an added benefit.

Sitagliptin: added benefit in one of five therapeutic indications

For the assessment of sitagliptin, the Federal Joint Committee (G-BA) distinguished between five subindications in total, depending on the previous treatments. It specified different appropriate comparator therapies for each of these.

The data presented did not show an advantage of sitagliptin for sitagliptin as monotherapy. No added benefit is proven for the combination with sulfonylurea, the combination with metformin and sulfonylurea, and the combination with insulin because suitable data were lacking or no data were presented at all.

Sitagliptin versus glimepiride: fewer hypoglycaemic events

A study testing the dual combination of sitagliptin with metformin versus glimepiride (the appropriate comparator therapy) and metformin did not show a relevant difference for most outcomes. Regarding side effects, the picture was mixed: On the one hand, severe hyperglycaemia (proven symptomatic hypoglycaemia) was less frequent under sitagliptin. On the other hand, participants in this treatment group discontinued treatment more frequently because of side effects.

In summary, IQWiG sees a hint of a minor added benefit. However, this only applies to those patients for whom the goal was to lower blood glucose to near-normal levels. No added benefit is proven for the other patients.

Sitagliptin versus glipizide: survival advantage in men

In the dual combination with metformin, sitagliptin was also superior in comparison with the sulfonylurea glipizide, which is not approved in Germany. Within the observation period of two years (104 weeks), one death occurred in the sitagliptin group, compared with eight deaths in the glipizide group – all nine people were men. This result is also limited to the treatment goal "near-normal blood glucose levels".

Sitagliptin also had advantages with respect to hyperglycaemias in this study – and this result was independent from sex: both severe and symptomatic hyperglycaemias were less frequent.

Like the comparison with glimepiride, these results are also subject to uncertainty: There was no information about whether these hypoglycaemias mainly occurred in the early phase of the study, i.e. in the titration phase. There are also no long-term data, particularly with regards to vascular late complications.

In summary, IQWiG considers there to be a hint of a major added benefit of sitagliptin in comparison with glipizide (both plus metformin) in men. There is also an added benefit in women, however, its extent is "non-quantifiable", but not more than "considerable".

Six years after approval still no long-term studies

The dossiers did not contain long-term studies for any of the drugs assessed, although some of them have already been on the market since 2007. "IQWiG already came to this conclusion in earlier assessments of antidiabetics. It is completely unacceptable that no data are available on the long-term effects of drugs that patients have to take over very long periods of time, even several years after these drugs were approved", says Thomas Kaiser, Head of the Drug Assessment Department at IQWiG. Because preventing micro- and macrovascular late complications is an important goal of diabetes treatment.

Shortly before the completion of the assessment of the established market, the manufacturer of saxagliptin announced that results of a long-term study would be presented. It is therefore particularly incomprehensible that long-term data are lacking for sitagliptin and vildagliptin, which, as early as March and September of 2007, were the first gliptins to be approved throughout Europe.

Poor data availability is unsatisfactory for all parties involved

In summary, with the exception of one subindication of sitagliptin, IQWiG could not confirm an added benefit of any of the gliptins. "This result is unsatisfactory for all parties involved – not only for the manufacturers, but also for the patients and their doctors", says Jürgen Windeler, Director of IQWiG on the assessment of this group of drugs.

"Manufacturers claim that the gliptins have benefits, and even constitute therapeutic progress. We do not deny this subjective conviction. It is our task, however, to objectively test. And we have found out that the manufacturers have not been able to prove this therapeutic progress also in studies. There is an urgent need to catch up", says Jürgen Windeler.

G-BA decides on the extent of added benefit

The dossier assessment is part of the overall procedure for early benefit assessments supervised by the G-BA. After publication of the manufacturer’s dossier and IQWiG’s assessment, the G-BA conducts a commenting procedure, which may provide further information and result in a change to the benefit assessment. The G-BA then decides on the extent of the added benefit, thus completing the early benefit assessment.

An overview of the results of IQWiG's benefit assessment is given by German-language executive summaries. In addition, the website www.gesundheitsinformation.de, published by IQWiG, provides easily understandable and brief German-language information on all the drugs.

The G-BA website contains both general English-language information on benefit assessment pursuant to §35a Social Code Book (SGB) V and specific German-language information on the assessments of the individual drugs.

More English-language information will be available soon (extracts of the dossier assessments as well as subsequently published health information on www.informedhealthonline.org). If you would like to be informed when these documents are available, please send an e-mail to info@iqwig.de.