Since May 2007, a new drug has been available for the treatment of patients with diabetes mellitus type 2 in Germany: exenatide (trade name: Byetta), which is marketed by the manufacturer Eli Lilly.
This drug was developed for patients who cannot sufficiently control their blood glucose levels with conventional oral antidiabetic agents, and who therefore need additional therapy with another oral antidiabetic agent or insulin. Like insulin, exenatide is also injected subcutaneously. According to current evidence, the blood-glucose lowering effect of exenatide has been demonstrated, but is not superior to the corresponding effect of insulin. Moreover, there is no evidence to show that the improved glycaemic control contributes to a reduction in the rate of late complications of diabetes. The long-term beneficial or detrimental effects of this new drug are still unclear.
This is the conclusion of a report by the German Institute for Quality and Efficiency in Health Care (IQWiG), Cologne, which was published in September 2007 and for which an English-language summary is now available.
Therapy only possible in combination with oral antidiabetics
The Federal Joint Committee commissioned IQWiG to prepare a rapid report to assess whether exenatide has a patient-relevant benefit. Exenatide is not permitted to be used as monotherapy. The drug is only approved for combination therapy with metformin and/or sulfonylurea. Consequently, IQWiG searched for studies that compared exenatide as add-on therapy to these oral antidiabetics, either with add-on placebo or with other add-on blood-glucose lowering drugs.
Five randomised controlled trials were identified that could be included in the evaluation. In 3 of these studies, patients in the control group received a placebo (placebo-controlled); in the 2 other studies, patients received insulin (active-controlled). In addition, patients in all treatment groups received metformin and/or sulfonylurea. Only studies with a duration of at least 12 weeks were included in the evaluation.
Comparable results for HbA1c levels and hypoglycaemia
Regarding the lowering of blood glucose levels, exenatide was superior to placebo and not inferior to insulin therapy: on average, patients treated with exenatide or insulin achieved a reduction in HbA1c levels of about 1%. The rate of severe hypoglycaemic episodes with exenatide was also comparable to the rates in both the placebo-controlled and the active controlled studies (with insulin aspart and insulin glargine).
More adverse events with exenatide
Regarding adverse events, the performance of exenatide was clearly poorer than that of placebo or insulin: patients who injected exenatide suffered more frequently from nausea, vomiting, or diarrhoea, and also discontinued the study more frequently due to adverse events. In patients receiving exenatide, the rate of adverse events and study discontinuations was dose-dependent.
Exenatide improves weight control
In all studies, patients in the exenatide groups were able to lose weight. They were slightly more successful than patients in the placebo groups. In contrast, patients in the insulin groups put on weight. In the active-controlled studies, the mean difference between exenatide and insulin, depending on study duration, was 4.1 kg at Week 26 (insulin glargine) and 5.5 kg at Week 52 (insulin aspart). However, it remains unclear what health effects the improvement in weight control have. Indications exist of a blood-pressure lowering effect. It is also unclear whether this leads to an additional benefit for patients by reducing the rate of late complications of diabetes type 2.
No robust data on quality of life and treatment satisfaction
Data on patients' health-related quality of life and treatment satisfaction were collected in both active-controlled studies, but have so far only been published for the clinical comparison between exenatide and insulin glargine. According to this, patients treated either with exenatide or with insulin glargine gained flexibility regarding meals and daily activities, and were generally more satisfied with treatment than before. Both groups achieved similarly good results. However, results may have been biased in favour of exenatide, as data from patients who discontinued the study due to adverse events were not included in the evaluation. Regarding the therapy goals "quality of life” and "treatment satisfaction”, IQWiG did not identify an advantage for either treatment option.
Long-term benefit or harm remains unclear
In its conclusion, IQWiG notes that although the blood-glucose lowering effect of exenatide has been demonstrated, a benefit has not. This is due to the fact that no relevant data from studies are available that allow statements on a positive or negative effect on late complications of diabetes, mortality, frequency of inpatient treatment, or frequency of comas caused by acute metabolic imbalance. To what extent the weight reduction helps reduce the rate of late complications of diabetes has not yet been investigated. Moreover, it is unclear whether and, if so, what adverse effects occur with long-term exenatide therapy. On the basis of the data available, a long-term (additional) benefit or harm can therefore neither be proven nor excluded.
Background: rapid report
The commission to evaluate the therapeutic benefits and harms of exenatide was to be performed in an accelerated procedure by means of a rapid report. During the preparation of a rapid report, in contrast to the usual procedure, the report plan and preliminary report are not published. Although the preliminary version of the rapid report undergoes an external review, no hearing takes place in which all interested persons can submit comments on this version. In addition, as no deadlines need to be kept for the publication of the report, the whole procedure is less time-consuming. The rapid report primarily serves to allow the Federal Joint Committee and other organisations involved to form an opinion. This report is usually not suitable to serve as a basis for policy-making decisions, as a submission of comments on the report prior to publication is not intended.
Exenatide is an incretin mimetic, i.e. it mimics the effects of an incretin produced in the body, GLP-1. Incretins are hormones that are produced in the gastrointestinal tract. In the pancreas, they stimulate insulin secretion and inhibit glucagon secretion, depending on the blood glucose level. In addition, they affect gastric as well as brain functions: they delay the emptying of the stomach and increase the feeling of satiety. In the body, the incretin GLP-1 is degraded by an enzyme, which is why the hormone itself is not a suitable drug. In the early 1990s, researchers discovered a hormone in the saliva of the North-American Gila monster; this hormone has a very similar structure to GLP-1, but is not degraded as rapidly in the human body. They further developed this original substance to the drug exenatide. Exenatide was approved in April 2005 in the USA as the first drug of this new drug class, and approved in Europe in November 2006. The manufacturer Eli Lilly introduced exenatide onto the German market in May 2007.