Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.
Byetta (Eli Lilly)
250 microgram/mL in 1.2 mL and 2.4 mL pre-filled pen injectors
Approved indication: type 2 diabetes
Australian Medicines Handbook section 10.1.4
An oral dose of glucose causes more insulin secretion than the same dose given intravenously. This is because glucose in the gut stimulates the release of hormones called incretins which increase insulin secretion. As this action would have a favourable effect in diabetes researchers have tried to develop drugs with a similar action.
One of the incretins is a glucagon-like peptide (GLP-1). The venom of a lizard (Heloderma suspectum) contains a peptide with a similar structure and this led to the development of exenatide, an injectable synthetic peptide that acts as a GLP-1 agonist.
Unlike GLP-1, exenatide is not rapidly inactivated. Instead it is cleared by the kidneys at a rate which enables twice-daily dosing. Plasma concentrations peak two hours after a subcutaneous injection so exenatide should be injected before morning and evening meals.
Postprandial and fasting glucose concentrations are reduced by exenatide. It also moderates glucagon secretion, slows gastric emptying and decreases appetite.
A 28-day study investigated different regimens of exenatide in patients being treated for type 2 diabetes. Compared to the 28 patients randomised to receive placebo, the 81 patients injecting exenatide had significantly greater reductions in glycated haemoglobin (HbA1c).1
A longer-term study looked at adding exenatide to the treatment of patients whose diabetes was not controlled by the maximum dose of sulfonylureas. Placebo injections were given to 123 patients, while 125 injected exenatide 5 microgram and 129 injected 10 microgram. All injections were given twice daily. At the start of the study the HbA1c averaged 8.6%. In the 30th week of the trial this had fallen by 0.46% with exenatide 5 microgram and by 0.86% with 10 microgram. In the placebo group HbA1c increased.2
A similar study compared the two doses of exenatide with placebo in 336 patients taking at least 1.5 g metformin daily. After 30 weeks HbA1c had declined by 0.4% with 5 microgram exenatide, 0.78% with 10 microgram, while it had increased in the placebo group.3
Another 30-week study enrolled patients who were already taking metformin and the maximum dose of a sulfonylurea. There were 247 patients who injected a placebo twice daily, 245 who injected exenatide 5 microgram and 241 who injected 10 microgram. At the end of the study, HbA1c had declined by 0.6% with exenatide 5 microgram, 0.8% with 10 microgram and had increased with placebo.4
Exenatide has also been studied in patients whose diabetes has not been controlled by a thiazolidinedione with or without metformin. A group of 121 patients injected exenatide and 112 injected a placebo twice daily. After 16 weeks the HbA1c had decreased by 0.89% with exenatide 10 microgram and increased by 0.09% in the placebo group.5
After the placebo-controlled trials, 668 patients who had taken exenatide continued using it in open-label extension studies. A total of 314 patients completed a further 52 weeks of treatment. The reduction in HbA1c seen at the end of the placebo-controlled studies was maintained.6
In the medium-term placebo-controlled studies, more patients dropped out of the exenatide groups because of adverse effects.2345 In the trial adding exenatide to a thiazolidinedione, 16% of the patients withdrew because of adverse effects compared with only 2% of the patients who added a placebo.5 A common problem with exenatide is nausea. It affects more than 40% of patients some of whom will vomit. Diarrhoea and dyspepsia are also more frequent than with placebo. There is an increased frequency of hypoglycaemia when exenatide is added to regimens containing a sulfonylurea. The dose of sulfonylurea may need to be reduced.
The exenatide molecule is not identical to human GLP-1. Some patients will develop antibodies against exenatide. Hypersensitivity reactions may occur and it is possible that high antibody titres could reduce the efficacy of exenatide.
Exenatide's role in therapy is unclear. If optimum therapy with oral hypoglycaemic drugs does not control a patient's type 2 diabetes, introducing insulin is the next step. Although exenatide appears to have a similar effect on HbA1c to once-daily insulin glargine7 or twice-daily insulin aspart8 in open-label studies, it causes more adverse effects. In the comparison with insulin glargine, 19.4% of the 282 patients injecting exenatide dropped out, compared with 9.7% of the 267 patients injecting insulin.7 In the comparison with insulin aspart the corresponding figures were 21.3% of the 253 patients injecting exenatide and 10.1% of the 248 patients injecting insulin.8 Gastrointestinal adverse reactions were common with exenatide and contributed to these withdrawals.
In Europe there is a risk management plan to monitor for safety concerns such as pancreatitis and anti-exenatide antibodies. Long-term outcomes with exenatide are currently unknown.
As it is relatively expensive, the use of exenatide may be limited to obese patients with insulin resistance, but this will require further study. At present, the Australian approval is for adjunctive therapy in patients who are not achieving adequate glycaemic control with metformin, a sulfonylurea, or both.
The Transparency Score () is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.
Notes on references
At the time the comment was prepared, information about this drug was available on the website of the Food and Drug Administration in the USA (www.fda.gov).
At the time the comment was prepared, a scientific
discussion about this drug was available on the website of
the European Medicines Agency (www.emea.eu).
- Fineman MS, Bicsak TA, Shen LZ, Taylor K, Gaines E, Varns A, et al. Effect on glycemic control of exenatide (synthetic exendin-4) additive to existing metformin and/or sulfonylurea treatment in patients with type 2 diabetes. Diabetes Care 2003;26:2370-7.
- Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD; the Exenatide-113 Clinical Study Group. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 2004;27:2628-35.
- De Fronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 2005;28:1092-100.
- Kendall DM, Riddle MC, Rosenstock J, Zhuang D, Kim DD, Fineman MS, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care 2005;28:1083-91.
- Zinman B, Hoogwerf BJ, Garcia SD, Milton DR, Glaconia JM, Kim DD, et al. The effect of adding exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes. A randomized trial. Ann Intern Med 2007;146:477-85.
- Blonde L, Klein EJ, Han J, Zhang B, Mac SM, Poon TH, et al. Interim analysis of the effects of exenatide treatment on A1C, weight and cardiovascular risk factors over 82 weeks in 314 overweight patients with type 2 diabetes. Diabetes Obes Metab 2006;8:436-47.
- Heine RJ, Van Gaal LF, Johns D, Mihm MJ, Widel MH, Brodows RG; the GWAA Study Group. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes. A randomized trial. Ann Intern Med 2005;143:559-69.
- Nauck MA, Duran S, Kim D, Johns D, Northrup J, Festa A, et al. A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study. Diabetologia 2007;50:259-67.