Glucagon-like peptide analogues for type 2 diabetes

Glucagon-like peptide analogues or agonists are a new kind of drug in the treatment of type 2 diabetes that are given by injection under the skin. They regulate glucose levels by stimulating glucose-dependent insulin secretion and biosynthesis, and by suppressing glucagon secretion, delaying gastric emptying and promoting satiety.  Various glucagon-like peptide-1 agonists are in use or in the licensing process, including exenatide, liraglutide, albiglutide, taspoglutide, lixisenatide and LY2189265.

Seventeen randomised controlled trials of mostly moderate to high quality randomised approximately 6899 people with type 2 diabetes mellitus. Studies were mostly of short duration, usually 26 weeks. The longest duration study was 30 weeks. Of the seventeen studies, one compared albiglutide with placebo, two compared exenatide 10 µg twice daily against exenatide 2 mg once weekly, one compared exenatide 2 mg once weekly against insulin glargine, one compared exenatide 2 mg once weekly against pioglitazone and sitagliptin, five compared liraglutide with placebo, two compared liraglutide with sulphonylurea, one each compared exenatide twice daily with liraglutide, liraglutide with sitagliptin, liraglutide with rosiglitazone and liraglutide with insulin glargine, two compared taspoglutide with placebo and one each compared lixisenatide with placebo and LY2189265 with placebo. In people already treated with oral anti-diabetes drugs, addition of glucagon-like peptide analogues improved blood sugar control in comparison to placebo, rosiglitazone, pioglitazone or sitagliptin, but not always in comparison to insulin (for exenatide) or glimepiride (a sulphonylurea). Glucagon-like peptide analogous caused more weight loss than any of the comparison treatments. However, more nausea and other gastrointestinal effects such as diarrhoea or vomiting were seen, though these tended to wear off and were not seen in all participants. There was slightly more hypoglycaemia with glucagon-like analogous than with placebo, but generally less than with other anti-diabetic treatments. The incidence of hypoglycaemia occurred more frequently in participants taking concomitant sulphonylurea. The studies were not long enough to assess long-term side effects. None of the studies investigated mortality or morbidity.

Authors' conclusions: 

GLP-1 agonists are effective in improving glycaemic control.

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Background: 

Glucagon-like peptide analogues are a new class of drugs used in the treatment of type 2 diabetes that mimic the endogenous hormone glucagon-like peptide 1 (GLP-1). GLP-1 is an incretin, a gastrointestinal hormone that is released into the circulation in response to ingested nutrients. GLP-1 regulates glucose levels by stimulating glucose-dependent insulin secretion and biosynthesis, and by suppressing glucagon secretion, delayed gastric emptying and promoting satiety.

Objectives: 

To assess the effects of glucagon-like peptide analogues in patients with type 2 diabetes mellitus.

Search strategy: 

Studies were obtained from electronic searches of The Cochrane Library (last search issue 1, 2011), MEDLINE (last search March 2011), EMBASE (last search March 2011), Web of Science (last search March 2011) and databases of ongoing trials.

Selection criteria: 

Studies were included if they were randomised controlled trials of a minimum duration of eight weeks comparing a GLP-1 analogue with placebo, insulin, an oral anti-diabetic agent, or another GLP-1 analogue in people with type 2 diabetes.

Data collection and analysis: 

Data extraction and quality assessment of studies were done by one reviewer and checked by a second. Data were analysed by type of GLP-1 agonist and comparison treatment. Where appropriate, data were summarised in a meta-analysis (mean differences and risk ratios summarised using a random-effects model).

Main results: 

Seventeen randomised controlled trials including relevant analyses for 6899 participants were included in the analysis. Studies were mostly of short duration, usually 26 weeks.

In comparison with placebo, all GLP-1 agonists reduced glycosylated haemoglobin A1c (HbA1c) levels by about 1%. Exenatide 2 mg once weekly and liraglutide 1.8 mg reduced it by 0.20% and 0.24% respectively more than insulin glargine. Exenatide 2 mg once weekly reduced HbA1c more than exenatide 10 μg twice daily, sitagliptin and pioglitazone. Liraglutide 1.8 mg reduced HbA1c by 0.33% more than exenatide 10 μg twice daily. Liraglutide led to similar improvements in HbA1c compared to sulphonylureas but reduced it more than sitagliptin and rosiglitazone.

Both exenatide and liraglutide led to greater weight loss than most active comparators, including in participants not experiencing nausea. Hypoglycaemia occurred more frequently in participants taking concomitant sulphonylurea. GLP-1 agonists caused gastrointestinal adverse effects, mainly nausea. These adverse events were strongest at the beginning and then subsided. Beta-cell function was improved with GLP-1 agonists but the effect did not persist after cessation of treatment.

None of the studies was long enough to assess long-term positive or negative effects.

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