Glucagon-like peptide analogues for type 2 diabetes mellitus

Abstract

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.

Authors' conclusions: GLP-1 agonists are effective in improving glycaemic control.

Conflict of interest statement

None known.

Figures

Figure 1

Study flow diagram.

Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Analysis 1.2

Comparison 1 Albiglutide versus placebo, Outcome 2 HbA1c ‐ with plot.

Analysis 1.5

Comparison 1 Albiglutide versus placebo, Outcome 5 Weight change ‐ with plot.

Analysis 2.1

Comparison 2 Exenatide 2 mg once weekly versus thiazolidinedione, Outcome 1 HbA1c (%).

Analysis 2.2

Comparison 2 Exenatide 2 mg once weekly versus thiazolidinedione, Outcome 2 HbA1c

Analysis 2.3

Comparison 2 Exenatide 2 mg once weekly versus thiazolidinedione, Outcome 3 Hypoglycaemia (minor).

Analysis 2.4

Comparison 2 Exenatide 2 mg once weekly versus thiazolidinedione, Outcome 4 Weight change (kg).

Analysis 2.8

Comparison 2 Exenatide 2 mg once weekly versus thiazolidinedione, Outcome 8 Fasting plasma glucose (mmol/L).

Analysis 3.1

Comparison 3 Exenatide 2 mg once weekly versus DPP‐4 inhibitors, Outcome 1 HbA1c (%).

Analysis 3.2

Comparison 3 Exenatide 2 mg once weekly versus DPP‐4 inhibitors, Outcome 2 HbA1c

Analysis 3.3

Comparison 3 Exenatide 2 mg once weekly versus DPP‐4 inhibitors, Outcome 3 Hypoglycaemia (minor).

Analysis 3.4

Comparison 3 Exenatide 2 mg once weekly versus DPP‐4 inhibitors, Outcome 4 Weight change (kg).

Analysis 3.8

Comparison 3 Exenatide 2 mg once weekly versus DPP‐4 inhibitors, Outcome 8 Fasting plasma glucose (mmol/L).

Analysis 4.1

Comparison 4 Exenatide 2 mg once weekly versus insulin glargine, Outcome 1 HbA1c (%).

Analysis 4.2

Comparison 4 Exenatide 2 mg once weekly versus insulin glargine, Outcome 2 HbA1c

Analysis 4.3

Comparison 4 Exenatide 2 mg once weekly versus insulin glargine, Outcome 3 Hypoglycaemia (symptoms only).

Analysis 4.4

Comparison 4 Exenatide 2 mg once weekly versus insulin glargine, Outcome 4 Hypoglycaemia (minor).

Analysis 4.6

Comparison 4 Exenatide 2 mg once weekly versus insulin glargine, Outcome 6 Weight change (kg).

Analysis 4.9

Comparison 4 Exenatide 2 mg once weekly versus insulin glargine, Outcome 9 Fasting plasma glucose (mmol/L).

Analysis 5.1

Comparison 5 Liraglutide 0.6 mg daily versus placebo, Outcome 1 HbA1c (%).

Analysis 5.2

Comparison 5 Liraglutide 0.6 mg daily versus placebo, Outcome 2 HbA1c

Analysis 6.1

Comparison 6 Liraglutide 0.9 mg daily versus placebo, Outcome 1 HbA1c (%).

Analysis 6.2

Comparison 6 Liraglutide 0.9 mg daily versus placebo, Outcome 2 HbA1c

Analysis 7.1

Comparison 7 Liraglutide 1.2 mg versus placebo, Outcome 1 HbA1c.

Analysis 7.2

Comparison 7 Liraglutide 1.2 mg versus placebo, Outcome 2 HbA1c

Analysis 7.3

Comparison 7 Liraglutide 1.2 mg versus placebo, Outcome 3 Hypoglycaemia.

Analysis 7.4

Comparison 7 Liraglutide 1.2 mg versus placebo, Outcome 4 Weight change.

Analysis 7.6

Comparison 7 Liraglutide 1.2 mg versus placebo, Outcome 6 Systolic blood pressure.

Analysis 7.7

Comparison 7 Liraglutide 1.2 mg versus placebo, Outcome 7 Fasting plasma glucose (mmol/L).

Analysis 7.9

Comparison 7 Liraglutide 1.2 mg versus placebo, Outcome 9 Triglycerides (mmol/L).

Analysis 7.10

Comparison 7 Liraglutide 1.2 mg versus placebo, Outcome 10 Total cholesterol (mmol/L).

Analysis 7.11

Comparison 7 Liraglutide 1.2 mg versus placebo, Outcome 11 HDL‐cholesterol (mmol/L).

Analysis 7.12

Comparison 7 Liraglutide 1.2 mg versus placebo, Outcome 12 LDL‐cholesterol (mmol/L).

Analysis 8.1

Comparison 8 Liraglutide 1.8 mg versus placebo, Outcome 1 HbA1c.

Analysis 8.2

Comparison 8 Liraglutide 1.8 mg versus placebo, Outcome 2 HbA1c

Analysis 8.3

Comparison 8 Liraglutide 1.8 mg versus placebo, Outcome 3 Hypoglycaemia.

Analysis 8.4

Comparison 8 Liraglutide 1.8 mg versus placebo, Outcome 4 Weight change.

Analysis 8.6

Comparison 8 Liraglutide 1.8 mg versus placebo, Outcome 6 Systolic blood pressure.

Analysis 8.7

Comparison 8 Liraglutide 1.8 mg versus placebo, Outcome 7 Fasting plasma glucose (mmol/L).

Analysis 8.9

Comparison 8 Liraglutide 1.8 mg versus placebo, Outcome 9 Triglycerides (mmol/L).

Analysis 8.10

Comparison 8 Liraglutide 1.8 mg versus placebo, Outcome 10 Total cholesterol (mmol/L).

Analysis 8.11

Comparison 8 Liraglutide 1.8 mg versus placebo, Outcome 11 HDL‐cholesterol (mmol/L).

Analysis 8.12

Comparison 8 Liraglutide 1.8 mg versus placebo, Outcome 12 LDL‐cholesterol (mmol/L).

Analysis 9.1

Comparison 9 Liraglutide 1.2 mg versus 1.8 mg, Outcome 1 HbA1c.

Analysis 9.2

Comparison 9 Liraglutide 1.2 mg versus 1.8 mg, Outcome 2 Patients reaching HbA1c

Analysis 9.3

Comparison 9 Liraglutide 1.2 mg versus 1.8 mg, Outcome 3 Weight.

Analysis 9.4

Comparison 9 Liraglutide 1.2 mg versus 1.8 mg, Outcome 4 Systolic blood pressure.

Analysis 10.1

Comparison 10 Liraglutide versus insulin glargine, Outcome 1 HbA1c.

Analysis 10.2

Comparison 10 Liraglutide versus insulin glargine, Outcome 2 HbA1c

Analysis 10.3

Comparison 10 Liraglutide versus insulin glargine, Outcome 3 Hypoglycaemia.

Analysis 10.4

Comparison 10 Liraglutide versus insulin glargine, Outcome 4 Weight change.

Analysis 10.6

Comparison 10 Liraglutide versus insulin glargine, Outcome 6 Systolic blood pressure.

Analysis 10.7

Comparison 10 Liraglutide versus insulin glargine, Outcome 7 Fasting plasma glucose (mmol/L).

Analysis 11.1

Comparison 11 Liraglutide 1.2 mg daily versus thiazolidinedione, Outcome 1 HbA1c (%).

Analysis 11.2

Comparison 11 Liraglutide 1.2 mg daily versus thiazolidinedione, Outcome 2 HbA1c

Analysis 11.3

Comparison 11 Liraglutide 1.2 mg daily versus thiazolidinedione, Outcome 3 Hypoglycaemia (mild/moderate/overall).

Analysis 11.5

Comparison 11 Liraglutide 1.2 mg daily versus thiazolidinedione, Outcome 5 Weight change.

Analysis 11.9

Comparison 11 Liraglutide 1.2 mg daily versus thiazolidinedione, Outcome 9 Fasting plasma glucose (mmol/L).

Analysis 12.1

Comparison 12 Liraglutide 1.8 mg daily versus thiazolidinedione, Outcome 1 HbA1c (%).

Analysis 12.2

Comparison 12 Liraglutide 1.8 mg daily versus thiazolidinedione, Outcome 2 HbA1c

Analysis 12.3

Comparison 12 Liraglutide 1.8 mg daily versus thiazolidinedione, Outcome 3 Hypoglycaemia.

Analysis 12.5

Comparison 12 Liraglutide 1.8 mg daily versus thiazolidinedione, Outcome 5 Weight change (kg).

Analysis 12.9

Comparison 12 Liraglutide 1.8 mg daily versus thiazolidinedione, Outcome 9 Fasting plasma glucose (mmol/L).

Analysis 13.1

Comparison 13 Liraglutide 1.2 mg daily versus DPP‐4 inhibitors, Outcome 1 HbA1c (%).

Analysis 13.2

Comparison 13 Liraglutide 1.2 mg daily versus DPP‐4 inhibitors, Outcome 2 HbA1c

Analysis 13.3

Comparison 13 Liraglutide 1.2 mg daily versus DPP‐4 inhibitors, Outcome 3 Hypoglycaemia (mild/moderate/overall).

Analysis 13.5

Comparison 13 Liraglutide 1.2 mg daily versus DPP‐4 inhibitors, Outcome 5 Weight change (kg).

Analysis 13.7

Comparison 13 Liraglutide 1.2 mg daily versus DPP‐4 inhibitors, Outcome 7 Systolic blood pressure (mm Hg).

Analysis 13.9

Comparison 13 Liraglutide 1.2 mg daily versus DPP‐4 inhibitors, Outcome 9 Fasting plasma glucose (mmol/L).

Analysis 14.1

Comparison 14 Liraglutide 1.8 mg daily versus DPP‐4 inhibitors, Outcome 1 HbA1c (%).

Analysis 14.2

Comparison 14 Liraglutide 1.8 mg daily versus DPP‐4 inhibitors, Outcome 2 HbA1c

Analysis 14.3

Comparison 14 Liraglutide 1.8 mg daily versus DPP‐4 inhibitors, Outcome 3 Hypoglycaemia.

Analysis 14.5

Comparison 14 Liraglutide 1.8 mg daily versus DPP‐4 inhibitors, Outcome 5 Weight change (kg).

Analysis 14.7

Comparison 14 Liraglutide 1.8 mg daily versus DPP‐4 inhibitors, Outcome 7 Systolic blood pressure (mm Hg).

Analysis 14.9

Comparison 14 Liraglutide 1.8 mg daily versus DPP‐4 inhibitors, Outcome 9 Fasting plasma glucose (mmol/L).

Analysis 15.2

Comparison 15 Lixisenatide versus placebo, Outcome 2 HbA1c

Analysis 15.3

Comparison 15 Lixisenatide versus placebo, Outcome 3 Symptomatic hypoglycaemia.

Analysis 15.4

Comparison 15 Lixisenatide versus placebo, Outcome 4 Weight change (kg).

Analysis 15.6

Comparison 15 Lixisenatide versus placebo, Outcome 6 Fasting plasma glucose (mmol/L).

Analysis 15.7

Comparison 15 Lixisenatide versus placebo, Outcome 7 Post‐prandial glucose (mmol/L).

Analysis 15.8

Comparison 15 Lixisenatide versus placebo, Outcome 8 Average self‐monitored 7‐point blood glucose (mmol/L).

Analysis 16.1

Comparison 16 Liraglutide 1.2 mg versus SU, Outcome 1 HbA1c.

Analysis 16.3

Comparison 16 Liraglutide 1.2 mg versus SU, Outcome 3 HbA1c

Analysis 16.4

Comparison 16 Liraglutide 1.2 mg versus SU, Outcome 4 Hypoglycaemia.

Analysis 16.5

Comparison 16 Liraglutide 1.2 mg versus SU, Outcome 5 Weight change.

Analysis 16.8

Comparison 16 Liraglutide 1.2 mg versus SU, Outcome 8 Systolic blood pressure.

Analysis 16.10

Comparison 16 Liraglutide 1.2 mg versus SU, Outcome 10 Fasting plasma glucose (mmol/L).

Analysis 17.1

Comparison 17 Liraglutide 1.8 mg daily versus SU, Outcome 1 HbA1c (%).

Analysis 17.3

Comparison 17 Liraglutide 1.8 mg daily versus SU, Outcome 3 HbA1c

Analysis 17.4

Comparison 17 Liraglutide 1.8 mg daily versus SU, Outcome 4 Hypoglycaemia.

Analysis 17.5

Comparison 17 Liraglutide 1.8 mg daily versus SU, Outcome 5 Weight change (kg).

Analysis 17.8

Comparison 17 Liraglutide 1.8 mg daily versus SU, Outcome 8 Systolic blood pressure (mm Hg).

Analysis 17.10

Comparison 17 Liraglutide 1.8 mg daily versus SU, Outcome 10 Fasting plasma glucose (mmol/L).

Analysis 18.1

Comparison 18 Taspoglutide versus placebo, Outcome 1 HbA1c (%).

Analysis 18.3

Comparison 18 Taspoglutide versus placebo, Outcome 3 HbA1c

Analysis 18.5

Comparison 18 Taspoglutide versus placebo, Outcome 5 Hypoglycaemia.

Analysis 18.7

Comparison 18 Taspoglutide versus placebo, Outcome 7 Weight change (kg).

Analysis 18.11

Comparison 18 Taspoglutide versus placebo, Outcome 11 Fasting plasma glucose (mmol/L).

Analysis 19.4

Comparison 19 LY2189265 versus placebo, Outcome 4 Weight change (kg).

Analysis 19.6

Comparison 19 LY2189265 versus placebo, Outcome 6 Systolic blood pressure (mm Hg).

Analysis 19.7

Comparison 19 LY2189265 versus placebo, Outcome 7 Diastolic blood pressure (mm Hg).

Analysis 20.1

Comparison 20 GLP‐1 agonist versus GLP‐1 agonist, Outcome 1 HbA1c.

Analysis 20.2

Comparison 20 GLP‐1 agonist versus GLP‐1 agonist, Outcome 2 HbA1c

Analysis 20.3

Comparison 20 GLP‐1 agonist versus GLP‐1 agonist, Outcome 3 Hypoglycaemia.

Analysis 20.5

Comparison 20 GLP‐1 agonist versus GLP‐1 agonist, Outcome 5 Weight change.

Analysis 20.9

Comparison 20 GLP‐1 agonist versus GLP‐1 agonist, Outcome 9 Systolic blood pressure.

Analysis 20.10

Comparison 20 GLP‐1 agonist versus GLP‐1 agonist, Outcome 10 Fasting plasma glucose (mmol/L).

Analysis 20.12

Comparison 20 GLP‐1 agonist versus GLP‐1 agonist, Outcome 12 Triglycerides (mmol/L).

Analysis 20.13

Comparison 20 GLP‐1 agonist versus GLP‐1 agonist, Outcome 13 Total cholesterol (mmol/L).

Analysis 20.14

Comparison 20 GLP‐1 agonist versus GLP‐1 agonist, Outcome 14 HDL‐cholesterol (mmol/L).

Analysis 20.15

Comparison 20 GLP‐1 agonist versus GLP‐1 agonist, Outcome 15 LDL‐cholesterol (mmol/L).