Table 3.
Summary of the main findings of trials investigating the use of glucagon-like peptide-1 analogues in type 1 diabetes
| Sarkar et al. [47] | Traina et al. [48] | Frandsen et al. [46] | Dejgaard et al. [44] | Methieu et al. (ADJUNCT ONE) [50] | Ahrén et al. (ADJUNCT TWO) [51] | Dubé et al. [45] | Weihao et al. [49] | |
|---|---|---|---|---|---|---|---|---|
| Year | 2014 | 2014 | 2015 | 2016 | 2016 | 2016 | 2018 | 2017 |
| Study design | Crossover RCT | Retrospective analysis | Placebo-controlled RCT | Placebo-controlled RCT | Placebo-controlled RCT | Placebo-controlled RCT | Crossover, placebo-controlled RCT | Systematic review and meta-analysis |
| Agent investigated | Exenatide | Exenatide | Liraglutide | Liraglutide | Liraglutide | Liraglutide | Liraglutide | Liraglutide and exenatide |
| No. of participants | 13 | 11, all of whom were treated with CSII | 40 | 100 | 1398 | 835 | 15 | 206 |
| Duration of study | 12 months (6 months on exenatide, 6 months off) | 3 months | 12 weeks | 24 weeks | 52 weeks | 26 weeks | 24 weeks for each arm of crossover | NA |
| Change in HbA1c | − 0.1% (p = 0.39) | − 0.6% (p = 0.013) | No difference | [− 0.2% (− 0.5, 0.1%), p > 0.1] |
Estimated treatment difference vs placebo 1.8 mg liraglutide − 0.20% [95% CI − 0.32; − 0.07] 1.2 mg liraglutide − 0.15% [95% CI − 0.27; − 0.03] 0.6 mg liraglutide − 0.09% [95% CI − 0.21; 0.03] |
Estimated treatment difference vs placebo 1.8 mg liraglutide –0.35% [95% CI –0.50; –0.20], p ≤ 0.0001 1.2 mg liraglutide –0.23% [95% CI –0.38; –0.08], p = 0.0021 0.6 mg liraglutide –0.24% [95% CI –0.39; –0.10], p = 0.0011 |
− 0.09% (p > 0.1) | −0.21 (−0.40, 0.02), p = 0.03 |
| Change in total daily insulin dose (units) | Average of 0.54 units/kg/day ± 0.13 whilst in control 6 months (off exenatide). Average of 0.47 units/kg/day whilst on exenatide. Statistical difference between groups of p = 0.007 | − 13% (p = 0.011) | Not reported | −5·8 (−10·7, −0·8), p = 0·0227 |
Expressed as estimated treatment ratios 1.8 mg liraglutide 0.92 [95% CI 0.88; 0.96] 1.2 mg liraglutide 0.95 [95% CI 0.91; 0.99] 0.6 mg liraglutide 1.00 [95% CI 0.96; 1.04] |
Expressed as estimated treatment ratio 1.8 mg liraglutide 0.90 [95% CI 0.86; 0.93], p ≤ 0.0001 1.2 mg liraglutide 0.93 [95% CI 0.90; 0.96], p ≤ 0.0001 0.6 mg liraglutide 0.95 [95% CI 0.92; 0.99], p = 0.0075 |
− 6.72 (p > 0.1) | Reduction in weight-adjusted insulin dose −0.11 (−0.23, 0.00), p = 0.05 |
| Change in weight (kg unless stated otherwise) | − 4.2 kg (p = 0.0003) | − 3.7% (p = 0.008) | − 4.3 (−5.7, −2.8), p < 0.001) | −6·8 (−12·2, −1·4), p = 0·0145 |
1.8 mg liraglutide − 4.9 kg [95% CI − 5.7; − 4.2] 1.2 mg liraglutide − 3.6 kg [95% CI − 4.3; − 2.8] 0.6 mg liraglutide − 2.2 kg [95% CI − 2.9; − 1.5] |
1.8 mg liraglutide –5.1 kg 1.2 mg liraglutide –4.0 kg 0.6 mg liraglutide –2.5 kg; All p ≤ 0.0.0001 vs placebo. |
− 4.83 (p = 0.0001) | −3.53 (−4.86, 2.19), p < 0.05 |
| Adverse events reported | None reported |
Nonsignificant increase in rate of hypoglycaemia. No significant adverse events reported |
Gastrointestinal side effects in both groups (statistical difference between groups not reported) Five participants required a temporary dose reduction in liraglutide group, and one participant had a maximum tolerated dose of 0.9 mg/day |
Increase in heart rate found in the liraglutide group (7.5 BPM, 95% CI 2.8–12.2, p = 0.0019) Increased number of gastrointestinal upsets in liraglutide group, but significance not reported |
Rates of symptomatic hypoglycaemia increased across all groups Significant increase in rate of hyperglycaemia with ketosis in the 1.8 mg liraglutide group (event rate ratio 2.22 [95% CI 1.13; 4.34]) |
Significantly higher rate of symptomatic hypoglycaemia in the 1.2 mg liraglutide group vs placebo (estimated rate ratio 1.31 [95% CI 1.03; 1.68], p = 0.0289) Increased rate of hyperglycaemia with ketosis (> 1.5 mmol/L) in the 1.8 mg liraglutide group vs placebo (estimated rate ratio 3.96 [95% CI 1.49; 10.55], p = 0.0059) |
93% of participants experienced nausea at some point in the study. None had to discontinue participation, and one participant had a maximum tolerated dose of liraglutide of 1.2 mg daily |
Concluded that combination therapy with GLP-1 RA and insulin did not cause increased rate of hypoglycaemic events Commented that gastrointestinal upset was common, but most participants could tolerate these effects |