Summary of findings 3. GLP‐1RA compared to placebo in people with CVD: efficacy outcomes.
| GLP‐1RA compared to placebo in people with CVD | ||||||
| Patient or population: CVD (ASCVD, HF, or both) Setting: outpatient Intervention: GLP‐1RA (lixisenatide, exenatide, albiglutide, liraglutide, semaglutide) Comparison: placebo | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
| Risk with placebo | Risk with GLP‐1RA | |||||
| Cardiovascular mortality Follow‐up duration: range 1.3 to 3.8 years |
44 per 1,000 | 39 per 1,000 (35 to 42) | OR 0.87 (0.79 to 0.95) | 46093 (6 RCTs) | ⊕⊕⊕⊕ HIGH | I2 showed low heterogeneity of 20%. All effect sizes were around 0.87 except PIONEER 6 trial (Husain 2019) with 0.50 and SUSTAIN trial (Marso 2016b) with 0.96. These studies showed wider 95% CIs due to lower event rates and smaller sample sizes when compared with the other 4 trials. PIONEER 6 trial (Husain 2019) showed 15 (0.9%) /1591 in intervention arm and 30 (1.9%) / 1592 in placebo arm. SUSTAIN 6 (Marso 2016b) revealed 44 (2.7%) / 1648 in intervention arm and 46 (2.8%) / 1679 in placebo arm. Other 4 trials showed 156 (5.1%) / 3034 vs 158 (5.2%) / 3024 in ELIXA (Pfeffer 2015), 340 (4.6%) / 7356 vs 383 (5.2%) / 7396 in EXSCEL (Holman 2017), 122 (3%) / 4731 vs 130 (3%) / 4732 in Harmony Outcomes (Hernandez 2018), and 219 (4.7%) / 4668 vs 278 (6.0%) / 4672 in LEADER trials (Marso 2016a). |
| Myocardial infarction (fatal or non‐fatal) Follow‐up duration: range 1.6 to 3.8 years |
65 per 1,000 | 58 per 1,000 (51 to 66) | OR 0.89 (0.78 to 1.01) | 42910 (5 RCTs) | ⊕⊕⊕⊝ MODERATE 1 | These 5 trials showed moderate heterogeneity (I2 = 57%). Harmony outcome (Hernandez 2018) only revealed that GLP‐1RA reduced the rate of myocardial infarction in intervention arm (3.8% vs 5.0%). This could induce significant heterogeneity among these 5 trials. Other 4 trials showed GLP‐1RA did not reduce the rate of myocardial infarction. |
| Stroke (fatal or non‐fatal) Follow‐up duration: range 1.6 to 3.8 years |
29 per 1,000 | 26 per 1,000 (23 to 29) | OR 0.87 (0.77 to 0.98) | 42910 (5 RCTs) | ⊕⊕⊕⊕ HIGH | Small heterogeneity (I2 = 1%). Apart from SUSTAIN 6 (Marso 2016b) (OR 0.61, 95% CI 0.37‐0.99), other 4 trials did not show GLP‐1RA reduced the rate of stroke. Outcome of each trial were as follows: ‐ELIXA (Pfeffer 2015) 2.2% vs 2.0% ‐EXSCEL (Holman 2017) 2.5% vs 2.9% ‐Harmony Outcomes (Hernandez 2018) 2%vs 2% ‐LEADER (Marso 2016a) 3.7% vs 4.3% ‐SUSTAIN 6 (Marso 2016b) 1.6% vs 2.7% Considering these, the outcome could be smaller to detect in each individual trial. |
| All‐cause mortality Follow‐up duration: range 0.5 to 3.8 years |
68 per 1,000 | 60 per 1,000 (57 to 65) | OR 0.88 (0.82 to 0.95) | 46393 (7 RCTs) | ⊕⊕⊕⊕ HIGH | I2 was 20%. Two relatively small studies (SUSTAIN 6 :Marso 2016b and FIGHT trial :Margulies 2016 revealed that their odds ratios slightly crossed 1.0 (no effects) and were not statistically significant (OR 1.04, 95% CI 0.72‐1.49; OR 1.14, 95% CI 0.56‐2.32, respectively). |
| Hospitalisation for HF Follow‐up duration: range 0.5 to 3.8 years |
40 per 1,000 | 38 per 1,000 (34 to 42) | OR 0.95 (0.85 to 1.06) | 36930 (6 RCTs) | ⊕⊕⊕⊕ HIGH | |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect | ||||||
1Graded down for inconsistency: moderate to substantial heterogeneity in effect. (‐1)
ASCVD: atherosclerotic cardiovascular disease, CI: confidence interval, CVD; cardiovascular disease, GLP‐1RA: glucagon‐like peptide‐1 receptor agonist, HF: heart failure, OR: odds ratio, RCT: randomized controlled trial