Effects of glucagon-like peptide-1 receptor agonists on major cardiovascular events in patients with Type 2 diabetes mellitus with or without established cardiovascular disease: a meta-analysis of randomized controlled trials (original) (raw)
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Department of Advanced Biomedical Sciences, University of Naples Federico II
, Via Pansini, 5, I-80131 Naples,
Italy
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Department of Advanced Biomedical Sciences, University of Naples Federico II
, Via Pansini, 5, I-80131 Naples,
Italy
Mediterranea Cardiocentro
, Via Orazio, 2, I-80122 Naples,
Italy
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Department of Advanced Biomedical Sciences, University of Naples Federico II
, Via Pansini, 5, I-80131 Naples,
Italy
Mediterranea Cardiocentro
, Via Orazio, 2, I-80122 Naples,
Italy
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Department of Public Health, University of Naples Federico II
, Naples,
Italy
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Department of Advanced Biomedical Sciences, University of Naples Federico II
, Via Pansini, 5, I-80131 Naples,
Italy
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Department of Advanced Biomedical Sciences, University of Naples Federico II
, Via Pansini, 5, I-80131 Naples,
Italy
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Department of Advanced Biomedical Sciences, University of Naples Federico II
, Via Pansini, 5, I-80131 Naples,
Italy
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Department of Advanced Biomedical Sciences, University of Naples Federico II
, Via Pansini, 5, I-80131 Naples,
Italy
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Istituto Diagnostico Varelli
, Via Cornelia dei Gracchi, 65, I-80126 Naples,
Italy
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Villa dei Fiori Clinic, Corso Italia
, I-80011, Acerra, Naples,
Italy
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Fabio Marsico and Stefania Paolillo contributed equally to the study and are considered as first authors.
Revision received:
20 September 2019
Accepted:
27 January 2020
Published:
20 February 2020
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Fabio Marsico, Stefania Paolillo, Paola Gargiulo, Dario Bruzzese, Simona Dell’Aversana, Immacolata Esposito, Francesco Renga, Luca Esposito, Caterina Marciano, Santo Dellegrottaglie, Ivana Iesu, Pasquale Perrone Filardi, Effects of glucagon-like peptide-1 receptor agonists on major cardiovascular events in patients with Type 2 diabetes mellitus with or without established cardiovascular disease: a meta-analysis of randomized controlled trials, European Heart Journal, Volume 41, Issue 35, 14 September 2020, Pages 3346–3358, https://doi.org/10.1093/eurheartj/ehaa082
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Abstract
Aims
Glucose-lowering, glucagon-like peptide-1 (GLP-1) receptor agonists reduce incidence of major cardiovascular (CV) events in patients with Type 2 diabetes mellitus (DM). However, randomized clinical trials reported inconsistent effects on myocardial infarction (MI) and stroke, and limited data in DM patients without established CV disease (CVD). Very recently, new relevant evidence was available from additional CV outcome trials (CVOTs) that also included large subgroups of patients with DM without established CVD. Thus, the aim of this meta-analysis was to investigate the effects of GLP-1 receptor agonists on major CV events and safety in DM patients with and without established CVD.
Methods and results
In this trial-level meta-analysis, we analysed data from randomized placebo-controlled CVOTs assessing efficacy and safety of GLP-1 receptor agonists in adult patients with Type 2 DM. We searched PubMed, Embase, Cochrane, ISI Web of Science, SCOPUS, and clinicaltrial.gov databases for eligible trials. Of 360 articles identified and screened for eligibility, seven CVOTs were included, with an overall of 56 004 patients included. The difference in efficacy with respect to the major adverse cardiovascular events (MACE) primary endpoint (including CV mortality, non-fatal MI, and non-fatal stroke) between patients with established CVD and patients with CV risk factors only was not significant [pooled interaction effect, expressed as ratio of hazard ratio (HR) 1.06, 95% confidence interval (CI) 0.85–1.34]. In the analysis of the whole population of DM patients, GLP-1 receptor agonists showed a significant 12% reduction in the hazard of the three-point MACE composite endpoint (HR 0.88, 95% CI 0.80–0.96) and a significant reduction in the risk of CV mortality (HR 0.88, 95% CI 0.79–0.98), all-cause mortality (HR 0.89, 95% CI 0.81–0.97), fatal and non-fatal stroke (HR 0.84, 95% CI 0.76–0.94), and heart failure (HF) hospitalization (HR 0.92, 95% CI 0.86–0.97). No significant effect was observed for fatal and non-fatal MI (HR 0.91, 95% CI 0.82–1.02), although in a sensitivity analysis, based on a less conservative statistical approach, the pooled HR become statistically significant (HR 0.91, 95% CI 0.83–1.00; P = 0.039). No excess of hypoglycaemia, pancreatitis, and pancreatic cancer was observed between GLP-1 receptor agonists and placebo.
Conclusion
Glucagon-like peptide-1 receptor agonists significantly reduce MACE, CV and total mortality stroke, and hospitalization for HF, with a trend for reduction of MI, in patients with Type 2 DM with and without established CVD.
See page 3359 for the editorial comment on this article (doi: 10.1093/eurheartj/ehaa174)
Introduction
Type 2 diabetes mellitus (DM) represents a major cardiovascular (CV) risk factor for ischaemic CV events and heart failure (HF) and is associated with increased mortality.1 Among new classes of glucose reducing drugs, glucagon-like peptide-1 (GLP-1) receptor agonists showed protective CV effects in randomized placebo-controlled cardiovascular outcome trials (CVOTs).2–10 Thus, a significant 10% reduction of the three-point major adverse cardiovascular events (MACE) composite outcome [including CV mortality, non-fatal myocardial infarction (MI), and non-fatal stroke], a 13% reduction of CV mortality and a 12% reduction of total mortality were reported in a previous meta-analysis11 of four CVOTs enrolling 33 457 patients. However, despite significant reduction of the composite MACE endpoint, effects on single components, and, in particular, on MI and stroke were inconsistent among trials and did not reach statistical significance in meta-analysis.11 Although GLP-1 receptor agonists share the same mechanism of action for the glucose-lowering effect, this heterogeneity might reflect different pharmacokinetic/pharmacodynamic effects as well as different glucose-lowering efficacy among different drugs.12–15 ADA/EASD Guidelines16 as well recent ESC/EASD guidelines17 recommend use of GLP-1 receptor agonists with proven CV benefit (i.e. liraglutide, semaglutide, dulaglutide, and albiglutide) or gliflozins as first line therapy (in naïve patients) or in addition to metformin (in patients already treated with metformin) in Type 2 DM patients at high/very high CV risk but without established CV disease (CVD). However, the effects of GLP-1 receptor agonists in DM patients without established CVD were only assessed in subgroups of patients in five CVOTs,3 , 5 , 7 , 9 , 10 and no systematic analysis was so far reported to assess the efficacy of these drugs in this relevant setting of DM patients. Thus, the aim of this meta-analysis was to investigate the efficacy on the three-point composite outcome (including mortality and CV morbidity) as well safety of GLP-1 receptor agonists in Type 2 DM patients with and without established CVD.
Methods
Search strategy and selection criteria
The meta-analysis was conducted according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) reporting guideline.18 We searched PubMed, Embase, Cochrane, ISI Web of Science, SCOPUS, and clinicaltrial.gov databases to identify all eligible trials with a primary outcome including three- or four-point MACE, CV mortality, non-fatal MI and stroke, and HF hospitalizations comparing efficacy and safety of GLP-1 receptor agonists with placebo in patients with and without established CVD. The terms used for the research, as suggested by an expert medical librarian (A.L.V.) were ‘glucagon-like peptide-1 receptor agonists’, ‘GLP-1 agonist’, ‘lixisenatide’, ‘liraglutide’, ‘semaglutide’, ‘exenatide’, ‘albiglutide’, ‘dulaglutide’, ‘placebo’, ‘cardiovascular disease’, ‘cardiovascular risk factors’, and ‘randomized controlled trials’. Searches were done up from 17 June 2019 until 16 December 2019. Study inclusion criteria were Phase 3 randomized and controlled allocation to GLP-1 receptor agonists vs. placebo, articles published from January 2012 to December 2019 assessing at least one of following major CV outcomes: three- or four-point MACE, CV mortality, non-fatal MI and stroke, and HF hospitalizations in diabetic patients with or without established CVD. We excluded observational non-randomized studies, registries, ongoing trials without results, duplicate series, meta-analysis, abstracts, and oral communications. Articles were screened for fulfilment of inclusion criteria by five independent reviewers (S.D.A., I.E., L.E., I.I., and F.R.). Reviewers compared selected trials and discrepancies were resolved by four other authors (F.M., S.P., P.G., and C.M.). Corresponding author was asked to provide full-text articles if those were not available. Neither ethics approval nor patient consent was required for this analysis. This meta-analysis was not prospectively registered in PROSPERO.
Data analysis
The primary efficacy outcome was the three-point composite of CV mortality, non-fatal MI, or non-fatal stroke. Secondary efficacy outcomes were CV mortality, fatal or non-fatal MI, fatal or non-fatal stroke, all-cause mortality, and hospital admission for HF. When data items were not available in the original studies for aggregate outcomes (e.g. fatal or non-fatal MI and fatal or non-fatal stroke), those reported in previous meta-analysis11 were used. In particular, SUSTAIN-6 trial did not report in the published analyses the HR’s for those outcomes in the aggregate form (both fatal and non-fatal) and thus, for this trial, the corresponding HR’s reported in Ref.11 were considered.
Statistical heterogeneity between studies was assessed using the Cochrane Q statistic and I 2 statistic. Standard thresholds were considered for judging the percentage of total variability across studies not due to sampling error (I 2): 25% or lower for low heterogeneity, 26–50% for moderate heterogeneity, and >50% for high heterogeneity.
The random-effects model of DerSimonian and Laird was a-priory selected to obtain pooled estimates of treatment effect with the 95% confidence intervals (CIs) for CV outcomes. Due to the small number of studies, the Hartung and Knapp (HK) adjustment was employed.19 Hartung and Knapp method applies a scale factor to the standard error of the pooled estimator and uses quantiles from a t ( n – 1) distribution instead of a standard normal distribution thus producing wider CIs and higher _P_-values. HR was used as summary measure as all primary and secondary CV efficacy outcomes were defined as time-to-event variables.
The primary aim was to assess the efficacy on the three-point composite outcome of GLP-1 receptor agonists in Type 2 DM patients with and without established CVD. For each CVOT, a within interaction effect was first computed, as the ratio of the reported HRs in CVD and CV risk factors subgroups. Standard errors of these ratios were then derived, on a log scale, as the square root of the sum of the variance of the two log HRs. These trial specific effects (ratios of HR’s) were then pooled using a random-effect model adjusted by the Knapp–Hartung method. The analysis was repeated twice as LEADER trial reported separate results for established CVD patients without previous MI or stroke and established CVD patients with previous MI or stroke.
Additional analysis was performed to estimate the effects of GLP-1 receptor agonists in the whole population with respect to the primary and secondary efficacy CV outcomes. Numbers needed to treat (NNTs) were computed according to the method of Altman and Andersen,20 using one minus the cumulative proportions of patients experiencing each of the CV outcome as survival probabilities.
Sensitivity analyses to test the robustness of the findings included standard D-L random-effect meta-analysis without HK adjustment.
A random-effect model, with HK adjustment, was further applied to obtain pooled estimates of odds ratio (OR) with the corresponding 95% CI for the main safety outcomes, i.e. severe hypoglycaemia, acute pancreatitis, and pancreatic cancer.
Statistical analysis was performed using the R statistical programming environment, Version 3.5.2 (http://www.r-project.org). Package meta 21 was used for all the meta-analysis elaborations.
Quality appraisal
The methodological quality of the selected trials was assessed using the Cochrane Collaboration’s tool for assessing risk of bias, with respect to the following items: (i) sequence generation, (ii) allocation concealment, (iii) blinding, (iv) incomplete outcome data, (v) selective outcome reporting, and (vi) other sources of bias. Risk of bias was graded as unclear, high, or low and presented in Table 1.
Table 1
Characteristics of trials included in the meta-analysis2 , 3 , 5 , 7–10
| ELIXA | LEADER | SUSTAIN-6 | EXSCEL | HARMONY | REWIND | PIONEER-6 | |
|---|---|---|---|---|---|---|---|
| Publication year | 2015 | 2016 | 2016 | 2017 | 2018 | 2019 | 2019 |
| Study design | Multicentre, randomized, double blind, placebo-controlled trial involving patients with Type 2 diabetes who had had a recent acute coronary syndrome. The trial was designed to assess the effects of lixisenatide on cardiovascular morbidity and mortality | Multicentre, double blind, placebo-controlled trial involving patients with Type 2 diabetes, with previous cardiovascular coexisting condition or at least one cardiovascular risk factor. The trial was designed to assess the effects of liraglutide on cardiovascular morbidity and mortality | Randomized, double blind, placebo-controlled trial involving patients with Type 2 diabetes, with established cardiovascular disease, or at least one cardiovascular risk factor. The trial was designed to assess the effects of semaglutide on cardiovascular morbidity and mortality | Randomized, double blind, placebo-controlled, event-driven trial involving patients with Type 2 diabetes, with previous cardiovascular event, or at least one cardiovascular risk factor. The trial was designed to assess the effects of exenatide on cardiovascular morbidity and mortality | Double blind, Randomized, placebo-controlled, event-driven trial involving patients with Type 2 diabetes, with established cardiovascular disease. The trial was designed to assess the effects of albiglutide on cardiovascular morbidity and mortality | Multicentre, randomized, double blind, placebo-controlled trial involving patients with Type 2 diabetes, with established cardiovascular disease or at least two cardiovascular risk factors. The trial was designed to assess the effects of dulaglutide on cardiovascular morbidity and mortality | Multicentre, randomized, double blind, placebo-controlled trial involving patients with established cardiovascular disease, or cardiovascular risk factors only. The trial was designed to assess the effects of oral semaglutide on cardiovascular morbidity and mortality |
| Sample size | 6068 | 9340 | 3297 | 14 752 | 9463 | 9901 | 3183 |
| Inclusion criteria | HbA1c 5.5–11.0% (36.6–96.7 mmol/mol); acute coronary syndrome within 180 days; age ≥30 years | HbA1c ≥7.0% (≥53.0 mmol/mol); age ≥50 years with cardiovascular disease, chronic heart failure (NYHA Class II or III), chronic kidney disease (Stage 3 or higher), or age ≥60 years with at least one cardiovascular risk factor | HbA1c ≥7.0% (≥53.0 mmol/mol); age ≥50 years with cardiovascular disease, chronic heart failure (NYHA Class II or III), chronic kidney disease (Stage 3 or higher), or age ≥60 years with at least one cardiovascular risk factor | HbA1c 6.5–10.0% (47.5–85.8 mmol/mol); established cardiovascular disease and primary prevention; age ≥18 years | HbA1c ≥7.0% (≥53.0 mmol/mol); age ≥40 years with established disease of the coronary, cerebrovascular, or peripheral arterial circulation | HbA1c ≤9.5% (80 mmol/mol) treated with up to two oral glucose-lowering drugs, with or without basal insulin therapy if BMI at least 23 kg/m2; age ≥50 years with previous vascular disease, or age ≥60 years with at least two cardiovascular risk factors | Male of female patients with Type 2 diabetes; age ≥50 years with established cardiovascular disease, or age ≥60 years with cardiovascular risk factors only |
| Exclusion criteria | Age <30 years; PCI within the previous 15 days, planned coronary revascularization procedure within 90 days after screening; eGFR of <30 mL/min/1.73 m2; HbA1c <5.5% (36.6 mmol/mol) or >11.0% (96.7 mmol/mol) | Type 1 diabetes; use of GLP-1 receptor agonists, DPP-4 inhibitors, pramlintide, or rapid-acting insulin; familial or personal history of multiple endocrine neoplasia Type 2 or medullary thyroid cancer; occurrence of an acute coronary or cerebrovascular event within 14 days before screening and randomization | Treatment with DPP-4 inhibitors within 30 days before screening or with GLP-1 receptor agonists or insulin other than basal or premixed within 90 days before screening; history of acute coronary or cerebrovascular event within 90 days before randomization; planned revascularization of a coronary, carotid, or peripheral artery; long-term dialysis | History of two or more episodes of severe hypoglycaemia during the preceding 12 months; end-stage kidney disease or an eGFR <30 mL/min/1.73 m2; personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia Type 2; baseline calcitonin level >40 ng/L; previous treatment with GLP-1 receptor agonists | eGFR <30 mL/min/1.73 m2; severe gastroparesis; previous pancreatitis or substantial risk factors for pancreatitis; personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia Type 2; history of pancreatic neuroendocrine tumours; current use of GLP-1 receptor agonists | eGFR <15 mL/min/1.73 m2; cancer in the previous 5 years; severe hypoglycaemia in the previous year; life expectancy <1 year; a coronary or cerebrovascular event within the previous 2 months, and plans for revascularization | Treatment with any GLP-1 receptor agonist, DPP-4 inhibitor, or pramlintide within 90 days before screening; NYHA Class IV heart failure; planned coronary artery, carotid artery, or peripheral artery revascularization; myocardial infarction, stroke, or hospitalization for unstable angina or transient ischaemic attack within 60 days before screening; long-term or intermittent haemodialysis or peritoneal dialysis, or severe renal impairment (eGFR < 30 mL/min/1.73 m2); and proliferative retinopathy or maculopathy resulting in active treatment |
| Follow-up period (years) | 2.1 | 3.8 | 2.1 | 3.2 (2.2–4.4) | 1.5 | 5.4 (5.1–5.9) | 1.3 (0.03–1.7) |
| Discontinuation therapy | 347 (11.4%) for lixisenatide and 217 (7.2%) for placebo | 444 (9.5%) for liraglutide and 339 (7.3%) for placebo | 350 (21.2%) for semaglutide and 310 (18.8%) for placebo | 3164 (43%) for exenatide and 3343 (45.2%) for placebo | 1140 (24%) for albiglutide and 1297 (27%) for placebo | 1328 (26.8%) for dulaglutide and 1432 (28.9%) for placebo | 225 (14.1%) for semaglutide and 152 (9.5%) for placebo |
| Primary outcomes | MACE-4 (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina) | MACE-3 (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke) | MACE-3 (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke) | MACE-3 (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke) | MACE-3 (death from cardiovascular causes, myocardial infarction, stroke) | MACE-3 (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke) | MACE-3 (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke) |
| Secondary outcomes | Composite of the primary outcome or hospitalization for heart failure, or coronary revascularization procedures | Composite of the primary outcome or hospitalization for unstable angina, or hospitalization for heart failure, or coronary revascularization; death from any cause; composite of renal and retinal microvascular outcome; neoplasm; pancreatitis | Composite of the primary outcome or hospitalization for unstable angina, or hospitalization for heart failure, or coronary revascularization; an additional composite outcome of death from all causes, non-fatal myocardial infarction, non-fatal stroke; individual components of the composite outcomes; retinopathy complications and new or worsening nephropathy | Secondary outcomes included death from any cause, death from cardiovascular causes, and the first occurrence of non-fatal or fatal myocardial infarction, non-fatal or fatal stroke, hospitalization for acute coronary syndrome, and hospitalization for heart failure | Four-component composite (the primary composite, with the addition of urgent revascularization for unstable angina), the individual components of the primary endpoint, and the composite of cardiovascular death or hospital admission because of heart failure | Composite clinical microvascular outcome comprising diabetic retinopathy or renal disease; hospital admission for unstable angina; each component of the primary composite cardiovascular outcome; death; and heart failure requiring either hospital admission or an urgent visit requiring therapy | Composite of the primary outcome plus unstable angina resulting in hospitalization or heart failure resulting in hospitalization; a composite of death from any cause, non-fatal myocardial infarction, or non-fatal stroke; the individual components of these composite outcomes |
| Risk of bias | Low | Low | Low | Low | Low | Low | Low |
| Trial registry reference | NCT01147250 | NCT01179048 | NCT01720446 | NCT01144338 | NCT02465515 | NCT01394952 | NCT02692716 |
| ELIXA | LEADER | SUSTAIN-6 | EXSCEL | HARMONY | REWIND | PIONEER-6 | |
|---|---|---|---|---|---|---|---|
| Publication year | 2015 | 2016 | 2016 | 2017 | 2018 | 2019 | 2019 |
| Study design | Multicentre, randomized, double blind, placebo-controlled trial involving patients with Type 2 diabetes who had had a recent acute coronary syndrome. The trial was designed to assess the effects of lixisenatide on cardiovascular morbidity and mortality | Multicentre, double blind, placebo-controlled trial involving patients with Type 2 diabetes, with previous cardiovascular coexisting condition or at least one cardiovascular risk factor. The trial was designed to assess the effects of liraglutide on cardiovascular morbidity and mortality | Randomized, double blind, placebo-controlled trial involving patients with Type 2 diabetes, with established cardiovascular disease, or at least one cardiovascular risk factor. The trial was designed to assess the effects of semaglutide on cardiovascular morbidity and mortality | Randomized, double blind, placebo-controlled, event-driven trial involving patients with Type 2 diabetes, with previous cardiovascular event, or at least one cardiovascular risk factor. The trial was designed to assess the effects of exenatide on cardiovascular morbidity and mortality | Double blind, Randomized, placebo-controlled, event-driven trial involving patients with Type 2 diabetes, with established cardiovascular disease. The trial was designed to assess the effects of albiglutide on cardiovascular morbidity and mortality | Multicentre, randomized, double blind, placebo-controlled trial involving patients with Type 2 diabetes, with established cardiovascular disease or at least two cardiovascular risk factors. The trial was designed to assess the effects of dulaglutide on cardiovascular morbidity and mortality | Multicentre, randomized, double blind, placebo-controlled trial involving patients with established cardiovascular disease, or cardiovascular risk factors only. The trial was designed to assess the effects of oral semaglutide on cardiovascular morbidity and mortality |
| Sample size | 6068 | 9340 | 3297 | 14 752 | 9463 | 9901 | 3183 |
| Inclusion criteria | HbA1c 5.5–11.0% (36.6–96.7 mmol/mol); acute coronary syndrome within 180 days; age ≥30 years | HbA1c ≥7.0% (≥53.0 mmol/mol); age ≥50 years with cardiovascular disease, chronic heart failure (NYHA Class II or III), chronic kidney disease (Stage 3 or higher), or age ≥60 years with at least one cardiovascular risk factor | HbA1c ≥7.0% (≥53.0 mmol/mol); age ≥50 years with cardiovascular disease, chronic heart failure (NYHA Class II or III), chronic kidney disease (Stage 3 or higher), or age ≥60 years with at least one cardiovascular risk factor | HbA1c 6.5–10.0% (47.5–85.8 mmol/mol); established cardiovascular disease and primary prevention; age ≥18 years | HbA1c ≥7.0% (≥53.0 mmol/mol); age ≥40 years with established disease of the coronary, cerebrovascular, or peripheral arterial circulation | HbA1c ≤9.5% (80 mmol/mol) treated with up to two oral glucose-lowering drugs, with or without basal insulin therapy if BMI at least 23 kg/m2; age ≥50 years with previous vascular disease, or age ≥60 years with at least two cardiovascular risk factors | Male of female patients with Type 2 diabetes; age ≥50 years with established cardiovascular disease, or age ≥60 years with cardiovascular risk factors only |
| Exclusion criteria | Age <30 years; PCI within the previous 15 days, planned coronary revascularization procedure within 90 days after screening; eGFR of <30 mL/min/1.73 m2; HbA1c <5.5% (36.6 mmol/mol) or >11.0% (96.7 mmol/mol) | Type 1 diabetes; use of GLP-1 receptor agonists, DPP-4 inhibitors, pramlintide, or rapid-acting insulin; familial or personal history of multiple endocrine neoplasia Type 2 or medullary thyroid cancer; occurrence of an acute coronary or cerebrovascular event within 14 days before screening and randomization | Treatment with DPP-4 inhibitors within 30 days before screening or with GLP-1 receptor agonists or insulin other than basal or premixed within 90 days before screening; history of acute coronary or cerebrovascular event within 90 days before randomization; planned revascularization of a coronary, carotid, or peripheral artery; long-term dialysis | History of two or more episodes of severe hypoglycaemia during the preceding 12 months; end-stage kidney disease or an eGFR <30 mL/min/1.73 m2; personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia Type 2; baseline calcitonin level >40 ng/L; previous treatment with GLP-1 receptor agonists | eGFR <30 mL/min/1.73 m2; severe gastroparesis; previous pancreatitis or substantial risk factors for pancreatitis; personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia Type 2; history of pancreatic neuroendocrine tumours; current use of GLP-1 receptor agonists | eGFR <15 mL/min/1.73 m2; cancer in the previous 5 years; severe hypoglycaemia in the previous year; life expectancy <1 year; a coronary or cerebrovascular event within the previous 2 months, and plans for revascularization | Treatment with any GLP-1 receptor agonist, DPP-4 inhibitor, or pramlintide within 90 days before screening; NYHA Class IV heart failure; planned coronary artery, carotid artery, or peripheral artery revascularization; myocardial infarction, stroke, or hospitalization for unstable angina or transient ischaemic attack within 60 days before screening; long-term or intermittent haemodialysis or peritoneal dialysis, or severe renal impairment (eGFR < 30 mL/min/1.73 m2); and proliferative retinopathy or maculopathy resulting in active treatment |
| Follow-up period (years) | 2.1 | 3.8 | 2.1 | 3.2 (2.2–4.4) | 1.5 | 5.4 (5.1–5.9) | 1.3 (0.03–1.7) |
| Discontinuation therapy | 347 (11.4%) for lixisenatide and 217 (7.2%) for placebo | 444 (9.5%) for liraglutide and 339 (7.3%) for placebo | 350 (21.2%) for semaglutide and 310 (18.8%) for placebo | 3164 (43%) for exenatide and 3343 (45.2%) for placebo | 1140 (24%) for albiglutide and 1297 (27%) for placebo | 1328 (26.8%) for dulaglutide and 1432 (28.9%) for placebo | 225 (14.1%) for semaglutide and 152 (9.5%) for placebo |
| Primary outcomes | MACE-4 (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina) | MACE-3 (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke) | MACE-3 (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke) | MACE-3 (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke) | MACE-3 (death from cardiovascular causes, myocardial infarction, stroke) | MACE-3 (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke) | MACE-3 (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke) |
| Secondary outcomes | Composite of the primary outcome or hospitalization for heart failure, or coronary revascularization procedures | Composite of the primary outcome or hospitalization for unstable angina, or hospitalization for heart failure, or coronary revascularization; death from any cause; composite of renal and retinal microvascular outcome; neoplasm; pancreatitis | Composite of the primary outcome or hospitalization for unstable angina, or hospitalization for heart failure, or coronary revascularization; an additional composite outcome of death from all causes, non-fatal myocardial infarction, non-fatal stroke; individual components of the composite outcomes; retinopathy complications and new or worsening nephropathy | Secondary outcomes included death from any cause, death from cardiovascular causes, and the first occurrence of non-fatal or fatal myocardial infarction, non-fatal or fatal stroke, hospitalization for acute coronary syndrome, and hospitalization for heart failure | Four-component composite (the primary composite, with the addition of urgent revascularization for unstable angina), the individual components of the primary endpoint, and the composite of cardiovascular death or hospital admission because of heart failure | Composite clinical microvascular outcome comprising diabetic retinopathy or renal disease; hospital admission for unstable angina; each component of the primary composite cardiovascular outcome; death; and heart failure requiring either hospital admission or an urgent visit requiring therapy | Composite of the primary outcome plus unstable angina resulting in hospitalization or heart failure resulting in hospitalization; a composite of death from any cause, non-fatal myocardial infarction, or non-fatal stroke; the individual components of these composite outcomes |
| Risk of bias | Low | Low | Low | Low | Low | Low | Low |
| Trial registry reference | NCT01147250 | NCT01179048 | NCT01720446 | NCT01144338 | NCT02465515 | NCT01394952 | NCT02692716 |
BMI, body mass index; DPP-4, dipeptidyl peptidase 4; eGFR, estimated glomerular filtration rate; GLP-1, glucagon-like peptide-1; HbA1c, glycated haemoglobin; MACE-3, three-point major adverse cardiovascular events (cardiovascular-related death, non-fatal myocardial infarction, and non-fatal stroke); MACE-4, four-point major adverse cardiovascular events (cardiovascular-related death, non-fatal myocardial infarction, non-fatal stroke, or unstable angina requiring hospital admission); NYHA, New York Heart Association; PCI, percutaneous coronary intervention.
Table 1
Characteristics of trials included in the meta-analysis2 , 3 , 5 , 7–10
| ELIXA | LEADER | SUSTAIN-6 | EXSCEL | HARMONY | REWIND | PIONEER-6 | |
|---|---|---|---|---|---|---|---|
| Publication year | 2015 | 2016 | 2016 | 2017 | 2018 | 2019 | 2019 |
| Study design | Multicentre, randomized, double blind, placebo-controlled trial involving patients with Type 2 diabetes who had had a recent acute coronary syndrome. The trial was designed to assess the effects of lixisenatide on cardiovascular morbidity and mortality | Multicentre, double blind, placebo-controlled trial involving patients with Type 2 diabetes, with previous cardiovascular coexisting condition or at least one cardiovascular risk factor. The trial was designed to assess the effects of liraglutide on cardiovascular morbidity and mortality | Randomized, double blind, placebo-controlled trial involving patients with Type 2 diabetes, with established cardiovascular disease, or at least one cardiovascular risk factor. The trial was designed to assess the effects of semaglutide on cardiovascular morbidity and mortality | Randomized, double blind, placebo-controlled, event-driven trial involving patients with Type 2 diabetes, with previous cardiovascular event, or at least one cardiovascular risk factor. The trial was designed to assess the effects of exenatide on cardiovascular morbidity and mortality | Double blind, Randomized, placebo-controlled, event-driven trial involving patients with Type 2 diabetes, with established cardiovascular disease. The trial was designed to assess the effects of albiglutide on cardiovascular morbidity and mortality | Multicentre, randomized, double blind, placebo-controlled trial involving patients with Type 2 diabetes, with established cardiovascular disease or at least two cardiovascular risk factors. The trial was designed to assess the effects of dulaglutide on cardiovascular morbidity and mortality | Multicentre, randomized, double blind, placebo-controlled trial involving patients with established cardiovascular disease, or cardiovascular risk factors only. The trial was designed to assess the effects of oral semaglutide on cardiovascular morbidity and mortality |
| Sample size | 6068 | 9340 | 3297 | 14 752 | 9463 | 9901 | 3183 |
| Inclusion criteria | HbA1c 5.5–11.0% (36.6–96.7 mmol/mol); acute coronary syndrome within 180 days; age ≥30 years | HbA1c ≥7.0% (≥53.0 mmol/mol); age ≥50 years with cardiovascular disease, chronic heart failure (NYHA Class II or III), chronic kidney disease (Stage 3 or higher), or age ≥60 years with at least one cardiovascular risk factor | HbA1c ≥7.0% (≥53.0 mmol/mol); age ≥50 years with cardiovascular disease, chronic heart failure (NYHA Class II or III), chronic kidney disease (Stage 3 or higher), or age ≥60 years with at least one cardiovascular risk factor | HbA1c 6.5–10.0% (47.5–85.8 mmol/mol); established cardiovascular disease and primary prevention; age ≥18 years | HbA1c ≥7.0% (≥53.0 mmol/mol); age ≥40 years with established disease of the coronary, cerebrovascular, or peripheral arterial circulation | HbA1c ≤9.5% (80 mmol/mol) treated with up to two oral glucose-lowering drugs, with or without basal insulin therapy if BMI at least 23 kg/m2; age ≥50 years with previous vascular disease, or age ≥60 years with at least two cardiovascular risk factors | Male of female patients with Type 2 diabetes; age ≥50 years with established cardiovascular disease, or age ≥60 years with cardiovascular risk factors only |
| Exclusion criteria | Age <30 years; PCI within the previous 15 days, planned coronary revascularization procedure within 90 days after screening; eGFR of <30 mL/min/1.73 m2; HbA1c <5.5% (36.6 mmol/mol) or >11.0% (96.7 mmol/mol) | Type 1 diabetes; use of GLP-1 receptor agonists, DPP-4 inhibitors, pramlintide, or rapid-acting insulin; familial or personal history of multiple endocrine neoplasia Type 2 or medullary thyroid cancer; occurrence of an acute coronary or cerebrovascular event within 14 days before screening and randomization | Treatment with DPP-4 inhibitors within 30 days before screening or with GLP-1 receptor agonists or insulin other than basal or premixed within 90 days before screening; history of acute coronary or cerebrovascular event within 90 days before randomization; planned revascularization of a coronary, carotid, or peripheral artery; long-term dialysis | History of two or more episodes of severe hypoglycaemia during the preceding 12 months; end-stage kidney disease or an eGFR <30 mL/min/1.73 m2; personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia Type 2; baseline calcitonin level >40 ng/L; previous treatment with GLP-1 receptor agonists | eGFR <30 mL/min/1.73 m2; severe gastroparesis; previous pancreatitis or substantial risk factors for pancreatitis; personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia Type 2; history of pancreatic neuroendocrine tumours; current use of GLP-1 receptor agonists | eGFR <15 mL/min/1.73 m2; cancer in the previous 5 years; severe hypoglycaemia in the previous year; life expectancy <1 year; a coronary or cerebrovascular event within the previous 2 months, and plans for revascularization | Treatment with any GLP-1 receptor agonist, DPP-4 inhibitor, or pramlintide within 90 days before screening; NYHA Class IV heart failure; planned coronary artery, carotid artery, or peripheral artery revascularization; myocardial infarction, stroke, or hospitalization for unstable angina or transient ischaemic attack within 60 days before screening; long-term or intermittent haemodialysis or peritoneal dialysis, or severe renal impairment (eGFR < 30 mL/min/1.73 m2); and proliferative retinopathy or maculopathy resulting in active treatment |
| Follow-up period (years) | 2.1 | 3.8 | 2.1 | 3.2 (2.2–4.4) | 1.5 | 5.4 (5.1–5.9) | 1.3 (0.03–1.7) |
| Discontinuation therapy | 347 (11.4%) for lixisenatide and 217 (7.2%) for placebo | 444 (9.5%) for liraglutide and 339 (7.3%) for placebo | 350 (21.2%) for semaglutide and 310 (18.8%) for placebo | 3164 (43%) for exenatide and 3343 (45.2%) for placebo | 1140 (24%) for albiglutide and 1297 (27%) for placebo | 1328 (26.8%) for dulaglutide and 1432 (28.9%) for placebo | 225 (14.1%) for semaglutide and 152 (9.5%) for placebo |
| Primary outcomes | MACE-4 (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina) | MACE-3 (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke) | MACE-3 (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke) | MACE-3 (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke) | MACE-3 (death from cardiovascular causes, myocardial infarction, stroke) | MACE-3 (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke) | MACE-3 (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke) |
| Secondary outcomes | Composite of the primary outcome or hospitalization for heart failure, or coronary revascularization procedures | Composite of the primary outcome or hospitalization for unstable angina, or hospitalization for heart failure, or coronary revascularization; death from any cause; composite of renal and retinal microvascular outcome; neoplasm; pancreatitis | Composite of the primary outcome or hospitalization for unstable angina, or hospitalization for heart failure, or coronary revascularization; an additional composite outcome of death from all causes, non-fatal myocardial infarction, non-fatal stroke; individual components of the composite outcomes; retinopathy complications and new or worsening nephropathy | Secondary outcomes included death from any cause, death from cardiovascular causes, and the first occurrence of non-fatal or fatal myocardial infarction, non-fatal or fatal stroke, hospitalization for acute coronary syndrome, and hospitalization for heart failure | Four-component composite (the primary composite, with the addition of urgent revascularization for unstable angina), the individual components of the primary endpoint, and the composite of cardiovascular death or hospital admission because of heart failure | Composite clinical microvascular outcome comprising diabetic retinopathy or renal disease; hospital admission for unstable angina; each component of the primary composite cardiovascular outcome; death; and heart failure requiring either hospital admission or an urgent visit requiring therapy | Composite of the primary outcome plus unstable angina resulting in hospitalization or heart failure resulting in hospitalization; a composite of death from any cause, non-fatal myocardial infarction, or non-fatal stroke; the individual components of these composite outcomes |
| Risk of bias | Low | Low | Low | Low | Low | Low | Low |
| Trial registry reference | NCT01147250 | NCT01179048 | NCT01720446 | NCT01144338 | NCT02465515 | NCT01394952 | NCT02692716 |
| ELIXA | LEADER | SUSTAIN-6 | EXSCEL | HARMONY | REWIND | PIONEER-6 | |
|---|---|---|---|---|---|---|---|
| Publication year | 2015 | 2016 | 2016 | 2017 | 2018 | 2019 | 2019 |
| Study design | Multicentre, randomized, double blind, placebo-controlled trial involving patients with Type 2 diabetes who had had a recent acute coronary syndrome. The trial was designed to assess the effects of lixisenatide on cardiovascular morbidity and mortality | Multicentre, double blind, placebo-controlled trial involving patients with Type 2 diabetes, with previous cardiovascular coexisting condition or at least one cardiovascular risk factor. The trial was designed to assess the effects of liraglutide on cardiovascular morbidity and mortality | Randomized, double blind, placebo-controlled trial involving patients with Type 2 diabetes, with established cardiovascular disease, or at least one cardiovascular risk factor. The trial was designed to assess the effects of semaglutide on cardiovascular morbidity and mortality | Randomized, double blind, placebo-controlled, event-driven trial involving patients with Type 2 diabetes, with previous cardiovascular event, or at least one cardiovascular risk factor. The trial was designed to assess the effects of exenatide on cardiovascular morbidity and mortality | Double blind, Randomized, placebo-controlled, event-driven trial involving patients with Type 2 diabetes, with established cardiovascular disease. The trial was designed to assess the effects of albiglutide on cardiovascular morbidity and mortality | Multicentre, randomized, double blind, placebo-controlled trial involving patients with Type 2 diabetes, with established cardiovascular disease or at least two cardiovascular risk factors. The trial was designed to assess the effects of dulaglutide on cardiovascular morbidity and mortality | Multicentre, randomized, double blind, placebo-controlled trial involving patients with established cardiovascular disease, or cardiovascular risk factors only. The trial was designed to assess the effects of oral semaglutide on cardiovascular morbidity and mortality |
| Sample size | 6068 | 9340 | 3297 | 14 752 | 9463 | 9901 | 3183 |
| Inclusion criteria | HbA1c 5.5–11.0% (36.6–96.7 mmol/mol); acute coronary syndrome within 180 days; age ≥30 years | HbA1c ≥7.0% (≥53.0 mmol/mol); age ≥50 years with cardiovascular disease, chronic heart failure (NYHA Class II or III), chronic kidney disease (Stage 3 or higher), or age ≥60 years with at least one cardiovascular risk factor | HbA1c ≥7.0% (≥53.0 mmol/mol); age ≥50 years with cardiovascular disease, chronic heart failure (NYHA Class II or III), chronic kidney disease (Stage 3 or higher), or age ≥60 years with at least one cardiovascular risk factor | HbA1c 6.5–10.0% (47.5–85.8 mmol/mol); established cardiovascular disease and primary prevention; age ≥18 years | HbA1c ≥7.0% (≥53.0 mmol/mol); age ≥40 years with established disease of the coronary, cerebrovascular, or peripheral arterial circulation | HbA1c ≤9.5% (80 mmol/mol) treated with up to two oral glucose-lowering drugs, with or without basal insulin therapy if BMI at least 23 kg/m2; age ≥50 years with previous vascular disease, or age ≥60 years with at least two cardiovascular risk factors | Male of female patients with Type 2 diabetes; age ≥50 years with established cardiovascular disease, or age ≥60 years with cardiovascular risk factors only |
| Exclusion criteria | Age <30 years; PCI within the previous 15 days, planned coronary revascularization procedure within 90 days after screening; eGFR of <30 mL/min/1.73 m2; HbA1c <5.5% (36.6 mmol/mol) or >11.0% (96.7 mmol/mol) | Type 1 diabetes; use of GLP-1 receptor agonists, DPP-4 inhibitors, pramlintide, or rapid-acting insulin; familial or personal history of multiple endocrine neoplasia Type 2 or medullary thyroid cancer; occurrence of an acute coronary or cerebrovascular event within 14 days before screening and randomization | Treatment with DPP-4 inhibitors within 30 days before screening or with GLP-1 receptor agonists or insulin other than basal or premixed within 90 days before screening; history of acute coronary or cerebrovascular event within 90 days before randomization; planned revascularization of a coronary, carotid, or peripheral artery; long-term dialysis | History of two or more episodes of severe hypoglycaemia during the preceding 12 months; end-stage kidney disease or an eGFR <30 mL/min/1.73 m2; personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia Type 2; baseline calcitonin level >40 ng/L; previous treatment with GLP-1 receptor agonists | eGFR <30 mL/min/1.73 m2; severe gastroparesis; previous pancreatitis or substantial risk factors for pancreatitis; personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia Type 2; history of pancreatic neuroendocrine tumours; current use of GLP-1 receptor agonists | eGFR <15 mL/min/1.73 m2; cancer in the previous 5 years; severe hypoglycaemia in the previous year; life expectancy <1 year; a coronary or cerebrovascular event within the previous 2 months, and plans for revascularization | Treatment with any GLP-1 receptor agonist, DPP-4 inhibitor, or pramlintide within 90 days before screening; NYHA Class IV heart failure; planned coronary artery, carotid artery, or peripheral artery revascularization; myocardial infarction, stroke, or hospitalization for unstable angina or transient ischaemic attack within 60 days before screening; long-term or intermittent haemodialysis or peritoneal dialysis, or severe renal impairment (eGFR < 30 mL/min/1.73 m2); and proliferative retinopathy or maculopathy resulting in active treatment |
| Follow-up period (years) | 2.1 | 3.8 | 2.1 | 3.2 (2.2–4.4) | 1.5 | 5.4 (5.1–5.9) | 1.3 (0.03–1.7) |
| Discontinuation therapy | 347 (11.4%) for lixisenatide and 217 (7.2%) for placebo | 444 (9.5%) for liraglutide and 339 (7.3%) for placebo | 350 (21.2%) for semaglutide and 310 (18.8%) for placebo | 3164 (43%) for exenatide and 3343 (45.2%) for placebo | 1140 (24%) for albiglutide and 1297 (27%) for placebo | 1328 (26.8%) for dulaglutide and 1432 (28.9%) for placebo | 225 (14.1%) for semaglutide and 152 (9.5%) for placebo |
| Primary outcomes | MACE-4 (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina) | MACE-3 (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke) | MACE-3 (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke) | MACE-3 (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke) | MACE-3 (death from cardiovascular causes, myocardial infarction, stroke) | MACE-3 (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke) | MACE-3 (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke) |
| Secondary outcomes | Composite of the primary outcome or hospitalization for heart failure, or coronary revascularization procedures | Composite of the primary outcome or hospitalization for unstable angina, or hospitalization for heart failure, or coronary revascularization; death from any cause; composite of renal and retinal microvascular outcome; neoplasm; pancreatitis | Composite of the primary outcome or hospitalization for unstable angina, or hospitalization for heart failure, or coronary revascularization; an additional composite outcome of death from all causes, non-fatal myocardial infarction, non-fatal stroke; individual components of the composite outcomes; retinopathy complications and new or worsening nephropathy | Secondary outcomes included death from any cause, death from cardiovascular causes, and the first occurrence of non-fatal or fatal myocardial infarction, non-fatal or fatal stroke, hospitalization for acute coronary syndrome, and hospitalization for heart failure | Four-component composite (the primary composite, with the addition of urgent revascularization for unstable angina), the individual components of the primary endpoint, and the composite of cardiovascular death or hospital admission because of heart failure | Composite clinical microvascular outcome comprising diabetic retinopathy or renal disease; hospital admission for unstable angina; each component of the primary composite cardiovascular outcome; death; and heart failure requiring either hospital admission or an urgent visit requiring therapy | Composite of the primary outcome plus unstable angina resulting in hospitalization or heart failure resulting in hospitalization; a composite of death from any cause, non-fatal myocardial infarction, or non-fatal stroke; the individual components of these composite outcomes |
| Risk of bias | Low | Low | Low | Low | Low | Low | Low |
| Trial registry reference | NCT01147250 | NCT01179048 | NCT01720446 | NCT01144338 | NCT02465515 | NCT01394952 | NCT02692716 |
BMI, body mass index; DPP-4, dipeptidyl peptidase 4; eGFR, estimated glomerular filtration rate; GLP-1, glucagon-like peptide-1; HbA1c, glycated haemoglobin; MACE-3, three-point major adverse cardiovascular events (cardiovascular-related death, non-fatal myocardial infarction, and non-fatal stroke); MACE-4, four-point major adverse cardiovascular events (cardiovascular-related death, non-fatal myocardial infarction, non-fatal stroke, or unstable angina requiring hospital admission); NYHA, New York Heart Association; PCI, percutaneous coronary intervention.
Results
Of 360 articles evaluated for eligibility, seven CVOTs (including 56 004 patients) were eligible and included in the meta-analysis (Figure 1). ELIXA (The Evaluation of Lixisenatide in Acute Coronary Syndrome) compared lixisenatide to placebo in 6068 patients with Type 2 DM who had suffered a recent acute coronary event, followed up for a median period of 2.1 years. LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of CV Outcome Results) compared liraglutide to placebo in 9340 patients with Type 2 DM and known CVD (6775 patients) or CV risk factors only (2565 patients), followed up for a median of 3.8 years. SUSTAIN-6 (Trial to Evaluate CV and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes) compared semaglutide to placebo in 3297 Type 2 diabetic patients and established CVD (2533 patients) or CV risk factors only (764 patients), followed up for a median of 2.1 years. EXSCEL (Exenatide Study of CV Event Lowering Trial) compared extended-release exenatide to placebo in 14 752 patients with Type 2 DM and established CVD (10 782 patients) or CV risk factors only (3970 patients), followed up for a median of 3.2 years. Harmony Outcomes (Albiglutide and CV outcomes in patients with Type 2 diabetes and CVD) compared albiglutide to placebo in 9463 Type 2 diabetic patients and known CVD, followed up for a median of 1.5 years. REWIND (Researching CV Events With a Weekly Incretin in Diabetes) compared dulaglutide to placebo in 9901 patients with Type 2 DM and previous CV event (3114 patients) or CV risk factors only (6221 patients), followed for a median of 5.4 years. PIONEER 6 (Peptide Innovation for Early Diabetes Treatment 6) compared oral semaglutide to placebo in 3183 patients with Type 2 DM and established CVD (2695 patients) or CV risk factors only (488 patients), followed for a median of 1.3 years.2 , 3 , 5 , 7–10 The primary outcome for LEADER, SUSTAIN-6, EXSCEL, Harmony Outcomes, REWIND, and PIONEER 6 was a three-point MACE, whereas ELIXA used a four-point MACE, including also hospital admission for unstable angina. Characteristics of trials and patients are reported, respectively, in Tables 1 and 2. Mean age of patients was 63.8 ± 2.2 years, 36 ± 5% were female, with a mean body mass index of 32.1 ± 0.9 kg/m2. Mean DM duration was 12.6 ± 2.1 years, with a mean baseline HbA1c of 8.2 ± 0.6%. The median duration of follow-up ranged from 1.3 to 5.4 years.
Table 2
Baseline characteristics of patients of included trials
| ELIXA (n = 6068) | LEADER (n = 9340) | SUSTAIN-6 (n = 3297) | EXSCEL (n = 14 752) | HARMONY (n = 9463) | REWIND (n = 9901) | PIONEER-6 (n = 3183) | |
|---|---|---|---|---|---|---|---|
| Known cardiovascular disease | 6068 | 6775 | 2533 | 10 782 | NA | 3114 | 2695 |
| Cardiovascular risk factors alone | NA | 2565 | 764 | 3970 | NA | 6221 | 488 |
| Age (years) | 59.9 (9.7) | 64.2 (7.2) | 64.6 (7.4) | 61.9 (9.4) | 64.1 (8.7) | 66.2 (6.5) | 66 (7) |
| Sex (female) | 1861 (31%) | 3337 (36%) | 1295 (39%) | 5603 (38%) | 2894 (31%) | 4589 (46%) | 1007 (32%) |
| BMI (kg/m2) | 30.1 (5.6) | 32.5 (6.3) | 32.8 (6.2) | 32.7 (6.4) | 32.3 (5.9) | 32.3 (5.7) | 32.3 (6.5) |
| White | 4576 (75%) | 7238 (78%) | 2736 (83%) | 11 175 (76%) | 6583 (70%) | 7498 (76%) | 2300 (72%) |
| Diabetes duration (years) | 9.2 (8.2) | 12.8 (8.0) | 13.9 (8.1) | 13.1 (8.3) | 14.1 (8.7) | 10.5 (7.3) | 14.9 (8.5) |
| HbA1c (%) | 7.7 (1.3) | 8.7 (1.6) | 8.7 (1.5) | 8.1 (1.0) | 8.7 (1.5) | 7.3 (1.1) | 8.2 (1.6) |
| Hypertension | 4635 (76%) | 8511 (91%) | NA | NA | 8184 (86%) | 9224 (93%) | 781 (24.5%) |
| Hypercholesterolaemia | NA | 7079 (76%) | NA | NA | NA | NA | NA |
| Smoke | 709 (12%) | 1130 (12%) | 406 (12%) | 7512 (51%) | 1488 (16%) | 1407 (14%) | 349 (11%) |
| Previous ischaemic heart disease | NA | 5059 (54%) | 3066 (93%) | 7794 (53%) | 6678 (71%) | NA | NA |
| Previous acute coronary syndrome | 6068 (100%) | 2248 (24%) | 1072 (33%) | NA | 4459 (47%) | 1602 (16.2) | 1150 (36.1%) |
| Previous coronary artery disease | NA | 2661 (28%) | 1994 (60%) | NA | 5895 (62%) | NA | 920 (28.9%) |
| Previous stroke | NA | 1632 (17%) | 401 (12%) | 2509 (17%) | 1681 (18%) | 687 (6.9) | 505 (15.9%) |
| Previous peripheral arterial disease | NA | 1666 (18%) | 453 (14%) | 2800 (19%) | 2354 (25%) | 856 (8.7) | NA |
| Insulin use | 2374 (39%) | 4159 (45%) | 1913 (58%) | 6838 (46%) | 5597 (59%) | 2363 (24%) | 962 (60.4%) |
| Metformin use | 4021 (66%) | 7136 (76%) | 2414 (73%) | 11 295 (77%) | 6968 (74%) | 8037 (81%) | NA |
| Sulfonylurea use | 2004 (33%) | 4721 (51%) | 1410 (43%) | 5401 (37%) | 2725 (29%) | 4552 (46%) | 510 (32%) |
| Thiazolidinedione use | 95 (2%) | 573 (6%) | 76 (2%) | 579 (4%) | 194 (2%) | 168 (2%) | 53 (3.3%) |
| DPP-4 inhibitor use | NA | 6 (<1%) | 5 (<1%) | 2203 (15%) | 1437 (15%) | 564 (6%) | 0 (0%) |
| SGLT2 inhibitor use | NA | NA | 5 (<1%) | 77 (1%) | 575 (6%) | 620 (6%) | 140 (8.8%) |
| Median duration of follow-up (years) | 2.1 | 3.8 | 2.1 | 3.2 (2.2–4.4) | 1.5 | 5.4 (5.1–5.9) | 1.3 (0.03–1.7) |
| Primary outcome | MACE-4 (non-inferiority) | MACE-3 (non-inferiority) | MACE-3 (non-inferiority) | MACE-3 (superiority for efficacy, non-inferiority for safety) | MACE-3 (superiority) | MACE-3 (non-inferiority) | MACE-3 (superiority) |
| Participants with a primary outcome | 805 | 1302 | 254 | 1744 | 766 | 1257 | 137 |
| Primary outcome (HR and 95% CI) | 1.02 (0.89–1.17) | 0.87 (0.78–0.97) | 0.74 (0.58–0.95) | 0.91 (0.83–1.00) | 0.78 (0.68–0.90) | 0.88 (0.79–0.99) | 0.79 (0.57–1.11) |
| Primary outcome in known cardiovascular disease + (HR and 95% CI) | NA | 1051 | 221 | 1508 | NA | 595 | 125 |
| NA | NA | 0.78 (0.61–1.01) | 0.90 (0.82–1.00) | 0.87 (0.74–1.02) | 0.83 (0.58–1.17) | ||
| Primary outcome in cardiovascular risk factors alone + (HR and 95% CI) | NA | 251 | 33 | 236 | NA | 594 | 12 |
| 0.87 (0.74–1.02) | 0.51 (0.15–1.68) | ||||||
| NA | 1.08 (0.84–1.38) | 0.48 (0.23–0.99) | 0.99 (0.77–1.28) |
| ELIXA (n = 6068) | LEADER (n = 9340) | SUSTAIN-6 (n = 3297) | EXSCEL (n = 14 752) | HARMONY (n = 9463) | REWIND (n = 9901) | PIONEER-6 (n = 3183) | |
|---|---|---|---|---|---|---|---|
| Known cardiovascular disease | 6068 | 6775 | 2533 | 10 782 | NA | 3114 | 2695 |
| Cardiovascular risk factors alone | NA | 2565 | 764 | 3970 | NA | 6221 | 488 |
| Age (years) | 59.9 (9.7) | 64.2 (7.2) | 64.6 (7.4) | 61.9 (9.4) | 64.1 (8.7) | 66.2 (6.5) | 66 (7) |
| Sex (female) | 1861 (31%) | 3337 (36%) | 1295 (39%) | 5603 (38%) | 2894 (31%) | 4589 (46%) | 1007 (32%) |
| BMI (kg/m2) | 30.1 (5.6) | 32.5 (6.3) | 32.8 (6.2) | 32.7 (6.4) | 32.3 (5.9) | 32.3 (5.7) | 32.3 (6.5) |
| White | 4576 (75%) | 7238 (78%) | 2736 (83%) | 11 175 (76%) | 6583 (70%) | 7498 (76%) | 2300 (72%) |
| Diabetes duration (years) | 9.2 (8.2) | 12.8 (8.0) | 13.9 (8.1) | 13.1 (8.3) | 14.1 (8.7) | 10.5 (7.3) | 14.9 (8.5) |
| HbA1c (%) | 7.7 (1.3) | 8.7 (1.6) | 8.7 (1.5) | 8.1 (1.0) | 8.7 (1.5) | 7.3 (1.1) | 8.2 (1.6) |
| Hypertension | 4635 (76%) | 8511 (91%) | NA | NA | 8184 (86%) | 9224 (93%) | 781 (24.5%) |
| Hypercholesterolaemia | NA | 7079 (76%) | NA | NA | NA | NA | NA |
| Smoke | 709 (12%) | 1130 (12%) | 406 (12%) | 7512 (51%) | 1488 (16%) | 1407 (14%) | 349 (11%) |
| Previous ischaemic heart disease | NA | 5059 (54%) | 3066 (93%) | 7794 (53%) | 6678 (71%) | NA | NA |
| Previous acute coronary syndrome | 6068 (100%) | 2248 (24%) | 1072 (33%) | NA | 4459 (47%) | 1602 (16.2) | 1150 (36.1%) |
| Previous coronary artery disease | NA | 2661 (28%) | 1994 (60%) | NA | 5895 (62%) | NA | 920 (28.9%) |
| Previous stroke | NA | 1632 (17%) | 401 (12%) | 2509 (17%) | 1681 (18%) | 687 (6.9) | 505 (15.9%) |
| Previous peripheral arterial disease | NA | 1666 (18%) | 453 (14%) | 2800 (19%) | 2354 (25%) | 856 (8.7) | NA |
| Insulin use | 2374 (39%) | 4159 (45%) | 1913 (58%) | 6838 (46%) | 5597 (59%) | 2363 (24%) | 962 (60.4%) |
| Metformin use | 4021 (66%) | 7136 (76%) | 2414 (73%) | 11 295 (77%) | 6968 (74%) | 8037 (81%) | NA |
| Sulfonylurea use | 2004 (33%) | 4721 (51%) | 1410 (43%) | 5401 (37%) | 2725 (29%) | 4552 (46%) | 510 (32%) |
| Thiazolidinedione use | 95 (2%) | 573 (6%) | 76 (2%) | 579 (4%) | 194 (2%) | 168 (2%) | 53 (3.3%) |
| DPP-4 inhibitor use | NA | 6 (<1%) | 5 (<1%) | 2203 (15%) | 1437 (15%) | 564 (6%) | 0 (0%) |
| SGLT2 inhibitor use | NA | NA | 5 (<1%) | 77 (1%) | 575 (6%) | 620 (6%) | 140 (8.8%) |
| Median duration of follow-up (years) | 2.1 | 3.8 | 2.1 | 3.2 (2.2–4.4) | 1.5 | 5.4 (5.1–5.9) | 1.3 (0.03–1.7) |
| Primary outcome | MACE-4 (non-inferiority) | MACE-3 (non-inferiority) | MACE-3 (non-inferiority) | MACE-3 (superiority for efficacy, non-inferiority for safety) | MACE-3 (superiority) | MACE-3 (non-inferiority) | MACE-3 (superiority) |
| Participants with a primary outcome | 805 | 1302 | 254 | 1744 | 766 | 1257 | 137 |
| Primary outcome (HR and 95% CI) | 1.02 (0.89–1.17) | 0.87 (0.78–0.97) | 0.74 (0.58–0.95) | 0.91 (0.83–1.00) | 0.78 (0.68–0.90) | 0.88 (0.79–0.99) | 0.79 (0.57–1.11) |
| Primary outcome in known cardiovascular disease + (HR and 95% CI) | NA | 1051 | 221 | 1508 | NA | 595 | 125 |
| NA | NA | 0.78 (0.61–1.01) | 0.90 (0.82–1.00) | 0.87 (0.74–1.02) | 0.83 (0.58–1.17) | ||
| Primary outcome in cardiovascular risk factors alone + (HR and 95% CI) | NA | 251 | 33 | 236 | NA | 594 | 12 |
| 0.87 (0.74–1.02) | 0.51 (0.15–1.68) | ||||||
| NA | 1.08 (0.84–1.38) | 0.48 (0.23–0.99) | 0.99 (0.77–1.28) |
BMI, body mass index; CI, confidence interval; DPP-4, dipeptidyl peptidase 4; HbA1c, glycated haemoglobin; HR, hazard ratio; MACE-3, three-point major adverse cardiovascular events (cardiovascular-related death, non-fatal myocardial infarction, and non-fatal stroke); MACE-4, four-point major adverse cardiovascular events (cardiovascular-related death, non-fatal myocardial infarction, non-fatal stroke, or unstable angina requiring hospital admission); NA, not available; SGLT2, sodium-glucose co-transporter 2.
Table 2
Baseline characteristics of patients of included trials
| ELIXA (n = 6068) | LEADER (n = 9340) | SUSTAIN-6 (n = 3297) | EXSCEL (n = 14 752) | HARMONY (n = 9463) | REWIND (n = 9901) | PIONEER-6 (n = 3183) | |
|---|---|---|---|---|---|---|---|
| Known cardiovascular disease | 6068 | 6775 | 2533 | 10 782 | NA | 3114 | 2695 |
| Cardiovascular risk factors alone | NA | 2565 | 764 | 3970 | NA | 6221 | 488 |
| Age (years) | 59.9 (9.7) | 64.2 (7.2) | 64.6 (7.4) | 61.9 (9.4) | 64.1 (8.7) | 66.2 (6.5) | 66 (7) |
| Sex (female) | 1861 (31%) | 3337 (36%) | 1295 (39%) | 5603 (38%) | 2894 (31%) | 4589 (46%) | 1007 (32%) |
| BMI (kg/m2) | 30.1 (5.6) | 32.5 (6.3) | 32.8 (6.2) | 32.7 (6.4) | 32.3 (5.9) | 32.3 (5.7) | 32.3 (6.5) |
| White | 4576 (75%) | 7238 (78%) | 2736 (83%) | 11 175 (76%) | 6583 (70%) | 7498 (76%) | 2300 (72%) |
| Diabetes duration (years) | 9.2 (8.2) | 12.8 (8.0) | 13.9 (8.1) | 13.1 (8.3) | 14.1 (8.7) | 10.5 (7.3) | 14.9 (8.5) |
| HbA1c (%) | 7.7 (1.3) | 8.7 (1.6) | 8.7 (1.5) | 8.1 (1.0) | 8.7 (1.5) | 7.3 (1.1) | 8.2 (1.6) |
| Hypertension | 4635 (76%) | 8511 (91%) | NA | NA | 8184 (86%) | 9224 (93%) | 781 (24.5%) |
| Hypercholesterolaemia | NA | 7079 (76%) | NA | NA | NA | NA | NA |
| Smoke | 709 (12%) | 1130 (12%) | 406 (12%) | 7512 (51%) | 1488 (16%) | 1407 (14%) | 349 (11%) |
| Previous ischaemic heart disease | NA | 5059 (54%) | 3066 (93%) | 7794 (53%) | 6678 (71%) | NA | NA |
| Previous acute coronary syndrome | 6068 (100%) | 2248 (24%) | 1072 (33%) | NA | 4459 (47%) | 1602 (16.2) | 1150 (36.1%) |
| Previous coronary artery disease | NA | 2661 (28%) | 1994 (60%) | NA | 5895 (62%) | NA | 920 (28.9%) |
| Previous stroke | NA | 1632 (17%) | 401 (12%) | 2509 (17%) | 1681 (18%) | 687 (6.9) | 505 (15.9%) |
| Previous peripheral arterial disease | NA | 1666 (18%) | 453 (14%) | 2800 (19%) | 2354 (25%) | 856 (8.7) | NA |
| Insulin use | 2374 (39%) | 4159 (45%) | 1913 (58%) | 6838 (46%) | 5597 (59%) | 2363 (24%) | 962 (60.4%) |
| Metformin use | 4021 (66%) | 7136 (76%) | 2414 (73%) | 11 295 (77%) | 6968 (74%) | 8037 (81%) | NA |
| Sulfonylurea use | 2004 (33%) | 4721 (51%) | 1410 (43%) | 5401 (37%) | 2725 (29%) | 4552 (46%) | 510 (32%) |
| Thiazolidinedione use | 95 (2%) | 573 (6%) | 76 (2%) | 579 (4%) | 194 (2%) | 168 (2%) | 53 (3.3%) |
| DPP-4 inhibitor use | NA | 6 (<1%) | 5 (<1%) | 2203 (15%) | 1437 (15%) | 564 (6%) | 0 (0%) |
| SGLT2 inhibitor use | NA | NA | 5 (<1%) | 77 (1%) | 575 (6%) | 620 (6%) | 140 (8.8%) |
| Median duration of follow-up (years) | 2.1 | 3.8 | 2.1 | 3.2 (2.2–4.4) | 1.5 | 5.4 (5.1–5.9) | 1.3 (0.03–1.7) |
| Primary outcome | MACE-4 (non-inferiority) | MACE-3 (non-inferiority) | MACE-3 (non-inferiority) | MACE-3 (superiority for efficacy, non-inferiority for safety) | MACE-3 (superiority) | MACE-3 (non-inferiority) | MACE-3 (superiority) |
| Participants with a primary outcome | 805 | 1302 | 254 | 1744 | 766 | 1257 | 137 |
| Primary outcome (HR and 95% CI) | 1.02 (0.89–1.17) | 0.87 (0.78–0.97) | 0.74 (0.58–0.95) | 0.91 (0.83–1.00) | 0.78 (0.68–0.90) | 0.88 (0.79–0.99) | 0.79 (0.57–1.11) |
| Primary outcome in known cardiovascular disease + (HR and 95% CI) | NA | 1051 | 221 | 1508 | NA | 595 | 125 |
| NA | NA | 0.78 (0.61–1.01) | 0.90 (0.82–1.00) | 0.87 (0.74–1.02) | 0.83 (0.58–1.17) | ||
| Primary outcome in cardiovascular risk factors alone + (HR and 95% CI) | NA | 251 | 33 | 236 | NA | 594 | 12 |
| 0.87 (0.74–1.02) | 0.51 (0.15–1.68) | ||||||
| NA | 1.08 (0.84–1.38) | 0.48 (0.23–0.99) | 0.99 (0.77–1.28) |
| ELIXA (n = 6068) | LEADER (n = 9340) | SUSTAIN-6 (n = 3297) | EXSCEL (n = 14 752) | HARMONY (n = 9463) | REWIND (n = 9901) | PIONEER-6 (n = 3183) | |
|---|---|---|---|---|---|---|---|
| Known cardiovascular disease | 6068 | 6775 | 2533 | 10 782 | NA | 3114 | 2695 |
| Cardiovascular risk factors alone | NA | 2565 | 764 | 3970 | NA | 6221 | 488 |
| Age (years) | 59.9 (9.7) | 64.2 (7.2) | 64.6 (7.4) | 61.9 (9.4) | 64.1 (8.7) | 66.2 (6.5) | 66 (7) |
| Sex (female) | 1861 (31%) | 3337 (36%) | 1295 (39%) | 5603 (38%) | 2894 (31%) | 4589 (46%) | 1007 (32%) |
| BMI (kg/m2) | 30.1 (5.6) | 32.5 (6.3) | 32.8 (6.2) | 32.7 (6.4) | 32.3 (5.9) | 32.3 (5.7) | 32.3 (6.5) |
| White | 4576 (75%) | 7238 (78%) | 2736 (83%) | 11 175 (76%) | 6583 (70%) | 7498 (76%) | 2300 (72%) |
| Diabetes duration (years) | 9.2 (8.2) | 12.8 (8.0) | 13.9 (8.1) | 13.1 (8.3) | 14.1 (8.7) | 10.5 (7.3) | 14.9 (8.5) |
| HbA1c (%) | 7.7 (1.3) | 8.7 (1.6) | 8.7 (1.5) | 8.1 (1.0) | 8.7 (1.5) | 7.3 (1.1) | 8.2 (1.6) |
| Hypertension | 4635 (76%) | 8511 (91%) | NA | NA | 8184 (86%) | 9224 (93%) | 781 (24.5%) |
| Hypercholesterolaemia | NA | 7079 (76%) | NA | NA | NA | NA | NA |
| Smoke | 709 (12%) | 1130 (12%) | 406 (12%) | 7512 (51%) | 1488 (16%) | 1407 (14%) | 349 (11%) |
| Previous ischaemic heart disease | NA | 5059 (54%) | 3066 (93%) | 7794 (53%) | 6678 (71%) | NA | NA |
| Previous acute coronary syndrome | 6068 (100%) | 2248 (24%) | 1072 (33%) | NA | 4459 (47%) | 1602 (16.2) | 1150 (36.1%) |
| Previous coronary artery disease | NA | 2661 (28%) | 1994 (60%) | NA | 5895 (62%) | NA | 920 (28.9%) |
| Previous stroke | NA | 1632 (17%) | 401 (12%) | 2509 (17%) | 1681 (18%) | 687 (6.9) | 505 (15.9%) |
| Previous peripheral arterial disease | NA | 1666 (18%) | 453 (14%) | 2800 (19%) | 2354 (25%) | 856 (8.7) | NA |
| Insulin use | 2374 (39%) | 4159 (45%) | 1913 (58%) | 6838 (46%) | 5597 (59%) | 2363 (24%) | 962 (60.4%) |
| Metformin use | 4021 (66%) | 7136 (76%) | 2414 (73%) | 11 295 (77%) | 6968 (74%) | 8037 (81%) | NA |
| Sulfonylurea use | 2004 (33%) | 4721 (51%) | 1410 (43%) | 5401 (37%) | 2725 (29%) | 4552 (46%) | 510 (32%) |
| Thiazolidinedione use | 95 (2%) | 573 (6%) | 76 (2%) | 579 (4%) | 194 (2%) | 168 (2%) | 53 (3.3%) |
| DPP-4 inhibitor use | NA | 6 (<1%) | 5 (<1%) | 2203 (15%) | 1437 (15%) | 564 (6%) | 0 (0%) |
| SGLT2 inhibitor use | NA | NA | 5 (<1%) | 77 (1%) | 575 (6%) | 620 (6%) | 140 (8.8%) |
| Median duration of follow-up (years) | 2.1 | 3.8 | 2.1 | 3.2 (2.2–4.4) | 1.5 | 5.4 (5.1–5.9) | 1.3 (0.03–1.7) |
| Primary outcome | MACE-4 (non-inferiority) | MACE-3 (non-inferiority) | MACE-3 (non-inferiority) | MACE-3 (superiority for efficacy, non-inferiority for safety) | MACE-3 (superiority) | MACE-3 (non-inferiority) | MACE-3 (superiority) |
| Participants with a primary outcome | 805 | 1302 | 254 | 1744 | 766 | 1257 | 137 |
| Primary outcome (HR and 95% CI) | 1.02 (0.89–1.17) | 0.87 (0.78–0.97) | 0.74 (0.58–0.95) | 0.91 (0.83–1.00) | 0.78 (0.68–0.90) | 0.88 (0.79–0.99) | 0.79 (0.57–1.11) |
| Primary outcome in known cardiovascular disease + (HR and 95% CI) | NA | 1051 | 221 | 1508 | NA | 595 | 125 |
| NA | NA | 0.78 (0.61–1.01) | 0.90 (0.82–1.00) | 0.87 (0.74–1.02) | 0.83 (0.58–1.17) | ||
| Primary outcome in cardiovascular risk factors alone + (HR and 95% CI) | NA | 251 | 33 | 236 | NA | 594 | 12 |
| 0.87 (0.74–1.02) | 0.51 (0.15–1.68) | ||||||
| NA | 1.08 (0.84–1.38) | 0.48 (0.23–0.99) | 0.99 (0.77–1.28) |
BMI, body mass index; CI, confidence interval; DPP-4, dipeptidyl peptidase 4; HbA1c, glycated haemoglobin; HR, hazard ratio; MACE-3, three-point major adverse cardiovascular events (cardiovascular-related death, non-fatal myocardial infarction, and non-fatal stroke); MACE-4, four-point major adverse cardiovascular events (cardiovascular-related death, non-fatal myocardial infarction, non-fatal stroke, or unstable angina requiring hospital admission); NA, not available; SGLT2, sodium-glucose co-transporter 2.
Effects of glucagon-like peptide-1 receptor agonists on major adverse cardiovascular events in patients with and without established cardiovascular disease
Of seven CVOTs included in the meta-analysis, five enrolled subgroups of DM patients with established CVD and CV risk factors only (n = 14 008). No difference for the three-point MACE composite outcome was observed between the two groups, indicating consistent protective effects also in patients without established CVD. In particular, the pooled ratio of the HR estimated in the cardiovascular risk factor patients vs. that observed in the CVD subgroup was 1.06 (95% CI 0.85–1.34; P = 0.495) in the analysis including LEADER with CVD group without prior MI or stroke, with low heterogeneity among trials (I 2 = 9%), and 1.08 (95% CI 0.79–1.46; P = 0.550) in the analysis including LEADER with CVD group with prior MI or stroke, with a moderate degree of heterogeneity among trials (I 2 = 33%) (Figure 2). Thus, lack of statistical significance (95% CI 0.85–1.34; P = 0.495) therefore indicates no effect differences between patients with CV risk factors only and those with established CVD.
Figure 2
Interaction analysis for the three-point major adverse cardiovascular events outcome between previous cardiovascular disease and cardiovascular risk factors only subgroups. LEADER trial is included twice since the study reported separate analysis for established cardiovascular disease patients without previous myocardial infarction or stroke (LEADER I) and established cardiovascular disease patients with previous myocardial infarction or stroke (LEADER II). CVD, cardiovascular disease; CRF, cardiovascular risk factors; GLP-1, glucagon-like peptide-1.
Effects of glucagon-like peptide-1 receptor agonists in the whole population
In the overall population of 56 004 DM patients enrolled in the seven CVOTs, GLP-1 receptor agonists significantly reduced the risk of the three-point MACE compared to placebo (HR 0.88, 95% CI 0.80–0.96; P = 0.011), with a moderate degree of heterogeneity among trials (I 2 = 39%) (Figure 3).
Figure 3
Cardiovascular primary outcome of three-point major adverse cardiovascular events (A), mortality outcomes cardiovascular mortality (B), and all-cause mortality (C). Three-point major adverse cardiovascular event is a composite of cardiovascular mortality, non-fatal myocardial infarction, and non-fatal stroke. GLP-1, glucagon-like peptide-1; MACE, major adverse cardiovascular events; NNT, numbers needed to treat.
There was a significant reduction, with respect to placebo, in the risk of CV mortality (HR 0.88, 95% CI 0.79–0.98; P = 0.025) and all-cause mortality (HR 0.89, 95% CI 0.81–0.97; P = 0.019), with low heterogeneity among trials for both outcomes (I 2 = 8% and I 2 = 18%, respectively) (Figure 3).
Glucagon-like peptide-1 receptor agonists reduced, although non significantly, the risk of fatal and non-fatal MI compared to placebo (HR 0.91, 95% CI 0.82–1.02; P = 0.082) and was associated with a significant reduction in the risk of fatal and non-fatal stroke (HR 0.84, 95% CI 0.76–0.94; P = 0.008), and of hospitalization for HF (HR 0.92, 95% CI 0.86–0.97; P = 0.014) with a moderate heterogeneity among trials for fatal and non-fatal MI (I 2 = 31%) and no observed heterogeneity for fatal and non-fatal stroke and for hospitalization for HF (I 2=0% for both) (Figure 4).
Figure 4
Cardiovascular secondary outcomes. (A) Fatal and non-fatal myocardial infarction. (B) Fatal and non-fatal stroke. (C) Heart failure hospitalization. GLP-1, glucagon-like peptide-1; NNT, numbers needed to treat.
Safety analysis showed no significant effect of GLP-1 receptor agonists on severe hypoglycaemia (OR 0.90, 95% CI 0.65–1.25; P = 0.474), although with high heterogeneity among trials (I 2 = 71%); also no significant effect of GLP-1 receptor agonists compared to placebo were seen on pancreatitis (OR 1.06, 95% CI 0.74–1.52; P = 0.708), and pancreatic cancer (OR 1.06, 95% CI 0.48–2.37; P = 0.856), with no observed heterogeneity among trials for pancreatitis (I 2 = 0%), and moderate heterogeneity for pancreatic cancer (I 2 = 45%) (Figure 5).
Figure 5
Safety outcomes. (A) Severe hypoglycaemia. (B) Pancreatitis. (C) Pancreatic cancer. GLP-1, glucagon-like peptide-1.
Sensitivity analysis
By applying D-L random-effect models without the HK correction to the primary and secondary CV outcomes, the only relevant difference refers to the fatal and non-fatal MI outcome where emerged a significant protective effect of GLP-1 receptor agonists with respect to placebo (HR 0.91, 95% CI 0.83–1.00; P = 0.039) (Supplementary material online).
Discussion
The results of the current meta-analysis, that included 56 004 Type 2 DM patients, 14 008 of whom without established CVD, demonstrate that GLP-1 receptor agonists significantly reduce MACE in DM patients with and without established CVD (Take home figure). The three-point MACE composite endpoint (including CV death, non-fatal MI, and non-fatal stroke) was reduced by 12%, with an NNT to prevent one MACE event of 73 (95% CI 45–212). GLP-1 receptor agonists also reduce total mortality by 11%, with an NNT to prevent one death of 118 (95% CI 69–494), CV mortality by 12%, with an NNT to prevent one death due to CVD of 170 (95% CI 98–908), stroke by 16%, with an NNT to prevent one stroke of 211 (95% CI 136–549), and hospitalization for HF by 8%, with an NNT to prevent one admission due to HF of 300 (95% CI 181–1004). No excess of adverse events compared to placebo were observed for GLP-1 receptor agonists administration.
Take home figure
Summary of GLP-1 receptor agonists effect. CV, cardiovascular; DM, diabetes mellitus; GLP-1, glucagon-like peptide-1.
In a previous trial-data meta-analysis of four CVOTs studies comparing GLP-1 receptor agonists to placebo in 33 457 diabetic patients, Bethel et al.,11 reported a significant 10% reduction of MACE, 13% reduction of CV mortality, and a 12% reduction of total mortality but were unable to show a statistically significant effect on stroke, MI, and hospitalization for HF, although a favourable trend was observed. In fact, among the four analysed studies, only two (LEADER and SUSTAIN-6) reported a significant reduction of MACE, although SUSTAIN-6 was designed for non-inferiority, whereas no study showed a significant reduction of stroke or admission for HF, and only the LEADER trial3 reported a borderline significant reduction of MI. Besides, no previous studies investigated whether the effects of GLP-1 receptor agonists are similar in DM patients with and without established CVD. Yet, recent ESC/EASD guidelines17 strongly recommend use of GLP-1 receptor agonists or gliflozins as first line classes of drug in naïve patients or in addition to metformin in DM patients at high/very high CV risk but without established CVD, assuming a favourable protective effect of these classes of drugs at earlier stages of the CVD in diabetic patients. Quite consistent and supportive of this new perspective and recommendation of guidelines, our interaction analysis, collecting all subgroups of DM patients without established CVD enrolled in CVOT studies, demonstrate that similar favourable effects of GLP-1 receptor agonists are observed in patients with and without established CVD.
At variance with previous analysis11 and due to the much larger number of patients included, we demonstrated a significant reduction of stroke and confirmed a trend for a reduction of MI (reaching statistical significance when the same statistical model of that previous meta-analysis was used; see Supplementary material online) that lend support to the hypothesized antiatherogenic effects of these drugs and, a small but significant reduction of hospital admission for HF. Although these observations are consistent with the observed direct and indirect effects of GLP-1 receptor agonists on conventional CV risk factors,22–27 mechanisms of the cardioprotective effects of GLP-1 receptor agonists can only be assessed in mechanistic studies. Our analysis also confirmed the safety of GLP-1 receptor agonists, showing no differences, compared to placebo, for the incidence of severe hypoglycaemia, pancreatitis, and pancreatic cancer, with significant heterogeneity among trials only for hypoglycaemia. We did not further investigate thyroid C cell cancer, due to no-events in Harmony Outcomes, REWIND, and PIONEER 6 trials, and, therefore, no-new information could be provided compared to the previous analysis.11
Statistical heterogeneity among trials was found moderate for the three-point MACE. EXSCEL, ELIXA, and PIONEER 6 trials did not demonstrate a significant superiority of study drug compared to placebo. While the EXSCEL and PIONEER six trials showed a trend [almost significant in EXSCEL for the three-point MACE (95% CI 0.83–1.00; P = 0.06)], the only trial showing a neutral effect was ELIXA. This could be explained by both use of a shorter-acting GLP-1 receptor agonist (lixisenatide) and by the characteristics of enrolled population. In fact, ELIXA enrolled patients within 6 months from an acute coronary syndrome, at variance with all other studies including chronic coronary artery disease patients and/or patients without CVD. This resulted in a selection of higher risk patients [as reflected by the large number of events observed (400 vs. 393)] who were followed up for only 2.1 years. In the EXSCEL trial,7 the level of discontinuation of study drug was the highest among all GLP-1 CVOTs (43%; Table 2), potentially blunting the effect of exenatide, whereas the PIONEER 6 study,10 that enrolled the smallest number of patients, reported a non-significant 21% reduction of the three-point MACE in patients treated with semaglutide. However, although we collected CVOTs testing drugs that share a common mechanism of action, different GLP-1 receptor agonists do not have similar pharmacokinetics effects and glucose-lowering efficacy12–15 and, therefore, the current analysis is not intended to investigate differences in the effects on CV outcomes among GLP-1 receptor agonists that can only be assessed in head-to-head comparative studies.
Limitations
As in previous studies, the current is a meta-analysis of trial data, and we acknowledge the superiority of patient-level meta-analysis. Use of aggregate data limits the possibility to investigate subgroups of patients or to fully understand the implications of any missing data. Our findings are also limited by the relatively short follow-up of the included CVOT, although REWIND study9 has a median follow-up of 5.4 years.
We acknowledge that HRs for MI and stroke of the SUSTAIN-6 trial5 were obtained from previously published meta-analysis,11 as they were not reported in the original study. Moreover, due to the small number of studies included in this meta-analysis, no attempt was made to formally evaluate potential publication bias. Finally, this meta-analysis was not prospectively registered in PROSPERO.
Conclusions
Glucagon-like peptide-1 receptor agonists significantly reduce the three-point MACE (including CV death, fatal and non-fatal MI, and fatal and non-fatal stroke) in DM patients with and without established CVD. They also significantly reduce total and CV mortality, stroke, and hospitalization for HF, with a trend for reduction of MI, with no excess of serious adverse events compared to placebo. These findings are consistent and supportive of ESC/EASD Guidelines17 recommending GLP-1 receptor agonists (and gliflozins) in Type 2 DM patients with or at high/very high risk of CVD.
Acknowledgements
Dr Andrea Lo Vecchio (MD, PhD) was involved as expert medical librarian in the revision of search terms used for the present meta-analysis. Dr Lo Vecchio is certified by the Italian Institute of Health as expert in research, evaluation, and grading of scientific literature.
Conflict of interest: none declared.
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Author notes
Fabio Marsico and Stefania Paolillo contributed equally to the study and are considered as first authors.
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.
Topic:
- cardiovascular diseases
- heart disease risk factors
- cerebrovascular accident
- ischemic stroke
- heart failure
- diabetes mellitus, type 2
- mortality
- glucagon-like peptide 1
- cardiovascular event
- glucagon-like peptide-1 agonists
Supplementary data
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