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Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials

https://doi.org/10.1016/S2213-8587(19)30249-9Get rights and content

Summary

Background

Glucagon-like peptide-1 (GLP-1) receptor agonists differ in their structure and duration of action and have been studied in trials of varying sizes and with different patient populations, with inconsistent effects on cardiovascular outcomes reported. We aimed to synthesise the available evidence by doing a systematic review and meta-analysis of cardiovascular outcome trials of these drugs.

Methods

We searched MEDLINE (via PubMed) and the Cochrane Central Register of Controlled Trials for eligible placebo-controlled trials reporting major adverse cardiovascular events (MACE; ie, cardiovascular death, stroke, or myocardial infarction) up to June 15, 2019. We did a meta-analysis using a random-effects model to estimate overall hazard ratios (HRs) for MACE, its components, death from any cause, hospital admission for heart failure, kidney outcomes, and key safety outcomes (severe hypoglycaemia, pancreatitis, and pancreatic cancer). We also examined MACE in several subgroups based on patient characteristics (history of cardiovascular disease, BMI, age, baseline HbA1c, and baseline estimated glomerular filtration rate), trial duration, treatment dosing interval, and structural homology.

Findings

Of 27 publications screened, seven trials, with a combined total of 56 004 participants, were included: ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide), EXSCEL (exenatide), Harmony Outcomes (albiglutide), REWIND (dulaglutide), and PIONEER 6 (oral semaglutide). Overall, GLP-1 receptor agonist treatment reduced MACE by 12% (HR 0·88, 95% CI 0·82–0·94; p<0·001). There was no statistically significant heterogeneity across the subgroups examined. HRs were 0·88 (95% CI 0·81–0·96; p=0·003) for death from cardiovascular causes, 0·84 (0·76–0·93; p<0·001) for fatal or non-fatal stroke, and 0·91 (0·84–1·00; p=0·043) for fatal or non-fatal myocardial infarction. GLP-1 receptor agonist treatment reduced all-cause mortality by 12% (0·88, 0·83–0·95; p=0·001), hospital admission for heart failure by 9% (0·91, 0·83–0·99; p=0·028), and a broad composite kidney outcome (development of new-onset macroalbuminuria, decline in estimated glomerular filtration rate [or increase in creatinine], progression to end-stage kidney disease, or death attributable to kidney causes) by 17% (0·83, 0·78–0·89; p<0·001), mainly due to a reduction in urinary albumin excretion. There was no increase in risk of severe hypoglycaemia, pancreatitis, or pancreatic cancer.

Interpretation

Treatment with GLP-1 receptor agonists has beneficial effects on cardiovascular, mortality, and kidney outcomes in patients with type 2 diabetes.

Funding

None.

Introduction

Prevention of non-fatal and fatal cardiovascular events is a key goal of the management of patients with type 2 diabetes.1, 2 In addition to blood pressure-lowering and cholesterol-lowering therapies, two of the newer classes of antihyperglycaemic drugs—sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists—have been shown to reduce cardiovascular risk.3

The GLP-1 receptor agonists decrease HbA1c by stimulating glucose-dependent insulin secretion and by reducing glucagon secretion, gastric emptying, and appetite.4, 5 GLP-1 receptor agonist treatment also leads to modest improvements in lipids and reductions in blood pressure and bodyweight, with a low risk of hypoglycaemia. However, the drugs in this class differ in their structure and duration of action and have been studied in trials of varying sizes and with different patient populations, and in individual trials the effects of these drugs on cardiovascular outcomes have not been consistent.6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16

We did a systematic review and meta-analysis of all the large, placebo-controlled, cardiovascular outcome trials of GLP-1 receptor agonists, to obtain robust estimates of the effects of this class of drugs on different cardiovascular outcomes overall and in various patient subgroups, as well as examining kidney outcomes and key safety outcomes.

Research in context

Evidence before this study

Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of glucose-lowering drugs used in the treatment of type 2 diabetes. We searched MEDLINE (via PubMed) and the Cochrane Central Register of Controlled Trials for eligible placebo-controlled trials reporting major adverse cardiovascular events (MACE; a composite of cardiovascular death, stroke, or myocardial infarction) up to June 15, 2019. Various drugs in this class with differing structures and durations of action have been studied in randomised, placebo-controlled, cardiovascular outcome trials of varying size and with different patient populations, with inconsistent effects on cardiovascular outcomes reported. Previous meta-analyses of cardiovascular outcome trials have not included some of the more recently reported major trials of drugs within the class.

Added value of this study

Our systematic review and meta-analysis includes data from seven large-scale cardiovascular outcome trials, pooling data for lixisenatide, liraglutide, injectable semaglutide, exenatide, albiglutide, dulaglutide, and oral semaglutide, making it the largest pooled study of the effect of GLP-1 receptor agonists on cardiovascular and kidney outcomes in patients with type 2 diabetes. Furthermore, compared with previous meta-analyses, it includes data for a greater number of patients without established cardiovascular disease and data for two additional drugs (dulaglutide and an oral form of semaglutide). Our results show that treatment with GLP-1 receptor agonists reduced the risk of MACE and its individual components, as well as all-cause mortality, hospital admission for heart failure, and a composite kidney outcome of development of new-onset macroalbuminuria, decline in estimated glomerular filtration rate (or increase in creatinine), progression to end-stage kidney disease, or death attributable to kidney causes. The benefit on MACE was consistent across all but one subgroup (with a suggestion of a possible lesser effect of exendin-4 based compounds), including consistent effects in subgroups defined by history of cardiovascular disease, BMI, age, baseline HbA1c, baseline estimated glomerular filtration rate, trial duration, and treatment dosing interval. The incidence of severe hypoglycaemia, pancreatitis, and pancreatic cancer did not differ between GLP-1 receptor agonist treatment and placebo.

Implications of all the available evidence

The cardioprotective effects of GLP-1 receptor agonists, as well as reductions in the risk of heart failure and worsening kidney function, represent an important treatment opportunity to reduce morbidity and mortality in patients with type 2 diabetes.

Section snippets

Search strategy and selection criteria

We aimed to identify published randomised, placebo-controlled trials testing GLP-1 receptor agonists in patients with type 2 diabetes. Both injectable and oral agents were included. We further restricted the search to trials with a primary outcome including cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. We searched MEDLINE (via PubMed) and the Cochrane Central Register of Controlled Trials for reports published up to June 15, 2019, using the following search terms:

Results

Of 27 articles screened for eligibility, seven trials with a total of 56 004 patients were included in the meta-analysis (figure 1). In order of when their primary results were reported, these were ELIXA (lixisenatide),7 LEADER (liraglutide),8, 14 SUSTAIN-6 (semaglutide),9 EXSCEL (exenatide),11 Harmony Outcomes (albiglutide),10 REWIND (dulaglutide),12, 13 and PIONEER 6 (oral semaglutide).15 The key trial and patient characteristics at baseline are presented in the table and in the appendix (pp

Discussion

Our meta-analysis includes data for 13 084 (30%) more patients, 1394 (29%) more MACE endpoint events, 1818 (95%) more kidney events, and about 56 000 more years of patient exposure than the largest previous study of this type.3, 22 The present report also includes data for 6709 (95%) more primary prevention patients (ie, with cardiovascular risk factors rather than established cardiovascular disease), an additional drug in the class (dulaglutide) with homology to human GLP-1 and a long duration

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