Cardiovascular outcomes, heart failure and mortality in type 2 diabetic patients treated with glucagon‐like peptide 1 receptor agonists (GLP‐1 RAs): A systematic review and meta‐analysis of observational cohort studies

Abstract

Background Cardiovascular outcomes trials (CVOTs) have assessed the effects of glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) on major adverse cardiovascular events (MACE) and mortality in high cardiovascular (CV) risk populations. Observational research can provide complementary evidence about these effects in unselected populations. Aim To systematically review retrospective observational cohort studies conducted in electronic healthcare databases (EHDs) assessing GLP‐1 RAs´ effects on MACE and/or hospitalisation for heart failure (HHF) and/or all‐cause mortality in Type 2 diabetes mellitus (T2DM) patients. Methods We systematically searched studies meeting inclusion criteria, compared design, methods and population characteristics, assessed risk for bias and did a meta‐analysis (MA) using a random‐effects model to calculate overall hazard ratios (HRs) and 95% CI (confidence intervals). Results Sixteen studies included 285,436 T2DM patients exposed to GLP‐1 RAs (exenatide bid, liraglutide, lixisenatide, long‐acting exenatide), n ranged from 219 to 160,803 patients. Comparators included: no exposure, other antidiabetic medications (OADs), combined OADs, canagliflozin or multiple comparators. Ten studies estimated all‐cause mortality, hazard ratios (HRs) ranged from 0.17 (95% CI 0.02‐1.22) to 1.29 (95% CI 0.54‐3.13). Thirteen studies assessed cardiovascular events and/or MACE; HRs ranged from 0.27 (95% CI 0.14‐0.53) to 1.11 (95% CI 0.99‐1.24). Eight studies assessed HHF, HRs ranged from 0.12 (95% CI 0.02‐0.66) to 1.64 (95% CI 1.28‐2.13). Excluding two studies because of temporal bias, we obtained pooled estimates for all‐cause mortality: HR 0.63 (0.44‐0.89), CV outcomes HR 0.84 (0.75‐0.94) and HHF; HR 0.94 (0.78‐1.14), (high between‐study variability: I2 = 83.35%; I2 = 70.3%; and I2 = 90.1%, respectively). Conclusion Pooled results of EHDs’ studies assessing GLP‐1 RAs effects favoured GLP‐1 RAs for all‐cause mortality and MACE while were neutral for HHF. Results should be interpreted cautiously because of studies’ substantial heterogeneity and limitations of observational research.

The Impact of Glucagon-Like Peptide-1 Receptor Agonist on the Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus: A Meta-Analysis and Systematic Review

“…Individual risk factors had been investigated as well. A systematic review and meta-analysis showed that GLP-1 RA reduced HHF significantly with no heterogenicity between the studies [ 3 ]. However, one observational study found that GLP-1 RA reduces the risk of HHF [ 30 ] and another study concluded the opposite [ 48 ].…”

“…Since the approval of exenatide, the first glucagon-like peptide 1 receptor agonist (GLP-1 RA) in 2005 [ 1 ], researchers have been interested in the cardioprotective effect of the new anti-hyperglycemic drugs. The GLP-1 RA activates GLP-1 receptors on the beta cells leading to increased insulin secretion and decreased inappropriate glucose-dependent glucagon secretion [ 2 , 3 ]. Additionally, GLP-1 RA has a potential effect on reducing body weight by reducing gastric emptying and increasing satiety [ 4 ].…”

“…Consequently, GLP-1 RA has become an attractive choice for the treatment of type 2 diabetes mellitus (T2DM) due to the effective reduction of glycosylated hemoglobin (HbA1c) with a lower risk of hypoglycemia and increased weight reduction [5]. Therefore, most of the clinical trials had been directed toward non-inferiority studies [3,6] to meet the US FDA-issued guidance and the European Medical Agency recommendations that focused on the cardiovascular (CV) [7] safety of the novel drugs [8][9][10].…”

Pharmacological treatment of type 2 diabetes in elderly patients with heart failure: randomized trials and beyond

“…The effect of GLP-1RA treatment on CV outcomes has been investigated in several observational studies, comparing GLP-1RAs to placebo or to other antidiabetic drugs [68,69]. GLP-1RAs have been compared to placebo or to other antidiabetic drugs, either DPP-4i or SGLT-2i regarding MACE and HF incidence in elderly patients (Table 1).…”

Insulin–glucagon‐like peptide‐1 receptor agonist relay and glucagon‐like peptide‐1 receptor agonist first regimens in individuals with type 2 diabetes: A randomized, open‐label trial study

“…Emerging evidence suggests that treatment with glucagon‐like peptide‐1 (GLP‐1) receptor agonists (RA) has beneficial effects on cardiovascular and mortality outcomes in patients with type 2 diabetes 1 , 2 . Recent guidelines recommend starting GLP‐1 RA among patients with type 2 diabetes who have established atherosclerotic cardiovascular diseases as part of glycemic management 3 .…”