Cardiovascular Outcomes and Safety of GLP-1 Receptor Agonists in Elderly Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis

Introduction

Type 2 diabetes mellitus (T2DM) is a chronic, progressive metabolic disorder with multiple pathogenic determinants. Aging is a risk factor for T2DM development. According to the latest International Diabetes Federation (IDF) projections, the prevalence will peak at 24.79% in individuals aged 75–79 years and reach 23.72% in those aged ≥65 years by 2050.¹ Elderly patients with T2DM are characterised by a higher baseline cardiovascular (CV) risk and increased susceptibility to treatment-related adverse events (AEs).^2,3 Consequently, the selection of antidiabetic drugs in elderly patients necessitates careful consideration due to their unique safety concerns and requirements.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a pharmacologic class of peptide-based, glucose-lowering agents.⁴ These agents have demonstrated significant improvements in glycemic control and weight reduction.^5–7 Additionally, several large randomized controlled trials (RCTs) and meta-analyses have reported efficacy of GLP-1 RAs in preventing CV events in patients with T2DM.^8–11 Accordingly, the American Diabetes Association guidelines recommend the initiation of a GLP-1 RA among patients with high cardiovascular risk or patients with established atherosclerotic cardiovascular disease.¹² Despite these benefits of GLP-1 RAs, it is crucial to recognize the occurrence of AEs, especially gastrointestinal - related AEs. Several studies have reported GLP-1 RAs significantly increased the incidence of gastrointestinal AEs compared with placebo or conventional treatment.^13,14

Evidence supporting the use of GLP-1 RAs in elderly patients remains limited. Age-related pharmacokinetic and pharmacodynamic alternations markedly impact drug absorption, distribution, metabolism and elimination, underscoring the need for prudent medication prescribing in elderly patients.¹⁵ Hence, this meta-analysis aimed to assess cardiovascular outcomes with GLP-1 RA initiation relative to placebo and evaluate the safety profile of these agents in elderly patients.

Methods

This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered with PROSPERO (CRD42024582164).

Search Strategy

PubMed, Embase and Web of Science were searched for randomized controlled trials (RCTs) published up to January 2024. Search terms included “glucagon-like peptide-1 receptor agonists”, “lixisenatide”, “liraglutide”, “semaglutide”, “exenatide”, “efpeglenatide”, “elderly”, “old”, “aged”, “advanced age” and “type 2 diabetes”. Only English-language studies were considered.

Inclusion Criteria

Eligible studies were RCTs evaluating GLP-1 RAs in patients with T2DM aged ≥65 years. Interventions included GLP-1 RA monotherapy, with placebo or another comparator as the control.

Exclusion Criteria

Studies were excluded if they were duplicate publications, involved non-T2DM patients (eg., type 1 diabetes), were protocols, abstracts, reviews, animal studies, or had methodological flaws, such as mismatched interventions or incomplete data.

Quality Assessment and Data Extraction

Two authors (X.C. and X.W.) independently screened studies and extracted data, disagreements were resolved with a third reviewer (W.G). Extracted CV outcomes included MACE, CV death, non-fatal stroke and non-fatal myocardial infarction (MI). Safety outcomes included gastrointestinal adverse events (eg., diarrhea, nausea, vomiting).

Risk of bias was assessed independently by two reviewers (X.C. and X.W.) using the Cochrane Collaboration’s tool, covering seven domains: (1) random sequence generation, (2) allocation concealment, (3) blinding of participants and personnel, (4) blinding of outcome assessment, (5) incomplete outcome data, (6) selective reporting and (7) other bias. Disagreements were resolved by consensus with W.G. Inter-study heterogeneity was quantified using the I² statistic, with thresholds of ≤25% (low), 26–50% (moderate) and >50% (high). Subgroup interactions were tested using heterogeneity analysis, with p < 0.05 considered significant.

Statistical Analysis

All analyses were conducted using a random-effects model. Publication bias was assessed with funnel plots. Statistical analyses were performed using Review Manager (version 5.4.1).

Results

A total of 2,425 records were identified, of which 544 were duplicates. After screening titles and abstracts, 1,854 studies were excluded. Ultimately, five full-text articles (reporting six independent RCTs, including two from Yabe et al, 2022) comprising 8,889 patients were included. All studies were assessed as having a low risk of bias (Figure 1). The study selection process is illustrated in Figure 2.

Figure 1 Quality assessment (Cochrane risk of bias tool) for included randomized controlled trials.

Figure 2 Flow diagram for study selection.

The characteristics of the five included studies are presented in Table 1. All included studies were large RCTs designed for the general T2DM population, and all of them reported separate data for the subgroup of patients aged ≥65 years. Semaglutide was investigated in three studies (n=2,165),^16–18 liraglutide in one (n=836)¹⁹ and albiglutide in one (n=5,888)²⁰ of these, two studies reported results for patients ≥ 75 years.^19,20

Table 1 Characteristics of Included Studies

CV Outcomes

GLP-1 RAs significantly reduced the risk of MACE by 21% compared with placebo (RR 0.79, 95% CI 0.70–0.90; p = 0.0003) and the risk of non-fatal MI by 25% (RR 0.75, 95% CI 0.62–0.91; p = 0.003). No heterogeneity was observed for either outcome (I² = 0%; Figure 3). In contrast, no significant differences were observed for CV death (RR 0.86, 95% CI 0.69–1.07; p = 0.17) or non-fatal stroke (RR 0.91, 95% CI 0.70–1.18; p = 0.49), with I² = 0% for both endpoints (I²=0%; Figure 3).

Figure 3 Forest plots of cardiovascular outcomes included in meta-analysis. *patients included aged ≥75 years; (A) Major adverse cardiovascular events; (B) Cardiovascular death; (C) non-fatal myocardial infarction; (D) non-fatal stroke.

Safety Outcomes

There was no significant difference in the incidence of severe hypoglycemia between GLP-1 RAs and placebo (RR 0.65, 95% CI 0.41–1.01; p = 0.06; I² = 0%; Figure 4). However, GLP-1 RAs were associated with a higher risk of diarrhea (RR 2.33, 95% CI 1.35–4.01; p = 0.002) and nausea (RR 2.94, 95% CI 1.66–5.21; p = 0.0002). The risk of vomiting was not significantly different, though it approached statistical significance (RR 1.67, 95% CI 1.00–2.81, p = 0.05).

Figure 4 Forest plots of safety outcomes included in meta-analysis. *patients included aged ≥75 years; (A) Hypoglycemia; (B) Diarrhea; (C) Nausea; (D) Vomiting.

Discussion

Incretin based therapies, such as the GLP-1 RAs, represent a major advancement in T2DM treatment. In the present meta-analysis, we analyzed 6 randomized control trials, including 8,889 participants. The analysis was designed to compare the cardiovascular outcomes and safety of GLP-1 RAs in older adults living with diabetes.

Compared to placebo, GLP-1 RAs significantly reduced the risk of MACE and non-fatal MI, confirming the benefit of GLP-1 RAs on cardiovascular outcomes in elderly patients with T2DM. These findings align with a recent network meta-analysis by Lin et al, which reported greater reductions in MACE among patients aged >65years.²¹ GLP-1 RAs and their cardioprotective effects have been a topic of interest ever since their introduction in 2005.⁸ This effect is attributed to its potential systematic anti-inflammatory properties, with its clinical significance deemed to extend far beyond mere hypoglycemia efficacy. GLP-1 RAs lower inflammatory biomarkers that are closely associated with CV risk, including interleukin-6, tumor necrosis factor-α, and c-reactive protein.²²

However, in this meta-analysis, we found no significant effect of GLP-1 RAs on non-fatal stroke or CV death. This contrasts with some prior reports suggesting benefit in these outcomes. A network meta-analysis conducted by Fei et al, GLP-1 RA drugs showed a significant reduction in the incidence of stroke²³ Another meta-analysis including 87,000 patients found that GLP-1 RA was associated with a low risk of CV death.²⁴ Notably, no dedicated subgroup analysis was performed for the elderly population in either study. Therefore, more high-quality studies specifically targeting elderly patients with diabetes are warranted.

With regard to safety, hypoglycemia is one of the most adverse events (AEs) related to glucose-lowering medications in patients with diabetes. It is a leading cause of hospital admissions and emergency department visits in older adults aged 65 years and older.^25,26 The risk of hypoglycemia is a critical consideration in the management of T2DM. In our analysis, GLP-1 RAs did not significantly increase the risk of severe hypoglycemia compared with controls, supporting their safety profile in this regard.

Meanwhile, important gastrointestinal adverse events (nausea, vomiting, and diarrhea) warrant mention. These typically occur within the first month of treatment and often diminish thereafter.²⁷ Indeed, the side effects were the reasons most commonly reported for discontinuing GLP-1 RAs, which occurs in about 5% of patients.²⁸ Gastrointestinal AEs are thought to result from delayed gastric emptying and activation of neural pathways.²⁹ Our analysis demonstrated that GLP-1 RAs significantly increased the risk of diarrhea and nausea, consistent with previous studies.^30–32 Regarding vomiting, our meta-analysis revealed a trend toward a higher incidence in the GLP-1 RAs group compared with controls. However, the magnitude of risk from vomiting is smaller than that observed for nausea and diarrhea. Thus, GLP-1 RAs may have a weak association with vomiting symptoms in elderly patients with T2DM.

This study has several limitations. First, only a small number of eligible trials met the inclusion criteria. Although most landmark RCTs do not exclude elderly patients, efficacy and safety outcomes for this subgroup are rarely reported, resulting in only five studies being included out of 2,425 screened. Second, all included data were derived from post hoc analyses, which may not fully reflect the baseline characteristics or prespecified outcomes of the original trials. Therefore, a large randomized, controlled, clinically comparative trials focusing on elderly populations are warranted.

Conclusion

In conclusion, GLP-1 RAs have demonstrated additional cardiovascular benefits among elderly patients with T2DM. However, gastrointestinal AEs remain a concern and should be closely monitored to guide individualized treatment decisions.