GLP-1 Agonists: Beneficial in Low-Risk Patients?


Do low-risk CVD patients with T2DM experience the same significantly lower all-cause and CV mortality seen in high-risk patients?

GLP-1 agonists are associated with decreased all-cause mortality compared to standard therapy in a broad range of patients with T2DM, according to a study published online in Diabetes & Metabolism.1

“Our findings suggest that GLP1a treatment, compared to conventional antidiabetic therapy in a real-world setting, may confer additional mortality benefit in patients with diabetes irrespective of their baseline CVD risk. This benefit seems to be consistent with either liraglutide or exenatide, sustained over the observation period and robust to adjustments with established risk factors,” wrote first author Konstantinos Toulis, PhD, of the University of Birmingham (Birmingham, UK) and General Military Hospital, Thessaloniki, Greece, and colleagues.

The study is the first to show a mortality benefit for GLP-1 agonists in patients at low risk for cardiovascular disease (CVD).

Past studies have found beneficial effects of GLP1 agonists on weight, blood pressure, and endothelial function, pointing to cardiovascular benefits for these drugs. The LEADER trial found that patients with high CVD risk and T2DM who were treated with liraglutide had significantly lower all-cause and CV mortality, compared to placebo. Incident CVD events were also lower with liraglutide, though the results did not reach statistical significance.2

However, the study did not include patients at low risk for CVD, raising the question whether the results apply to a broader range of people with T2DM. Questions also remained about whether the benefits are a class effect and apply outside of clinical trials.

To address these questions, researchers did a population-based retrospective cohort study using data from the Health Improvement Network database, which houses records from about 12 million patients seen at over 640 general practitioners in the UK. The study included 24,886 adults with T2DM who received antihyperglycemics between January 2008 and September 2015.

Researchers compared all-cause mortality (primary outcome) for patients on GLP-1 agonists (n=8345) vs those on standard antihyperglyemics excluding GLP-1 agonists (n=16,541). They also evaluated a subset of low-risk patients without prior history of CVD (n=19,689). In the low-risk subset, researchers assessed a composite measure of CVD, which included myocardial infarction, ischemic heart disease, stroke, TIA, and heart failure (secondary outcome).

Patients were matched by age, gender, body mass index, T2DM duration, and smoking status. Results were adjusted for potential confounders, including HbA1c, systolic blood pressure, antilipidemics, insulin, estimated glomerular filtration rate, hypertension, social deprivation, and comorbidities.

Overall, the mean age was 57.6 years, with a mean BMI of 37.1 kg/m2, mean diabetes duration of 8.7 years, and mean HbA1c of 7.8%. Among those on GLP-1 agonists, 55% were on liraglutide, 42% on exenatide 42%, and 3% on lisixenatide. The median follow-up was 3.2 years, during which time 1146 patients died.

Key Results:

• Significantly lower all-cause mortality with GLP-1 agonists vs standard therapy (adjusted incident rate ratio [aIRR] 0.64, 95% CI: 0.56–0.74, P<0.0001)

♦ Persistent effect in the elderly and across baseline HbA1c categories

• Low risk group:

♦ Significantly lower all-cause mortality with GLP-1 agonists vs standard therapy (aIRR: 0.64, 95% CI: 0.53–0.76, P=0.0001)

♦ No significant difference in incident CVD (aIRR: 0.93, 95% CI: 0.83–1.12, P=0.616)

• Specific agents:

♦ Liraglutide: Significantly lower all-cause mortality vs standard therapy (aIRR: 0.56, 95% CI: 0.46–0.67, P<0.0001)

♦ Exenatide: Significantly lower all-cause mortality vs standard therapy (aIRR: 0.72, 95% CI: 0.61–0.85, P<0.0001)

♦ Lisixenatide: Number too few to assess

The authors noted that these results confirm and extend the findings from the LEADER trial, by suggesting that the CV benefits of GLP-1 agonists may apply to low risk patients. Results also point to the CV benefits of GLP-1 agonists as a class effect.

In addition, the persistent findings in elderly patients and across baseline HbA1c levels may imply that GLP-1 agonists could benefit older patients and those with adequate baseline glycemic control.

A clinical trial is needed to confirm the results and evaluate other factors that may have an impact on them, such as lipid-lowering drugs and antihypertensives.

“In case an incremental mortality benefit is confirmed in subsequent studies, GLP1a treatment might then be considered a reasonable option for a broad range of patients with T2DM,” the authors concluded.

Take-home Points

• Retrospective cohort study suggests GLP-1 agonists are associated with decreased all-cause mortality among a broad range of patients with T2DM in the real-world setting.

• GLP-1 agonists were linked to decreased all-cause mortality in patients at low risk for CVD.

• Results extended to the elderly, across baseline HbA1c categories, and to liraglutide and exenatide.

• A clinical trial is needed to confirm the results. 

The study was partially funded by the University Hospital of Birmingham, NHS Foundation Trust, UK.

One or more authors reports advisory board membership, honoraria, institutional financial support, consulting fees, partial funding for one or more of the following:  Astra Zeneca, Boehringer Ingelheim, MSD, Takeda, Novo Nordisk, Eli Lilly, Pfizer, Eli Lilly, NIHR through the Collaborations for Leadership in Applied Health Research and Care for West Midlands (CLAHRCWM).


1. Toulis KA, et al. All-cause mortality in patients with diabetes under glucagon-like peptide-1 agonists: a population-based, open cohort study. Diabetes Metab. 2017 Mar 18.

2. Marso SP, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311-322.

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