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Cardiovascular Outcomes Associated With Glucose-Lowering Medications in Patients With Type 2 Diabetes
TAKE-HOME MESSAGE
- In patients with type 2 diabetes and low cardiovascular risk, the effects of glucose-lowering medications on cardiovascular outcomes are unclear. GRADE evaluated the cardiovascular outcomes of insulin glargine, glimepiride, liraglutide, and sitagliptin, in addition to metformin. This 5-year study found no significant differences in the incidence of major adverse cardiovascular events among the treatment groups. However, compared with other treatments, liraglutide was associated with lower risks of major adverse cardiovascular events, coronary revascularization, and hospitalization for heart failure.
- This study suggests that, compared with other glucose-lowering medications, liraglutide may reduce the risk of cardiovascular events in patients with type 2 diabetes at relatively low cardiovascular risk.
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
Cardiovascular disease is a major cause of morbidity and mortality in patients with type 2 diabetes. The effects of glucose-lowering medications on cardiovascular outcomes in individuals with type 2 diabetes and low cardiovascular risk are unclear. We investigated cardiovascular outcomes by treatment group in participants randomly assigned to insulin glargine, glimepiride, liraglutide, or sitagliptin, added to baseline metformin, in GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study).
METHODS
A total of 5047 participants with a mean±SD age of 57.2±10.0 years, type 2 diabetes duration of 4.0±2.7 years, and low baseline prevalence of cardiovascular disease (myocardial infarction, 5.1%; cerebrovascular accident, 2.0%) were followed for a median of 5 years. Prespecified outcomes included between-group time-to-first event analyses of MACE-3 (composite of major adverse cardiovascular events: cardiovascular death, myocardial infarction, and stroke), MACE-4 (MACE-3+unstable angina requiring hospitalization or revascularization), MACE-5 (MACE-4+coronary revascularization), MACE-6 (MACE-5+hospitalization for heart failure), and the individual components. MACE outcomes and hospitalization for heart failure in the liraglutide-treated group were compared with the other groups combined using Cox proportional hazards models. MACE-6 was also analyzed as recurrent events using a proportional rate model to compare all treatment groups.
RESULTS
We observed no statistically significant differences in the cumulative incidence of first MACE-3, MACE-4, MACE-5, or MACE-6, or their individual components, by randomized treatment group. However, when compared with the other treatment groups combined, the liraglutide-treated group had a significantly lower risk of MACE-5 (adjusted hazard ratio, 0.70 [95% CI, 0.54-0.91]; P=0.021), MACE-6 (adjusted hazard ratio, 0.70 [95% CI, 0.55-0.90]; P=0.021), and hospitalization for heart failure (adjusted hazard ratio, 0.49 [95% CI, 0.28-0.86]; P=0.022). Compared with the liraglutide group, significantly higher rates of recurrent MACE-6 events occurred in the groups treated with glimepiride (rate ratio, 1.61 [95% CI, 1.13-2.29]) or sitagliptin (rate ratio 1.75; [95% CI, 1.24-2.48]).
CONCLUSIONS
This comparative effectiveness study of a contemporary cohort of adults with type 2 diabetes, largely without established cardiovascular disease, suggests that liraglutide treatment may reduce the risk of cardiovascular events in patients at relatively low risk compared with other commonly used glucose-lowering medications.
Additional Info
Disclosure statements are available on the authors' profiles:
Cardiovascular Outcomes in GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study)
Circulation 2024 Feb 12;[EPub Ahead of Print], JB Green, BM Everett, A Ghosh, N Younes, H Krause-Steinrauf, J Barzilay, C Desouza, SE Inzucchi, Y Pokharel, D Schade, A Scrymgeour, MH Tan, KM Utzschneider, S MudaliarFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
A new publication in Circulation reports detailed cardiovascular (CV) outcomes from the GRADE study. GRADE compared the addition of four common glucose-lowering medication classes, the sulfonylurea glimepridie, the DPP-4 inhibitor sitagliptin, the GLP-1 receptor agonist liraglutide, and U-100 insulin glargine, with metformin in 5047 people with type 2 diabetes with HbA1c levels between 6.8% to 8.5% and very low rates of CV disease (<8.0%) and chronic kidney disease (<16% with albuminuria) at baseline. Given the low baseline risk, GRADE was not expected to have power to detect differences in CV outcomes. Nonetheless, all CV events were prospectively captured adjudicated during the trial. GRADE previously reported a benefit of liraglutide compared with the other three medications combined in a broad CV outcome composed of all adjudicated CV events.1
The current paper takes a deeper dive into detailed CV endpoints and recurrent endpoints. Increasing the specificity of the earlier finding, the authors report a benefit of liraglutide compared with the other three medications combined on a composite outcome of time to first MI, stroke, CV death, unstable angina requiring hospitalization, and coronary revascularization (together termed MACE-5), MACE-5 plus hospitalization for heart failure (MACE-6), and hospitalization for heart failure alone. In addition, the authors performed a current (total) events analysis, and found differences in between-drug comparisons adjusted for multiple testing, with glimepiride and sitagliptin-treated groups having a higher risk ratio of MACE-6 compared with liraglutide (1.61 and 1.75, respectively). The total number of MACE-6 events per group was 180 for sitagliptin group, 164 for glimepiride, 153 for glargine, and 102 for liraglutide. These findings add to the evidence regarding CV benefit of a GLP-1 receptor agonist compared with other medication classes in people with type 2 diabetes.
Reference