Glucagon-Like Peptide-1 Receptor Agonists May Lower Cardiovascular Risk in Type 2 Diabetes

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Glucagon-like peptide-1 receptor agonist therapy was associated with lower risk for acute MI, stroke, and all-cause mortality.

Glucagon-like peptide-1 receptor agonist (GLP-1 RA) is an injectable diabetes medication that may lower the risk for death and cardiovascular (CV) events in patients with type 2 diabetes mellitus (T2DM), according to a study published in Diabetes, Obesity and Metabolism.1

Although GLP-1 RA therapy is used to lower blood glucose in T2DM, it also has other beneficial effects, such as decreasing free fatty acid and triglyceride levels2,3 and inducing weight loss. In fact, 1 GLP-1 RA agent, liraglutide, is approved in the United States as a treatment for weight loss. GLP-1 RA therapy has also been shown to lower diastolic and systolic blood pressure and highly sensitive C-reactive protein, a marker of inflammation.4

Recent data demonstrated that GLP-1 RA therapy reduced the risk for the composite outcome of nonfatal myocardial infarction (MI), nonfatal stroke, and cardiac-related death in patients with T2DM at high risk for CV events. However, these findings were driven by reductions in CV death in 1 study and in nonfatal stroke in another study.5,6 Another study in patients with postcoronary syndrome did not show any protective effects on CV outcomes.7         

“The available studies that reported a reduction in the risk [for] CV death and nonfatal stroke were conducted using populations of high-risk CV patients, including many patients with established CV disease. Thus, we embarked on the current study to evaluate the effect of GLP-1 RA therapy on CV events and mortality in the real-world setting, using a broader range of [patients with T2DM] (low to high risk),” Kevin M. Pantalone, DO, from Cleveland Clinic in Ohio, said in an interview with Cardiology Advisor.

The researchers, led by Dr Pantalone and Robert S. Zimmerman, MD, also from Cleveland Clinic, evaluated the effect of GLP-1 RA therapy on CV outcomes in patients with T2DM with and without known CV disease, using electronic health record data. The primary outcomes included the individual components and composite of stroke, acute MI (AMI), and all-cause mortality.1

Of 105,862 patients with T2DM, 8% had been exposed to GLP-1 RA therapy. Compared with periods off GLP-1 RA therapy, periods on GLP-1 RA therapy were associated with a significantly lower risk for stroke (hazard ratio [HR], 0.82; 95% CI, 0.74-0.91; P <.001), AMI (HR, 0.80; 95% CI, 0.65-0.99; P =.045), and all-cause mortality (HR, 0.48; 95% CI, 0.41-0.57; P <.001). Rates of the composite outcome were also reduced with GLP-1 RA use (HR, 0.82; 95% CI, 0.74-0.91; P <.002).1

When patients with and without CV disease were considered separately, GLP-1 RA therapy also correlated with significantly lower rates of all-cause mortality, stroke, and the composite outcome. No significant effect on AMI was observed with GLP-1 RA use in either subgroup.1

Although these results suggest that GLP-1 RA therapy may reduce the risk for CV outcomes, Dr Pantalone noted that this study has important limitations.

“It is difficult to know how long the patients in our study may have had T2DM, or what medications they may have been exposed to (and for how long), prior to them entering our health system,” Dr Pantalone said in an interview with Cardiology Advisor. “Conducting additional studies using an incidence cohort of patients (ie, those with a known date of T2DM diagnosis/duration of disease) would be helpful in determining if lower-risk CV patients with T2DM may also benefit from a CV standpoint from GLP-1 RA therapy.”

This study was funded by Novo Nordisk. Dr Pantalone reports financial relationships with Novo Nordisk, Merck, Sanofi, Eli Lilly, AstraZeneca, and Bristol-Myers Squibb. Dr Zimmerman reports funding from Novo Nordisk, Merck, and Johnson & Johnson. The other authors also report financial relationships with various.

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1. Zimmerman RS, Hobbs TM, Wells BJ, et al. Association of glucagon-like peptide-1 receptor agonist (GLP-1 RA) use and rates of acute myocardial infarction, stroke, and overall mortality in patients with type 2 diabetes mellitus in a large integrated health system [published online April 13, 2017]. Diabetes Obes Metab. doi:10.1111/dom.12969

2. Pi-Sunyer X, Astrup A, Fujioka K, et al. A randomized controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med. 2015;373(1):11-22. doi:10.1056/NEJMoa1411892

3. Petrie JR. The cardiovascular safety of incretin-based therapies: a review of the evidence. Cardiovasc Diabetol. 2013;12:130. doi:10.1186/1475-2840-12-130

4. Davis MJ, Bergenstal R, Bode B, et al. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial. JAMA. 2015;314(7):687-699. doi:10.1001/jama.2015.9676

5. Marso SP, Daniels GH, Brown-Frandsen K, et al; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322. doi:10.1056/NEJMoa1603827

6. Marso SP, Bain SC, Consoli A, et al; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834-1844. doi:10.1056/NEJMoa1607141.

7. Pfeffer MA, Claggett B, Diaz Ret al; ELIXA Investigators. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373(23):2247-2257. doi:10.1056/NEJMoa1509225