Can glucagon-like peptide-1 receptor agonists effectively prevent ischemic stroke? Let’s explore this topic through today’s article:
Given the health burden of cardiovascular disease (CVD) complications on patients with type 2 diabetes (T2DM), there is increasing attention to the co-management of T2DM and CVD. Glycemic control remains the main basis for the management of T2DM, and although the importance of intensive glycemic control in preventing microvascular complications and cardiovascular disease in patients with type 1 diabetes has been well established [ 1 , 2 ], its role in reducing cardiovascular risk in patients with T2DM has not been clear [ 3 , 4 , 5 ]. Therefore, the most effective way to prevent macrovascular complications seems to be to reduce multiple risk factors (smoking cessation, abstinence from alcohol, healthy diet, maintenance of exercise, active blood sugar and blood pressure control, treatment of dyslipidemia, etc.).
To this end, today's diabetes treatment guidelines have been updated to provide recommendations on how to prevent and manage CVD [ 6 ], coupled with increasing pressure from health regulatory agencies that antidiabetic treatments demonstrate cardiovascular safety and benefit, particularly with respect to major cardiovascular events such as cardiovascular mortality, nonfatal myocardial infarction, and stroke [ 7 , 8 ]. In accordance with the requirements of these regulatory agencies, several cardiovascular event assessment trials (CVOTs) have been completed, and the results of the trials showed a low CVD risk with certain antidiabetic treatments [9, 10, 11, 12].
A significant reduction in the incidence of major cardiovascular events (MACE) was observed in T2DM patients treated with glucagon-like peptide 1 receptor agonists (GLP-1RA), indicating that certain classes of drugs may have a cardioprotective effect on patients [13, 14]. However, the improvement of cardiovascular events by GLP-1RA appears to be more significant in patients with T2DM and previous CVD compared with patients with CV risk factors alone [15, 16, 17, 18]. In particular, the use of GLP-1RAs, including lixisenatide, exenatide, liraglutide, semaglutide, albiglutide and dulaglutide, can significantly reduce the risk of MACE in T2DM patients with a history of CVD by 14%, while the risk in patients without a history of CVD is only reduced by 6% [17].
In a meta-analysis of CVOT of GLP-1RAs [19], use of GLP-1RAs in patients with T2DM was associated with reduced incidence of nonfatal stroke, all strokes, and MACE, and these drugs were associated with reduced cardiovascular and all-cause mortality. Furthermore, secondary prevention with GLP-1RA was only associated with a reduction in MACE and did not affect stroke recurrence.
These results were consistent for all stroke and fatal events in patients with T2DM treated with GLP-1 RAs. In most randomized controlled trials (RCTs), the benefit is greater for stroke events than for other cardiovascular events. In addition to reducing MACE, GLP-1RAs were well tolerated and had good compliance, with few major adverse events or hypoglycemic events. These benefits of primary stroke prevention can be attributed to reductions in HbA1c, body weight, LDL cholesterol values, and systolic blood pressure. GLP-1RA can also improve endothelial cell and platelet function, provide neuroprotective benefits and reduce atherosclerosis, vasoconstriction and vascular inflammatory responses [17].
According to the latest treatment guidelines from the American Stroke Association (ASA)[20], once the cause of a stroke or transient ischaemic attack (TIA) is determined, specific prevention strategies can be developed to reduce the risk of additional strokes. Because having a stroke or TIA increases the risk of other strokes in the future. As prevention strategies improve, research notes that stroke recurrence rates have decreased from 8.7 percent in the 1960s to 5.0 percent in the 2000s, but many risk factors for a second stroke remain poorly managed among stroke survivors, according to a news release from the American Heart Association.
Recent clinical trials mentioned in this guideline show that at least 1 of 3 classes of antidiabetic drugs can reduce the risk of MACE in patients with T2DM and established atherosclerotic vascular disease (ASCVD) (including ischemic stroke or high risk): thiazolidinediones, GLP-1 RA, and sodium-glucose cotransporter 2 inhibitor (SGL-2i). Unlike data on thiazolidinediones and some GLP-1RAs, the Cardiovascular Event Assessment Trial of SGLT-2i did not show an effect on stroke, but rather on cardiovascular death, myocardial infarction, and heart failure. In patients with established ASCVD, including ischemic stroke, when prevention of further vascular events should be a priority, GLP-1 RA therapy should be added to metformin, regardless of the prevailing HbA1c value.
While it is currently not proven that good control of metabolic syndrome reduces the risk of stroke, some antidiabetic drugs with vascular benefits, such as GLP-1RAs, have been shown to reduce these effects when added to routine care, both in primary prevention in patients with T2DM and in patients at high vascular risk or already suffering from ASCVD.
