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FAQs for Stroke Prevention With GLP1 RAs
Frequently Asked Questions in Stroke Prevention With GLP-1 RAs in Patients With Diabetes

Released: October 25, 2024

Expiration: October 24, 2025

Jay H. Shubrook
Jay H. Shubrook, DO, FACOFP, FAAFP
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Key Takeaways
  • GLP-1 RAs should be considered to be more than just glucose-lowering or weight-reduction agents; they are also atherosclerosis-modifying therapies and reduce vascular disease risk.
  • In clinical trials in people with type 2 diabetes, GLP-1 RAs have been shown to reduce cardiovascular outcomes including stroke.
  • The American Diabetes Association recommends GLP-1 RAs be preferentially used in people with type 2 diabetes to reduce the risk of cardiovascular disease, chronic kidney disease, and stroke.

In this commentary, experts answer important clinical questions about the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for stroke prevention in patients with diabetes and address the most recent evidence supporting the use of GLP-1 RAs.

Are there any stroke prevention data in patients with prediabetes receiving GLP-1 RAs?
In the SELECT study, participants had obesity and did not have diabetes, but approximately two-thirds of those patients had prediabetes (A1C of 5.7% to 6.4%). Those who were randomized to receive semaglutide had a statistically significant 20% reduction in nonfatal stroke. In addition, in the IRIS trial, pioglitazone showed benefit in stroke prevention and a reduced risk of myocardial infarction in patients with abnormal glucose tolerance.

Should GLP-1 RAs be the first-line recommendation for all patients with diabetes instead of metformin, considering their numerous benefits?  
The American Diabetes Association recommends GLP-1 RAs be first-line therapy if there is a compelling indication, but their cost compared with metformin may limit GLP-1 RAs to first-line use only for patients with atherosclerotic cardiovascular disease or chronic kidney disease where glucose lowering is not the primary concern. In this scenario, prioritizing the reduction in adverse outcomes is more important than lowering glucose levels.

I see these medications as more than just glucose-lowering or weight-reduction agents; they are also atherosclerosis-modifying therapies. GLP-1 RAs not only are treat blood sugar but also offer the advantage of modification of vascular disease risk.

If someone is intolerant to one GLP-1 RA, is it feasible to switch to a different one or will they also have intolerance?
Yes, if someone does not tolerate one GLP-1 RA, it is worthwhile to switch to a different one. The adverse effects may differ for individuals even though the medications are in the same class. It is worth trying a different GLP-1 RA, especially for the glycemic and extraglycemic benefits.

In addition, remember to titrate GLP-1RAs slowly. There is no rush to increase the dose within 1 month. If patients still feel nauseated  on the medication, consider keeping them on the same dose for another couple of weeks or months and then gradually increase. 

When prescribing GLP-1 RA and sodium-glucose cotransporter-2 inhibitors, should the goal be to attempt to reduce the insulin dosage in patients with obesity?
First, although there are no specific studies looking at this, there appears to be data that support the additive cardiovascular and kidney benefits of using these medications together.

In terms of removing glucose-centric medications like insulin, I think reducing the insulin dose can be useful for 3 reasons. One reason is to avoid precipitating hypoglycemia when initiating these powerful glucose-lowering medications. The second reason is that reducing the insulin dosage can facilitate weight loss without compromising glycemic control. Finally, patients are often excited about the possibility of reducing or stopping insulin, which improves patient engagement.

Is there a role for a GLP-1 RA in a patient who is doing well on a low-caloric diet and maintaining an A1C between 5.8% and 6.0%?
If the GLP-1 RA is being used only for glycemic control, it may not be needed. Although GLP-1 RAs have been shown to delay progression to type 2 diabetes, it may be cost-prohibitive in this group. However, if the GLP-1 RA is being used for cardiovascular disease, chronic kidney disease, or metabolic dysfunction–associated steatotic liver disease, it is recommended to use them. There are 3 GLP-1 RAs indicated to treat patients with obesity, and a GLP-1 RA would be also appropriate to consider now.

Could ezetimibe also be used for its limited stroke reduction in people with diabetes?  
First and of most importance, we should optimize statin therapy in these patients. After optimizing statin therapy with a high-intensity statin (eg, rosuvastatin 20-40 mg or atorvastatin 40-80 mg), then you can add on ezetimibe for patients who have experienced stroke. 

Are there any data regarding the use of GLP-1 RAs and the potential risk of depression or exacerbation of depression in individuals with preexisting depression?  
This question has been raised, in particular, in the context of weight loss. What is known is that in obesity trials, people were screened for depression, and there was no increase in suicidality or any cause of concern in these patients. It appears that patients with depression may show improvement, possibly as a secondary effect of weight loss and becoming more active. Patients with obesity and history of stroke may develop higher self-esteem as they increase their activity level.  

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