GLP-1 and SGLT2 inhibitors show promise in preventing recurrent stroke and heart attack

GLP-1 receptor agonists and SGLT2 inhibitors, two classes of medications most commonly prescribed to treat Type 2 diabetes or weight loss, may reduce the risk of heart attack, second strokes and death in adults who had an initial stroke, according to a preliminary study to be presented at the American Heart Association's Scientific Sessions 2024. The meeting, Nov. 16-18, 2024, in Chicago, is a premier global exchange of the latest scientific advancements, research and evidence-based clinical practice updates in cardiovascular science.

Unfortunately, a quarter of people who survive a stroke will have another stroke, and they are also at risk for other cardiovascular events such as a heart attack since many of the risk factors of a stroke are also associated with other forms of heart disease. Managing these risks, as well as looking at novel approaches to help lower the chances of another stroke, heart attack or death among this population are all critical steps in increasing stroke survival and improving the quality of life for people who have had a stroke."

M. Ali Sheffeh, M.D., lead study author, internal medicine physician and research scholar at the Mayo Clinic in Rochester, Minnesota

In this study, Sheffeh and colleagues evaluated whether two classes of medications for treating Type 2 diabetes are associated with a decreased risk of heart attacks, secondary stroke or death in stroke survivors.

One of the classes of medications ­­– glucagon-like peptide-1 receptor agonists (GLP-1) – treats Type 2 diabetes by stimulating insulin release by the pancreas, delaying gastric emptying, and decreasing the release of glucagon, a hormone in the body that raises blood sugar.

The GLP-1 medications liraglutide and semaglutide, as well as the dual GLP-1 and glucose-independent insulinotropic polypeptide (GIP) tirzepatide, are approved by the U.S. Food & Drug Administration for weight loss and to reduce the risk of cardiovascular disease for people with obesity or overweight.

The other medication class, sodium-glucose cotransporter 2 inhibitors (SGLT2), lowers blood sugar levels by inducing the kidneys to remove excess glucose from the body through the urine. The SGLT2 medications canagliflozin, dapagliflozin, empagliflozin and ertugliflozin are approved by the FDA for the treatment of Type 2 diabetes.

To analyze the impact of these two classes of medications, this study reviewed medical records for more than 7,000 adults who had clot-caused, or ischemic, strokes between January 2000 and June 2022. All participants had received stroke care at hospitals within multiple health systems in Minnesota or Wisconsin. Researchers assessed outcomes for people who were prescribed either a GLP-1 or an SGLT2 medication after their initial stroke to determine if there was a potential impact on the risk of having a second stroke, a heart attack or dying.

After an average follow-up of three years, the analysis found:

• Adults who were taking either a GLP-1 or an SGLT2 had a 74% lower risk of death and an 84% lower risk of having a heart attack.
• Adults who were taking an SGLT2 were also at a 67% lower risk of having another stroke.
• All decreased risks noted were present even when researchers accounted for other factors that may have affected or increased some patients' risk. These included age, sex, smoking status, hypertension status, Type 2 diabetes status, peripheral artery disease, hyperlipidemia, chronic kidney disease and a history of heart attack or a history of heart failure.
• Within the entire study period, the death rate among stroke survivors who took either a GLP-1 or an SGLT2 was 11.8%, compared to 54% among patients who did not take either class of medication. The rate of heart attacks among patients receiving either medication was also 1.5%, compared to 6.1% among patients not taking either class of medication.
• The rate of having another stroke was similar between patients who did and did not receive either medication, at approximately 6%.

"When comparing multiple variables, we can still conclude that treatment with either medication was associated with lower risk of recurrent stroke even though the rate was similar between patients who did and did not receive either medication," Sheffeh said. He noted that the medications significantly lowered the risk of recurrent stroke in an analysis that compared multiple variables, including patients' risk factors for recurrent stroke-;age, sex, hypertension status, Type 2 diabetes status, peripheral artery disease and a history of heart attack or a history of heart failure. However, the risk of recurrent stroke was not significantly lower in an analysis comparing medication use with recurrent stroke and no additional variables.

"The potential protective effects of the medications were hidden because those in the treatment group may have more high-risk features than the patients who were not taking either medication, hiding any protective effect. What the multivariate adjusting does is account for those differences and tease out any independent effect," Sheffeh said. "The results of the study are consistent with other research about the preventive role of these medications against cardiovascular disease in people with obesity or heart failure."

The researchers also conducted a subanalysis of patients who took the medications for at least six months to confirm if the medications' association with a lower risk of heart attack, recurrent stroke and death could be attributed to the medications. The results were similar to those in the primary study: the medications were associated with lower risk of heart attack, recurrent stroke and death, Sheffeh noted.

Study background and details:

• The study included health data for 7,044 adults admitted to a hospital for acute ischemic stroke between January 2000 and June 2022 in the Rochester Epidemiology Project. The database collects data from a collaboration of clinics, hospitals and other medical facilities including those in the Mayo Clinic, Olmstead Medical Center, Olmsted County Public Health Services or Zumbro Valley Health Center in Minnesota, as well as the Mayo Clinic Sealth system in Wisconsin.
• Participants were an average age of 72 years; 52% self-identified as men and 48% self-identified as women; 94% self-identified as white adults, 1.5% as Black adults, 1.5% as Asian adults and 3% identified as adults of "other" race. 

Study limitations include that the analysis was conducted on health data for people treated within one health system in the U.S., and that most patients in the analysis were white and from one geographic area, meaning the results may not apply to people living in other places or people of other races or ethnicities. Additionally, the database did not indicate why patients were prescribed either of the medications, though 93% of the patients who received either medication had Type 2 diabetes, Sheffeh noted. The researchers were also unable to evaluate the burden that stroke had on each patient because this information was not available in the database.

Stroke is a leading cause of disability and the fifth leading cause of death in the U.S. Ischemic strokes, which account for about 85% of all strokes, are caused by a lack of blood flow to the brain due to a clot. This occurs when a vessel supplying blood to the brain is obstructed due to plaque, or fatty deposits, within the wall of the vessel. The plaque can either cause the vessels to be narrowed, which inhibits blood flow, or it can cause a clot to break off in another part of the body and travel to smaller vessels near the brain where it causes a blockage.

"For several years now, we have seen from randomized controlled trials that SGLT2 inhibitors and GLP-1 receptor agonists have the ability to reduce the risk of cardiovascular disease, which includes stroke, heart attack and death. These new findings are in line with what we would expect, and we have seen that these outcomes are evident in patients with Type 2 diabetes and obesity and in patients with obesity without Type 2 diabetes," said Cheryl Bushnell, M.D., M.H.S., FAHA, professor and vice chair of research in the department of neurology at Wake Forest University School of Medicine in Winston-Salem, North Carolina.

Bushnell is chair of the writing group for the Association's 2024 Guideline for the Primary Prevention of Stroke, which details a variety of prevention strategies for individuals with no prior history of stroke. The new guideline provides evidence-based recommendations for strategies to support brain health and prevent stroke throughout a person's lifespan by improving healthy lifestyle behaviors and preventive care.

Bushnell also noted the ability of GLP-1 receptor agonists to decrease blood pressure and to decrease plaque formation associated with atherosclerosis, which is a risk factor for heart attack and stroke. "Another mechanism that could be very important for this current study is that GLP-1 receptor agonists can actually decrease clumping of blood platelets, and that, in itself, could decrease the risk of clotting and lead to a lower risk of stroke," she said. "We need a clinical trial to know whether these SGLT2 inhibitors and GLP-1 receptor agonists could actually change practice, how we can help patients to prevent a second or recurrent stroke. These medications could be really important, however, we just don't have that data yet."