GLP Drugs: How they work and is there an impact on coagulation factors
by Donna Castellone • January 20, 2025
INTRODUCTION:
Well, I can't believe it, but we are entering another year! We have gone through a quarter of this century! What will you do this year- spend more time with family, exercise more, read more, travel more and of course the lose weight scenario. The GLP drugs have now helped to make that a more reasonable goal for many people, especially in patients with type 2 diabetes (T2DM). How do they work, and is coagulation involved in the process?
HOW DO THESE DRUGS WORK:
The GLP-1 medications include liraglutide and semaglutide ((Rybelsus, Ozempic, Wegovy), as well as the dual GLP-1 and glucose-independent insulinotropic polypeptide (GIP) tirzepatide (Mounjaro, Zepbound). These drugs work by mimicking the GLP-1 (Glucagon-like peptide 1) hormone responsible for controlling blood sugar levels and reducing appetite. GLP-1 regulates blood sugar by stimulating insulin release and inhibiting glucagon secretion. Insulin lowers blood sugar level and glucagon raises levels. They bind to GLP-1 receptors in the pancreas and triggers insulin release simultaneously it reduces the amount of glucagon your liver releases and also slows down the emptying of the stomach allowing a feeling of fullness longer reducing appetite and leads to weight loss. It has been approved for type 2 diabetes to manage glucose levels and for weight loss in obese patients. It has raised concern regarding the risk of blood clots.1
Patients with type 2 diabetes mellitus (T2DM) pathophysiology includes high glucose toxicity, lipotoxicity and insulin resistance. This affects the integrity of the blood vessel wall resulting in increased inflammation, endothelial dysfunction, enhanced platelet aggregation and coagulation factor dysfunction. This contributes to a 2-4-fold increase risk in thrombosis and cardiovascular disease with cardiovascular disease accounting for 65% of the mortality rate in T2DM. It is important to also control obesity, hypertension, hyperlipidemia, and blood hypercoagulability.2
There are an estimated 100,000 US adults who have a VTE annually with the incidence on the rise increasing almost 20% over the last decade. Obesity is a known risk factor for VTE responsible for between 10-30% of all cases.3
Common causes and risk factors for blood clots include inactivity and immobility, injury and surgery, medical conditions (cancer, heart disease, and inflammatory conditions), medications and lifestyle factors including smoking, overweight and being sedentary.1
GLP mechanism and their contribution to blood clot formation is complex. The mechanism may involve changes in blood composition or in vessel walls that promote clotting under certain conditions and may increase clotting. However, most of the research has shown that there is an advantage to using these drugs and how they are more likely to prevent clotting.4
DVT AND PE:
A large retrospective study that used a database looked at more than half a million patients with Type 2 diabetes. Using propensity-score matched analysis results showed that who were treated with a GLP-1 receptor agonist at 1 year VTE rates were 20% lower when compared to patients on a DDP-4 inhibitor. Based on a subgroup analysis the risk was lower for PE (3.1 vs 3.9) and DVT (4.2 vs 5.0).3
The VTE risk reduction was observed across most BMI categories. Preclinical studies have shown that GLP-1 receptors exist on platelets and endothelial studies. The study cohorts included type 2 diabetes patients starting on either GLP-1 drugs or DDP-4 inhibitors selected as the control antidiabetic medication since it is not associated with weight loss. Exclusion criteria included previous VTE, using a DOAC or had AF, as well as if patients were on both medications. Matched patients included 279,064 patients on GLP-1 drugs and 279,064 on a DPP-4 inhibitor. Regardless of BMI at baseline, GLP-1 drugs were associated with a lower risk of VTE at 12 months.3
- BMI 18.5-24.9: HR 0.61 (95% CI 0.42-0.89)
- BMI 25-29.9: HR 0.82 (95% CI 0.66-1.03)
- BMI 30-34.9: HR 0.77 (95% CI 0.63-0.94)
- BMI 35-39.9: HR 0.60 (95% CI 0.47-0.77)
- BMI ≥40: HR 0.74 (95% CI 0.60-0.91)3
A limitation of the study was changes in patients' weight was not captured so it could not determine the impact of weight loss and VTE incidence.
At one year, an average of 6.5 people per every 1,000 patients experienced a VTE clot among the group taking a GLP-1 med, compared to 7.9 per 1,000 among those getting the other form of diabetes drug.5
STROKE:
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 blockage.6
In an analysis of more than 7000 stroke survivors it was observed that in patients taking a GLP-1 receptor agonist had a lower risk of subsequent stroke, heart attack or death when compared to peers who were not taking the drug after a 3 year follow up. The study included health data for 7,044 adults admitted to a hospital for acute ischemic stroke between January 2000 and June 2022 Average age was 72 years, 52% male, 94% were white, 1.5% as Black adults, 1.5% as Asian adults and 3% identified as adults of "other" race. Limitations include that the data came from 1 health system in the US, most patients were white, and it was unknown why patients were prescribed this medication, although 93% were diabetic.6
Up to a quarter of people who survive a stroke will have another stroke or possible heart attack, so it is important to manage this risk. Results showed that adults taking a GLP-1 has a 74% lower risk of death and an 84% lower risk of a heart attack. This risk was still evident after adjusting for confounding or contributing variables. The death rate was 11.8% vs 54% in patients who did not take the drug. The rate of heart attack was 1.5% vs 6.1 %, while the risk of subsequent stroke was the same (6%) in those with and without the GLP-1 inhibitor.6
GLP agonists have the ability to decrease blood pressure and decrease plaque formation. They also decrease clumping of platelets which can contribute to a lower risk of stroke.6
CARDIOVASCULAR EVENTS:
GLP drugs have multiple metabolic effects including cardiovascular benefits demonstrating a significant reduction of cardiovascular and all cause mortality. Semaglutide and liraglutide demonstrated a reduction in cardiovascular events, with similar rates on cardiovascular mortality. Ongoing trials assess the cardiovascular benefits and side effects of dulaglutide treatment. Exenatide and liraglutide demonstrated the decrease of blood pressure values, weight reduction and improvement of dyslipidemia. Liraglutide induced, both
GLP drugs impact coagulation factors and platelets by impairing thromboxane-dependent platelet aggregation and prolonging bleeding time. The exact mechanisms through which semaglutide could influence clotting are not fully understood. GLP-1 agonists may also have beneficial effects on cardiovascular outcomes by modulating other risk factors, such as endothelial dysfunction, arterial blood pressure, dyslipidemia, and platelet function.7
EFFECT ON COAGULATION FACTORS AND PLATELET AGGREGATION:
A study looked at 30 new diagnosed type 2 diabetes patients that were also matched to 30 healthy controls. Study patients received a GLP-1 drug for 8 weeks and were tested for peripheral blood platelet count, coagulation index, nitric oxide (NO), platelet membrane glycoprotein (CD62p), platelet activation complex-1 (PAC-1) and platelet aggregation induced by collagen, epinephrine (EPI), arachidonic acid (AA), and adenosine diphosphate (ADP). Prothrombin time (PT), activated partial thromboplastin time (APTT), the international normalized ratio (INR), and fibrinogen (FIB) were measured by magnetic bead coagulation method; and fibrin degradation products (FDP) and dimer (DD) were detected by immunoturbidimetry (AYL-4-013, Stago, France). Platelet rich plasma and the PACKS-4 platelet aggregation instrument was used with the agonists of inducers EPI (final concentration of 200 μM), ADP (final concentration of 10.0 μM), AA (final concentration of 2.5 μg/mL), and collagen (final concentration of 5.0 µg/mL).2
Patient results pretreatment showed an elevated fibrinogen, CD62p, PAC-1, and platelet aggregation rates when compared to the controls, while NO was lower in this cohort when compared to controls. There was no significant correlation with , PLT, PT, PTA, APTT, TT, INR, FDP, DD, and FIB (p>0.05) After 8 weeks of treatment the CD62p, PAC-1, and platelet aggregation rates were lower than before treatment, NO was increased and had a positive correlation with body mass index waist circumference, weight, blood lipids, fasting plasma glucose, haemoglobin A1c, fibrinogen, CD62p, and PAC-1 and negatively correlated with the changes in high-density lipoprotein and NO (p<0.05). Multiple linear regression analysis showed that the changes in NO, CD62p and PAC-1 were independent risk factors affecting the changes in platelet aggregation rates. BMI, waist circumference, SBP, TCH, TG, LDL-C, FPG, HbA1c, FIB, CD62p and PAC-1 and the platelet aggregation rates induced by epinephrine and AA were significantly decreased in the case group compared with the 0-week group (p<0.05). The levels of HDL-C and NO were significantly increased (p<0.05), while DBP, PLT, PT, PTA, APTT, INR, TT, FDP, DD and platelet aggregation rates (collagen and ADP as inducers) were not significantly different before and after treatment (p>0.05).2
The mechanism of enhanced platelet aggregation in T2DM patients is not fully understood. Initial studies have shown that insulin resistance becomes less effective in inhibiting platelet hyperfunction. Having an elevated glucose increases glycosylation of the platelet membrane resulting in a reduction of membrane fluidity promoting platelet aggregation. High levels of triglycerides can also trigger platelet function and increased fibrinogen may be caused by the combined effect of inflammatory cytokines and insulin on the liver. In addition to decreasing the fluidity of the platelet membrane and promoting platelet aggregation, coagulation factors and PAI-1 (plasminogen activator inhibitor-1) will also increase under the condition of hyperglycemia, breaking the balance of coagulation and fibrinolysis and promoting thrombosis.2
MECHANISM OF THROMBUS FORMATION:
Specific markers including CD62p and PAC-1 are released during platelet activation. When stimulated the surface expression of platelets increases to mediate the adhesion function of activated endothelial cells, mononuclear cells and neutrophils which play a role in promoting fibrin deposition and the role in the inflammatory response and thrombosis. When activated platelets are treated with anti-CD62p antibodies they lose their adhesiveness. PAC 1 is a platelet membrane glycoprotein IIb/IIIa complex and abundant platelet surface glycoprotein. Its binding site are specific to fibrinogen, fibronectin, and von Willebrand factor (vWF). PAC-1 receptors do not have ligand binding activity until platelet activation and then contributes to platelet thrombus formation.2
FIB levels were significantly lower after 8 weeks. Coagulation is a protein that is synthesized in the liver and is the highest coagulation factor with the highest content in plasma. It is a marker of thrombosis and inflammation and participates in thrombosis. A study looked at a link between fibrinogen and platelet activation. Using thromboelastogram (TEG) to measure fibrinolysis post treatment with GLP drugs the results of T2DM patients the results were prolonged. This suggests that the reduction in platelet aggregation may be related to the inhibition of inflammation and influence on the production of the liver, resulting in a decreased fibrinogen level.2
CONCLUSION:
GLP-1R agonists have the potential, at least in theory, to regulate platelet activation directly through the effect on platelet function and indirectly through the control of body weight and metabolism. GLP drugs can help to improve weight loss, lower blood pressure, blood lipid regulation, and improved endothelial dysfunction caused by hyperglycaemia and hyperlipidaemia. There is constant research on these drugs and the results seem to be positive in many aspects from lowering the risk of dementia to improved kidney function. Long term data needs to be evaluated to truly understand the impact of the GLP receptor drugs. Presently they have a positive impact on controlling T2DM as well as contributing to improving cardiovascular health as well as significant weight loss.
Whatever your resolutions are for 2025, I wish you and yours a happy and healthy year!
REFERENCES:
- Kevin Kargman, Semaglutide and Blood Clots: What You Need to Know for Safety and Health, May 29, 2024 https://bmidoctors.com/semaglutide-and-blood-clots-what-you-need-to-know-for-safety-and-health/
- Yaqin Zhang, Ruofei Chen, Yangyang Jia, Mingwei Chen, Zongwen Shuai, Effects of Exenatide on Coagulation and Platelet Aggregation in Patients with Type 2 Diabetes, Drug Des Devel Ther 2021 Jul 12;15:3027–3040 https://pmc.ncbi.nlm.nih.gov/articles/PMC8285923/"
- Ingram, I., GLP-1 Drugs Tied to Reduced Risk of Dangerous Blood Clots, MedPage TodayDecember 8, 2024, https://www.medpagetoday.com/meetingcoverage/ashhematology/113275?xid=nl_mpt_morningbreak2024-12-09&mh=acdb0ff366de7236110ee3b46560fe4d&utm_source=Sailthru&utm_medium=email&utm_campaign=MorningBreak_120924&utm_term=NL_Gen_Int_Daily_News_Update_active
ABSTRACT: Patell R "Glucagon-like peptide 1 receptor agonists reduce the risk of venous thromboembolism in patients with diabetes irrespective of obesity: a propensity score-matched multicenter database analysis" ASH 2024; Abstract 701. - Ozempic & Deep Vein Thrombosis (DVT) / Blood Clot Risks February 20, 2024, https://ozempicinjuries.org/ozempic-deep-vein-thrombosis/
- Ernie Mundell, GLP-1 Meds May Lower Clot Risk in People With Diabetes, Dec 10, 2024, https://www.healthday.com/health-news/diabetes/glp-1-meds-may-lower-clot-risk-in-people-with-diabetes
- American Heart Association Scientific Sessions, GLP-1, SGLT2 medications may lower stroke survivor’s risk of future heart attack, stroke2024, Abstract 4148007 https://newsroom.heart.org/news/glp-1-sglt2-medications-may-lower-stroke-survivors-risk-of-future-heart-attack-stroke
- Roua Anamaria Iorga, Nicolae Bacalbasa, Mara Carsote, Ovidiu Gabriel Bratu, Ana Maria Alexandra Stanescu, Simona Bungau, Carmen Pantis, Camelia Cristina Diaconu, Metabolic and cardiovascular benefits of GLP-1 agonists, besides the hypoglycemic effect (Review) Exp Ther Med 2020 May 5;20(3):2396–2400. https://pmc.ncbi.nlm.nih.gov/articles/PMC7401476/