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Six Updates on Stroke Management
This video transcript has been edited for clarity.
Dear colleagues, I am Christoph Diener, from the Faculty of Medicine at the University Duisburg-Essen in Germany. In this video, I would like to cover six publications on stroke, which were published this fall.
The Best Thrombolytic?
Let me start with systemic thrombolysis. We now have two thrombolytic agents available. One is the well-known alteplase, and newly approved for the treatment of stroke is tenecteplase. The ATTEST-2 study in the United Kingdom, published in The Lancet Neurology, compared tenecteplase 0.25 mg/kg body weight as a bolus with alteplase 0.9 mg/kg body weight as an infusion over 60 minutes in the 4.5-hour time window in 1777 patients with ischemic stroke.
There was no significant difference between the two thrombolytics for the primary endpoint of modified Rankin Scale score after 90 days. There was also no difference with respect to mortality, intracranial bleeding, or extracranial bleeding.
We finally have 11 randomized controlled trials that compared tenecteplase and alteplase in acute ischemic stroke. A meta-analysis of these randomized trials was published in Neurology. The analysis included 3700 patients treated with tenecteplase and 3700 patients treated with alteplase. For the primary endpoint, excellent functional outcome defined as modified Rankin Scale score 0-1 after 90 days, there was a significant benefit for tenecteplase (relative risk, 1.05), but the absolute difference was very small, at 3%. There was no difference in mortality or bleeding complications.
In conclusion, I think both substances are great. They are effective. Tenecteplase is most probably the drug which should be used in people who have to transfer from a primary stroke center to a dedicated stroke center that provides thrombectomy. Otherwise, I think it’s a choice of the physician as to which thrombolytic agent to use.
Mobile Stroke Units
A highly debated topic is mobile stroke units. These stroke units have a CT scanner and laboratory on board, and this makes it possible to perform thrombolysis on the way to the hospital. A retrospective, observational study collected data between 2018 and 2023, and included 19,400 patients with acute stroke, of whom 1237, or 6.4%, were treated in a mobile stroke unit. This study was published in JAMA Neurology.
The modified Rankin Scale score at the time of discharge was better in patients treated with a mobile stroke unit, but the absolute benefit was only 0.03 points on the modified Rankin Scale. The question is whether this is cost-effective, and can we really do this at times when there is a traumatic shortage of physicians and nursing staff in the hospital?
DOAC Reversal Agents
Oral anticoagulation, as you know, is usually considered a contraindication for systemic thrombolysis. Idarucizumab, a monoclonal antibody, was developed to reverse the biological activity of dabigatran and then allow systemic thrombolysis.
A recent publication in Neurology analyzed 13 cohort studies with 553 stroke patients on dabigatran who received idarucizumab prior to systemic thrombolysis, and the rate of intracranial hemorrhage was 4%. This means it’s obviously possible to perform thrombolysis when the activity of dabigatran is neutralized by idarucizumab.
Unfortunately, until today, we have no data on whether this can also be done with andexanet alfa in people who are treated with a factor Xa inhibitor like, for example, apixaban, rivaroxaban, or edoxaban.
Anticoagulation in ESUS
My next topic is ESUS, or embolic stroke of undetermined source. We have four large randomized trials and three smaller trials that compared antiplatelet therapy with DOACs in patients with ESUS. A group in Neurology published a meta-analysis of seven randomized controlled studies with, altogether, 14,800 patients with ESUS.
The comparison between antiplatelet therapy and anticoagulants showed no difference for recurrent ischemic stroke, and also not for major subgroups. This means that people with ESUS should receive antiplatelet therapy, most probably aspirin.
Anticoagulation Post–Ischemic Stroke With AF
My final topic is the optimal time to start anticoagulation in people with atrial fibrillation who suffer an ischemic stroke. The OPTIMAS study, published in The Lancet, randomized 3650 patients who were anticoagulated with DOACs early (which means less than 4 days) or delayed (between 7 and 14 days). There was no difference in the primary endpoint, which was recurrent ischemic stroke, intracranial hemorrhage, or systemic embolism at 90 days.
The conclusion is that, in most cases, we can probably initiate anticoagulation in people with ischemic stroke and atrial fibrillation within the first 4 days.
Dear colleagues, this is an exciting time for the stroke field. I presented six new studies that have impact, I think, on the management of patients with ischemic stroke.
Dr. Diener is a professor in the Department of Neurology, Stroke Center-Headache Center, University Duisburg-Essen in Germany. He reported conflicts of interest with Abbott, AbbVie, Boehringer Ingelheim, Lundbeck, Novartis, Orion Pharma, Teva, WebMD, and The German Research Council. He also serves on the editorial boards of Cephalalgia, Lancet Neurology, and Drugs.
A version of this article first appeared on Medscape.com.
This video transcript has been edited for clarity.
Dear colleagues, I am Christoph Diener, from the Faculty of Medicine at the University Duisburg-Essen in Germany. In this video, I would like to cover six publications on stroke, which were published this fall.
The Best Thrombolytic?
Let me start with systemic thrombolysis. We now have two thrombolytic agents available. One is the well-known alteplase, and newly approved for the treatment of stroke is tenecteplase. The ATTEST-2 study in the United Kingdom, published in The Lancet Neurology, compared tenecteplase 0.25 mg/kg body weight as a bolus with alteplase 0.9 mg/kg body weight as an infusion over 60 minutes in the 4.5-hour time window in 1777 patients with ischemic stroke.
There was no significant difference between the two thrombolytics for the primary endpoint of modified Rankin Scale score after 90 days. There was also no difference with respect to mortality, intracranial bleeding, or extracranial bleeding.
We finally have 11 randomized controlled trials that compared tenecteplase and alteplase in acute ischemic stroke. A meta-analysis of these randomized trials was published in Neurology. The analysis included 3700 patients treated with tenecteplase and 3700 patients treated with alteplase. For the primary endpoint, excellent functional outcome defined as modified Rankin Scale score 0-1 after 90 days, there was a significant benefit for tenecteplase (relative risk, 1.05), but the absolute difference was very small, at 3%. There was no difference in mortality or bleeding complications.
In conclusion, I think both substances are great. They are effective. Tenecteplase is most probably the drug which should be used in people who have to transfer from a primary stroke center to a dedicated stroke center that provides thrombectomy. Otherwise, I think it’s a choice of the physician as to which thrombolytic agent to use.
Mobile Stroke Units
A highly debated topic is mobile stroke units. These stroke units have a CT scanner and laboratory on board, and this makes it possible to perform thrombolysis on the way to the hospital. A retrospective, observational study collected data between 2018 and 2023, and included 19,400 patients with acute stroke, of whom 1237, or 6.4%, were treated in a mobile stroke unit. This study was published in JAMA Neurology.
The modified Rankin Scale score at the time of discharge was better in patients treated with a mobile stroke unit, but the absolute benefit was only 0.03 points on the modified Rankin Scale. The question is whether this is cost-effective, and can we really do this at times when there is a traumatic shortage of physicians and nursing staff in the hospital?
DOAC Reversal Agents
Oral anticoagulation, as you know, is usually considered a contraindication for systemic thrombolysis. Idarucizumab, a monoclonal antibody, was developed to reverse the biological activity of dabigatran and then allow systemic thrombolysis.
A recent publication in Neurology analyzed 13 cohort studies with 553 stroke patients on dabigatran who received idarucizumab prior to systemic thrombolysis, and the rate of intracranial hemorrhage was 4%. This means it’s obviously possible to perform thrombolysis when the activity of dabigatran is neutralized by idarucizumab.
Unfortunately, until today, we have no data on whether this can also be done with andexanet alfa in people who are treated with a factor Xa inhibitor like, for example, apixaban, rivaroxaban, or edoxaban.
Anticoagulation in ESUS
My next topic is ESUS, or embolic stroke of undetermined source. We have four large randomized trials and three smaller trials that compared antiplatelet therapy with DOACs in patients with ESUS. A group in Neurology published a meta-analysis of seven randomized controlled studies with, altogether, 14,800 patients with ESUS.
The comparison between antiplatelet therapy and anticoagulants showed no difference for recurrent ischemic stroke, and also not for major subgroups. This means that people with ESUS should receive antiplatelet therapy, most probably aspirin.
Anticoagulation Post–Ischemic Stroke With AF
My final topic is the optimal time to start anticoagulation in people with atrial fibrillation who suffer an ischemic stroke. The OPTIMAS study, published in The Lancet, randomized 3650 patients who were anticoagulated with DOACs early (which means less than 4 days) or delayed (between 7 and 14 days). There was no difference in the primary endpoint, which was recurrent ischemic stroke, intracranial hemorrhage, or systemic embolism at 90 days.
The conclusion is that, in most cases, we can probably initiate anticoagulation in people with ischemic stroke and atrial fibrillation within the first 4 days.
Dear colleagues, this is an exciting time for the stroke field. I presented six new studies that have impact, I think, on the management of patients with ischemic stroke.
Dr. Diener is a professor in the Department of Neurology, Stroke Center-Headache Center, University Duisburg-Essen in Germany. He reported conflicts of interest with Abbott, AbbVie, Boehringer Ingelheim, Lundbeck, Novartis, Orion Pharma, Teva, WebMD, and The German Research Council. He also serves on the editorial boards of Cephalalgia, Lancet Neurology, and Drugs.
A version of this article first appeared on Medscape.com.
This video transcript has been edited for clarity.
Dear colleagues, I am Christoph Diener, from the Faculty of Medicine at the University Duisburg-Essen in Germany. In this video, I would like to cover six publications on stroke, which were published this fall.
The Best Thrombolytic?
Let me start with systemic thrombolysis. We now have two thrombolytic agents available. One is the well-known alteplase, and newly approved for the treatment of stroke is tenecteplase. The ATTEST-2 study in the United Kingdom, published in The Lancet Neurology, compared tenecteplase 0.25 mg/kg body weight as a bolus with alteplase 0.9 mg/kg body weight as an infusion over 60 minutes in the 4.5-hour time window in 1777 patients with ischemic stroke.
There was no significant difference between the two thrombolytics for the primary endpoint of modified Rankin Scale score after 90 days. There was also no difference with respect to mortality, intracranial bleeding, or extracranial bleeding.
We finally have 11 randomized controlled trials that compared tenecteplase and alteplase in acute ischemic stroke. A meta-analysis of these randomized trials was published in Neurology. The analysis included 3700 patients treated with tenecteplase and 3700 patients treated with alteplase. For the primary endpoint, excellent functional outcome defined as modified Rankin Scale score 0-1 after 90 days, there was a significant benefit for tenecteplase (relative risk, 1.05), but the absolute difference was very small, at 3%. There was no difference in mortality or bleeding complications.
In conclusion, I think both substances are great. They are effective. Tenecteplase is most probably the drug which should be used in people who have to transfer from a primary stroke center to a dedicated stroke center that provides thrombectomy. Otherwise, I think it’s a choice of the physician as to which thrombolytic agent to use.
Mobile Stroke Units
A highly debated topic is mobile stroke units. These stroke units have a CT scanner and laboratory on board, and this makes it possible to perform thrombolysis on the way to the hospital. A retrospective, observational study collected data between 2018 and 2023, and included 19,400 patients with acute stroke, of whom 1237, or 6.4%, were treated in a mobile stroke unit. This study was published in JAMA Neurology.
The modified Rankin Scale score at the time of discharge was better in patients treated with a mobile stroke unit, but the absolute benefit was only 0.03 points on the modified Rankin Scale. The question is whether this is cost-effective, and can we really do this at times when there is a traumatic shortage of physicians and nursing staff in the hospital?
DOAC Reversal Agents
Oral anticoagulation, as you know, is usually considered a contraindication for systemic thrombolysis. Idarucizumab, a monoclonal antibody, was developed to reverse the biological activity of dabigatran and then allow systemic thrombolysis.
A recent publication in Neurology analyzed 13 cohort studies with 553 stroke patients on dabigatran who received idarucizumab prior to systemic thrombolysis, and the rate of intracranial hemorrhage was 4%. This means it’s obviously possible to perform thrombolysis when the activity of dabigatran is neutralized by idarucizumab.
Unfortunately, until today, we have no data on whether this can also be done with andexanet alfa in people who are treated with a factor Xa inhibitor like, for example, apixaban, rivaroxaban, or edoxaban.
Anticoagulation in ESUS
My next topic is ESUS, or embolic stroke of undetermined source. We have four large randomized trials and three smaller trials that compared antiplatelet therapy with DOACs in patients with ESUS. A group in Neurology published a meta-analysis of seven randomized controlled studies with, altogether, 14,800 patients with ESUS.
The comparison between antiplatelet therapy and anticoagulants showed no difference for recurrent ischemic stroke, and also not for major subgroups. This means that people with ESUS should receive antiplatelet therapy, most probably aspirin.
Anticoagulation Post–Ischemic Stroke With AF
My final topic is the optimal time to start anticoagulation in people with atrial fibrillation who suffer an ischemic stroke. The OPTIMAS study, published in The Lancet, randomized 3650 patients who were anticoagulated with DOACs early (which means less than 4 days) or delayed (between 7 and 14 days). There was no difference in the primary endpoint, which was recurrent ischemic stroke, intracranial hemorrhage, or systemic embolism at 90 days.
The conclusion is that, in most cases, we can probably initiate anticoagulation in people with ischemic stroke and atrial fibrillation within the first 4 days.
Dear colleagues, this is an exciting time for the stroke field. I presented six new studies that have impact, I think, on the management of patients with ischemic stroke.
Dr. Diener is a professor in the Department of Neurology, Stroke Center-Headache Center, University Duisburg-Essen in Germany. He reported conflicts of interest with Abbott, AbbVie, Boehringer Ingelheim, Lundbeck, Novartis, Orion Pharma, Teva, WebMD, and The German Research Council. He also serves on the editorial boards of Cephalalgia, Lancet Neurology, and Drugs.
A version of this article first appeared on Medscape.com.
Is There a Role for GLP-1s in Neurology and Psychiatry?
This transcript has been edited for clarity.
I usually report five or six studies in the field of neurology that were published in the last months, but July was a vacation month.
I decided to cover another topic, which is the role of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists beyond diabetes and obesity, and in particular, for the field of neurology and psychiatry. Until a few years ago, the treatment of diabetes with traditional antidiabetic drugs was frustrating for vascular neurologists.
These drugs would lower glucose and had an impact on small-vessel disease, but they had no impact on large-vessel disease, stroke, and vascular mortality. This changed with the sodium-glucose cotransporter 2 antagonists because these drugs were not only effective for diabetes, but they also lowered cardiac mortality, in particular, in patients with cardiac failure.
The next generation of antidiabetic drugs were the GLP-1 receptor agonists and the combined GIP/GLP-1 receptor agonists. These two polypeptides and their receptors play a very important role in diabetes and in obesity. The receptors are found not only in the pancreas but also in the intestinal system, the liver, and the central nervous system.
We have a number of preclinical models, mostly in transgenic mice, which show that these drugs are not effective only in diabetes and obesity, but also in liver disease, kidney failure, and neurodegenerative diseases. GLP-1 receptor agonists also have powerful anti-inflammatory properties. These drugs reduce body weight, and they have positive effects on blood pressure and lipid metabolism.
In the studies on the use of GLP-1 receptor agonists in diabetes, a meta-analysis with more than 58,000 patients showed a significant risk reduction for stroke compared with placebo, and this risk reduction was in the range of 80%.
Stroke, Smoking, and Alcohol
A meta-analysis on the use of GLP-1 receptor agonists in over 30,000 nondiabetic patients with obesity found a significant reduction in blood pressure, mortality, and the risk of myocardial infarction. There was no significant decrease in the risk of stroke, but most probably this is due to the fact that strokes are much less frequent in obesity than in diabetes.
You all know that obesity is also a major risk factor for sleep apnea syndrome. Recently, two large studies with the GIP/GLP-1 receptor agonist tirzepatide found a significant improvement in sleep apnea syndrome compared to placebo, regardless of whether patients needed continuous positive airway pressure therapy or not.
In the therapy studies on diabetes and obesity, there were indications that some smokers in the studies stopped their nicotine consumption. A small pilot study with exenatide in 84 overweight patients who were smokers showed that 46% of patients on exenatide stopped smoking compared with 27% in the placebo group. This could be an indication that GLP-1 receptor agonists have activity on the reward system in the brain. Currently, there are a number of larger placebo-controlled trials ongoing.
Another aspect is alcohol consumption. An epidemiologic study in Denmark using data from the National Health Registry showed that the incidence of alcohol-related events decreased significantly in almost 40,000 patients with diabetes when they were treated with GLP-1 receptor agonists compared with other antidiabetic drugs.
A retrospective cohort study from the United States with over 80,000 patients with obesity showed that treatment with GLP-1 receptor agonists was associated with a 50%-60% lower risk for occurrence or recurrence of high alcohol consumption. There is only one small study with exenatide, which was not really informative.
There are a number of studies underway for GLP-1 receptor agonists compared with placebo in patients with alcohol dependence or alcohol consumption. Preclinical models also indicate that these drugs might be effective in cocaine abuse, and there is one placebo-controlled study ongoing.
Parkinson’s Disease
Let’s come to neurology. Preclinical models of Parkinson’s disease have shown neuroprotective activities of GLP-1. Until now, we have three randomized placebo-controlled trials with exenatide, NLY01, and lixisenatide. Two of these studies were positive, showing that the symptoms of Parkinson’s disease were stable over time and deteriorated with placebo. One study was neutral. This means we need more large-scale placebo-controlled studies in the early phases of Parkinson’s disease.
Another potential use of GIP/GLP-1 receptor agonists is in dementia. These substances, as you know, have positive effects on high blood pressure and vascular risk factors.
A working group in China analyzed 27 studies on the treatment of diabetes. A small number of randomized studies and a large number of cohort studies showed that modern antidiabetic drugs reduce the risk for dementia. The risk reduction for dementia for the GLP-1 receptor agonists was 75%. At the moment, there are only small prospective studies and they are not conclusive. Again, we need large-scale placebo-controlled studies.
The most important limitation at the moment beyond the cost is the other adverse drug reactions with the GLP-1 receptor agonists; these include nausea, vomiting, diarrhea, and constipation. There might be a slightly increased risk for pancreatitis. The US Food and Drug Administration recently reported there is no increased risk for suicide. Another potential adverse drug reaction is nonatherosclerotic anterior optic neuropathy.
These drugs, GLP-1 receptor agonists and GIP agonists, are also investigated in a variety of other non-neurologic diseases. The focus here is on metabolic liver disease, such as fatty liver and kidney diseases. Smaller, positive studies have been conducted in this area, and large placebo-controlled trials for both indications are currently underway.
If these diverse therapeutic properties would turn out to be really the case with GLP-1 receptor agonists, this would lead to a significant expansion of the range of indications. If we consider cost, this would be the end of our healthcare systems because we cannot afford this. In addition, the new antidiabetic drugs and the treatment of obesity are available only to a limited extent.
Finally, at least for neurology, it’s unclear whether the impact of these diseases is in the brain or whether it’s indirect, due to the effectiveness on vascular risk factors and concomitant diseases.
Dr. Diener is Professor in the Department of Neurology, Stroke Center-Headache Center, University Duisburg-Essen, Essen, Germany; he has disclosed conflicts of interest with numerous pharmaceutical companies.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
I usually report five or six studies in the field of neurology that were published in the last months, but July was a vacation month.
I decided to cover another topic, which is the role of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists beyond diabetes and obesity, and in particular, for the field of neurology and psychiatry. Until a few years ago, the treatment of diabetes with traditional antidiabetic drugs was frustrating for vascular neurologists.
These drugs would lower glucose and had an impact on small-vessel disease, but they had no impact on large-vessel disease, stroke, and vascular mortality. This changed with the sodium-glucose cotransporter 2 antagonists because these drugs were not only effective for diabetes, but they also lowered cardiac mortality, in particular, in patients with cardiac failure.
The next generation of antidiabetic drugs were the GLP-1 receptor agonists and the combined GIP/GLP-1 receptor agonists. These two polypeptides and their receptors play a very important role in diabetes and in obesity. The receptors are found not only in the pancreas but also in the intestinal system, the liver, and the central nervous system.
We have a number of preclinical models, mostly in transgenic mice, which show that these drugs are not effective only in diabetes and obesity, but also in liver disease, kidney failure, and neurodegenerative diseases. GLP-1 receptor agonists also have powerful anti-inflammatory properties. These drugs reduce body weight, and they have positive effects on blood pressure and lipid metabolism.
In the studies on the use of GLP-1 receptor agonists in diabetes, a meta-analysis with more than 58,000 patients showed a significant risk reduction for stroke compared with placebo, and this risk reduction was in the range of 80%.
Stroke, Smoking, and Alcohol
A meta-analysis on the use of GLP-1 receptor agonists in over 30,000 nondiabetic patients with obesity found a significant reduction in blood pressure, mortality, and the risk of myocardial infarction. There was no significant decrease in the risk of stroke, but most probably this is due to the fact that strokes are much less frequent in obesity than in diabetes.
You all know that obesity is also a major risk factor for sleep apnea syndrome. Recently, two large studies with the GIP/GLP-1 receptor agonist tirzepatide found a significant improvement in sleep apnea syndrome compared to placebo, regardless of whether patients needed continuous positive airway pressure therapy or not.
In the therapy studies on diabetes and obesity, there were indications that some smokers in the studies stopped their nicotine consumption. A small pilot study with exenatide in 84 overweight patients who were smokers showed that 46% of patients on exenatide stopped smoking compared with 27% in the placebo group. This could be an indication that GLP-1 receptor agonists have activity on the reward system in the brain. Currently, there are a number of larger placebo-controlled trials ongoing.
Another aspect is alcohol consumption. An epidemiologic study in Denmark using data from the National Health Registry showed that the incidence of alcohol-related events decreased significantly in almost 40,000 patients with diabetes when they were treated with GLP-1 receptor agonists compared with other antidiabetic drugs.
A retrospective cohort study from the United States with over 80,000 patients with obesity showed that treatment with GLP-1 receptor agonists was associated with a 50%-60% lower risk for occurrence or recurrence of high alcohol consumption. There is only one small study with exenatide, which was not really informative.
There are a number of studies underway for GLP-1 receptor agonists compared with placebo in patients with alcohol dependence or alcohol consumption. Preclinical models also indicate that these drugs might be effective in cocaine abuse, and there is one placebo-controlled study ongoing.
Parkinson’s Disease
Let’s come to neurology. Preclinical models of Parkinson’s disease have shown neuroprotective activities of GLP-1. Until now, we have three randomized placebo-controlled trials with exenatide, NLY01, and lixisenatide. Two of these studies were positive, showing that the symptoms of Parkinson’s disease were stable over time and deteriorated with placebo. One study was neutral. This means we need more large-scale placebo-controlled studies in the early phases of Parkinson’s disease.
Another potential use of GIP/GLP-1 receptor agonists is in dementia. These substances, as you know, have positive effects on high blood pressure and vascular risk factors.
A working group in China analyzed 27 studies on the treatment of diabetes. A small number of randomized studies and a large number of cohort studies showed that modern antidiabetic drugs reduce the risk for dementia. The risk reduction for dementia for the GLP-1 receptor agonists was 75%. At the moment, there are only small prospective studies and they are not conclusive. Again, we need large-scale placebo-controlled studies.
The most important limitation at the moment beyond the cost is the other adverse drug reactions with the GLP-1 receptor agonists; these include nausea, vomiting, diarrhea, and constipation. There might be a slightly increased risk for pancreatitis. The US Food and Drug Administration recently reported there is no increased risk for suicide. Another potential adverse drug reaction is nonatherosclerotic anterior optic neuropathy.
These drugs, GLP-1 receptor agonists and GIP agonists, are also investigated in a variety of other non-neurologic diseases. The focus here is on metabolic liver disease, such as fatty liver and kidney diseases. Smaller, positive studies have been conducted in this area, and large placebo-controlled trials for both indications are currently underway.
If these diverse therapeutic properties would turn out to be really the case with GLP-1 receptor agonists, this would lead to a significant expansion of the range of indications. If we consider cost, this would be the end of our healthcare systems because we cannot afford this. In addition, the new antidiabetic drugs and the treatment of obesity are available only to a limited extent.
Finally, at least for neurology, it’s unclear whether the impact of these diseases is in the brain or whether it’s indirect, due to the effectiveness on vascular risk factors and concomitant diseases.
Dr. Diener is Professor in the Department of Neurology, Stroke Center-Headache Center, University Duisburg-Essen, Essen, Germany; he has disclosed conflicts of interest with numerous pharmaceutical companies.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
I usually report five or six studies in the field of neurology that were published in the last months, but July was a vacation month.
I decided to cover another topic, which is the role of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists beyond diabetes and obesity, and in particular, for the field of neurology and psychiatry. Until a few years ago, the treatment of diabetes with traditional antidiabetic drugs was frustrating for vascular neurologists.
These drugs would lower glucose and had an impact on small-vessel disease, but they had no impact on large-vessel disease, stroke, and vascular mortality. This changed with the sodium-glucose cotransporter 2 antagonists because these drugs were not only effective for diabetes, but they also lowered cardiac mortality, in particular, in patients with cardiac failure.
The next generation of antidiabetic drugs were the GLP-1 receptor agonists and the combined GIP/GLP-1 receptor agonists. These two polypeptides and their receptors play a very important role in diabetes and in obesity. The receptors are found not only in the pancreas but also in the intestinal system, the liver, and the central nervous system.
We have a number of preclinical models, mostly in transgenic mice, which show that these drugs are not effective only in diabetes and obesity, but also in liver disease, kidney failure, and neurodegenerative diseases. GLP-1 receptor agonists also have powerful anti-inflammatory properties. These drugs reduce body weight, and they have positive effects on blood pressure and lipid metabolism.
In the studies on the use of GLP-1 receptor agonists in diabetes, a meta-analysis with more than 58,000 patients showed a significant risk reduction for stroke compared with placebo, and this risk reduction was in the range of 80%.
Stroke, Smoking, and Alcohol
A meta-analysis on the use of GLP-1 receptor agonists in over 30,000 nondiabetic patients with obesity found a significant reduction in blood pressure, mortality, and the risk of myocardial infarction. There was no significant decrease in the risk of stroke, but most probably this is due to the fact that strokes are much less frequent in obesity than in diabetes.
You all know that obesity is also a major risk factor for sleep apnea syndrome. Recently, two large studies with the GIP/GLP-1 receptor agonist tirzepatide found a significant improvement in sleep apnea syndrome compared to placebo, regardless of whether patients needed continuous positive airway pressure therapy or not.
In the therapy studies on diabetes and obesity, there were indications that some smokers in the studies stopped their nicotine consumption. A small pilot study with exenatide in 84 overweight patients who were smokers showed that 46% of patients on exenatide stopped smoking compared with 27% in the placebo group. This could be an indication that GLP-1 receptor agonists have activity on the reward system in the brain. Currently, there are a number of larger placebo-controlled trials ongoing.
Another aspect is alcohol consumption. An epidemiologic study in Denmark using data from the National Health Registry showed that the incidence of alcohol-related events decreased significantly in almost 40,000 patients with diabetes when they were treated with GLP-1 receptor agonists compared with other antidiabetic drugs.
A retrospective cohort study from the United States with over 80,000 patients with obesity showed that treatment with GLP-1 receptor agonists was associated with a 50%-60% lower risk for occurrence or recurrence of high alcohol consumption. There is only one small study with exenatide, which was not really informative.
There are a number of studies underway for GLP-1 receptor agonists compared with placebo in patients with alcohol dependence or alcohol consumption. Preclinical models also indicate that these drugs might be effective in cocaine abuse, and there is one placebo-controlled study ongoing.
Parkinson’s Disease
Let’s come to neurology. Preclinical models of Parkinson’s disease have shown neuroprotective activities of GLP-1. Until now, we have three randomized placebo-controlled trials with exenatide, NLY01, and lixisenatide. Two of these studies were positive, showing that the symptoms of Parkinson’s disease were stable over time and deteriorated with placebo. One study was neutral. This means we need more large-scale placebo-controlled studies in the early phases of Parkinson’s disease.
Another potential use of GIP/GLP-1 receptor agonists is in dementia. These substances, as you know, have positive effects on high blood pressure and vascular risk factors.
A working group in China analyzed 27 studies on the treatment of diabetes. A small number of randomized studies and a large number of cohort studies showed that modern antidiabetic drugs reduce the risk for dementia. The risk reduction for dementia for the GLP-1 receptor agonists was 75%. At the moment, there are only small prospective studies and they are not conclusive. Again, we need large-scale placebo-controlled studies.
The most important limitation at the moment beyond the cost is the other adverse drug reactions with the GLP-1 receptor agonists; these include nausea, vomiting, diarrhea, and constipation. There might be a slightly increased risk for pancreatitis. The US Food and Drug Administration recently reported there is no increased risk for suicide. Another potential adverse drug reaction is nonatherosclerotic anterior optic neuropathy.
These drugs, GLP-1 receptor agonists and GIP agonists, are also investigated in a variety of other non-neurologic diseases. The focus here is on metabolic liver disease, such as fatty liver and kidney diseases. Smaller, positive studies have been conducted in this area, and large placebo-controlled trials for both indications are currently underway.
If these diverse therapeutic properties would turn out to be really the case with GLP-1 receptor agonists, this would lead to a significant expansion of the range of indications. If we consider cost, this would be the end of our healthcare systems because we cannot afford this. In addition, the new antidiabetic drugs and the treatment of obesity are available only to a limited extent.
Finally, at least for neurology, it’s unclear whether the impact of these diseases is in the brain or whether it’s indirect, due to the effectiveness on vascular risk factors and concomitant diseases.
Dr. Diener is Professor in the Department of Neurology, Stroke Center-Headache Center, University Duisburg-Essen, Essen, Germany; he has disclosed conflicts of interest with numerous pharmaceutical companies.
A version of this article first appeared on Medscape.com.