Clinician Reviews

Final results of the SELECT trial have shown that the antiobesity drug semaglutide (Wegovy) produced a consistent reduction of around 20% versus placebo across major cardiovascular event endpoints over the approximately 3-year follow-up in patients with overweight or obesity and cardiovascular disease but not diabetes.

“This is a very exciting set of results. I think it is going to have a big impact on a large number of people,” lead investigator A. Michael Lincoff, MD, vice chair for research in the department of cardiovascular medicine at the Cleveland Clinic, said in an interview. 

“And from a scientific standpoint, these data show that we now have a new pathway or a new modifiable risk factor for cardiovascular disease that we can use in our patients who have overweight or obesity,” he added.

The trial involved 17,604 patients with a history of cardiovascular disease and a body mass index of 27 kg/m² or above (mean BMI was 33), who were randomly assigned to the glucagonlike peptide–1 (GLP-1) agonist semaglutide, given by subcutaneous injection once weekly at a gradually escalating dose up to 2.4 mg daily by week 16, or placebo. The mean baseline glycated hemoglobin level was 5.8% and 66.4% of patients met the criteria for prediabetes.

Patients lost a mean of 9.4% of body weight over the first 2 years with semaglutide versus 0.88% with placebo.

The primary cardiovascular endpoint – a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke – was reduced significantly, with a hazard ratio of 0.80 (95% confidence interval, 0.72-0.90; P < .001).  

Death from cardiovascular causes, the first confirmatory secondary endpoint, showed a 15% reduction (HR, 0.85; P = .07) but this missed meeting criteria for statistical significance, and because of the hierarchical design of the trial, this meant that superiority testing was not performed for the remaining confirmatory secondary endpoints.

However, results showed reductions of around 20% for the heart failure composite endpoint and for all-cause mortality, with confidence intervals that did not cross 1.0, and directionally consistent effects were observed for all supportive secondary endpoints.

The HR for the heart failure composite endpoint was 0.82 (95% CI, 0.71-0.96), and the HR for death from any cause was 0.81 (95% CI, 0.71-0.93). Nonfatal MI was reduced by 28% (HR 0.72; 95% CI, 0.61-0.85).

The effects of semaglutide on the primary endpoint appeared to be similar across all prespecified subgroups.

Adverse events leading to discontinuation of treatment occurred in 16.6% in the semaglutide group, mostly gastrointestinal effects, and in 8.2% in the placebo group.

The trial results were presented by Dr. Lincoff at the annual scientific sessions of the American Heart Association . They were also simultaneously published online in the New England Journal of Medicine.

Dr. Lincoff explained that there is a growing pandemic of overweight and obesity worldwide with clear evidence for years that these conditions increase the risk of cardiovascular events – and yet there has been no evidence, until now, that any pharmacologic or lifestyle therapy can reduce the increased risk conferred by overweight/obesity. 

“Patients in the trial were already taking standard of care therapies for other risk factors, such as hypertension and cholesterol, so this drug is giving additional benefit,” he said.

Dr. Lincoff believes these data will lead to a large increase in use of semaglutide, which is already available for the treatment of obesity and diabetes but can be difficult to get reimbursed.

“There is a lot of difficulty getting payors to pay for this drug for weight management. But with this new data from the SELECT trial there should be more willingness – at least in the population with a history of cardiovascular disease,” he commented. In diabetes, where it is already established that there is a cardiovascular risk reduction, it is easier to get these drugs reimbursed, he noted.

On the outcome data, Dr. Lincoff said he could not explain why cardiovascular death was not significantly reduced while all-cause mortality appeared to be cut more definitively.

“The cardiovascular death curves separated, then merged, then separated again. We don’t really know what is going on there. It may be that some deaths were misclassified. This trial was conducted through the COVID era and there may have been less information available on some patients because of that.”

But he added: “The all-cause mortality is more reassuring, as it doesn’t depend on classifying cause of death. Because of the design of the trial, we can’t formally claim a reduction in all-cause mortality, but the results do suggest there is an effect on this endpoint. And all the different types of cardiovascular events were similarly reduced in a consistent way, with similar effects seen across all subgroups. That is very reassuring.”
 

‘A new era’ for patients with obesity

Outside experts in the field were also impressed with the data.

Designated discussant of the trial at the AHA meeting, Ania Jastreboff, MD, associate professor medicine (endocrinology) at Yale University, New Haven, Conn., said the SELECT trial was “a turning point in the treatment of obesity and a call to action.

“Now is the time to treat obesity to improve health outcomes in people with cardiovascular disease,” she said.

Dr. Jastreboff noted that high BMI was estimated to have accounted for 4 million deaths worldwide in 2015, two-thirds of which were caused by cardiovascular disease. And she presented data showing that U.S. individuals meeting the SELECT criteria increased from 4.3 million in 2011-12 to 6.6 million in 2017-18.

She highlighted one major limitation of the SELECT trial: it enrolled a low number of women (38%) and ethnic minorities, with only 12% of the trial population being Black.

Deepak L. Bhatt, MD, director of Mount Sinai Fuster Heart Hospital, New York, described the SELECT results as “altogether a compelling package of data.”

“These results are even better than I had expected,” Dr. Bhatt said in an interview. “There is a significant reduction in MI as I had anticipated, but additionally, there is a reduction in all-cause death. One can debate the statistics, though on a common-sense level, I think it is a real finding,” he noted.

“Given that MI, heart failure, nephropathy, and revascularization are all reduced, and even stroke is numerically lower, it makes sense that all-cause mortality would be reduced,” he said. “To me, apart from the GI side effects, this counts as a home run.”

Steve Nissen, MD, chief academic officer at the Cleveland Clinic’s Heart, Vascular and Thoracic Institute, was similarly upbeat.

“These data prove what many of us have long suspected – that losing weight can reduce cardiovascular morbidity and mortality. This is great news for patients living with obesity. The obesity epidemic is out of control,” he added. “We need to have therapies that improve cardiovascular outcomes caused by obesity and this shows that semaglutide can do that. I think this is the beginning of a whole new era for patients with obesity.”

Michelle O’Donoghue, MD, associate professor of medicine at Harvard Medical School, Boston, called the results of SELECT “both intriguing and compelling. Certainly, these findings lend further support to the use of semaglutide in a much broader secondary prevention population of individuals with obesity.”

Christie Ballantyne, MD, director of the center for cardiometabolic disease prevention at Baylor College of Medicine, Houston, described the SELECT study as “a landmark trial which will change the practice of medicine in regard to how we treat obesity.”

He compared it with the landmark 4S trial in 1994, the first study in the area of cholesterol lowering therapy to show a clear benefit in reducing cardiovascular events and total mortality, and “began a drastic change in the way that physicians approached treatment of cholesterol.”

On the more robust reduction in all-cause death, compared with cardiovascular death,

Dr. Ballantyne pointed out: “Adjudication of dead or alive is something that everyone gets right. In contrast, the cause of death is sometime difficult to ascertain. Most importantly, the benefit on total mortality also provides assurance that this therapy does not have some adverse effect on increasing noncardiovascular deaths.”
 

Gastrointestinal adverse effects

On the side effects seen with semaglutide, Dr. Lincoff reported that 10% of patients in the semaglutide group discontinued treatment because of GI side effects versus 2% in the placebo arm. He said this was “an expected issue.”

“GI effects, such as nausea, vomiting and diarrhea, are known side effects of this whole class of drugs. The dose is slowly escalated to manage these adverse effects but there will be a proportion of patients who can’t tolerate it, although the vast majority are able to continue.”

He noted that, while dose reduction was allowed, of the patients who were still on the drug at 2 years, 77% were on the full dose, and 23% were on a reduced dose.

Dr. Lincoff pointed out that there were no serious adverse events with semaglutide. “This is the largest database by far now on the drug with a long-term follow up and we didn’t see the emergence of any new safety signals, which is very reassuring.”  

Dr. Nissen said the 16% rate of patients stopping the drug because of tolerability “is not a trivial number.”

He noted that the semaglutide dose used in this study was larger than that used in diabetes.

“They did this to try to achieve more weight loss but then you get more issues with tolerability. It’s a trade-off. If patients are experiencing adverse effects, the dose can be reduced, but then you will lose some effect. All the GLP-1 agonists have GI side effects – it’s part of the way that they work.”
 

Just weight loss or other actions too?

Speculating on the mechanism behind the reduction in cardiovascular events with semaglutide, Dr. Lincoff does not think it is just weight reduction.

“The event curves start to diverge very soon after the start of the trial and yet the maximum weight loss doesn’t occur until about 65 weeks. I think something else is going on.”

In the paper, the researchers noted that GLP-1 agonists have been shown in animal studies to reduce inflammation, improve endothelial and left ventricular function, promote plaque stability, and decrease platelet aggregation. In this trial, semaglutide was associated with changes in multiple biomarkers of cardiovascular risk, including blood pressure, waist circumference, glycemic control, nephropathy, and levels of lipids and C-reactive protein.

Dr. Lincoff also pointed out that similar benefits were seen in patients with different levels of overweight, and in those who were prediabetic and those who weren’t, so benefit was not dependent on baseline BMI or glycated hemoglobin levels.

Dr. O’Donoghue agreed that other effects, as well as weight loss, could be involved. “The reduction in events with semaglutide appeared very early after initiation and far preceded the drug’s maximal effects on weight reduction. This might suggest that the drug offers other cardioprotective effects through pathways independent of weight loss. Certainly, semaglutide and the other GLP-1 agonists appear to attenuate inflammation, and the patterns of redistribution of adipose tissue may also be of interest.”

She also pointed out that the reduction in cardiovascular events appeared even earlier in this population of obese nondiabetic patients with cardiovascular disease than in prior studies of patients with diabetes. “It may suggest that there is particular benefit for this type of therapy in patients with an inflammatory milieu. I look forward to seeing further analyses to help tease apart the correlation between changes in inflammation, observed weight loss and cardiovascular benefit.”
 

Effect on clinical practice

With the majority of patients with cardiovascular disease being overweight, these results are obviously going to increase demand for semaglutide, but cost and availability are going to be an issue.

Dr. Bhatt noted that semaglutide is already very popular. “Weight loss drugs are somewhat different from other medications. I can spend 30 minutes trying to convince a patient to take a statin, but here people realize it’s going to cause weight loss and they come in asking for it even if they don’t strictly need it. I think it’s good to have cardiovascular outcome data because now at least for this population of patients, we have evidence to prescribe it.”

He agreed with Dr. Lincoff that these new data should encourage insurance companies to cover the drug, because in reducing cardiovascular events it should also improve downstream health care costs.

“It is providing clear cardiovascular and kidney benefit, so it is in the best interest to the health care system to fund this drug,” he said. “I hope insurers look at it rationally in this way, but they may also be frightened of the explosion of patients wanting this drug and now doctors wanting to prescribe it and how that would affect their shorter-term costs.”

Dr. Lincoff said it would not be easy to prioritize certain groups. “We couldn’t identify any subgroup who showed particularly more benefit than any others. But in the evolution of any therapy, there is a time period where it is in short supply and prohibitively expensive, then over time when there is some competition and pricing deals occur as more people are advocating for it, they become more available.”
 

‘A welcome treatment option’

In an editorial accompanying publication of the trial, Amit Khera, MD, University of Texas Southwestern Medical Center, Dallas, and Tiffany Powell-Wiley, MD, MPH, National Institutes of Health, Bethesda, noted that baseline risk factors such as LDL cholesterol (78 mg/dL) and systolic blood pressure (131 mm Hg) were not ideal in the semaglutide group in this trial, and they suggest that the benefits of semaglutide may be attenuated when these measures are better controlled.

But given that more than 20 million people in the United States have coronary artery disease, with the majority having overweight or obesity and only approximately 30% having concomitant diabetes, they said that, even in the context of well-controlled risk factors and very low LDL cholesterol levels, the residual risk of atherosclerotic cardiovascular disease in these persons is unacceptably high. “Thus, the SELECT trial provides a welcome treatment option that can be extended to millions of additional patients.”

However, the editorialists cautioned that semaglutide at current pricing comes with a significant cost to both patients and society, which makes this treatment inaccessible for many. 

They added that intensive lifestyle interventions and bariatric surgery remain effective but underutilized options for obesity, and that the prevention of obesity before it develops should be the primary goal.

The SELECT trial was supported by Novo Nordisk, and several coauthors are employees of the company. Dr. Lincoff is a consultant for Novo Nordisk. Dr. Bhatt and Dr. Nissen are involved in a cardiovascular outcomes trial with a new investigational weight loss drug from Lilly. Dr. Bhatt and Dr. Ballantyne are also investigators in a Novo Nordisk trial of a new anti-inflammatory drug.

Final results of the SELECT trial have shown that the antiobesity drug semaglutide (Wegovy) produced a consistent reduction of around 20% versus placebo across major cardiovascular event endpoints over the approximately 3-year follow-up in patients with overweight or obesity and cardiovascular disease but not diabetes.

“This is a very exciting set of results. I think it is going to have a big impact on a large number of people,” lead investigator A. Michael Lincoff, MD, vice chair for research in the department of cardiovascular medicine at the Cleveland Clinic, said in an interview. 

“And from a scientific standpoint, these data show that we now have a new pathway or a new modifiable risk factor for cardiovascular disease that we can use in our patients who have overweight or obesity,” he added.

The trial involved 17,604 patients with a history of cardiovascular disease and a body mass index of 27 kg/m² or above (mean BMI was 33), who were randomly assigned to the glucagonlike peptide–1 (GLP-1) agonist semaglutide, given by subcutaneous injection once weekly at a gradually escalating dose up to 2.4 mg daily by week 16, or placebo. The mean baseline glycated hemoglobin level was 5.8% and 66.4% of patients met the criteria for prediabetes.

Patients lost a mean of 9.4% of body weight over the first 2 years with semaglutide versus 0.88% with placebo.

The primary cardiovascular endpoint – a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke – was reduced significantly, with a hazard ratio of 0.80 (95% confidence interval, 0.72-0.90; P < .001).  

Death from cardiovascular causes, the first confirmatory secondary endpoint, showed a 15% reduction (HR, 0.85; P = .07) but this missed meeting criteria for statistical significance, and because of the hierarchical design of the trial, this meant that superiority testing was not performed for the remaining confirmatory secondary endpoints.

However, results showed reductions of around 20% for the heart failure composite endpoint and for all-cause mortality, with confidence intervals that did not cross 1.0, and directionally consistent effects were observed for all supportive secondary endpoints.

The HR for the heart failure composite endpoint was 0.82 (95% CI, 0.71-0.96), and the HR for death from any cause was 0.81 (95% CI, 0.71-0.93). Nonfatal MI was reduced by 28% (HR 0.72; 95% CI, 0.61-0.85).

The effects of semaglutide on the primary endpoint appeared to be similar across all prespecified subgroups.

Adverse events leading to discontinuation of treatment occurred in 16.6% in the semaglutide group, mostly gastrointestinal effects, and in 8.2% in the placebo group.

The trial results were presented by Dr. Lincoff at the annual scientific sessions of the American Heart Association . They were also simultaneously published online in the New England Journal of Medicine.

Dr. Lincoff explained that there is a growing pandemic of overweight and obesity worldwide with clear evidence for years that these conditions increase the risk of cardiovascular events – and yet there has been no evidence, until now, that any pharmacologic or lifestyle therapy can reduce the increased risk conferred by overweight/obesity. 

“Patients in the trial were already taking standard of care therapies for other risk factors, such as hypertension and cholesterol, so this drug is giving additional benefit,” he said.

Dr. Lincoff believes these data will lead to a large increase in use of semaglutide, which is already available for the treatment of obesity and diabetes but can be difficult to get reimbursed.

“There is a lot of difficulty getting payors to pay for this drug for weight management. But with this new data from the SELECT trial there should be more willingness – at least in the population with a history of cardiovascular disease,” he commented. In diabetes, where it is already established that there is a cardiovascular risk reduction, it is easier to get these drugs reimbursed, he noted.

On the outcome data, Dr. Lincoff said he could not explain why cardiovascular death was not significantly reduced while all-cause mortality appeared to be cut more definitively.

“The cardiovascular death curves separated, then merged, then separated again. We don’t really know what is going on there. It may be that some deaths were misclassified. This trial was conducted through the COVID era and there may have been less information available on some patients because of that.”

But he added: “The all-cause mortality is more reassuring, as it doesn’t depend on classifying cause of death. Because of the design of the trial, we can’t formally claim a reduction in all-cause mortality, but the results do suggest there is an effect on this endpoint. And all the different types of cardiovascular events were similarly reduced in a consistent way, with similar effects seen across all subgroups. That is very reassuring.”
 

‘A new era’ for patients with obesity

Outside experts in the field were also impressed with the data.

Designated discussant of the trial at the AHA meeting, Ania Jastreboff, MD, associate professor medicine (endocrinology) at Yale University, New Haven, Conn., said the SELECT trial was “a turning point in the treatment of obesity and a call to action.

“Now is the time to treat obesity to improve health outcomes in people with cardiovascular disease,” she said.

Dr. Jastreboff noted that high BMI was estimated to have accounted for 4 million deaths worldwide in 2015, two-thirds of which were caused by cardiovascular disease. And she presented data showing that U.S. individuals meeting the SELECT criteria increased from 4.3 million in 2011-12 to 6.6 million in 2017-18.

She highlighted one major limitation of the SELECT trial: it enrolled a low number of women (38%) and ethnic minorities, with only 12% of the trial population being Black.

Deepak L. Bhatt, MD, director of Mount Sinai Fuster Heart Hospital, New York, described the SELECT results as “altogether a compelling package of data.”

“These results are even better than I had expected,” Dr. Bhatt said in an interview. “There is a significant reduction in MI as I had anticipated, but additionally, there is a reduction in all-cause death. One can debate the statistics, though on a common-sense level, I think it is a real finding,” he noted.

“Given that MI, heart failure, nephropathy, and revascularization are all reduced, and even stroke is numerically lower, it makes sense that all-cause mortality would be reduced,” he said. “To me, apart from the GI side effects, this counts as a home run.”

Steve Nissen, MD, chief academic officer at the Cleveland Clinic’s Heart, Vascular and Thoracic Institute, was similarly upbeat.

“These data prove what many of us have long suspected – that losing weight can reduce cardiovascular morbidity and mortality. This is great news for patients living with obesity. The obesity epidemic is out of control,” he added. “We need to have therapies that improve cardiovascular outcomes caused by obesity and this shows that semaglutide can do that. I think this is the beginning of a whole new era for patients with obesity.”

Michelle O’Donoghue, MD, associate professor of medicine at Harvard Medical School, Boston, called the results of SELECT “both intriguing and compelling. Certainly, these findings lend further support to the use of semaglutide in a much broader secondary prevention population of individuals with obesity.”

Christie Ballantyne, MD, director of the center for cardiometabolic disease prevention at Baylor College of Medicine, Houston, described the SELECT study as “a landmark trial which will change the practice of medicine in regard to how we treat obesity.”

He compared it with the landmark 4S trial in 1994, the first study in the area of cholesterol lowering therapy to show a clear benefit in reducing cardiovascular events and total mortality, and “began a drastic change in the way that physicians approached treatment of cholesterol.”

On the more robust reduction in all-cause death, compared with cardiovascular death,

Dr. Ballantyne pointed out: “Adjudication of dead or alive is something that everyone gets right. In contrast, the cause of death is sometime difficult to ascertain. Most importantly, the benefit on total mortality also provides assurance that this therapy does not have some adverse effect on increasing noncardiovascular deaths.”
 

Gastrointestinal adverse effects

On the side effects seen with semaglutide, Dr. Lincoff reported that 10% of patients in the semaglutide group discontinued treatment because of GI side effects versus 2% in the placebo arm. He said this was “an expected issue.”

“GI effects, such as nausea, vomiting and diarrhea, are known side effects of this whole class of drugs. The dose is slowly escalated to manage these adverse effects but there will be a proportion of patients who can’t tolerate it, although the vast majority are able to continue.”

He noted that, while dose reduction was allowed, of the patients who were still on the drug at 2 years, 77% were on the full dose, and 23% were on a reduced dose.

Dr. Lincoff pointed out that there were no serious adverse events with semaglutide. “This is the largest database by far now on the drug with a long-term follow up and we didn’t see the emergence of any new safety signals, which is very reassuring.”  

Dr. Nissen said the 16% rate of patients stopping the drug because of tolerability “is not a trivial number.”

He noted that the semaglutide dose used in this study was larger than that used in diabetes.

“They did this to try to achieve more weight loss but then you get more issues with tolerability. It’s a trade-off. If patients are experiencing adverse effects, the dose can be reduced, but then you will lose some effect. All the GLP-1 agonists have GI side effects – it’s part of the way that they work.”
 

Just weight loss or other actions too?

Speculating on the mechanism behind the reduction in cardiovascular events with semaglutide, Dr. Lincoff does not think it is just weight reduction.

“The event curves start to diverge very soon after the start of the trial and yet the maximum weight loss doesn’t occur until about 65 weeks. I think something else is going on.”

In the paper, the researchers noted that GLP-1 agonists have been shown in animal studies to reduce inflammation, improve endothelial and left ventricular function, promote plaque stability, and decrease platelet aggregation. In this trial, semaglutide was associated with changes in multiple biomarkers of cardiovascular risk, including blood pressure, waist circumference, glycemic control, nephropathy, and levels of lipids and C-reactive protein.

Dr. Lincoff also pointed out that similar benefits were seen in patients with different levels of overweight, and in those who were prediabetic and those who weren’t, so benefit was not dependent on baseline BMI or glycated hemoglobin levels.

Dr. O’Donoghue agreed that other effects, as well as weight loss, could be involved. “The reduction in events with semaglutide appeared very early after initiation and far preceded the drug’s maximal effects on weight reduction. This might suggest that the drug offers other cardioprotective effects through pathways independent of weight loss. Certainly, semaglutide and the other GLP-1 agonists appear to attenuate inflammation, and the patterns of redistribution of adipose tissue may also be of interest.”

She also pointed out that the reduction in cardiovascular events appeared even earlier in this population of obese nondiabetic patients with cardiovascular disease than in prior studies of patients with diabetes. “It may suggest that there is particular benefit for this type of therapy in patients with an inflammatory milieu. I look forward to seeing further analyses to help tease apart the correlation between changes in inflammation, observed weight loss and cardiovascular benefit.”
 

Effect on clinical practice

With the majority of patients with cardiovascular disease being overweight, these results are obviously going to increase demand for semaglutide, but cost and availability are going to be an issue.

Dr. Bhatt noted that semaglutide is already very popular. “Weight loss drugs are somewhat different from other medications. I can spend 30 minutes trying to convince a patient to take a statin, but here people realize it’s going to cause weight loss and they come in asking for it even if they don’t strictly need it. I think it’s good to have cardiovascular outcome data because now at least for this population of patients, we have evidence to prescribe it.”

He agreed with Dr. Lincoff that these new data should encourage insurance companies to cover the drug, because in reducing cardiovascular events it should also improve downstream health care costs.

“It is providing clear cardiovascular and kidney benefit, so it is in the best interest to the health care system to fund this drug,” he said. “I hope insurers look at it rationally in this way, but they may also be frightened of the explosion of patients wanting this drug and now doctors wanting to prescribe it and how that would affect their shorter-term costs.”

Dr. Lincoff said it would not be easy to prioritize certain groups. “We couldn’t identify any subgroup who showed particularly more benefit than any others. But in the evolution of any therapy, there is a time period where it is in short supply and prohibitively expensive, then over time when there is some competition and pricing deals occur as more people are advocating for it, they become more available.”
 

‘A welcome treatment option’

In an editorial accompanying publication of the trial, Amit Khera, MD, University of Texas Southwestern Medical Center, Dallas, and Tiffany Powell-Wiley, MD, MPH, National Institutes of Health, Bethesda, noted that baseline risk factors such as LDL cholesterol (78 mg/dL) and systolic blood pressure (131 mm Hg) were not ideal in the semaglutide group in this trial, and they suggest that the benefits of semaglutide may be attenuated when these measures are better controlled.

But given that more than 20 million people in the United States have coronary artery disease, with the majority having overweight or obesity and only approximately 30% having concomitant diabetes, they said that, even in the context of well-controlled risk factors and very low LDL cholesterol levels, the residual risk of atherosclerotic cardiovascular disease in these persons is unacceptably high. “Thus, the SELECT trial provides a welcome treatment option that can be extended to millions of additional patients.”

However, the editorialists cautioned that semaglutide at current pricing comes with a significant cost to both patients and society, which makes this treatment inaccessible for many. 

They added that intensive lifestyle interventions and bariatric surgery remain effective but underutilized options for obesity, and that the prevention of obesity before it develops should be the primary goal.

The SELECT trial was supported by Novo Nordisk, and several coauthors are employees of the company. Dr. Lincoff is a consultant for Novo Nordisk. Dr. Bhatt and Dr. Nissen are involved in a cardiovascular outcomes trial with a new investigational weight loss drug from Lilly. Dr. Bhatt and Dr. Ballantyne are also investigators in a Novo Nordisk trial of a new anti-inflammatory drug.

Final results of the SELECT trial have shown that the antiobesity drug semaglutide (Wegovy) produced a consistent reduction of around 20% versus placebo across major cardiovascular event endpoints over the approximately 3-year follow-up in patients with overweight or obesity and cardiovascular disease but not diabetes.

“This is a very exciting set of results. I think it is going to have a big impact on a large number of people,” lead investigator A. Michael Lincoff, MD, vice chair for research in the department of cardiovascular medicine at the Cleveland Clinic, said in an interview. 

“And from a scientific standpoint, these data show that we now have a new pathway or a new modifiable risk factor for cardiovascular disease that we can use in our patients who have overweight or obesity,” he added.

The trial involved 17,604 patients with a history of cardiovascular disease and a body mass index of 27 kg/m² or above (mean BMI was 33), who were randomly assigned to the glucagonlike peptide–1 (GLP-1) agonist semaglutide, given by subcutaneous injection once weekly at a gradually escalating dose up to 2.4 mg daily by week 16, or placebo. The mean baseline glycated hemoglobin level was 5.8% and 66.4% of patients met the criteria for prediabetes.

Patients lost a mean of 9.4% of body weight over the first 2 years with semaglutide versus 0.88% with placebo.

The primary cardiovascular endpoint – a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke – was reduced significantly, with a hazard ratio of 0.80 (95% confidence interval, 0.72-0.90; P < .001).  

Death from cardiovascular causes, the first confirmatory secondary endpoint, showed a 15% reduction (HR, 0.85; P = .07) but this missed meeting criteria for statistical significance, and because of the hierarchical design of the trial, this meant that superiority testing was not performed for the remaining confirmatory secondary endpoints.

However, results showed reductions of around 20% for the heart failure composite endpoint and for all-cause mortality, with confidence intervals that did not cross 1.0, and directionally consistent effects were observed for all supportive secondary endpoints.

The HR for the heart failure composite endpoint was 0.82 (95% CI, 0.71-0.96), and the HR for death from any cause was 0.81 (95% CI, 0.71-0.93). Nonfatal MI was reduced by 28% (HR 0.72; 95% CI, 0.61-0.85).

The effects of semaglutide on the primary endpoint appeared to be similar across all prespecified subgroups.

Adverse events leading to discontinuation of treatment occurred in 16.6% in the semaglutide group, mostly gastrointestinal effects, and in 8.2% in the placebo group.

The trial results were presented by Dr. Lincoff at the annual scientific sessions of the American Heart Association . They were also simultaneously published online in the New England Journal of Medicine.

Dr. Lincoff explained that there is a growing pandemic of overweight and obesity worldwide with clear evidence for years that these conditions increase the risk of cardiovascular events – and yet there has been no evidence, until now, that any pharmacologic or lifestyle therapy can reduce the increased risk conferred by overweight/obesity. 

“Patients in the trial were already taking standard of care therapies for other risk factors, such as hypertension and cholesterol, so this drug is giving additional benefit,” he said.

Dr. Lincoff believes these data will lead to a large increase in use of semaglutide, which is already available for the treatment of obesity and diabetes but can be difficult to get reimbursed.

“There is a lot of difficulty getting payors to pay for this drug for weight management. But with this new data from the SELECT trial there should be more willingness – at least in the population with a history of cardiovascular disease,” he commented. In diabetes, where it is already established that there is a cardiovascular risk reduction, it is easier to get these drugs reimbursed, he noted.

On the outcome data, Dr. Lincoff said he could not explain why cardiovascular death was not significantly reduced while all-cause mortality appeared to be cut more definitively.

“The cardiovascular death curves separated, then merged, then separated again. We don’t really know what is going on there. It may be that some deaths were misclassified. This trial was conducted through the COVID era and there may have been less information available on some patients because of that.”

But he added: “The all-cause mortality is more reassuring, as it doesn’t depend on classifying cause of death. Because of the design of the trial, we can’t formally claim a reduction in all-cause mortality, but the results do suggest there is an effect on this endpoint. And all the different types of cardiovascular events were similarly reduced in a consistent way, with similar effects seen across all subgroups. That is very reassuring.”
 

‘A new era’ for patients with obesity

Outside experts in the field were also impressed with the data.

Designated discussant of the trial at the AHA meeting, Ania Jastreboff, MD, associate professor medicine (endocrinology) at Yale University, New Haven, Conn., said the SELECT trial was “a turning point in the treatment of obesity and a call to action.

“Now is the time to treat obesity to improve health outcomes in people with cardiovascular disease,” she said.

Dr. Jastreboff noted that high BMI was estimated to have accounted for 4 million deaths worldwide in 2015, two-thirds of which were caused by cardiovascular disease. And she presented data showing that U.S. individuals meeting the SELECT criteria increased from 4.3 million in 2011-12 to 6.6 million in 2017-18.

She highlighted one major limitation of the SELECT trial: it enrolled a low number of women (38%) and ethnic minorities, with only 12% of the trial population being Black.

Deepak L. Bhatt, MD, director of Mount Sinai Fuster Heart Hospital, New York, described the SELECT results as “altogether a compelling package of data.”

“These results are even better than I had expected,” Dr. Bhatt said in an interview. “There is a significant reduction in MI as I had anticipated, but additionally, there is a reduction in all-cause death. One can debate the statistics, though on a common-sense level, I think it is a real finding,” he noted.

“Given that MI, heart failure, nephropathy, and revascularization are all reduced, and even stroke is numerically lower, it makes sense that all-cause mortality would be reduced,” he said. “To me, apart from the GI side effects, this counts as a home run.”

Steve Nissen, MD, chief academic officer at the Cleveland Clinic’s Heart, Vascular and Thoracic Institute, was similarly upbeat.

“These data prove what many of us have long suspected – that losing weight can reduce cardiovascular morbidity and mortality. This is great news for patients living with obesity. The obesity epidemic is out of control,” he added. “We need to have therapies that improve cardiovascular outcomes caused by obesity and this shows that semaglutide can do that. I think this is the beginning of a whole new era for patients with obesity.”

Michelle O’Donoghue, MD, associate professor of medicine at Harvard Medical School, Boston, called the results of SELECT “both intriguing and compelling. Certainly, these findings lend further support to the use of semaglutide in a much broader secondary prevention population of individuals with obesity.”

Christie Ballantyne, MD, director of the center for cardiometabolic disease prevention at Baylor College of Medicine, Houston, described the SELECT study as “a landmark trial which will change the practice of medicine in regard to how we treat obesity.”

He compared it with the landmark 4S trial in 1994, the first study in the area of cholesterol lowering therapy to show a clear benefit in reducing cardiovascular events and total mortality, and “began a drastic change in the way that physicians approached treatment of cholesterol.”

On the more robust reduction in all-cause death, compared with cardiovascular death,

Dr. Ballantyne pointed out: “Adjudication of dead or alive is something that everyone gets right. In contrast, the cause of death is sometime difficult to ascertain. Most importantly, the benefit on total mortality also provides assurance that this therapy does not have some adverse effect on increasing noncardiovascular deaths.”
 

Gastrointestinal adverse effects

On the side effects seen with semaglutide, Dr. Lincoff reported that 10% of patients in the semaglutide group discontinued treatment because of GI side effects versus 2% in the placebo arm. He said this was “an expected issue.”

“GI effects, such as nausea, vomiting and diarrhea, are known side effects of this whole class of drugs. The dose is slowly escalated to manage these adverse effects but there will be a proportion of patients who can’t tolerate it, although the vast majority are able to continue.”

He noted that, while dose reduction was allowed, of the patients who were still on the drug at 2 years, 77% were on the full dose, and 23% were on a reduced dose.

Dr. Lincoff pointed out that there were no serious adverse events with semaglutide. “This is the largest database by far now on the drug with a long-term follow up and we didn’t see the emergence of any new safety signals, which is very reassuring.”  

Dr. Nissen said the 16% rate of patients stopping the drug because of tolerability “is not a trivial number.”

He noted that the semaglutide dose used in this study was larger than that used in diabetes.

“They did this to try to achieve more weight loss but then you get more issues with tolerability. It’s a trade-off. If patients are experiencing adverse effects, the dose can be reduced, but then you will lose some effect. All the GLP-1 agonists have GI side effects – it’s part of the way that they work.”
 

Just weight loss or other actions too?

Speculating on the mechanism behind the reduction in cardiovascular events with semaglutide, Dr. Lincoff does not think it is just weight reduction.

“The event curves start to diverge very soon after the start of the trial and yet the maximum weight loss doesn’t occur until about 65 weeks. I think something else is going on.”

In the paper, the researchers noted that GLP-1 agonists have been shown in animal studies to reduce inflammation, improve endothelial and left ventricular function, promote plaque stability, and decrease platelet aggregation. In this trial, semaglutide was associated with changes in multiple biomarkers of cardiovascular risk, including blood pressure, waist circumference, glycemic control, nephropathy, and levels of lipids and C-reactive protein.

Dr. Lincoff also pointed out that similar benefits were seen in patients with different levels of overweight, and in those who were prediabetic and those who weren’t, so benefit was not dependent on baseline BMI or glycated hemoglobin levels.

Dr. O’Donoghue agreed that other effects, as well as weight loss, could be involved. “The reduction in events with semaglutide appeared very early after initiation and far preceded the drug’s maximal effects on weight reduction. This might suggest that the drug offers other cardioprotective effects through pathways independent of weight loss. Certainly, semaglutide and the other GLP-1 agonists appear to attenuate inflammation, and the patterns of redistribution of adipose tissue may also be of interest.”

She also pointed out that the reduction in cardiovascular events appeared even earlier in this population of obese nondiabetic patients with cardiovascular disease than in prior studies of patients with diabetes. “It may suggest that there is particular benefit for this type of therapy in patients with an inflammatory milieu. I look forward to seeing further analyses to help tease apart the correlation between changes in inflammation, observed weight loss and cardiovascular benefit.”
 

Effect on clinical practice

With the majority of patients with cardiovascular disease being overweight, these results are obviously going to increase demand for semaglutide, but cost and availability are going to be an issue.

Dr. Bhatt noted that semaglutide is already very popular. “Weight loss drugs are somewhat different from other medications. I can spend 30 minutes trying to convince a patient to take a statin, but here people realize it’s going to cause weight loss and they come in asking for it even if they don’t strictly need it. I think it’s good to have cardiovascular outcome data because now at least for this population of patients, we have evidence to prescribe it.”

He agreed with Dr. Lincoff that these new data should encourage insurance companies to cover the drug, because in reducing cardiovascular events it should also improve downstream health care costs.

“It is providing clear cardiovascular and kidney benefit, so it is in the best interest to the health care system to fund this drug,” he said. “I hope insurers look at it rationally in this way, but they may also be frightened of the explosion of patients wanting this drug and now doctors wanting to prescribe it and how that would affect their shorter-term costs.”

Dr. Lincoff said it would not be easy to prioritize certain groups. “We couldn’t identify any subgroup who showed particularly more benefit than any others. But in the evolution of any therapy, there is a time period where it is in short supply and prohibitively expensive, then over time when there is some competition and pricing deals occur as more people are advocating for it, they become more available.”
 

‘A welcome treatment option’

In an editorial accompanying publication of the trial, Amit Khera, MD, University of Texas Southwestern Medical Center, Dallas, and Tiffany Powell-Wiley, MD, MPH, National Institutes of Health, Bethesda, noted that baseline risk factors such as LDL cholesterol (78 mg/dL) and systolic blood pressure (131 mm Hg) were not ideal in the semaglutide group in this trial, and they suggest that the benefits of semaglutide may be attenuated when these measures are better controlled.

But given that more than 20 million people in the United States have coronary artery disease, with the majority having overweight or obesity and only approximately 30% having concomitant diabetes, they said that, even in the context of well-controlled risk factors and very low LDL cholesterol levels, the residual risk of atherosclerotic cardiovascular disease in these persons is unacceptably high. “Thus, the SELECT trial provides a welcome treatment option that can be extended to millions of additional patients.”

However, the editorialists cautioned that semaglutide at current pricing comes with a significant cost to both patients and society, which makes this treatment inaccessible for many. 

They added that intensive lifestyle interventions and bariatric surgery remain effective but underutilized options for obesity, and that the prevention of obesity before it develops should be the primary goal.

The SELECT trial was supported by Novo Nordisk, and several coauthors are employees of the company. Dr. Lincoff is a consultant for Novo Nordisk. Dr. Bhatt and Dr. Nissen are involved in a cardiovascular outcomes trial with a new investigational weight loss drug from Lilly. Dr. Bhatt and Dr. Ballantyne are also investigators in a Novo Nordisk trial of a new anti-inflammatory drug.

Two biomarkers – pregnancy-associated plasma protein A2 (PAPP-A2) and activin A – when added to relevant clinical information have a better positive predictive value than and a comparable negative predictive value to the currently used ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF), new research suggests.

The third-trimester sFlt-1:PlGF ratio can predict short-term absence of preeclampsia. By contrast, PAPP-A2 and activin A could serve as biomarkers to predict the occurrence as well as the absence of preeclampsia, according to the authors.

Preeclampsia has “potentially devastating maternal and fetal complications, [including] significantly increased cardiovascular risk for affected women later in life,” study author Stella S. Daskalopoulou, MD, PhD, associate professor of medicine at McGill University Health Centre in Montreal, said in an interview.

“A more accurate prediction of preeclampsia is expected to improve risk stratification and clinical care and shape clinical practice guidelines,” she said.

The study was published online in the Canadian Journal of Cardiology.
 

Better predictive value

For a prospective cohort study, the investigators recruited 192 women with first-trimester high-risk singleton pregnancies from tertiary obstetric clinics in Montreal.

At baseline, they collected clinical information, including height, prepregnancy weight, personal and family medical history, and medication use.

At each trimester, blood pressure was measured, and blood samples were collected to quantify sFlt-1, PlGF, PAPP-A2, PAPP-A, activin A, inhibin A, follistatin, and glycosylated fibronectin. For the sFlt-1:PlGF ratio, the researchers used a cutoff point of 38, based on prior evidence. Because there are no agreed-upon cutoff points for the other biomarkers, they chose cutoff points that maximized sensitivity and specificity.

Pregnancies were considered high risk if the mother had any of the following conditions: prepregnancy BMI ≥ 25, maternal age ≥ 35 years, chronic hypertension, diabetes, renal disease, conception via in vitro fertilization, or maternal or first-degree family history of preeclampsia.

The primary outcome was preeclampsia, which was defined according to the Society of Obstetrics and Gynecology guidelines as systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure of ≥ mm Hg together with either proteinuria or maternal end-organ dysfunction.

A total of 18 women (9.38%) developed preeclampsia. Those women had higher blood pressure at baseline (although it was within normal limits) and were more likely to have preexisting diabetes or a previous pregnancy with preeclampsia. They were also more likely to report Black race. Serum levels of PAPP-A, PAPP-A2, activin A, and inhibin A were significantly different between patients who developed preeclampsia and those who did not. These levels were increased throughout pregnancy.

Alongside the sFlt-1:PlGF ratio, two biomarkers, PAPP-A2 (odds ratio, 1.78) and activin A (OR, 1.84), were significantly associated with the primary outcome after adjustment for age, prepregnancy BMI, race, and mean arterial pressure.

When added to a model that included those clinical factors, a positive third-trimester result for both PAPP-A2 and activin A had a better positive predictive value than the sFlt-1:PlGF ratio added to the clinical model (91.67% vs. 66.67%). The two biomarkers also had a negative predictive value that was comparable to that of the sFlt-1:PlGF ratio (97.69% vs. 96%).

Study limitations include the small sample size and missing covariates for some participants. Furthermore, the findings cannot be generalized to low-risk populations.

“Whereas the third-trimester sFlt-1:PlGF ratio can predict short-term absence of preeclampsia, PAPP-A2 and activin A had both high positive and negative predictive values and thus could serve as biomarkers to predict the occurrence (and absence) of preeclampsia; these findings will be validated in future studies,” the authors concluded.

Dr. Daskalopoulou said that her group is currently performing a large multinational study, PULSE, “which will be the ideal platform to validate and extend our findings. The aim of the study is to predict preeclampsia using a multimodal approach that includes arterial stiffness measurements and blood biomarkers.”

She expanded on the potential benefits of this research. “Finding an accurate predictive tool would not only help design appropriate early care plans for truly high-risk pregnant women, including monitoring and delivery planning, but also facilitate the development of novel strategies for the prevention and treatment of preeclampsia, improving the life of millions of young mothers and their offspring around the world.”
 

Promising biomarkers

Commenting on the study, Nieca Goldberg, MD, clinical associate professor of medicine at NYU Langone Health and medical director of Atria, both in New York, said, “These biomarkers are promising, as the current biomarker, sFlt-1:PlGF, is good at ruling out preeclampsia in the short term, while the new biomarkers show that they are better at ruling in preeclampsia” as well as ruling it out. Dr. Goldberg was not involved in the research.

“The current study is small, some participant data points are missing, and the researchers only studied high-risk pregnancies,” she added. “We need larger studies of all the risk markers, in both high- and low-risk pregnancies that are followed throughout pregnancy.”

This work was supported by the Fonds de recherche du Québec Santé (FRQS), Heart and Stroke Foundation of Canada, McGill University Department of Obstetrics and Gynecology Academic Enrichment Fund, and Canadian Foundation for Women›s Health. Dr. Daskalopoulou is a senior clinician-scientist supported by a FRQS Clinician Scientist-Senior salary award. Dr. Daskalopoulou and Dr. Goldberg disclosed no conflicts of interest.

A version of this article appeared on Medscape.com.

Two biomarkers – pregnancy-associated plasma protein A2 (PAPP-A2) and activin A – when added to relevant clinical information have a better positive predictive value than and a comparable negative predictive value to the currently used ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF), new research suggests.

The third-trimester sFlt-1:PlGF ratio can predict short-term absence of preeclampsia. By contrast, PAPP-A2 and activin A could serve as biomarkers to predict the occurrence as well as the absence of preeclampsia, according to the authors.

Preeclampsia has “potentially devastating maternal and fetal complications, [including] significantly increased cardiovascular risk for affected women later in life,” study author Stella S. Daskalopoulou, MD, PhD, associate professor of medicine at McGill University Health Centre in Montreal, said in an interview.

“A more accurate prediction of preeclampsia is expected to improve risk stratification and clinical care and shape clinical practice guidelines,” she said.

The study was published online in the Canadian Journal of Cardiology.
 

Better predictive value

For a prospective cohort study, the investigators recruited 192 women with first-trimester high-risk singleton pregnancies from tertiary obstetric clinics in Montreal.

At baseline, they collected clinical information, including height, prepregnancy weight, personal and family medical history, and medication use.

At each trimester, blood pressure was measured, and blood samples were collected to quantify sFlt-1, PlGF, PAPP-A2, PAPP-A, activin A, inhibin A, follistatin, and glycosylated fibronectin. For the sFlt-1:PlGF ratio, the researchers used a cutoff point of 38, based on prior evidence. Because there are no agreed-upon cutoff points for the other biomarkers, they chose cutoff points that maximized sensitivity and specificity.

Pregnancies were considered high risk if the mother had any of the following conditions: prepregnancy BMI ≥ 25, maternal age ≥ 35 years, chronic hypertension, diabetes, renal disease, conception via in vitro fertilization, or maternal or first-degree family history of preeclampsia.

The primary outcome was preeclampsia, which was defined according to the Society of Obstetrics and Gynecology guidelines as systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure of ≥ mm Hg together with either proteinuria or maternal end-organ dysfunction.

A total of 18 women (9.38%) developed preeclampsia. Those women had higher blood pressure at baseline (although it was within normal limits) and were more likely to have preexisting diabetes or a previous pregnancy with preeclampsia. They were also more likely to report Black race. Serum levels of PAPP-A, PAPP-A2, activin A, and inhibin A were significantly different between patients who developed preeclampsia and those who did not. These levels were increased throughout pregnancy.

Alongside the sFlt-1:PlGF ratio, two biomarkers, PAPP-A2 (odds ratio, 1.78) and activin A (OR, 1.84), were significantly associated with the primary outcome after adjustment for age, prepregnancy BMI, race, and mean arterial pressure.

When added to a model that included those clinical factors, a positive third-trimester result for both PAPP-A2 and activin A had a better positive predictive value than the sFlt-1:PlGF ratio added to the clinical model (91.67% vs. 66.67%). The two biomarkers also had a negative predictive value that was comparable to that of the sFlt-1:PlGF ratio (97.69% vs. 96%).

Study limitations include the small sample size and missing covariates for some participants. Furthermore, the findings cannot be generalized to low-risk populations.

“Whereas the third-trimester sFlt-1:PlGF ratio can predict short-term absence of preeclampsia, PAPP-A2 and activin A had both high positive and negative predictive values and thus could serve as biomarkers to predict the occurrence (and absence) of preeclampsia; these findings will be validated in future studies,” the authors concluded.

Dr. Daskalopoulou said that her group is currently performing a large multinational study, PULSE, “which will be the ideal platform to validate and extend our findings. The aim of the study is to predict preeclampsia using a multimodal approach that includes arterial stiffness measurements and blood biomarkers.”

She expanded on the potential benefits of this research. “Finding an accurate predictive tool would not only help design appropriate early care plans for truly high-risk pregnant women, including monitoring and delivery planning, but also facilitate the development of novel strategies for the prevention and treatment of preeclampsia, improving the life of millions of young mothers and their offspring around the world.”
 

Promising biomarkers

Commenting on the study, Nieca Goldberg, MD, clinical associate professor of medicine at NYU Langone Health and medical director of Atria, both in New York, said, “These biomarkers are promising, as the current biomarker, sFlt-1:PlGF, is good at ruling out preeclampsia in the short term, while the new biomarkers show that they are better at ruling in preeclampsia” as well as ruling it out. Dr. Goldberg was not involved in the research.

“The current study is small, some participant data points are missing, and the researchers only studied high-risk pregnancies,” she added. “We need larger studies of all the risk markers, in both high- and low-risk pregnancies that are followed throughout pregnancy.”

This work was supported by the Fonds de recherche du Québec Santé (FRQS), Heart and Stroke Foundation of Canada, McGill University Department of Obstetrics and Gynecology Academic Enrichment Fund, and Canadian Foundation for Women›s Health. Dr. Daskalopoulou is a senior clinician-scientist supported by a FRQS Clinician Scientist-Senior salary award. Dr. Daskalopoulou and Dr. Goldberg disclosed no conflicts of interest.

A version of this article appeared on Medscape.com.

Two biomarkers – pregnancy-associated plasma protein A2 (PAPP-A2) and activin A – when added to relevant clinical information have a better positive predictive value than and a comparable negative predictive value to the currently used ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF), new research suggests.

The third-trimester sFlt-1:PlGF ratio can predict short-term absence of preeclampsia. By contrast, PAPP-A2 and activin A could serve as biomarkers to predict the occurrence as well as the absence of preeclampsia, according to the authors.

Preeclampsia has “potentially devastating maternal and fetal complications, [including] significantly increased cardiovascular risk for affected women later in life,” study author Stella S. Daskalopoulou, MD, PhD, associate professor of medicine at McGill University Health Centre in Montreal, said in an interview.

“A more accurate prediction of preeclampsia is expected to improve risk stratification and clinical care and shape clinical practice guidelines,” she said.

The study was published online in the Canadian Journal of Cardiology.
 

Better predictive value

For a prospective cohort study, the investigators recruited 192 women with first-trimester high-risk singleton pregnancies from tertiary obstetric clinics in Montreal.

At baseline, they collected clinical information, including height, prepregnancy weight, personal and family medical history, and medication use.

At each trimester, blood pressure was measured, and blood samples were collected to quantify sFlt-1, PlGF, PAPP-A2, PAPP-A, activin A, inhibin A, follistatin, and glycosylated fibronectin. For the sFlt-1:PlGF ratio, the researchers used a cutoff point of 38, based on prior evidence. Because there are no agreed-upon cutoff points for the other biomarkers, they chose cutoff points that maximized sensitivity and specificity.

Pregnancies were considered high risk if the mother had any of the following conditions: prepregnancy BMI ≥ 25, maternal age ≥ 35 years, chronic hypertension, diabetes, renal disease, conception via in vitro fertilization, or maternal or first-degree family history of preeclampsia.

The primary outcome was preeclampsia, which was defined according to the Society of Obstetrics and Gynecology guidelines as systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure of ≥ mm Hg together with either proteinuria or maternal end-organ dysfunction.

A total of 18 women (9.38%) developed preeclampsia. Those women had higher blood pressure at baseline (although it was within normal limits) and were more likely to have preexisting diabetes or a previous pregnancy with preeclampsia. They were also more likely to report Black race. Serum levels of PAPP-A, PAPP-A2, activin A, and inhibin A were significantly different between patients who developed preeclampsia and those who did not. These levels were increased throughout pregnancy.

Alongside the sFlt-1:PlGF ratio, two biomarkers, PAPP-A2 (odds ratio, 1.78) and activin A (OR, 1.84), were significantly associated with the primary outcome after adjustment for age, prepregnancy BMI, race, and mean arterial pressure.

When added to a model that included those clinical factors, a positive third-trimester result for both PAPP-A2 and activin A had a better positive predictive value than the sFlt-1:PlGF ratio added to the clinical model (91.67% vs. 66.67%). The two biomarkers also had a negative predictive value that was comparable to that of the sFlt-1:PlGF ratio (97.69% vs. 96%).

Study limitations include the small sample size and missing covariates for some participants. Furthermore, the findings cannot be generalized to low-risk populations.

“Whereas the third-trimester sFlt-1:PlGF ratio can predict short-term absence of preeclampsia, PAPP-A2 and activin A had both high positive and negative predictive values and thus could serve as biomarkers to predict the occurrence (and absence) of preeclampsia; these findings will be validated in future studies,” the authors concluded.

Dr. Daskalopoulou said that her group is currently performing a large multinational study, PULSE, “which will be the ideal platform to validate and extend our findings. The aim of the study is to predict preeclampsia using a multimodal approach that includes arterial stiffness measurements and blood biomarkers.”

She expanded on the potential benefits of this research. “Finding an accurate predictive tool would not only help design appropriate early care plans for truly high-risk pregnant women, including monitoring and delivery planning, but also facilitate the development of novel strategies for the prevention and treatment of preeclampsia, improving the life of millions of young mothers and their offspring around the world.”
 

Promising biomarkers

Commenting on the study, Nieca Goldberg, MD, clinical associate professor of medicine at NYU Langone Health and medical director of Atria, both in New York, said, “These biomarkers are promising, as the current biomarker, sFlt-1:PlGF, is good at ruling out preeclampsia in the short term, while the new biomarkers show that they are better at ruling in preeclampsia” as well as ruling it out. Dr. Goldberg was not involved in the research.

“The current study is small, some participant data points are missing, and the researchers only studied high-risk pregnancies,” she added. “We need larger studies of all the risk markers, in both high- and low-risk pregnancies that are followed throughout pregnancy.”

This work was supported by the Fonds de recherche du Québec Santé (FRQS), Heart and Stroke Foundation of Canada, McGill University Department of Obstetrics and Gynecology Academic Enrichment Fund, and Canadian Foundation for Women›s Health. Dr. Daskalopoulou is a senior clinician-scientist supported by a FRQS Clinician Scientist-Senior salary award. Dr. Daskalopoulou and Dr. Goldberg disclosed no conflicts of interest.

A version of this article appeared on Medscape.com.

NEW YORK – As a result of recent progress in the control of prurigo nodularis, failure to recognize the differences in presentation across skin types threatens prolonged but preventable morbidity from a disease with a devastating clinical impact, according to an expert evaluating current approaches at the Skin of Color Update 2023.

“As dermatologists, prurigo nodularis is one of the most severe diseases we treat, said Shawn G. Kwatra, MD, director of the Johns Hopkins Itch Center, Baltimore. Now with one approved therapy and more coming, “it offers one of the most important opportunities we have to dramatically improve someone’s entire life.”

Ted Bosworth/MDedge News

Prior to the September 2022 approval of dupilumab for the treatment of prurigo nodularis (the first treatment approved for this indication), Dr. Kwatra said that the limited options for control of pruritus made him anxious. Prurigo nodularis is characterized by highly itchy nodules that can produce symptoms patients describe as unbearable.
 

Itch typically severe

On a scale for which 10 represents the worst itch imaginable, scores of 8 or greater are not unusual, according to Dr. Kwatra. Nodules on the trunk and the extensor surfaces of the arms and legs are characteristic, but the persistent itch is the immediate target of treatment once the diagnosis is made. For that reason, he urged clinicians to be familiar with the presentation in patients with darker skin types to reduce time to treatment.

In addition to the difficulty of seeing the characteristic red that is typical of erythema in lighter skin, patients with darker skin types tend to have larger nodules that might vary in shape relative to lighter skin types, Dr. Kwatra said. Given that the presentation of prurigo nodularis is highly heterogeneous even among the same skin types, the nuances in patients with darker skin can be that much more confusing for those without prior experience.

Among Blacks in particular, the nodules in some cases “can be huge,” he added. “They can almost look like keloids due to their thickened and fibrotic appearance.”
 

Phenotypes appear to be racially linked

In Black patients, the appearance can vary enough relative to lighter skin individuals, that “there seems to be something a little bit different going on,” he said, and this is, in fact, supported by a cluster analysis of circulating biomarkers reported by Dr. Kwatra and colleagues in 2022, in the Journal of Investigative Dermatology.

In that study, the biomarker profile distinguished two distinct groups. Whites were more common in a cluster with relatively low expression of inflammatory markers (cluster 1), while Blacks were more common in a cluster with an inflammatory plasma profile (cluster 2), with higher relative expression of multiple cytokines, C-reactive protein, eosinophils, and other markers of up-regulated inflammation.

In addition to a lower rate of myelopathy in cluster 2 than cluster 1 (18% vs. 67%; P = .028), patients in cluster 2 had a significantly worse itch than those in cluster 1 on the Numeric Rating Scale for itch and a significantly lower quality of life based on the Dermatology Life Quality Index score.

Other work at Dr. Kwatra’s center that is based on genetic sequencing has provided evidence that Blacks – and Asians to a lesser extent – are predisposed genetically to develop nodules, perhaps explaining why the nodules tend to be larger than those seen in Whites.

The significance of the evidence that prurigo nodularis is associated with a more up-regulated inflammatory profile in Blacks than in Whites is that they might be particularly likely to respond to dupilumab or other targeted immunomodulating therapies that are in development, according to Dr. Kwatra. Although he did not provide data on response by race, he did provide several case examples of complete itch control following dupilumab therapy in Black patients.

In his experience, high levels of blood eosinophils and other inflammatory markers are predictors of response to dupilumab regardless of skin type, but he expressed concern that time to diagnosis is sometimes longer in Black patients if the nuances of disease expression are not appreciated.

For treating prurigo nodularis in Blacks as well as Whites, Dr. Kwatra suggested that clinicians stay current with what he predicted will be a growing array of treatment options. He did not discuss nemolizumab, an interleukin-31 receptor alpha antagonist. Soon after the meeting, results of a phase 3 trial of nemolizumab in patients with moderate to severe prurigo nodularis were published in the New England Journal of Medicine. (Dr. Kwatra is the lead author of the study but did not specifically discuss this treatment at the meeting.)

In the international placebo-controlled trial, called OLYMPIA 2, treatment was associated with a significant reduction in the signs and symptoms of prurigo nodularis, including reductions in itch, at 16 weeks, although only 4% of patients in the study were Black.

Given the expanding array of therapies, the message of considering prurigo nodularis in Black patients in order to accelerate the time to diagnosis is timely, Andrew F. Alexis, MD, MPH, professor of clinical dermatology and vice-chair for diversity and inclusion for the department of dermatology, Weill Cornell Medicine, New York.

“Current studies suggest a higher prevalence and greater severity of prurigo nodularis among Black patients compared to White patients,” said Dr. Alexis, agreeing with Dr. Kwatra. Referring to evidence that Blacks might mount a greater inflammatory response to prurigo nodularis than Whites, Dr. Alexis called for “a better understanding of the pathomechanisms” of this disease in order “to address unmet needs and reduce disparities for our diverse population of patients who suffer from prurigo nodularis.’

Dr. Kwatra reported financial relationships with AbbVie, Amgen, Arcutis, ASLAN, Cara, Castle Biosciences, Celldex, Galderma, Incyte, Johnson & Johnson, LEO pharma, Novartis, Pfizer, Regeneron, and Sanofi.

NEW YORK – As a result of recent progress in the control of prurigo nodularis, failure to recognize the differences in presentation across skin types threatens prolonged but preventable morbidity from a disease with a devastating clinical impact, according to an expert evaluating current approaches at the Skin of Color Update 2023.

“As dermatologists, prurigo nodularis is one of the most severe diseases we treat, said Shawn G. Kwatra, MD, director of the Johns Hopkins Itch Center, Baltimore. Now with one approved therapy and more coming, “it offers one of the most important opportunities we have to dramatically improve someone’s entire life.”

Ted Bosworth/MDedge News

Prior to the September 2022 approval of dupilumab for the treatment of prurigo nodularis (the first treatment approved for this indication), Dr. Kwatra said that the limited options for control of pruritus made him anxious. Prurigo nodularis is characterized by highly itchy nodules that can produce symptoms patients describe as unbearable.
 

Itch typically severe

On a scale for which 10 represents the worst itch imaginable, scores of 8 or greater are not unusual, according to Dr. Kwatra. Nodules on the trunk and the extensor surfaces of the arms and legs are characteristic, but the persistent itch is the immediate target of treatment once the diagnosis is made. For that reason, he urged clinicians to be familiar with the presentation in patients with darker skin types to reduce time to treatment.

In addition to the difficulty of seeing the characteristic red that is typical of erythema in lighter skin, patients with darker skin types tend to have larger nodules that might vary in shape relative to lighter skin types, Dr. Kwatra said. Given that the presentation of prurigo nodularis is highly heterogeneous even among the same skin types, the nuances in patients with darker skin can be that much more confusing for those without prior experience.

Among Blacks in particular, the nodules in some cases “can be huge,” he added. “They can almost look like keloids due to their thickened and fibrotic appearance.”
 

Phenotypes appear to be racially linked

In Black patients, the appearance can vary enough relative to lighter skin individuals, that “there seems to be something a little bit different going on,” he said, and this is, in fact, supported by a cluster analysis of circulating biomarkers reported by Dr. Kwatra and colleagues in 2022, in the Journal of Investigative Dermatology.

In that study, the biomarker profile distinguished two distinct groups. Whites were more common in a cluster with relatively low expression of inflammatory markers (cluster 1), while Blacks were more common in a cluster with an inflammatory plasma profile (cluster 2), with higher relative expression of multiple cytokines, C-reactive protein, eosinophils, and other markers of up-regulated inflammation.

In addition to a lower rate of myelopathy in cluster 2 than cluster 1 (18% vs. 67%; P = .028), patients in cluster 2 had a significantly worse itch than those in cluster 1 on the Numeric Rating Scale for itch and a significantly lower quality of life based on the Dermatology Life Quality Index score.

Other work at Dr. Kwatra’s center that is based on genetic sequencing has provided evidence that Blacks – and Asians to a lesser extent – are predisposed genetically to develop nodules, perhaps explaining why the nodules tend to be larger than those seen in Whites.

The significance of the evidence that prurigo nodularis is associated with a more up-regulated inflammatory profile in Blacks than in Whites is that they might be particularly likely to respond to dupilumab or other targeted immunomodulating therapies that are in development, according to Dr. Kwatra. Although he did not provide data on response by race, he did provide several case examples of complete itch control following dupilumab therapy in Black patients.

In his experience, high levels of blood eosinophils and other inflammatory markers are predictors of response to dupilumab regardless of skin type, but he expressed concern that time to diagnosis is sometimes longer in Black patients if the nuances of disease expression are not appreciated.

For treating prurigo nodularis in Blacks as well as Whites, Dr. Kwatra suggested that clinicians stay current with what he predicted will be a growing array of treatment options. He did not discuss nemolizumab, an interleukin-31 receptor alpha antagonist. Soon after the meeting, results of a phase 3 trial of nemolizumab in patients with moderate to severe prurigo nodularis were published in the New England Journal of Medicine. (Dr. Kwatra is the lead author of the study but did not specifically discuss this treatment at the meeting.)

In the international placebo-controlled trial, called OLYMPIA 2, treatment was associated with a significant reduction in the signs and symptoms of prurigo nodularis, including reductions in itch, at 16 weeks, although only 4% of patients in the study were Black.

Given the expanding array of therapies, the message of considering prurigo nodularis in Black patients in order to accelerate the time to diagnosis is timely, Andrew F. Alexis, MD, MPH, professor of clinical dermatology and vice-chair for diversity and inclusion for the department of dermatology, Weill Cornell Medicine, New York.

“Current studies suggest a higher prevalence and greater severity of prurigo nodularis among Black patients compared to White patients,” said Dr. Alexis, agreeing with Dr. Kwatra. Referring to evidence that Blacks might mount a greater inflammatory response to prurigo nodularis than Whites, Dr. Alexis called for “a better understanding of the pathomechanisms” of this disease in order “to address unmet needs and reduce disparities for our diverse population of patients who suffer from prurigo nodularis.’

Dr. Kwatra reported financial relationships with AbbVie, Amgen, Arcutis, ASLAN, Cara, Castle Biosciences, Celldex, Galderma, Incyte, Johnson & Johnson, LEO pharma, Novartis, Pfizer, Regeneron, and Sanofi.

NEW YORK – As a result of recent progress in the control of prurigo nodularis, failure to recognize the differences in presentation across skin types threatens prolonged but preventable morbidity from a disease with a devastating clinical impact, according to an expert evaluating current approaches at the Skin of Color Update 2023.

“As dermatologists, prurigo nodularis is one of the most severe diseases we treat, said Shawn G. Kwatra, MD, director of the Johns Hopkins Itch Center, Baltimore. Now with one approved therapy and more coming, “it offers one of the most important opportunities we have to dramatically improve someone’s entire life.”

Ted Bosworth/MDedge News

Prior to the September 2022 approval of dupilumab for the treatment of prurigo nodularis (the first treatment approved for this indication), Dr. Kwatra said that the limited options for control of pruritus made him anxious. Prurigo nodularis is characterized by highly itchy nodules that can produce symptoms patients describe as unbearable.
 

Itch typically severe

On a scale for which 10 represents the worst itch imaginable, scores of 8 or greater are not unusual, according to Dr. Kwatra. Nodules on the trunk and the extensor surfaces of the arms and legs are characteristic, but the persistent itch is the immediate target of treatment once the diagnosis is made. For that reason, he urged clinicians to be familiar with the presentation in patients with darker skin types to reduce time to treatment.

In addition to the difficulty of seeing the characteristic red that is typical of erythema in lighter skin, patients with darker skin types tend to have larger nodules that might vary in shape relative to lighter skin types, Dr. Kwatra said. Given that the presentation of prurigo nodularis is highly heterogeneous even among the same skin types, the nuances in patients with darker skin can be that much more confusing for those without prior experience.

Among Blacks in particular, the nodules in some cases “can be huge,” he added. “They can almost look like keloids due to their thickened and fibrotic appearance.”
 

Phenotypes appear to be racially linked

In Black patients, the appearance can vary enough relative to lighter skin individuals, that “there seems to be something a little bit different going on,” he said, and this is, in fact, supported by a cluster analysis of circulating biomarkers reported by Dr. Kwatra and colleagues in 2022, in the Journal of Investigative Dermatology.

In that study, the biomarker profile distinguished two distinct groups. Whites were more common in a cluster with relatively low expression of inflammatory markers (cluster 1), while Blacks were more common in a cluster with an inflammatory plasma profile (cluster 2), with higher relative expression of multiple cytokines, C-reactive protein, eosinophils, and other markers of up-regulated inflammation.

In addition to a lower rate of myelopathy in cluster 2 than cluster 1 (18% vs. 67%; P = .028), patients in cluster 2 had a significantly worse itch than those in cluster 1 on the Numeric Rating Scale for itch and a significantly lower quality of life based on the Dermatology Life Quality Index score.

Other work at Dr. Kwatra’s center that is based on genetic sequencing has provided evidence that Blacks – and Asians to a lesser extent – are predisposed genetically to develop nodules, perhaps explaining why the nodules tend to be larger than those seen in Whites.

The significance of the evidence that prurigo nodularis is associated with a more up-regulated inflammatory profile in Blacks than in Whites is that they might be particularly likely to respond to dupilumab or other targeted immunomodulating therapies that are in development, according to Dr. Kwatra. Although he did not provide data on response by race, he did provide several case examples of complete itch control following dupilumab therapy in Black patients.

In his experience, high levels of blood eosinophils and other inflammatory markers are predictors of response to dupilumab regardless of skin type, but he expressed concern that time to diagnosis is sometimes longer in Black patients if the nuances of disease expression are not appreciated.

For treating prurigo nodularis in Blacks as well as Whites, Dr. Kwatra suggested that clinicians stay current with what he predicted will be a growing array of treatment options. He did not discuss nemolizumab, an interleukin-31 receptor alpha antagonist. Soon after the meeting, results of a phase 3 trial of nemolizumab in patients with moderate to severe prurigo nodularis were published in the New England Journal of Medicine. (Dr. Kwatra is the lead author of the study but did not specifically discuss this treatment at the meeting.)

In the international placebo-controlled trial, called OLYMPIA 2, treatment was associated with a significant reduction in the signs and symptoms of prurigo nodularis, including reductions in itch, at 16 weeks, although only 4% of patients in the study were Black.

Given the expanding array of therapies, the message of considering prurigo nodularis in Black patients in order to accelerate the time to diagnosis is timely, Andrew F. Alexis, MD, MPH, professor of clinical dermatology and vice-chair for diversity and inclusion for the department of dermatology, Weill Cornell Medicine, New York.

“Current studies suggest a higher prevalence and greater severity of prurigo nodularis among Black patients compared to White patients,” said Dr. Alexis, agreeing with Dr. Kwatra. Referring to evidence that Blacks might mount a greater inflammatory response to prurigo nodularis than Whites, Dr. Alexis called for “a better understanding of the pathomechanisms” of this disease in order “to address unmet needs and reduce disparities for our diverse population of patients who suffer from prurigo nodularis.’

Dr. Kwatra reported financial relationships with AbbVie, Amgen, Arcutis, ASLAN, Cara, Castle Biosciences, Celldex, Galderma, Incyte, Johnson & Johnson, LEO pharma, Novartis, Pfizer, Regeneron, and Sanofi.

Good news for people struggling with sensory problems after a bout of COVID-19. Although mild cases of the disease often impair the ability to taste and smell, and the problem can drag on for months, a new study from Italy shows that most people return to their senses, as it were, within 3 years.

“In the vast majority of cases, the loss of the sense of smell is not irreversible,” said Paolo Boscolo-Rizzo, MD, a professor of medicine, surgery, and health sciences at the University of Trieste (Italy), and a co-author of the study, published as a research letter in JAMA Otolaryngology–Head & Neck Surgery.

Dr. Boscolo-Rizzo and his colleagues analyzed data from 88 adults with mild COVID-19, which was defined as having no lower respiratory disease and blood oxygen saturation of 94% or greater. Another group of 88 adults who never contracted the virus but sometimes had difficulties with smell and taste were also studied. In both groups, the average age was 49 years, all participants were White, and 58% were women.

The researchers tested participants’ sense of smell with sticks that contained different odors and checked their sense of taste with strips that had different tastes. Over time, fewer people had difficulty distinguishing odors. Three years after developing COVID-19, only 12 people had impaired smell, compared with 36 people at year 1 and 24 people at year 2. And at the 3-year mark, all participants had at least a partial ability to smell. 

The story was similar with sense of taste, with 10 of 88 people reporting impairments 3 years later. By then, people with COVID-19 were no more likely to have trouble with smell or taste than people who did not get the virus. 

A study this past June showed a strong correlation between severity of COVID-19 symptoms and impaired sense of taste and smell and estimated that millions of Americans maintained altered senses. More than 10% of people in the Italian study still had trouble with smell or taste 3 years later.
 

Emerging treatments, psychological concerns

“We’re seeing fewer people with this problem, but there are still people suffering from it,” said Fernando Carnavali, MD, an internal medicine physician and a site director for the Center for Post-COVID Care at the Icahn School of Medicine at Mount Sinai, New York City.

Dr. Carnavali wasn’t part of this study, but he did find the new results encouraging, and he called for similar studies in diverse populations that have experienced COVID-19. He also noted that an impaired sense of smell is distressing.

“It really has a significant psychological impact,” Dr. Carnavali said.

He recalled a patient crying in his office because her inability to smell made it impossible for her to cook. Dr. Carnavali recommended clinicians refer patients facing protracted loss of smell or taste to mental health professionals for support.

Treatments are emerging for COVID-19 smell loss. One approach is to inject platelet-rich plasma into a patient’s nasal cavities to help neurons related to smell repair themselves.

A randomized trial showed platelet-rich plasma significantly outperformed placebo in patients with smell loss up to a year after getting COVID-19.

“I wish more people would do it,” said Zara Patel, MD, an otolaryngologist at Stanford (Calif.) Medicine, who helped conduct that trial. She said some physicians may be nervous about injecting plasma so close to the skull and are therefore hesitant to try this approach. 

Another technique may help to address the olfactory condition known as parosmia, in which patients generally experience a benign odor as rancid, according to otolaryngologist Nyssa Farrell, MD, of Washington University School of Medicine, St. Louis. Dr. Farrell said around two-thirds of patients who contract COVID-19 develop the condition, and the rates of long-term parosmia range from 10%-50% depending on various studies.

“It is almost always foul; this can profoundly affect someone’s quality of life,” impairing their ability to eat or to be intimate with a partner who now smells unpleasant, said Dr. Farrell, who wasn’t associated with this research.

The treatment, called a stellate ganglion block, is provided through a shot into nerves in the neck. People with parosmia associated with COVID-19 often report that this method cures them. Dr. Patel said that may be because their psychological health is improving, not their sense of smell, because the area of the body where the stellate ganglion block is applied is not part of the olfactory system.

Earlier this year, Dr. Farrell and colleagues reported that parosmia linked to COVID-19 is associated with an increased risk for depression, anxiety, and suicidal ideation. 

One coauthor reported receiving grants from Smell and Taste Lab, Takasago, Baia Foods, and Frequency Therapeutics. The other authors reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Good news for people struggling with sensory problems after a bout of COVID-19. Although mild cases of the disease often impair the ability to taste and smell, and the problem can drag on for months, a new study from Italy shows that most people return to their senses, as it were, within 3 years.

“In the vast majority of cases, the loss of the sense of smell is not irreversible,” said Paolo Boscolo-Rizzo, MD, a professor of medicine, surgery, and health sciences at the University of Trieste (Italy), and a co-author of the study, published as a research letter in JAMA Otolaryngology–Head & Neck Surgery.

Dr. Boscolo-Rizzo and his colleagues analyzed data from 88 adults with mild COVID-19, which was defined as having no lower respiratory disease and blood oxygen saturation of 94% or greater. Another group of 88 adults who never contracted the virus but sometimes had difficulties with smell and taste were also studied. In both groups, the average age was 49 years, all participants were White, and 58% were women.

The researchers tested participants’ sense of smell with sticks that contained different odors and checked their sense of taste with strips that had different tastes. Over time, fewer people had difficulty distinguishing odors. Three years after developing COVID-19, only 12 people had impaired smell, compared with 36 people at year 1 and 24 people at year 2. And at the 3-year mark, all participants had at least a partial ability to smell. 

The story was similar with sense of taste, with 10 of 88 people reporting impairments 3 years later. By then, people with COVID-19 were no more likely to have trouble with smell or taste than people who did not get the virus. 

A study this past June showed a strong correlation between severity of COVID-19 symptoms and impaired sense of taste and smell and estimated that millions of Americans maintained altered senses. More than 10% of people in the Italian study still had trouble with smell or taste 3 years later.
 

Emerging treatments, psychological concerns

“We’re seeing fewer people with this problem, but there are still people suffering from it,” said Fernando Carnavali, MD, an internal medicine physician and a site director for the Center for Post-COVID Care at the Icahn School of Medicine at Mount Sinai, New York City.

Dr. Carnavali wasn’t part of this study, but he did find the new results encouraging, and he called for similar studies in diverse populations that have experienced COVID-19. He also noted that an impaired sense of smell is distressing.

“It really has a significant psychological impact,” Dr. Carnavali said.

He recalled a patient crying in his office because her inability to smell made it impossible for her to cook. Dr. Carnavali recommended clinicians refer patients facing protracted loss of smell or taste to mental health professionals for support.

Treatments are emerging for COVID-19 smell loss. One approach is to inject platelet-rich plasma into a patient’s nasal cavities to help neurons related to smell repair themselves.

A randomized trial showed platelet-rich plasma significantly outperformed placebo in patients with smell loss up to a year after getting COVID-19.

“I wish more people would do it,” said Zara Patel, MD, an otolaryngologist at Stanford (Calif.) Medicine, who helped conduct that trial. She said some physicians may be nervous about injecting plasma so close to the skull and are therefore hesitant to try this approach. 

Another technique may help to address the olfactory condition known as parosmia, in which patients generally experience a benign odor as rancid, according to otolaryngologist Nyssa Farrell, MD, of Washington University School of Medicine, St. Louis. Dr. Farrell said around two-thirds of patients who contract COVID-19 develop the condition, and the rates of long-term parosmia range from 10%-50% depending on various studies.

“It is almost always foul; this can profoundly affect someone’s quality of life,” impairing their ability to eat or to be intimate with a partner who now smells unpleasant, said Dr. Farrell, who wasn’t associated with this research.

The treatment, called a stellate ganglion block, is provided through a shot into nerves in the neck. People with parosmia associated with COVID-19 often report that this method cures them. Dr. Patel said that may be because their psychological health is improving, not their sense of smell, because the area of the body where the stellate ganglion block is applied is not part of the olfactory system.

Earlier this year, Dr. Farrell and colleagues reported that parosmia linked to COVID-19 is associated with an increased risk for depression, anxiety, and suicidal ideation. 

One coauthor reported receiving grants from Smell and Taste Lab, Takasago, Baia Foods, and Frequency Therapeutics. The other authors reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Good news for people struggling with sensory problems after a bout of COVID-19. Although mild cases of the disease often impair the ability to taste and smell, and the problem can drag on for months, a new study from Italy shows that most people return to their senses, as it were, within 3 years.

“In the vast majority of cases, the loss of the sense of smell is not irreversible,” said Paolo Boscolo-Rizzo, MD, a professor of medicine, surgery, and health sciences at the University of Trieste (Italy), and a co-author of the study, published as a research letter in JAMA Otolaryngology–Head & Neck Surgery.

Dr. Boscolo-Rizzo and his colleagues analyzed data from 88 adults with mild COVID-19, which was defined as having no lower respiratory disease and blood oxygen saturation of 94% or greater. Another group of 88 adults who never contracted the virus but sometimes had difficulties with smell and taste were also studied. In both groups, the average age was 49 years, all participants were White, and 58% were women.

The researchers tested participants’ sense of smell with sticks that contained different odors and checked their sense of taste with strips that had different tastes. Over time, fewer people had difficulty distinguishing odors. Three years after developing COVID-19, only 12 people had impaired smell, compared with 36 people at year 1 and 24 people at year 2. And at the 3-year mark, all participants had at least a partial ability to smell. 

The story was similar with sense of taste, with 10 of 88 people reporting impairments 3 years later. By then, people with COVID-19 were no more likely to have trouble with smell or taste than people who did not get the virus. 

A study this past June showed a strong correlation between severity of COVID-19 symptoms and impaired sense of taste and smell and estimated that millions of Americans maintained altered senses. More than 10% of people in the Italian study still had trouble with smell or taste 3 years later.
 

Emerging treatments, psychological concerns

“We’re seeing fewer people with this problem, but there are still people suffering from it,” said Fernando Carnavali, MD, an internal medicine physician and a site director for the Center for Post-COVID Care at the Icahn School of Medicine at Mount Sinai, New York City.

Dr. Carnavali wasn’t part of this study, but he did find the new results encouraging, and he called for similar studies in diverse populations that have experienced COVID-19. He also noted that an impaired sense of smell is distressing.

“It really has a significant psychological impact,” Dr. Carnavali said.

He recalled a patient crying in his office because her inability to smell made it impossible for her to cook. Dr. Carnavali recommended clinicians refer patients facing protracted loss of smell or taste to mental health professionals for support.

Treatments are emerging for COVID-19 smell loss. One approach is to inject platelet-rich plasma into a patient’s nasal cavities to help neurons related to smell repair themselves.

A randomized trial showed platelet-rich plasma significantly outperformed placebo in patients with smell loss up to a year after getting COVID-19.

“I wish more people would do it,” said Zara Patel, MD, an otolaryngologist at Stanford (Calif.) Medicine, who helped conduct that trial. She said some physicians may be nervous about injecting plasma so close to the skull and are therefore hesitant to try this approach. 

Another technique may help to address the olfactory condition known as parosmia, in which patients generally experience a benign odor as rancid, according to otolaryngologist Nyssa Farrell, MD, of Washington University School of Medicine, St. Louis. Dr. Farrell said around two-thirds of patients who contract COVID-19 develop the condition, and the rates of long-term parosmia range from 10%-50% depending on various studies.

“It is almost always foul; this can profoundly affect someone’s quality of life,” impairing their ability to eat or to be intimate with a partner who now smells unpleasant, said Dr. Farrell, who wasn’t associated with this research.

The treatment, called a stellate ganglion block, is provided through a shot into nerves in the neck. People with parosmia associated with COVID-19 often report that this method cures them. Dr. Patel said that may be because their psychological health is improving, not their sense of smell, because the area of the body where the stellate ganglion block is applied is not part of the olfactory system.

Earlier this year, Dr. Farrell and colleagues reported that parosmia linked to COVID-19 is associated with an increased risk for depression, anxiety, and suicidal ideation. 

One coauthor reported receiving grants from Smell and Taste Lab, Takasago, Baia Foods, and Frequency Therapeutics. The other authors reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Artificial intelligence can accurately predict the optimal retrieval date in fertility treatment cycles, according to preliminary research presented at the annual meeting of the American Society for Reproductive Medicine. According to the researchers, such an algorithm is needed due to the increased demand for fertility treatments, as well as the high day-to-day variability in lab workload.

According to the study investigators, predicting retrieval dates in advance for ongoing cycles is of major importance for both patients and clinicians.

“The population requiring fertility treatments, including genetic testing and fertility preservation, has massively increased, and this causes many more cycles and a high day-to-day variability in IVF activity, especially in the lab workload,” said Rohi Hourvitz, MBA, from FertilAI, an Israeli health care company focused on developing technologies that improve fertility treatments.

“We also need to accommodate and reschedule for non-working days, which causes a big issue with managing the workload in many clinics around the world,” added Mr. Hourvitz, who presented the research highlighting AI’s growing role in reproductive medicine.

In addition, AI has recently emerged as an effective tool for assisting in clinical decision-making in assisted reproductive technology, prompting further research in this space, he said.

The new study used a dataset of 9,550 predictable antagonist cycles (defined as having all necessary data) gathered from one lab with over 50 physicians between August 2018 and October 2022. The data were split into two subsets: one for training the AI model and the other for prospective testing. 

To train and test the AI model, data from nearly 6,000 predictable antagonist cycles were used. Key factors used for each cycle included estrogen levels, mean follicle size, primary follicle size, and various patient demographics. Other features were considered, but Mr. Hourvitz noted that primary follicle size influenced the algorithm most, “because that is what most of us use when we want to trigger.”

Mr. Hourvitz explained that these patient data were run through an algorithm that produced a graph predicting the most probable date for a cycle retrieval.

“We could accurately predict when those ‘peak days’ were going to be happening in the clinic, and we could also give a pretty good estimate on how many cycles you’re going to have every day,” Mr. Hourvitz said, explaining that this information could help clinics more efficiently allocate resources and manage patients.

According to Mr. Hourvitz, the predictions derived from this study could improve various aspects of fertility treatments and related procedures, including better staff planning and caseload management in IVF labs, as well as higher-quality eggs at retrieval. Patients would have a clearer timeline for their treatment cycles.   

Nikica Zaninovic, PhD, MS, director of the embryology lab at Weill Cornell Medical College, New York City, cautioned that the new findings are not yet ready for clinical application but emphasized the importance of more AI research focusing on the quality of oocytes, not only embryos.

“We’re so focused on the end of the process: the embryo,” Dr. Zaninovic, who was not involved in the research, said in an interview. “I think the focus should be on the beginning – the quality of eggs and sperm, not just the quantity – because that’s what the embryos will depend on.”

He noted the increasing numbers of young women in the United States undergoing egg freezing.

“Cornell is the largest academic IVF center in the United States; 20%-30% of all of the patients that we treat are actually freezing their eggs,” he said. “It’s a huge population.”

“When they come to us, they ask how many eggs they’ll need to guarantee one or two children in the future,” Dr. Zaninovic continued. “We don’t have that answer, so we always tell them [we’ll retrieve] as many as we can. That’s not the answer; we need to be more precise. We’re still lacking these tools, and I think that’s where the research will go.”

The study was funded by FertilAI. Mr. Hourvitz is a shareholder and CEO of FertilAI. Dr. Zaninovic is president of the AI Fertility Society.

A version of this article appeared on Medscape.com.

Artificial intelligence can accurately predict the optimal retrieval date in fertility treatment cycles, according to preliminary research presented at the annual meeting of the American Society for Reproductive Medicine. According to the researchers, such an algorithm is needed due to the increased demand for fertility treatments, as well as the high day-to-day variability in lab workload.

According to the study investigators, predicting retrieval dates in advance for ongoing cycles is of major importance for both patients and clinicians.

“The population requiring fertility treatments, including genetic testing and fertility preservation, has massively increased, and this causes many more cycles and a high day-to-day variability in IVF activity, especially in the lab workload,” said Rohi Hourvitz, MBA, from FertilAI, an Israeli health care company focused on developing technologies that improve fertility treatments.

“We also need to accommodate and reschedule for non-working days, which causes a big issue with managing the workload in many clinics around the world,” added Mr. Hourvitz, who presented the research highlighting AI’s growing role in reproductive medicine.

In addition, AI has recently emerged as an effective tool for assisting in clinical decision-making in assisted reproductive technology, prompting further research in this space, he said.

The new study used a dataset of 9,550 predictable antagonist cycles (defined as having all necessary data) gathered from one lab with over 50 physicians between August 2018 and October 2022. The data were split into two subsets: one for training the AI model and the other for prospective testing. 

To train and test the AI model, data from nearly 6,000 predictable antagonist cycles were used. Key factors used for each cycle included estrogen levels, mean follicle size, primary follicle size, and various patient demographics. Other features were considered, but Mr. Hourvitz noted that primary follicle size influenced the algorithm most, “because that is what most of us use when we want to trigger.”

Mr. Hourvitz explained that these patient data were run through an algorithm that produced a graph predicting the most probable date for a cycle retrieval.

“We could accurately predict when those ‘peak days’ were going to be happening in the clinic, and we could also give a pretty good estimate on how many cycles you’re going to have every day,” Mr. Hourvitz said, explaining that this information could help clinics more efficiently allocate resources and manage patients.

According to Mr. Hourvitz, the predictions derived from this study could improve various aspects of fertility treatments and related procedures, including better staff planning and caseload management in IVF labs, as well as higher-quality eggs at retrieval. Patients would have a clearer timeline for their treatment cycles.   

Nikica Zaninovic, PhD, MS, director of the embryology lab at Weill Cornell Medical College, New York City, cautioned that the new findings are not yet ready for clinical application but emphasized the importance of more AI research focusing on the quality of oocytes, not only embryos.

“We’re so focused on the end of the process: the embryo,” Dr. Zaninovic, who was not involved in the research, said in an interview. “I think the focus should be on the beginning – the quality of eggs and sperm, not just the quantity – because that’s what the embryos will depend on.”

He noted the increasing numbers of young women in the United States undergoing egg freezing.

“Cornell is the largest academic IVF center in the United States; 20%-30% of all of the patients that we treat are actually freezing their eggs,” he said. “It’s a huge population.”

“When they come to us, they ask how many eggs they’ll need to guarantee one or two children in the future,” Dr. Zaninovic continued. “We don’t have that answer, so we always tell them [we’ll retrieve] as many as we can. That’s not the answer; we need to be more precise. We’re still lacking these tools, and I think that’s where the research will go.”

The study was funded by FertilAI. Mr. Hourvitz is a shareholder and CEO of FertilAI. Dr. Zaninovic is president of the AI Fertility Society.

A version of this article appeared on Medscape.com.

Artificial intelligence can accurately predict the optimal retrieval date in fertility treatment cycles, according to preliminary research presented at the annual meeting of the American Society for Reproductive Medicine. According to the researchers, such an algorithm is needed due to the increased demand for fertility treatments, as well as the high day-to-day variability in lab workload.

According to the study investigators, predicting retrieval dates in advance for ongoing cycles is of major importance for both patients and clinicians.

“The population requiring fertility treatments, including genetic testing and fertility preservation, has massively increased, and this causes many more cycles and a high day-to-day variability in IVF activity, especially in the lab workload,” said Rohi Hourvitz, MBA, from FertilAI, an Israeli health care company focused on developing technologies that improve fertility treatments.

“We also need to accommodate and reschedule for non-working days, which causes a big issue with managing the workload in many clinics around the world,” added Mr. Hourvitz, who presented the research highlighting AI’s growing role in reproductive medicine.

In addition, AI has recently emerged as an effective tool for assisting in clinical decision-making in assisted reproductive technology, prompting further research in this space, he said.

The new study used a dataset of 9,550 predictable antagonist cycles (defined as having all necessary data) gathered from one lab with over 50 physicians between August 2018 and October 2022. The data were split into two subsets: one for training the AI model and the other for prospective testing. 

To train and test the AI model, data from nearly 6,000 predictable antagonist cycles were used. Key factors used for each cycle included estrogen levels, mean follicle size, primary follicle size, and various patient demographics. Other features were considered, but Mr. Hourvitz noted that primary follicle size influenced the algorithm most, “because that is what most of us use when we want to trigger.”

Mr. Hourvitz explained that these patient data were run through an algorithm that produced a graph predicting the most probable date for a cycle retrieval.

“We could accurately predict when those ‘peak days’ were going to be happening in the clinic, and we could also give a pretty good estimate on how many cycles you’re going to have every day,” Mr. Hourvitz said, explaining that this information could help clinics more efficiently allocate resources and manage patients.

According to Mr. Hourvitz, the predictions derived from this study could improve various aspects of fertility treatments and related procedures, including better staff planning and caseload management in IVF labs, as well as higher-quality eggs at retrieval. Patients would have a clearer timeline for their treatment cycles.   

Nikica Zaninovic, PhD, MS, director of the embryology lab at Weill Cornell Medical College, New York City, cautioned that the new findings are not yet ready for clinical application but emphasized the importance of more AI research focusing on the quality of oocytes, not only embryos.

“We’re so focused on the end of the process: the embryo,” Dr. Zaninovic, who was not involved in the research, said in an interview. “I think the focus should be on the beginning – the quality of eggs and sperm, not just the quantity – because that’s what the embryos will depend on.”

He noted the increasing numbers of young women in the United States undergoing egg freezing.

“Cornell is the largest academic IVF center in the United States; 20%-30% of all of the patients that we treat are actually freezing their eggs,” he said. “It’s a huge population.”

“When they come to us, they ask how many eggs they’ll need to guarantee one or two children in the future,” Dr. Zaninovic continued. “We don’t have that answer, so we always tell them [we’ll retrieve] as many as we can. That’s not the answer; we need to be more precise. We’re still lacking these tools, and I think that’s where the research will go.”

The study was funded by FertilAI. Mr. Hourvitz is a shareholder and CEO of FertilAI. Dr. Zaninovic is president of the AI Fertility Society.

A version of this article appeared on Medscape.com.

WASHINGTON – The approval last year of the interleukin (IL)-36 receptor antagonist spesolimab for treating generalized pustular psoriasis flares brightened the treatment landscape for this rare condition, and a recently published phase 2 study suggests a potential role of spesolimab for flare prevention. But when it comes to pustular disease localized to the hands and feet – palmoplantar pustulosis – treatment options have only modest efficacy, and spesolimab appears not to work, according to speakers at the annual research symposium of the National Psoriasis Foundation.

“The IL-36 receptor antagonists don’t seem to be quite the answer for [palmoplantar pustulosis] that they are for generalized pustular psoriasis [GPP],” Megan H. Noe, MD, MPH, assistant professor of dermatology at Harvard Medical School and a dermatologist at Brigham and Women’s Hospital, Boston, said at the meeting.

Psoriasis affecting the hands and feet – both pustular and nonpustular – has a higher impact on quality of life and higher functional disability than does non-acral psoriasis, is less responsive to treatment, and has a “very confusing nomenclature” that complicates research and thus management, said Jason Ezra Hawkes, MD, a dermatologist in Rocklin, Calif., and former faculty member of several departments of dermatology. Both he and Dr. Noe spoke during a tough-to-treat session at the NPF meeting.

IL-17 and IL-23 blockade, as well as tumor necrosis factor (TNF) inhibition, are effective overall for palmoplantar psoriasis (nonpustular), but in general, responses are lower than for plaque psoriasis. Apremilast (Otezla), a phosphodiesterase-4 inhibitor, has some efficacy for pustular variants, but for hyperkeratotic variants it “does not perform as well as more selective inhibition of IL-17 and IL-23 blockade,” he said.

Dr. Hawkes

Palmoplantar pustulosis, and a word on generalized disease

Dermatologists are using a variety of treatments for palmoplantar pustulosis, with no clear first-line choices, Dr. Noe said. In a case series of almost 200 patients with palmoplantar pustulosis across 20 dermatology practices, published in JAMA Dermatology, 35% of patients received a systemic therapy prescription at their initial encounter – most commonly acitretin, followed by methotrexate and phototherapy. “Biologics were used, but use was varied and not as often as with oral agents,” said Dr. Noe, a coauthor of the study.

TNF blockers led to improvements ranging from 57% to 84%, depending on the agent, in a 2020 retrospective study of patients with palmoplantar pustulosis or acrodermatitis continua of Hallopeau, Dr. Noe noted. However, rates of complete clearance were only 20%-29%.

Apremilast showed modest efficacy after 5 months of treatment, with 62% of patients achieving at least a 50% improvement in the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) in a 2021 open-label, phase 2 study involving 21 patients. “This may represent a potential treatment option,” Dr. Noe said. “It’s something, but not what we’re used to seeing in our plaque psoriasis patients.”

A 2021 phase 2a, double-blind, randomized, placebo-controlled study of spesolimab in patients with palmoplantar pustulosis, meanwhile, failed to meet its primary endpoint, with only 32% of patients achieving a 50% improvement at 16 weeks, compared with 24% of patients in the placebo arm. And a recently published network meta-analysis found that none of the five drugs studied in seven randomized controlled trials – biologic or oral – was more effective than placebo for clearance or improvement of palmoplantar pustulosis.

The spesolimab (Spevigo) results have been disappointing considering the biologic’s newfound efficacy and role as the first Food and Drug Administration–approved therapy for generalized pustular disease, according to Dr. Noe. The ability of a single 900-mg intravenous dose of the IL-36 receptor antagonist to completely clear pustules at 1 week in 54% of patients with generalized disease, compared with 6% of the placebo group, was “groundbreaking,” she said, referring to results of the pivotal trial published in the New England Journal of Medicine.

And given that “preventing GPP flares is ultimately what we want,” she said, more good news was reported this year in The Lancet: The finding from an international, randomized, placebo-controlled study that high-dose subcutaneous spesolimab significantly reduced the risk of a flare over 48 weeks. “There are lots of ongoing studies right now to understand the best way to dose spesolimab,” she said.

Moreover, another IL-36 receptor antagonist, imsidolimab, is being investigated in a phase 3 trial for generalized pustular disease, she noted. A phase 2, open-label study of patients with GPP found that “more than half of patients were very much improved at 4 weeks, and some patients started showing improvement at day 3,” Dr. Noe said.

An area of research she is interested in is the potential for Janus kinase (JAK) inhibitors as a treatment for palmoplantar pustulosis. For pustulosis on the hands and feet, recent case reports describing the efficacy of JAK inhibitors have caught her eye. “Right now, all we have is this case report data, mostly with tofacitinib, but I think it’s exciting,” she said, noting a recently published report in the British Journal of Dermatology.

Palmoplantar psoriasis

Pustular psoriatic disease can be localized to the hand and/or feet only, or can co-occur with generalized pustular disease, just as palmoplantar psoriasis can be localized to the hands and/or feet or, more commonly, can co-occur with widespread plaque psoriasis. Research has shown, Dr. Hawkes said, that with both types of acral disease, many patients have or have had plaque psoriasis outside of acral sites.

The nomenclature and acronyms for palmoplantar psoriatic disease have complicated patient education, communication, and research, Dr. Hawkes said. Does PPP refer to palmoplantar psoriasis, or palmoplantar pustulosis, for instance? What is the difference between palmoplantar pustulosis (coined PPP) and palmoplantar pustular psoriasis (referred to as PPPP)?

What if disease is only on the hands, only on the feet, or only on the backs of the hands? And at what point is disease not classified as palmoplantar psoriasis, but plaque psoriasis with involvement of the hands and feet? Inconsistencies and lack of clarification lead to “confusing” literature, he said.

Heterogeneity in populations across trials resulting from “inconsistent categorization and phenotype inclusion” may partly account for the recalcitrance to treatment reported in the literature, he said. Misdiagnosis as psoriasis in cases of localized disease (confusion with eczema, for instance), and the fact that hands and feet are subject to increased trauma and injury, compared with non-acral sites, are also at play.

Trials may also allow insufficient time for improvement, compared with non-acral sites. “What we’ve learned about the hands and feet is that it takes a much longer time for disease to improve,” Dr. Hawkes said, so primary endpoints must take this into account.

There is unique immunologic signaling in palmoplantar disease that differs from the predominant signaling in traditional plaque psoriasis, he emphasized, and “mixed immunophenotypes” that need to be unraveled.

Dr. Hawkes disclosed ties with AbbVie, Arcutis, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, LEO, Lilly, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma, and UCB. Dr. Noe disclosed ties to Bristol-Myers Squibb and Boehringer Ingelheim.

WASHINGTON – The approval last year of the interleukin (IL)-36 receptor antagonist spesolimab for treating generalized pustular psoriasis flares brightened the treatment landscape for this rare condition, and a recently published phase 2 study suggests a potential role of spesolimab for flare prevention. But when it comes to pustular disease localized to the hands and feet – palmoplantar pustulosis – treatment options have only modest efficacy, and spesolimab appears not to work, according to speakers at the annual research symposium of the National Psoriasis Foundation.

“The IL-36 receptor antagonists don’t seem to be quite the answer for [palmoplantar pustulosis] that they are for generalized pustular psoriasis [GPP],” Megan H. Noe, MD, MPH, assistant professor of dermatology at Harvard Medical School and a dermatologist at Brigham and Women’s Hospital, Boston, said at the meeting.

Psoriasis affecting the hands and feet – both pustular and nonpustular – has a higher impact on quality of life and higher functional disability than does non-acral psoriasis, is less responsive to treatment, and has a “very confusing nomenclature” that complicates research and thus management, said Jason Ezra Hawkes, MD, a dermatologist in Rocklin, Calif., and former faculty member of several departments of dermatology. Both he and Dr. Noe spoke during a tough-to-treat session at the NPF meeting.

IL-17 and IL-23 blockade, as well as tumor necrosis factor (TNF) inhibition, are effective overall for palmoplantar psoriasis (nonpustular), but in general, responses are lower than for plaque psoriasis. Apremilast (Otezla), a phosphodiesterase-4 inhibitor, has some efficacy for pustular variants, but for hyperkeratotic variants it “does not perform as well as more selective inhibition of IL-17 and IL-23 blockade,” he said.

Dr. Hawkes

Palmoplantar pustulosis, and a word on generalized disease

Dermatologists are using a variety of treatments for palmoplantar pustulosis, with no clear first-line choices, Dr. Noe said. In a case series of almost 200 patients with palmoplantar pustulosis across 20 dermatology practices, published in JAMA Dermatology, 35% of patients received a systemic therapy prescription at their initial encounter – most commonly acitretin, followed by methotrexate and phototherapy. “Biologics were used, but use was varied and not as often as with oral agents,” said Dr. Noe, a coauthor of the study.

TNF blockers led to improvements ranging from 57% to 84%, depending on the agent, in a 2020 retrospective study of patients with palmoplantar pustulosis or acrodermatitis continua of Hallopeau, Dr. Noe noted. However, rates of complete clearance were only 20%-29%.

Apremilast showed modest efficacy after 5 months of treatment, with 62% of patients achieving at least a 50% improvement in the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) in a 2021 open-label, phase 2 study involving 21 patients. “This may represent a potential treatment option,” Dr. Noe said. “It’s something, but not what we’re used to seeing in our plaque psoriasis patients.”

A 2021 phase 2a, double-blind, randomized, placebo-controlled study of spesolimab in patients with palmoplantar pustulosis, meanwhile, failed to meet its primary endpoint, with only 32% of patients achieving a 50% improvement at 16 weeks, compared with 24% of patients in the placebo arm. And a recently published network meta-analysis found that none of the five drugs studied in seven randomized controlled trials – biologic or oral – was more effective than placebo for clearance or improvement of palmoplantar pustulosis.

The spesolimab (Spevigo) results have been disappointing considering the biologic’s newfound efficacy and role as the first Food and Drug Administration–approved therapy for generalized pustular disease, according to Dr. Noe. The ability of a single 900-mg intravenous dose of the IL-36 receptor antagonist to completely clear pustules at 1 week in 54% of patients with generalized disease, compared with 6% of the placebo group, was “groundbreaking,” she said, referring to results of the pivotal trial published in the New England Journal of Medicine.

And given that “preventing GPP flares is ultimately what we want,” she said, more good news was reported this year in The Lancet: The finding from an international, randomized, placebo-controlled study that high-dose subcutaneous spesolimab significantly reduced the risk of a flare over 48 weeks. “There are lots of ongoing studies right now to understand the best way to dose spesolimab,” she said.

Moreover, another IL-36 receptor antagonist, imsidolimab, is being investigated in a phase 3 trial for generalized pustular disease, she noted. A phase 2, open-label study of patients with GPP found that “more than half of patients were very much improved at 4 weeks, and some patients started showing improvement at day 3,” Dr. Noe said.

An area of research she is interested in is the potential for Janus kinase (JAK) inhibitors as a treatment for palmoplantar pustulosis. For pustulosis on the hands and feet, recent case reports describing the efficacy of JAK inhibitors have caught her eye. “Right now, all we have is this case report data, mostly with tofacitinib, but I think it’s exciting,” she said, noting a recently published report in the British Journal of Dermatology.

Palmoplantar psoriasis

Pustular psoriatic disease can be localized to the hand and/or feet only, or can co-occur with generalized pustular disease, just as palmoplantar psoriasis can be localized to the hands and/or feet or, more commonly, can co-occur with widespread plaque psoriasis. Research has shown, Dr. Hawkes said, that with both types of acral disease, many patients have or have had plaque psoriasis outside of acral sites.

The nomenclature and acronyms for palmoplantar psoriatic disease have complicated patient education, communication, and research, Dr. Hawkes said. Does PPP refer to palmoplantar psoriasis, or palmoplantar pustulosis, for instance? What is the difference between palmoplantar pustulosis (coined PPP) and palmoplantar pustular psoriasis (referred to as PPPP)?

What if disease is only on the hands, only on the feet, or only on the backs of the hands? And at what point is disease not classified as palmoplantar psoriasis, but plaque psoriasis with involvement of the hands and feet? Inconsistencies and lack of clarification lead to “confusing” literature, he said.

Heterogeneity in populations across trials resulting from “inconsistent categorization and phenotype inclusion” may partly account for the recalcitrance to treatment reported in the literature, he said. Misdiagnosis as psoriasis in cases of localized disease (confusion with eczema, for instance), and the fact that hands and feet are subject to increased trauma and injury, compared with non-acral sites, are also at play.

Trials may also allow insufficient time for improvement, compared with non-acral sites. “What we’ve learned about the hands and feet is that it takes a much longer time for disease to improve,” Dr. Hawkes said, so primary endpoints must take this into account.

There is unique immunologic signaling in palmoplantar disease that differs from the predominant signaling in traditional plaque psoriasis, he emphasized, and “mixed immunophenotypes” that need to be unraveled.

Dr. Hawkes disclosed ties with AbbVie, Arcutis, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, LEO, Lilly, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma, and UCB. Dr. Noe disclosed ties to Bristol-Myers Squibb and Boehringer Ingelheim.

WASHINGTON – The approval last year of the interleukin (IL)-36 receptor antagonist spesolimab for treating generalized pustular psoriasis flares brightened the treatment landscape for this rare condition, and a recently published phase 2 study suggests a potential role of spesolimab for flare prevention. But when it comes to pustular disease localized to the hands and feet – palmoplantar pustulosis – treatment options have only modest efficacy, and spesolimab appears not to work, according to speakers at the annual research symposium of the National Psoriasis Foundation.

“The IL-36 receptor antagonists don’t seem to be quite the answer for [palmoplantar pustulosis] that they are for generalized pustular psoriasis [GPP],” Megan H. Noe, MD, MPH, assistant professor of dermatology at Harvard Medical School and a dermatologist at Brigham and Women’s Hospital, Boston, said at the meeting.

Psoriasis affecting the hands and feet – both pustular and nonpustular – has a higher impact on quality of life and higher functional disability than does non-acral psoriasis, is less responsive to treatment, and has a “very confusing nomenclature” that complicates research and thus management, said Jason Ezra Hawkes, MD, a dermatologist in Rocklin, Calif., and former faculty member of several departments of dermatology. Both he and Dr. Noe spoke during a tough-to-treat session at the NPF meeting.

IL-17 and IL-23 blockade, as well as tumor necrosis factor (TNF) inhibition, are effective overall for palmoplantar psoriasis (nonpustular), but in general, responses are lower than for plaque psoriasis. Apremilast (Otezla), a phosphodiesterase-4 inhibitor, has some efficacy for pustular variants, but for hyperkeratotic variants it “does not perform as well as more selective inhibition of IL-17 and IL-23 blockade,” he said.

Dr. Hawkes

Palmoplantar pustulosis, and a word on generalized disease

Dermatologists are using a variety of treatments for palmoplantar pustulosis, with no clear first-line choices, Dr. Noe said. In a case series of almost 200 patients with palmoplantar pustulosis across 20 dermatology practices, published in JAMA Dermatology, 35% of patients received a systemic therapy prescription at their initial encounter – most commonly acitretin, followed by methotrexate and phototherapy. “Biologics were used, but use was varied and not as often as with oral agents,” said Dr. Noe, a coauthor of the study.

TNF blockers led to improvements ranging from 57% to 84%, depending on the agent, in a 2020 retrospective study of patients with palmoplantar pustulosis or acrodermatitis continua of Hallopeau, Dr. Noe noted. However, rates of complete clearance were only 20%-29%.

Apremilast showed modest efficacy after 5 months of treatment, with 62% of patients achieving at least a 50% improvement in the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) in a 2021 open-label, phase 2 study involving 21 patients. “This may represent a potential treatment option,” Dr. Noe said. “It’s something, but not what we’re used to seeing in our plaque psoriasis patients.”

A 2021 phase 2a, double-blind, randomized, placebo-controlled study of spesolimab in patients with palmoplantar pustulosis, meanwhile, failed to meet its primary endpoint, with only 32% of patients achieving a 50% improvement at 16 weeks, compared with 24% of patients in the placebo arm. And a recently published network meta-analysis found that none of the five drugs studied in seven randomized controlled trials – biologic or oral – was more effective than placebo for clearance or improvement of palmoplantar pustulosis.

The spesolimab (Spevigo) results have been disappointing considering the biologic’s newfound efficacy and role as the first Food and Drug Administration–approved therapy for generalized pustular disease, according to Dr. Noe. The ability of a single 900-mg intravenous dose of the IL-36 receptor antagonist to completely clear pustules at 1 week in 54% of patients with generalized disease, compared with 6% of the placebo group, was “groundbreaking,” she said, referring to results of the pivotal trial published in the New England Journal of Medicine.

And given that “preventing GPP flares is ultimately what we want,” she said, more good news was reported this year in The Lancet: The finding from an international, randomized, placebo-controlled study that high-dose subcutaneous spesolimab significantly reduced the risk of a flare over 48 weeks. “There are lots of ongoing studies right now to understand the best way to dose spesolimab,” she said.

Moreover, another IL-36 receptor antagonist, imsidolimab, is being investigated in a phase 3 trial for generalized pustular disease, she noted. A phase 2, open-label study of patients with GPP found that “more than half of patients were very much improved at 4 weeks, and some patients started showing improvement at day 3,” Dr. Noe said.

An area of research she is interested in is the potential for Janus kinase (JAK) inhibitors as a treatment for palmoplantar pustulosis. For pustulosis on the hands and feet, recent case reports describing the efficacy of JAK inhibitors have caught her eye. “Right now, all we have is this case report data, mostly with tofacitinib, but I think it’s exciting,” she said, noting a recently published report in the British Journal of Dermatology.

Palmoplantar psoriasis

Pustular psoriatic disease can be localized to the hand and/or feet only, or can co-occur with generalized pustular disease, just as palmoplantar psoriasis can be localized to the hands and/or feet or, more commonly, can co-occur with widespread plaque psoriasis. Research has shown, Dr. Hawkes said, that with both types of acral disease, many patients have or have had plaque psoriasis outside of acral sites.

The nomenclature and acronyms for palmoplantar psoriatic disease have complicated patient education, communication, and research, Dr. Hawkes said. Does PPP refer to palmoplantar psoriasis, or palmoplantar pustulosis, for instance? What is the difference between palmoplantar pustulosis (coined PPP) and palmoplantar pustular psoriasis (referred to as PPPP)?

What if disease is only on the hands, only on the feet, or only on the backs of the hands? And at what point is disease not classified as palmoplantar psoriasis, but plaque psoriasis with involvement of the hands and feet? Inconsistencies and lack of clarification lead to “confusing” literature, he said.

Heterogeneity in populations across trials resulting from “inconsistent categorization and phenotype inclusion” may partly account for the recalcitrance to treatment reported in the literature, he said. Misdiagnosis as psoriasis in cases of localized disease (confusion with eczema, for instance), and the fact that hands and feet are subject to increased trauma and injury, compared with non-acral sites, are also at play.

Trials may also allow insufficient time for improvement, compared with non-acral sites. “What we’ve learned about the hands and feet is that it takes a much longer time for disease to improve,” Dr. Hawkes said, so primary endpoints must take this into account.

There is unique immunologic signaling in palmoplantar disease that differs from the predominant signaling in traditional plaque psoriasis, he emphasized, and “mixed immunophenotypes” that need to be unraveled.

Dr. Hawkes disclosed ties with AbbVie, Arcutis, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, LEO, Lilly, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma, and UCB. Dr. Noe disclosed ties to Bristol-Myers Squibb and Boehringer Ingelheim.

From Ayurveda to the teachings of Hippocrates, medicine’s earliest traditions advanced a belief that the gut was the foundation of all health and disease. It wasn’t until recently, however, that Western medicine has adopted the notion of gut-barrier dysfunction as a pathologic phenomenon critical to not only digestive health but also chronic allergic, inflammatory, and autoimmune disease.

To learn more, Medscape contributor Akash Goel, MD, interviewed Elena Ivanina, DO, MPH, an integrative gastroenterologist, on the role of the gut barrier. Dr. Ivanina is the founder of the Center for Integrative Gut Health and the former director of Neurogastroenterology and Motility at Lenox Hill Hospital in New York. She runs the educational platform for all things gut health, gutlove.com.

What is the role of the gut barrier in overall health and disease?

The gut contains the human body’s largest interface between a person and their external environment. The actual interface is at the gut barrier, where there needs to be an ideal homeostasis and selectivity mechanism to allow the absorption of healthy nutrients, but on the other hand prevent the penetration of harmful microbes, food antigens, and other proinflammatory factors and toxins.

The gut barrier is made up of the mucus layer, gut microbiome, epithelial cells, and immune cells in the lamina propria. When this apparatus is disrupted by factors such as infection, low-fiber diet, antibiotics, and alcohol, then it cannot function normally to selectively keep out the harmful intraluminal substances.

Gut-barrier disruption leads to translocation of dangerous intraluminal components, such as bacteria and their components, into the gut wall and, most importantly, exposes the immune system to them. This causes improper immune activation and dysregulation, which has been shown to lead to various diseases, including gastrointestinal inflammatory disorders such as inflammatory bowel disease (IBD) and celiac disease, systemic autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, and metabolic diseases such as obesity and diabetes.



Is disruption of this barrier what is usually referred to as “leaky gut”?

Leaky gut is a colloquial term for increased intestinal permeability or intestinal hyperpermeability. In a 2019 review article, Dr. Michael Camilleri exposes leaky gut as a term that can be misleading and confusing to the general population. It calls upon clinicians to have an increased awareness of the potential of barrier dysfunction in diseases, and to consider the barrier as a target for treatment.



Is leaky gut more of a mechanism of underlying chronic disease or is it a disease of its own?

Intestinal permeability is a pathophysiologic process in the gut with certain risk factors that in some conditions has been shown to precede chronic disease. There has not been any convincing evidence that it can be diagnosed and treated as its own entity, but research is ongoing.

In IBD, the Crohn’s and Colitis Canada Genetic, Environmental, Microbial Project research consortium has been studying individuals at increased risk for Crohn’s disease because of a first-degree family member with Crohn’s disease. They found an increased abundance of Ruminococcus torques in the microbiomes of at-risk individuals who went on to develop the disease. R. torques are mucin degraders that induce an increase in other mucin-using bacteria, which can contribute to gut-barrier compromise.

In other studies, patients have been found to have asymptomatic intestinal hyperpermeability years before their diagnosis of Crohn’s disease. This supports understanding more about the potential of intestinal hyperpermeability as its own diagnosis that, if addressed, could possibly prevent disease development.
 

The many possible sources of gut-barrier disruption

What causes leaky gut, and when should physicians and patients be suspicious if they have it?

There are many risk factors that have been associated with leaky gut in both human studies and animal studies, including acrolein (food toxin), aging, alcohol, antacid drugs, antibiotics, burn injury, chemotherapy, circadian rhythm disruption, corticosteroids, emulsifiers (food additives), strenuous exercise (≥ 2 hours) at 60% VO₂ max, starvation, fructose, fructans, gliadin (wheat protein), high-fat diet, high-salt diet, high-sugar diet, hyperglycemia, low-fiber diet, nonsteroidal anti-inflammatory drugs, pesticide, proinflammatory cytokines, psychological stress, radiation, sleep deprivation, smoking, and sweeteners.

Patients may be completely asymptomatic with leaky gut. Physicians should be suspicious if there is a genetic predisposition to chronic disease or if any risk factors are unveiled after assessing diet and lifestyle exposures.



What is the role of the Western diet and processed food consumption in driving disruptions of the gut barrier?

The Western diet reduces gut-barrier mucus thickness, leading to increased gut permeability. People who consume a Western diet typically eat less than 15 grams of fiber per day, which is significantly less than many other cultures, including the hunter-gatherers of Tanzania (Hadza), who get 100 or more grams of fiber a day in their food.

With a fiber-depleted diet, gut microbiota that normally feed on fiber gradually disappear and other commensals shift their metabolism to degrade the gut-barrier mucus layer.

A low-fiber diet also decreases short-chain fatty acid production, which reduces production of mucus and affects tight junction regulation.
 

Emerging evidence on causality

New evidence is demonstrating that previous functional conditions of the gastrointestinal tract, like functional dyspepsia, are associated with abnormalities to the intestinal barrier. What is the association between conditions like functional dyspepsia and irritable bowel syndrome (IBS) with gut-barrier disruption?

Conditions such as functional dyspepsia and IBS are similar in that their pathophysiology is incompletely understood and likely attributable to contributions from many different underlying mechanisms. This makes it difficult for clinicians to explain the condition to patients and often to treat without specific therapeutic targets.

Emerging evidence with new diagnostic tools, such as confocal laser endomicroscopy, has demonstrated altered mucosal barrier function in both conditions.

In patients with IBS who have a suspected food intolerance, studies looking at exposure to the food antigens found that the food caused immediate breaks, increased intervillous spaces, and increased inflammatory cells in the gut mucosa. These changes were associated with patient responses to exclusion diets.

In functional dyspepsia, another study, using confocal laser endomicroscopy, has shown that affected patients have significantly greater epithelial gap density in the duodenum, compared with healthy controls. There was also impaired duodenal-epithelial barrier integrity and evidence of increased cellular pyroptosis in the duodenal mucosa.

These findings suggest that while IBS and functional dyspepsia are still likely multifactorial, there may be a common preclinical state that can be further investigated as far as preventing its development and using it as a therapeutic target.



What diagnostic testing are you using to determine whether patients have disruptions to the gut barrier? Are they validated or more experimental?

There are various testing strategies that have been used in research to diagnose intestinal hyperpermeability. In a 2021 analysis, Dr. Michael Camilleri found that the optimal probes for measuring small intestinal and colonic permeability are the mass excreted of 13C-mannitol at 0-2 hours and lactulose during 2-8 hours or sucralose during 8-24 hours. Studies looking at postinfectious IBS have incorporated elevated urinary lactulose/mannitol ratios. Dr. Alessio Fasano and others have looked at using zonulin as a biomarker of impaired gut-barrier function. These tests are still considered experimental.



Is there an association between alterations in the gut microbiome and gut-barrier disruption?

There is an integral relationship between the gut microbiome and gut-barrier function, and dysbiosis can disrupt gut-barrier functionality.

The microbiota produce a variety of metabolites in close proximity to the gut epithelium, impacting gut-barrier function and immune response. For example, short-chain fatty acids produced by Bifidobacterium, Bacteroides, Enterobacter, Faecalibacterium, and Roseburia species impact host immune cell differentiation and metabolism as well as influence susceptibility to pathogens.

Studies have shown that sodium butyrate significantly improves epithelial-barrier function. Other experiments have used transplantation of the intestinal microbiota to show that introduction of certain microbial phenotypes can significantly increase gut permeability.
 

Practical advice for clinicians and patients

How do you advise patients to avoid gut-barrier disruption?

It is important to educate and counsel patients about the long list of risk factors, many of which are closely related to a Western diet and lifestyle, which can increase their risk for leaky gut.

Once one has it, can it be repaired? Can you share a bit about your protocols in general terms?

Many interventions have been shown to improve intestinal permeability. They include berberine, butyrate, caloric restriction and fasting, curcumin, dietary fiber (prebiotics), moderate exercise, fermented food, fish oil, glutamine, quercetin, probiotics, vagus nerve stimulation, vitamin D, and zinc.

Protocols have to be tailored to patients and their risk factors, diet, and lifestyle.

What are some tips from a nutrition and lifestyle standpoint that patients can follow to ensure a robust gut barrier?

It is important to emphasize a high-fiber diet with naturally fermented food, incorporating time-restricted eating, such as eating an early dinner and nothing else before bedtime, a moderate exercise routine, and gut-brain modulation with techniques such as acupuncture that can incorporate vagus nerve stimulation. Limited safe precision supplementation can be discussed on an individual basis based on the patient’s interest, additional testing, and other existing health conditions.
 

Dr. Akash Goel is a clinical assistant professor of medicine at Weill Cornell in gastroenterology and hepatology. He has disclosed no relevant financial relationships. His work has appeared on networks and publications such as CNN, The New York Times, Time Magazine, and Financial Times. He has a deep interest in nutrition, food as medicine, and the intersection between the gut microbiome and human health.

A version of this article appeared on Medscape.com.

From Ayurveda to the teachings of Hippocrates, medicine’s earliest traditions advanced a belief that the gut was the foundation of all health and disease. It wasn’t until recently, however, that Western medicine has adopted the notion of gut-barrier dysfunction as a pathologic phenomenon critical to not only digestive health but also chronic allergic, inflammatory, and autoimmune disease.

To learn more, Medscape contributor Akash Goel, MD, interviewed Elena Ivanina, DO, MPH, an integrative gastroenterologist, on the role of the gut barrier. Dr. Ivanina is the founder of the Center for Integrative Gut Health and the former director of Neurogastroenterology and Motility at Lenox Hill Hospital in New York. She runs the educational platform for all things gut health, gutlove.com.

What is the role of the gut barrier in overall health and disease?

The gut contains the human body’s largest interface between a person and their external environment. The actual interface is at the gut barrier, where there needs to be an ideal homeostasis and selectivity mechanism to allow the absorption of healthy nutrients, but on the other hand prevent the penetration of harmful microbes, food antigens, and other proinflammatory factors and toxins.

The gut barrier is made up of the mucus layer, gut microbiome, epithelial cells, and immune cells in the lamina propria. When this apparatus is disrupted by factors such as infection, low-fiber diet, antibiotics, and alcohol, then it cannot function normally to selectively keep out the harmful intraluminal substances.

Gut-barrier disruption leads to translocation of dangerous intraluminal components, such as bacteria and their components, into the gut wall and, most importantly, exposes the immune system to them. This causes improper immune activation and dysregulation, which has been shown to lead to various diseases, including gastrointestinal inflammatory disorders such as inflammatory bowel disease (IBD) and celiac disease, systemic autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, and metabolic diseases such as obesity and diabetes.



Is disruption of this barrier what is usually referred to as “leaky gut”?

Leaky gut is a colloquial term for increased intestinal permeability or intestinal hyperpermeability. In a 2019 review article, Dr. Michael Camilleri exposes leaky gut as a term that can be misleading and confusing to the general population. It calls upon clinicians to have an increased awareness of the potential of barrier dysfunction in diseases, and to consider the barrier as a target for treatment.



Is leaky gut more of a mechanism of underlying chronic disease or is it a disease of its own?

Intestinal permeability is a pathophysiologic process in the gut with certain risk factors that in some conditions has been shown to precede chronic disease. There has not been any convincing evidence that it can be diagnosed and treated as its own entity, but research is ongoing.

In IBD, the Crohn’s and Colitis Canada Genetic, Environmental, Microbial Project research consortium has been studying individuals at increased risk for Crohn’s disease because of a first-degree family member with Crohn’s disease. They found an increased abundance of Ruminococcus torques in the microbiomes of at-risk individuals who went on to develop the disease. R. torques are mucin degraders that induce an increase in other mucin-using bacteria, which can contribute to gut-barrier compromise.

In other studies, patients have been found to have asymptomatic intestinal hyperpermeability years before their diagnosis of Crohn’s disease. This supports understanding more about the potential of intestinal hyperpermeability as its own diagnosis that, if addressed, could possibly prevent disease development.
 

The many possible sources of gut-barrier disruption

What causes leaky gut, and when should physicians and patients be suspicious if they have it?

There are many risk factors that have been associated with leaky gut in both human studies and animal studies, including acrolein (food toxin), aging, alcohol, antacid drugs, antibiotics, burn injury, chemotherapy, circadian rhythm disruption, corticosteroids, emulsifiers (food additives), strenuous exercise (≥ 2 hours) at 60% VO₂ max, starvation, fructose, fructans, gliadin (wheat protein), high-fat diet, high-salt diet, high-sugar diet, hyperglycemia, low-fiber diet, nonsteroidal anti-inflammatory drugs, pesticide, proinflammatory cytokines, psychological stress, radiation, sleep deprivation, smoking, and sweeteners.

Patients may be completely asymptomatic with leaky gut. Physicians should be suspicious if there is a genetic predisposition to chronic disease or if any risk factors are unveiled after assessing diet and lifestyle exposures.



What is the role of the Western diet and processed food consumption in driving disruptions of the gut barrier?

The Western diet reduces gut-barrier mucus thickness, leading to increased gut permeability. People who consume a Western diet typically eat less than 15 grams of fiber per day, which is significantly less than many other cultures, including the hunter-gatherers of Tanzania (Hadza), who get 100 or more grams of fiber a day in their food.

With a fiber-depleted diet, gut microbiota that normally feed on fiber gradually disappear and other commensals shift their metabolism to degrade the gut-barrier mucus layer.

A low-fiber diet also decreases short-chain fatty acid production, which reduces production of mucus and affects tight junction regulation.
 

Emerging evidence on causality

New evidence is demonstrating that previous functional conditions of the gastrointestinal tract, like functional dyspepsia, are associated with abnormalities to the intestinal barrier. What is the association between conditions like functional dyspepsia and irritable bowel syndrome (IBS) with gut-barrier disruption?

Conditions such as functional dyspepsia and IBS are similar in that their pathophysiology is incompletely understood and likely attributable to contributions from many different underlying mechanisms. This makes it difficult for clinicians to explain the condition to patients and often to treat without specific therapeutic targets.

Emerging evidence with new diagnostic tools, such as confocal laser endomicroscopy, has demonstrated altered mucosal barrier function in both conditions.

In patients with IBS who have a suspected food intolerance, studies looking at exposure to the food antigens found that the food caused immediate breaks, increased intervillous spaces, and increased inflammatory cells in the gut mucosa. These changes were associated with patient responses to exclusion diets.

In functional dyspepsia, another study, using confocal laser endomicroscopy, has shown that affected patients have significantly greater epithelial gap density in the duodenum, compared with healthy controls. There was also impaired duodenal-epithelial barrier integrity and evidence of increased cellular pyroptosis in the duodenal mucosa.

These findings suggest that while IBS and functional dyspepsia are still likely multifactorial, there may be a common preclinical state that can be further investigated as far as preventing its development and using it as a therapeutic target.



What diagnostic testing are you using to determine whether patients have disruptions to the gut barrier? Are they validated or more experimental?

There are various testing strategies that have been used in research to diagnose intestinal hyperpermeability. In a 2021 analysis, Dr. Michael Camilleri found that the optimal probes for measuring small intestinal and colonic permeability are the mass excreted of 13C-mannitol at 0-2 hours and lactulose during 2-8 hours or sucralose during 8-24 hours. Studies looking at postinfectious IBS have incorporated elevated urinary lactulose/mannitol ratios. Dr. Alessio Fasano and others have looked at using zonulin as a biomarker of impaired gut-barrier function. These tests are still considered experimental.



Is there an association between alterations in the gut microbiome and gut-barrier disruption?

There is an integral relationship between the gut microbiome and gut-barrier function, and dysbiosis can disrupt gut-barrier functionality.

The microbiota produce a variety of metabolites in close proximity to the gut epithelium, impacting gut-barrier function and immune response. For example, short-chain fatty acids produced by Bifidobacterium, Bacteroides, Enterobacter, Faecalibacterium, and Roseburia species impact host immune cell differentiation and metabolism as well as influence susceptibility to pathogens.

Studies have shown that sodium butyrate significantly improves epithelial-barrier function. Other experiments have used transplantation of the intestinal microbiota to show that introduction of certain microbial phenotypes can significantly increase gut permeability.
 

Practical advice for clinicians and patients

How do you advise patients to avoid gut-barrier disruption?

It is important to educate and counsel patients about the long list of risk factors, many of which are closely related to a Western diet and lifestyle, which can increase their risk for leaky gut.

Once one has it, can it be repaired? Can you share a bit about your protocols in general terms?

Many interventions have been shown to improve intestinal permeability. They include berberine, butyrate, caloric restriction and fasting, curcumin, dietary fiber (prebiotics), moderate exercise, fermented food, fish oil, glutamine, quercetin, probiotics, vagus nerve stimulation, vitamin D, and zinc.

Protocols have to be tailored to patients and their risk factors, diet, and lifestyle.

What are some tips from a nutrition and lifestyle standpoint that patients can follow to ensure a robust gut barrier?

It is important to emphasize a high-fiber diet with naturally fermented food, incorporating time-restricted eating, such as eating an early dinner and nothing else before bedtime, a moderate exercise routine, and gut-brain modulation with techniques such as acupuncture that can incorporate vagus nerve stimulation. Limited safe precision supplementation can be discussed on an individual basis based on the patient’s interest, additional testing, and other existing health conditions.
 

Dr. Akash Goel is a clinical assistant professor of medicine at Weill Cornell in gastroenterology and hepatology. He has disclosed no relevant financial relationships. His work has appeared on networks and publications such as CNN, The New York Times, Time Magazine, and Financial Times. He has a deep interest in nutrition, food as medicine, and the intersection between the gut microbiome and human health.

A version of this article appeared on Medscape.com.

From Ayurveda to the teachings of Hippocrates, medicine’s earliest traditions advanced a belief that the gut was the foundation of all health and disease. It wasn’t until recently, however, that Western medicine has adopted the notion of gut-barrier dysfunction as a pathologic phenomenon critical to not only digestive health but also chronic allergic, inflammatory, and autoimmune disease.

To learn more, Medscape contributor Akash Goel, MD, interviewed Elena Ivanina, DO, MPH, an integrative gastroenterologist, on the role of the gut barrier. Dr. Ivanina is the founder of the Center for Integrative Gut Health and the former director of Neurogastroenterology and Motility at Lenox Hill Hospital in New York. She runs the educational platform for all things gut health, gutlove.com.

What is the role of the gut barrier in overall health and disease?

The gut contains the human body’s largest interface between a person and their external environment. The actual interface is at the gut barrier, where there needs to be an ideal homeostasis and selectivity mechanism to allow the absorption of healthy nutrients, but on the other hand prevent the penetration of harmful microbes, food antigens, and other proinflammatory factors and toxins.

The gut barrier is made up of the mucus layer, gut microbiome, epithelial cells, and immune cells in the lamina propria. When this apparatus is disrupted by factors such as infection, low-fiber diet, antibiotics, and alcohol, then it cannot function normally to selectively keep out the harmful intraluminal substances.

Gut-barrier disruption leads to translocation of dangerous intraluminal components, such as bacteria and their components, into the gut wall and, most importantly, exposes the immune system to them. This causes improper immune activation and dysregulation, which has been shown to lead to various diseases, including gastrointestinal inflammatory disorders such as inflammatory bowel disease (IBD) and celiac disease, systemic autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, and metabolic diseases such as obesity and diabetes.



Is disruption of this barrier what is usually referred to as “leaky gut”?

Leaky gut is a colloquial term for increased intestinal permeability or intestinal hyperpermeability. In a 2019 review article, Dr. Michael Camilleri exposes leaky gut as a term that can be misleading and confusing to the general population. It calls upon clinicians to have an increased awareness of the potential of barrier dysfunction in diseases, and to consider the barrier as a target for treatment.



Is leaky gut more of a mechanism of underlying chronic disease or is it a disease of its own?

Intestinal permeability is a pathophysiologic process in the gut with certain risk factors that in some conditions has been shown to precede chronic disease. There has not been any convincing evidence that it can be diagnosed and treated as its own entity, but research is ongoing.

In IBD, the Crohn’s and Colitis Canada Genetic, Environmental, Microbial Project research consortium has been studying individuals at increased risk for Crohn’s disease because of a first-degree family member with Crohn’s disease. They found an increased abundance of Ruminococcus torques in the microbiomes of at-risk individuals who went on to develop the disease. R. torques are mucin degraders that induce an increase in other mucin-using bacteria, which can contribute to gut-barrier compromise.

In other studies, patients have been found to have asymptomatic intestinal hyperpermeability years before their diagnosis of Crohn’s disease. This supports understanding more about the potential of intestinal hyperpermeability as its own diagnosis that, if addressed, could possibly prevent disease development.
 

The many possible sources of gut-barrier disruption

What causes leaky gut, and when should physicians and patients be suspicious if they have it?

There are many risk factors that have been associated with leaky gut in both human studies and animal studies, including acrolein (food toxin), aging, alcohol, antacid drugs, antibiotics, burn injury, chemotherapy, circadian rhythm disruption, corticosteroids, emulsifiers (food additives), strenuous exercise (≥ 2 hours) at 60% VO₂ max, starvation, fructose, fructans, gliadin (wheat protein), high-fat diet, high-salt diet, high-sugar diet, hyperglycemia, low-fiber diet, nonsteroidal anti-inflammatory drugs, pesticide, proinflammatory cytokines, psychological stress, radiation, sleep deprivation, smoking, and sweeteners.

Patients may be completely asymptomatic with leaky gut. Physicians should be suspicious if there is a genetic predisposition to chronic disease or if any risk factors are unveiled after assessing diet and lifestyle exposures.



What is the role of the Western diet and processed food consumption in driving disruptions of the gut barrier?

The Western diet reduces gut-barrier mucus thickness, leading to increased gut permeability. People who consume a Western diet typically eat less than 15 grams of fiber per day, which is significantly less than many other cultures, including the hunter-gatherers of Tanzania (Hadza), who get 100 or more grams of fiber a day in their food.

With a fiber-depleted diet, gut microbiota that normally feed on fiber gradually disappear and other commensals shift their metabolism to degrade the gut-barrier mucus layer.

A low-fiber diet also decreases short-chain fatty acid production, which reduces production of mucus and affects tight junction regulation.
 

Emerging evidence on causality

New evidence is demonstrating that previous functional conditions of the gastrointestinal tract, like functional dyspepsia, are associated with abnormalities to the intestinal barrier. What is the association between conditions like functional dyspepsia and irritable bowel syndrome (IBS) with gut-barrier disruption?

Conditions such as functional dyspepsia and IBS are similar in that their pathophysiology is incompletely understood and likely attributable to contributions from many different underlying mechanisms. This makes it difficult for clinicians to explain the condition to patients and often to treat without specific therapeutic targets.

Emerging evidence with new diagnostic tools, such as confocal laser endomicroscopy, has demonstrated altered mucosal barrier function in both conditions.

In patients with IBS who have a suspected food intolerance, studies looking at exposure to the food antigens found that the food caused immediate breaks, increased intervillous spaces, and increased inflammatory cells in the gut mucosa. These changes were associated with patient responses to exclusion diets.

In functional dyspepsia, another study, using confocal laser endomicroscopy, has shown that affected patients have significantly greater epithelial gap density in the duodenum, compared with healthy controls. There was also impaired duodenal-epithelial barrier integrity and evidence of increased cellular pyroptosis in the duodenal mucosa.

These findings suggest that while IBS and functional dyspepsia are still likely multifactorial, there may be a common preclinical state that can be further investigated as far as preventing its development and using it as a therapeutic target.



What diagnostic testing are you using to determine whether patients have disruptions to the gut barrier? Are they validated or more experimental?

There are various testing strategies that have been used in research to diagnose intestinal hyperpermeability. In a 2021 analysis, Dr. Michael Camilleri found that the optimal probes for measuring small intestinal and colonic permeability are the mass excreted of 13C-mannitol at 0-2 hours and lactulose during 2-8 hours or sucralose during 8-24 hours. Studies looking at postinfectious IBS have incorporated elevated urinary lactulose/mannitol ratios. Dr. Alessio Fasano and others have looked at using zonulin as a biomarker of impaired gut-barrier function. These tests are still considered experimental.



Is there an association between alterations in the gut microbiome and gut-barrier disruption?

There is an integral relationship between the gut microbiome and gut-barrier function, and dysbiosis can disrupt gut-barrier functionality.

The microbiota produce a variety of metabolites in close proximity to the gut epithelium, impacting gut-barrier function and immune response. For example, short-chain fatty acids produced by Bifidobacterium, Bacteroides, Enterobacter, Faecalibacterium, and Roseburia species impact host immune cell differentiation and metabolism as well as influence susceptibility to pathogens.

Studies have shown that sodium butyrate significantly improves epithelial-barrier function. Other experiments have used transplantation of the intestinal microbiota to show that introduction of certain microbial phenotypes can significantly increase gut permeability.
 

Practical advice for clinicians and patients

How do you advise patients to avoid gut-barrier disruption?

It is important to educate and counsel patients about the long list of risk factors, many of which are closely related to a Western diet and lifestyle, which can increase their risk for leaky gut.

Once one has it, can it be repaired? Can you share a bit about your protocols in general terms?

Many interventions have been shown to improve intestinal permeability. They include berberine, butyrate, caloric restriction and fasting, curcumin, dietary fiber (prebiotics), moderate exercise, fermented food, fish oil, glutamine, quercetin, probiotics, vagus nerve stimulation, vitamin D, and zinc.

Protocols have to be tailored to patients and their risk factors, diet, and lifestyle.

What are some tips from a nutrition and lifestyle standpoint that patients can follow to ensure a robust gut barrier?

It is important to emphasize a high-fiber diet with naturally fermented food, incorporating time-restricted eating, such as eating an early dinner and nothing else before bedtime, a moderate exercise routine, and gut-brain modulation with techniques such as acupuncture that can incorporate vagus nerve stimulation. Limited safe precision supplementation can be discussed on an individual basis based on the patient’s interest, additional testing, and other existing health conditions.
 

Dr. Akash Goel is a clinical assistant professor of medicine at Weill Cornell in gastroenterology and hepatology. He has disclosed no relevant financial relationships. His work has appeared on networks and publications such as CNN, The New York Times, Time Magazine, and Financial Times. He has a deep interest in nutrition, food as medicine, and the intersection between the gut microbiome and human health.

A version of this article appeared on Medscape.com.

PHILADELPHIA – A proprietary formula showed good performance stratifying the risk of adults with early-stage chronic kidney disease (CKD) advancing to more severe kidney dysfunction and increased health care needs. The analyses offer the possibility of focusing intensified medical management of early-stage CKD on those patients who could potentially receive the most benefit.

The Klinrisk model predicts the risk of an adult with early-stage CKD developing either a 40% or greater drop in estimated glomerular filtration rate or kidney failure. It calculates risk based on 20 lab-measured variables that include serum creatinine, urine albumin-to-creatinine ratio, and other values taken from routinely ordered tests such as complete blood cell counts, chemistry panels, comprehensive metabolic panels, and urinalysis.

Mitchel L. Zoler/MDedge News

In the most recent and largest external validation study using data from 4.6 million American adults enrolled in commercial and Medicare insurance plans, the results showed Klinrisk correctly predicted CKD progression in 80%-83% of individuals over 2 years and in 78%-83% of individuals over 5 years, depending on the insurance provider, Navdeep Tangri, MD, PhD, reported at the annual meeting of the American Society of Nephrology. When urinalysis data were available, the model correctly predicted CKD progression in 81%-87% of individuals over 2 years and in 80%-87% of individuals over 5 years. These results follow prior reports of several other successful validations of Klinrisk.
 

‘Ready to implement’

“The Klinrisk model is ready to implement by any payer, health system, or clinic where the needed lab data are available,” said Dr. Tangri, a nephrologist and professor at the University of Manitoba, Winnipeg, and founder of Klinrisk Inc., the company developing and commercializing the Klinrisk assessment tool.

For the time being, Dr. Tangri sees Klinrisk as a population health device that can allow insurers and health systems to track management quality and quality improvement and to target patients who stand to benefit most from relatively expensive resources. This includes prescriptions for finerenone (Kerendia, Bayer) for people who also have type 2 diabetes, and agents from the class of sodium-glucose cotransporter 2 (SGLT2) inhibitors such as dapagliflozin (Farxiga, AstraZeneca) and empagliflozin (Jardiance, Boehringer Ingelheim and Lilly).

He has also begun discussions with the Food and Drug Administration about the data the agency will need to consider Klinrisk for potential approval as a new medical device, perhaps in 2025. That’s how he envisions getting a Klinrisk assessment into the hands of caregivers that they could use with individual patients to create an appropriate treatment plan.

Results from his new analysis showed that “all the kidney disease action is in the 10%-20% of people with the highest risk on Klinrisk, while not much happens in those in the bottom half,” Dr. Tangri said during his presentation.

“We’re trying to find the patients who get the largest [absolute] benefit from intensified treatment,” he added in an interview. “Klinrisk finds people with high-risk kidney disease early on, when kidney function is still normal or near normal. High-risk patients are often completely unrecognized. Risk-based management” that identifies the early-stage CKD patients who would benefit most from treatment with an SGLT2 inhibitor, finerenone, and other foundational treatments to slow CKD progression “is better than the free-for-all that occurs today.”

Simplified data collection

“Klinrisk is very effective,” but requires follow-up by clinicians and health systems to implement its findings, commented Josef Coresh, MD, a professor of clinical epidemiology at Johns Hopkins Bloomberg, Baltimore. Dr. Coresh compared it with a free equation that estimates a person’s risk for a 40% drop in kidney function over the next 3 years developed by Dr. Tangri, Dr. Coresh, and many collaborators led by Morgan C. Grams, MD, PhD, of New York University that they published in 2022, and posted on a website of the CKD Prognosis Consortium.

Mitchel L. Zoler/MDedge News

The CKD Prognosis Consortium formula “takes a different approach” from Klinrisk. The commercial formula “is simpler, only using lab measures, and avoids inputs taken from physical examination such as systolic blood pressure and body mass index and health history data such as smoking, noted Dr. Coresh. He also speculated that “a commercial formula that must be paid for may counterintuitively result in better follow-up for making management changes if it uses some of the resources for education and system changes.”

Using data from multiple sources, like the CKD Prognosis Consortium equation, can create implementation challenges, said Dr. Tangri. “Lab results don’t vary much,” which makes Klinrisk “quite an improvement for implementation. It’s easier to implement.”

Other findings from the newest validation study that Dr. Tangri presented were that the people studied with Klinrisk scores in the top 10% had, over the next 2 years of follow-up and compared with people in the bottom half for Klinrisk staging, a 3- to 5-fold higher rate of all-cause medical costs, a 13-30-fold increase in CKD-related costs, and a 5- to 10-fold increase in hospitalizations and ED visits.

Early identification of CKD and early initiation of intensified treatment for high-risk patients can reduce the rate of progression to dialysis, reduce hospitalizations for heart failure, and lower the cost of care, Dr. Tangri said.

The validation study in 4.6 million Americans was sponsored by Boehringer Ingelheim. Dr. Tangri founded and has an ownership interest in Klinrisk. He has also received honoraria from, has ownership interests in, and has been a consultant to multiple pharmaceutical companies. Dr. Coresh had no disclosures.

PHILADELPHIA – A proprietary formula showed good performance stratifying the risk of adults with early-stage chronic kidney disease (CKD) advancing to more severe kidney dysfunction and increased health care needs. The analyses offer the possibility of focusing intensified medical management of early-stage CKD on those patients who could potentially receive the most benefit.

The Klinrisk model predicts the risk of an adult with early-stage CKD developing either a 40% or greater drop in estimated glomerular filtration rate or kidney failure. It calculates risk based on 20 lab-measured variables that include serum creatinine, urine albumin-to-creatinine ratio, and other values taken from routinely ordered tests such as complete blood cell counts, chemistry panels, comprehensive metabolic panels, and urinalysis.

Mitchel L. Zoler/MDedge News

In the most recent and largest external validation study using data from 4.6 million American adults enrolled in commercial and Medicare insurance plans, the results showed Klinrisk correctly predicted CKD progression in 80%-83% of individuals over 2 years and in 78%-83% of individuals over 5 years, depending on the insurance provider, Navdeep Tangri, MD, PhD, reported at the annual meeting of the American Society of Nephrology. When urinalysis data were available, the model correctly predicted CKD progression in 81%-87% of individuals over 2 years and in 80%-87% of individuals over 5 years. These results follow prior reports of several other successful validations of Klinrisk.
 

‘Ready to implement’

“The Klinrisk model is ready to implement by any payer, health system, or clinic where the needed lab data are available,” said Dr. Tangri, a nephrologist and professor at the University of Manitoba, Winnipeg, and founder of Klinrisk Inc., the company developing and commercializing the Klinrisk assessment tool.

For the time being, Dr. Tangri sees Klinrisk as a population health device that can allow insurers and health systems to track management quality and quality improvement and to target patients who stand to benefit most from relatively expensive resources. This includes prescriptions for finerenone (Kerendia, Bayer) for people who also have type 2 diabetes, and agents from the class of sodium-glucose cotransporter 2 (SGLT2) inhibitors such as dapagliflozin (Farxiga, AstraZeneca) and empagliflozin (Jardiance, Boehringer Ingelheim and Lilly).

He has also begun discussions with the Food and Drug Administration about the data the agency will need to consider Klinrisk for potential approval as a new medical device, perhaps in 2025. That’s how he envisions getting a Klinrisk assessment into the hands of caregivers that they could use with individual patients to create an appropriate treatment plan.

Results from his new analysis showed that “all the kidney disease action is in the 10%-20% of people with the highest risk on Klinrisk, while not much happens in those in the bottom half,” Dr. Tangri said during his presentation.

“We’re trying to find the patients who get the largest [absolute] benefit from intensified treatment,” he added in an interview. “Klinrisk finds people with high-risk kidney disease early on, when kidney function is still normal or near normal. High-risk patients are often completely unrecognized. Risk-based management” that identifies the early-stage CKD patients who would benefit most from treatment with an SGLT2 inhibitor, finerenone, and other foundational treatments to slow CKD progression “is better than the free-for-all that occurs today.”

Simplified data collection

“Klinrisk is very effective,” but requires follow-up by clinicians and health systems to implement its findings, commented Josef Coresh, MD, a professor of clinical epidemiology at Johns Hopkins Bloomberg, Baltimore. Dr. Coresh compared it with a free equation that estimates a person’s risk for a 40% drop in kidney function over the next 3 years developed by Dr. Tangri, Dr. Coresh, and many collaborators led by Morgan C. Grams, MD, PhD, of New York University that they published in 2022, and posted on a website of the CKD Prognosis Consortium.

Mitchel L. Zoler/MDedge News

The CKD Prognosis Consortium formula “takes a different approach” from Klinrisk. The commercial formula “is simpler, only using lab measures, and avoids inputs taken from physical examination such as systolic blood pressure and body mass index and health history data such as smoking, noted Dr. Coresh. He also speculated that “a commercial formula that must be paid for may counterintuitively result in better follow-up for making management changes if it uses some of the resources for education and system changes.”

Using data from multiple sources, like the CKD Prognosis Consortium equation, can create implementation challenges, said Dr. Tangri. “Lab results don’t vary much,” which makes Klinrisk “quite an improvement for implementation. It’s easier to implement.”

Other findings from the newest validation study that Dr. Tangri presented were that the people studied with Klinrisk scores in the top 10% had, over the next 2 years of follow-up and compared with people in the bottom half for Klinrisk staging, a 3- to 5-fold higher rate of all-cause medical costs, a 13-30-fold increase in CKD-related costs, and a 5- to 10-fold increase in hospitalizations and ED visits.

Early identification of CKD and early initiation of intensified treatment for high-risk patients can reduce the rate of progression to dialysis, reduce hospitalizations for heart failure, and lower the cost of care, Dr. Tangri said.

The validation study in 4.6 million Americans was sponsored by Boehringer Ingelheim. Dr. Tangri founded and has an ownership interest in Klinrisk. He has also received honoraria from, has ownership interests in, and has been a consultant to multiple pharmaceutical companies. Dr. Coresh had no disclosures.

PHILADELPHIA – A proprietary formula showed good performance stratifying the risk of adults with early-stage chronic kidney disease (CKD) advancing to more severe kidney dysfunction and increased health care needs. The analyses offer the possibility of focusing intensified medical management of early-stage CKD on those patients who could potentially receive the most benefit.

The Klinrisk model predicts the risk of an adult with early-stage CKD developing either a 40% or greater drop in estimated glomerular filtration rate or kidney failure. It calculates risk based on 20 lab-measured variables that include serum creatinine, urine albumin-to-creatinine ratio, and other values taken from routinely ordered tests such as complete blood cell counts, chemistry panels, comprehensive metabolic panels, and urinalysis.

Mitchel L. Zoler/MDedge News

In the most recent and largest external validation study using data from 4.6 million American adults enrolled in commercial and Medicare insurance plans, the results showed Klinrisk correctly predicted CKD progression in 80%-83% of individuals over 2 years and in 78%-83% of individuals over 5 years, depending on the insurance provider, Navdeep Tangri, MD, PhD, reported at the annual meeting of the American Society of Nephrology. When urinalysis data were available, the model correctly predicted CKD progression in 81%-87% of individuals over 2 years and in 80%-87% of individuals over 5 years. These results follow prior reports of several other successful validations of Klinrisk.
 

‘Ready to implement’

“The Klinrisk model is ready to implement by any payer, health system, or clinic where the needed lab data are available,” said Dr. Tangri, a nephrologist and professor at the University of Manitoba, Winnipeg, and founder of Klinrisk Inc., the company developing and commercializing the Klinrisk assessment tool.

For the time being, Dr. Tangri sees Klinrisk as a population health device that can allow insurers and health systems to track management quality and quality improvement and to target patients who stand to benefit most from relatively expensive resources. This includes prescriptions for finerenone (Kerendia, Bayer) for people who also have type 2 diabetes, and agents from the class of sodium-glucose cotransporter 2 (SGLT2) inhibitors such as dapagliflozin (Farxiga, AstraZeneca) and empagliflozin (Jardiance, Boehringer Ingelheim and Lilly).

He has also begun discussions with the Food and Drug Administration about the data the agency will need to consider Klinrisk for potential approval as a new medical device, perhaps in 2025. That’s how he envisions getting a Klinrisk assessment into the hands of caregivers that they could use with individual patients to create an appropriate treatment plan.

Results from his new analysis showed that “all the kidney disease action is in the 10%-20% of people with the highest risk on Klinrisk, while not much happens in those in the bottom half,” Dr. Tangri said during his presentation.

“We’re trying to find the patients who get the largest [absolute] benefit from intensified treatment,” he added in an interview. “Klinrisk finds people with high-risk kidney disease early on, when kidney function is still normal or near normal. High-risk patients are often completely unrecognized. Risk-based management” that identifies the early-stage CKD patients who would benefit most from treatment with an SGLT2 inhibitor, finerenone, and other foundational treatments to slow CKD progression “is better than the free-for-all that occurs today.”

Simplified data collection

“Klinrisk is very effective,” but requires follow-up by clinicians and health systems to implement its findings, commented Josef Coresh, MD, a professor of clinical epidemiology at Johns Hopkins Bloomberg, Baltimore. Dr. Coresh compared it with a free equation that estimates a person’s risk for a 40% drop in kidney function over the next 3 years developed by Dr. Tangri, Dr. Coresh, and many collaborators led by Morgan C. Grams, MD, PhD, of New York University that they published in 2022, and posted on a website of the CKD Prognosis Consortium.

Mitchel L. Zoler/MDedge News

The CKD Prognosis Consortium formula “takes a different approach” from Klinrisk. The commercial formula “is simpler, only using lab measures, and avoids inputs taken from physical examination such as systolic blood pressure and body mass index and health history data such as smoking, noted Dr. Coresh. He also speculated that “a commercial formula that must be paid for may counterintuitively result in better follow-up for making management changes if it uses some of the resources for education and system changes.”

Using data from multiple sources, like the CKD Prognosis Consortium equation, can create implementation challenges, said Dr. Tangri. “Lab results don’t vary much,” which makes Klinrisk “quite an improvement for implementation. It’s easier to implement.”

Other findings from the newest validation study that Dr. Tangri presented were that the people studied with Klinrisk scores in the top 10% had, over the next 2 years of follow-up and compared with people in the bottom half for Klinrisk staging, a 3- to 5-fold higher rate of all-cause medical costs, a 13-30-fold increase in CKD-related costs, and a 5- to 10-fold increase in hospitalizations and ED visits.

Early identification of CKD and early initiation of intensified treatment for high-risk patients can reduce the rate of progression to dialysis, reduce hospitalizations for heart failure, and lower the cost of care, Dr. Tangri said.

The validation study in 4.6 million Americans was sponsored by Boehringer Ingelheim. Dr. Tangri founded and has an ownership interest in Klinrisk. He has also received honoraria from, has ownership interests in, and has been a consultant to multiple pharmaceutical companies. Dr. Coresh had no disclosures.

BOSTON – The nomenclature may have changed, but the steady rise in the most common form of liver disease – metabolic dysfunction–associated steatotic liver disease (MASLD, formerly known as NAFLD) – is predicted to continue into the middle of this century.

That’s according to Phuc Le, PhD, MPH, and colleagues at the Cleveland Clinic. They created a mathematical model incorporating data on the growth of the U.S. population and the natural history of MASLD/NAFLD. The model projected a relative 23% increase in MASLD among U.S. adults from 2020 to 2050.

Cleveland Clinic

“Our model forecasts a substantial clinical burden of NAFLD over the next 3 decades. In the absence of effective treatments, health systems should plan for large increases in the number of liver cancer cases and the need for liver transplant,” Dr. Le said in a media briefing held on Nov. 7 prior to her presentation of the data at the annual meeting of the American Association for the Study of Liver Diseases.

The estimated worldwide prevalence of MASLD is 38%. In the United States, an estimated 27.8% of adults had MASLD as of 2020.

Dr. Le and colleagues wanted to get a clearer picture of the expected increase in the clinical burden of MASLD in the coming decades. The researchers used data from the medical literature to create an individual-level state transition model. They took into account projections of the growth of the U.S. population and the progression of MASLD and metabolic dysfunction–associated steatohepatitis (MASH, formerly NASH) through stages of fibrosis to decompensation, hepatocellular carcinoma (HCC), transplant, and liver-related death as a proportion of all-cause mortality.
 

Validated model

They validated the model by testing it against liver outcomes from 2000 through 2018 and published data on the U.S. population. The model closely matched trends in MASLD prevalence, MASH proportion, HCC and liver transplant incidences, and overall survival rates for patients with MASLD.

As noted, the model predicted a steady increase in MASLD prevalence, from 27.8% in 2020 to 34.3% by 2050, a relative increase of about 23%. The model also predicted a slight uptick in the proportion of MASH among patients with MASLD, from 20% to 21.8%.

The investigators said that the prevalence of MASLD/MASH would likely remain relatively stable among people aged 18-29 years but would increase significantly for all other age groups.

In addition, the model predicted an increase in the proportion of cirrhosis in patients with MASLD from 1.9% to 3.1%, as well as a rise in liver-related deaths from 0.4% of all deaths in 2020 to 1% by 2050.

The investigators also foresaw a rise in HCC cases, from 10,400 annually to 19,300 by 2050 and a more than twofold increase in liver transplants, from 1,700 in 2020 to 4,200 in 2050.
 

A “tsunami” of liver disease

In the question-and-answer portion of the briefing, Norah Terrault, MD, AASLD president and chief of gastroenterology and hepatology at the University of Southern California, Los Angeles, commented on the study findings and “the frightening trajectory in terms of disease burden.

“I’m thinking to myself there’s no way we’re going to be able to transplant our way out of this tsunami of disease that’s coming our way,” she said, and asked Dr. Le what policy or societal approaches might be implemented to help stem the tide.

“This is a really huge question,” Dr. Le acknowledged. The study only provides estimates of what the future burden of disease might be if there are no changes in clinical care for patients with MASLD or if the trajectory of contributing factors, such as obesity, diabetes, and other metabolic diseases, continued to increase, she cautioned.

Raising awareness of MASLD/MASH and working to improve collaboration among liver specialists and general practitioners could help to flatten the curve, she suggested.

The study was supported by a grant from the Agency for Healthcare Research and Quality. Dr. Le and Dr. Terrault have disclosed no relevant financial relations.


A version of this article first appeared on Medscape.com.

BOSTON – The nomenclature may have changed, but the steady rise in the most common form of liver disease – metabolic dysfunction–associated steatotic liver disease (MASLD, formerly known as NAFLD) – is predicted to continue into the middle of this century.

That’s according to Phuc Le, PhD, MPH, and colleagues at the Cleveland Clinic. They created a mathematical model incorporating data on the growth of the U.S. population and the natural history of MASLD/NAFLD. The model projected a relative 23% increase in MASLD among U.S. adults from 2020 to 2050.

Cleveland Clinic

“Our model forecasts a substantial clinical burden of NAFLD over the next 3 decades. In the absence of effective treatments, health systems should plan for large increases in the number of liver cancer cases and the need for liver transplant,” Dr. Le said in a media briefing held on Nov. 7 prior to her presentation of the data at the annual meeting of the American Association for the Study of Liver Diseases.

The estimated worldwide prevalence of MASLD is 38%. In the United States, an estimated 27.8% of adults had MASLD as of 2020.

Dr. Le and colleagues wanted to get a clearer picture of the expected increase in the clinical burden of MASLD in the coming decades. The researchers used data from the medical literature to create an individual-level state transition model. They took into account projections of the growth of the U.S. population and the progression of MASLD and metabolic dysfunction–associated steatohepatitis (MASH, formerly NASH) through stages of fibrosis to decompensation, hepatocellular carcinoma (HCC), transplant, and liver-related death as a proportion of all-cause mortality.
 

Validated model

They validated the model by testing it against liver outcomes from 2000 through 2018 and published data on the U.S. population. The model closely matched trends in MASLD prevalence, MASH proportion, HCC and liver transplant incidences, and overall survival rates for patients with MASLD.

As noted, the model predicted a steady increase in MASLD prevalence, from 27.8% in 2020 to 34.3% by 2050, a relative increase of about 23%. The model also predicted a slight uptick in the proportion of MASH among patients with MASLD, from 20% to 21.8%.

The investigators said that the prevalence of MASLD/MASH would likely remain relatively stable among people aged 18-29 years but would increase significantly for all other age groups.

In addition, the model predicted an increase in the proportion of cirrhosis in patients with MASLD from 1.9% to 3.1%, as well as a rise in liver-related deaths from 0.4% of all deaths in 2020 to 1% by 2050.

The investigators also foresaw a rise in HCC cases, from 10,400 annually to 19,300 by 2050 and a more than twofold increase in liver transplants, from 1,700 in 2020 to 4,200 in 2050.
 

A “tsunami” of liver disease

In the question-and-answer portion of the briefing, Norah Terrault, MD, AASLD president and chief of gastroenterology and hepatology at the University of Southern California, Los Angeles, commented on the study findings and “the frightening trajectory in terms of disease burden.

“I’m thinking to myself there’s no way we’re going to be able to transplant our way out of this tsunami of disease that’s coming our way,” she said, and asked Dr. Le what policy or societal approaches might be implemented to help stem the tide.

“This is a really huge question,” Dr. Le acknowledged. The study only provides estimates of what the future burden of disease might be if there are no changes in clinical care for patients with MASLD or if the trajectory of contributing factors, such as obesity, diabetes, and other metabolic diseases, continued to increase, she cautioned.

Raising awareness of MASLD/MASH and working to improve collaboration among liver specialists and general practitioners could help to flatten the curve, she suggested.

The study was supported by a grant from the Agency for Healthcare Research and Quality. Dr. Le and Dr. Terrault have disclosed no relevant financial relations.


A version of this article first appeared on Medscape.com.

BOSTON – The nomenclature may have changed, but the steady rise in the most common form of liver disease – metabolic dysfunction–associated steatotic liver disease (MASLD, formerly known as NAFLD) – is predicted to continue into the middle of this century.

That’s according to Phuc Le, PhD, MPH, and colleagues at the Cleveland Clinic. They created a mathematical model incorporating data on the growth of the U.S. population and the natural history of MASLD/NAFLD. The model projected a relative 23% increase in MASLD among U.S. adults from 2020 to 2050.

Cleveland Clinic

“Our model forecasts a substantial clinical burden of NAFLD over the next 3 decades. In the absence of effective treatments, health systems should plan for large increases in the number of liver cancer cases and the need for liver transplant,” Dr. Le said in a media briefing held on Nov. 7 prior to her presentation of the data at the annual meeting of the American Association for the Study of Liver Diseases.

The estimated worldwide prevalence of MASLD is 38%. In the United States, an estimated 27.8% of adults had MASLD as of 2020.

Dr. Le and colleagues wanted to get a clearer picture of the expected increase in the clinical burden of MASLD in the coming decades. The researchers used data from the medical literature to create an individual-level state transition model. They took into account projections of the growth of the U.S. population and the progression of MASLD and metabolic dysfunction–associated steatohepatitis (MASH, formerly NASH) through stages of fibrosis to decompensation, hepatocellular carcinoma (HCC), transplant, and liver-related death as a proportion of all-cause mortality.
 

Validated model

They validated the model by testing it against liver outcomes from 2000 through 2018 and published data on the U.S. population. The model closely matched trends in MASLD prevalence, MASH proportion, HCC and liver transplant incidences, and overall survival rates for patients with MASLD.

As noted, the model predicted a steady increase in MASLD prevalence, from 27.8% in 2020 to 34.3% by 2050, a relative increase of about 23%. The model also predicted a slight uptick in the proportion of MASH among patients with MASLD, from 20% to 21.8%.

The investigators said that the prevalence of MASLD/MASH would likely remain relatively stable among people aged 18-29 years but would increase significantly for all other age groups.

In addition, the model predicted an increase in the proportion of cirrhosis in patients with MASLD from 1.9% to 3.1%, as well as a rise in liver-related deaths from 0.4% of all deaths in 2020 to 1% by 2050.

The investigators also foresaw a rise in HCC cases, from 10,400 annually to 19,300 by 2050 and a more than twofold increase in liver transplants, from 1,700 in 2020 to 4,200 in 2050.
 

A “tsunami” of liver disease

In the question-and-answer portion of the briefing, Norah Terrault, MD, AASLD president and chief of gastroenterology and hepatology at the University of Southern California, Los Angeles, commented on the study findings and “the frightening trajectory in terms of disease burden.

“I’m thinking to myself there’s no way we’re going to be able to transplant our way out of this tsunami of disease that’s coming our way,” she said, and asked Dr. Le what policy or societal approaches might be implemented to help stem the tide.

“This is a really huge question,” Dr. Le acknowledged. The study only provides estimates of what the future burden of disease might be if there are no changes in clinical care for patients with MASLD or if the trajectory of contributing factors, such as obesity, diabetes, and other metabolic diseases, continued to increase, she cautioned.

Raising awareness of MASLD/MASH and working to improve collaboration among liver specialists and general practitioners could help to flatten the curve, she suggested.

The study was supported by a grant from the Agency for Healthcare Research and Quality. Dr. Le and Dr. Terrault have disclosed no relevant financial relations.


A version of this article first appeared on Medscape.com.

TOPLINE:

Obtaining standing office blood pressure measurements improves detection of hypertension, either alone or when added to a seated BP reading, results of a new study suggest.

METHODOLOGY:

• The study included 125 adults, mean age 49 years and 62% female, who were free of cardiovascular disease and had no previous history of hypertension.
• Researchers collected data on 24-hour ambulatory blood pressure monitoring (ABPM), and three BP measurements in the seated position, then three in the standing position.
• They assessed overall diagnostic accuracy of seated and standing BP using the area under the receiver operating characteristic (AUROC) curve and considered a Bayes factor (BF) of 3 or greater as significant.
• They defined the presence of hypertension (HTN) by the 2017 American College of Cardiology/American Heart Association and 2023 European Society of Hypertension HTN guidelines based on ABPM.
• Sensitivity and specificity of standing BP was determined using cutoffs derived from Youden index, while sensitivity and specificity of seated BP was determined using the cutoff of 130/80 mm Hg and by 140/90 mm Hg.

TAKEAWAY:

• The AUROC for standing office systolic blood pressure (SBP; 0.81; 0.71-0.92) was significantly higher than for seated office SBP (0.70; 0.49-0.91) in diagnosing HTN when defined as an average 24-hour SBP ≥ 125 mm Hg (BF = 11.8), and significantly higher for seated versus standing office diastolic blood pressure (DBP; 0.65; 0.49-0.82) in diagnosing HTN when defined as an average 24-hour DBP ≥ 75 mm Hg (BF = 4.9).
• The AUROCs for adding standing office BP to seated office BP improved the accuracy of detecting HTN, compared with seated office BP alone when HTN was defined as an average 24-hour SBP/DBP ≥ 125/75 mm Hg or daytime SBP/DBP ≥ 130/80 mm Hg, or when defined as an average 24-hour SBP/DBP ≥ 130/80 mm Hg or daytime SBP/DBP ≥ 135/85 mm Hg (all BFs > 3).
• Sensitivity of standing SBP was 71%, compared with 43% for seated SBP.

IN PRACTICE:

The “excellent diagnostic performance” for standing BP measures revealed by the study “highlights that standing office BP has acceptable discriminative capabilities in identifying the presence of hypertension in adults,” the authors write.

SOURCE:

The study was conducted by John M. Giacona, Hypertension Section, department of internal medicine, University of Texas Southwestern Medical Center, Dallas, and colleagues. It was published online in Scientific Reports.

LIMITATIONS:

As the study enrolled only adults free of comorbidities who were not taking antihypertensive medications, the results may not be applicable to other patients. The study design was retrospective, and the order of BP measurements was not randomized (standing BP measurements were obtained only after seated BP).

DISCLOSURES:

The study was supported by the National Institutes of Health. The authors have no relevant conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Obtaining standing office blood pressure measurements improves detection of hypertension, either alone or when added to a seated BP reading, results of a new study suggest.

METHODOLOGY:

• The study included 125 adults, mean age 49 years and 62% female, who were free of cardiovascular disease and had no previous history of hypertension.
• Researchers collected data on 24-hour ambulatory blood pressure monitoring (ABPM), and three BP measurements in the seated position, then three in the standing position.
• They assessed overall diagnostic accuracy of seated and standing BP using the area under the receiver operating characteristic (AUROC) curve and considered a Bayes factor (BF) of 3 or greater as significant.
• They defined the presence of hypertension (HTN) by the 2017 American College of Cardiology/American Heart Association and 2023 European Society of Hypertension HTN guidelines based on ABPM.
• Sensitivity and specificity of standing BP was determined using cutoffs derived from Youden index, while sensitivity and specificity of seated BP was determined using the cutoff of 130/80 mm Hg and by 140/90 mm Hg.

TAKEAWAY:

• The AUROC for standing office systolic blood pressure (SBP; 0.81; 0.71-0.92) was significantly higher than for seated office SBP (0.70; 0.49-0.91) in diagnosing HTN when defined as an average 24-hour SBP ≥ 125 mm Hg (BF = 11.8), and significantly higher for seated versus standing office diastolic blood pressure (DBP; 0.65; 0.49-0.82) in diagnosing HTN when defined as an average 24-hour DBP ≥ 75 mm Hg (BF = 4.9).
• The AUROCs for adding standing office BP to seated office BP improved the accuracy of detecting HTN, compared with seated office BP alone when HTN was defined as an average 24-hour SBP/DBP ≥ 125/75 mm Hg or daytime SBP/DBP ≥ 130/80 mm Hg, or when defined as an average 24-hour SBP/DBP ≥ 130/80 mm Hg or daytime SBP/DBP ≥ 135/85 mm Hg (all BFs > 3).
• Sensitivity of standing SBP was 71%, compared with 43% for seated SBP.

IN PRACTICE:

The “excellent diagnostic performance” for standing BP measures revealed by the study “highlights that standing office BP has acceptable discriminative capabilities in identifying the presence of hypertension in adults,” the authors write.

SOURCE:

The study was conducted by John M. Giacona, Hypertension Section, department of internal medicine, University of Texas Southwestern Medical Center, Dallas, and colleagues. It was published online in Scientific Reports.

LIMITATIONS:

As the study enrolled only adults free of comorbidities who were not taking antihypertensive medications, the results may not be applicable to other patients. The study design was retrospective, and the order of BP measurements was not randomized (standing BP measurements were obtained only after seated BP).

DISCLOSURES:

The study was supported by the National Institutes of Health. The authors have no relevant conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Obtaining standing office blood pressure measurements improves detection of hypertension, either alone or when added to a seated BP reading, results of a new study suggest.

METHODOLOGY:

• The study included 125 adults, mean age 49 years and 62% female, who were free of cardiovascular disease and had no previous history of hypertension.
• Researchers collected data on 24-hour ambulatory blood pressure monitoring (ABPM), and three BP measurements in the seated position, then three in the standing position.
• They assessed overall diagnostic accuracy of seated and standing BP using the area under the receiver operating characteristic (AUROC) curve and considered a Bayes factor (BF) of 3 or greater as significant.
• They defined the presence of hypertension (HTN) by the 2017 American College of Cardiology/American Heart Association and 2023 European Society of Hypertension HTN guidelines based on ABPM.
• Sensitivity and specificity of standing BP was determined using cutoffs derived from Youden index, while sensitivity and specificity of seated BP was determined using the cutoff of 130/80 mm Hg and by 140/90 mm Hg.

TAKEAWAY:

• The AUROC for standing office systolic blood pressure (SBP; 0.81; 0.71-0.92) was significantly higher than for seated office SBP (0.70; 0.49-0.91) in diagnosing HTN when defined as an average 24-hour SBP ≥ 125 mm Hg (BF = 11.8), and significantly higher for seated versus standing office diastolic blood pressure (DBP; 0.65; 0.49-0.82) in diagnosing HTN when defined as an average 24-hour DBP ≥ 75 mm Hg (BF = 4.9).
• The AUROCs for adding standing office BP to seated office BP improved the accuracy of detecting HTN, compared with seated office BP alone when HTN was defined as an average 24-hour SBP/DBP ≥ 125/75 mm Hg or daytime SBP/DBP ≥ 130/80 mm Hg, or when defined as an average 24-hour SBP/DBP ≥ 130/80 mm Hg or daytime SBP/DBP ≥ 135/85 mm Hg (all BFs > 3).
• Sensitivity of standing SBP was 71%, compared with 43% for seated SBP.

IN PRACTICE:

The “excellent diagnostic performance” for standing BP measures revealed by the study “highlights that standing office BP has acceptable discriminative capabilities in identifying the presence of hypertension in adults,” the authors write.

SOURCE:

The study was conducted by John M. Giacona, Hypertension Section, department of internal medicine, University of Texas Southwestern Medical Center, Dallas, and colleagues. It was published online in Scientific Reports.

LIMITATIONS:

As the study enrolled only adults free of comorbidities who were not taking antihypertensive medications, the results may not be applicable to other patients. The study design was retrospective, and the order of BP measurements was not randomized (standing BP measurements were obtained only after seated BP).

DISCLOSURES:

The study was supported by the National Institutes of Health. The authors have no relevant conflicts of interest.

A version of this article appeared on Medscape.com.